Ward, Milledge and West’s High Altitude Medicine and Physiology [6 ed.] 0367001357, 9780367001353

Citation preview

Ward, Milledge and West’s High Altitude Medicine and Physiology

Ward, Milledge and West’s High Altitude Medicine and Physiology SIXTH EDITION

Andrew M. Luks Professor, Division of Pulmonary, Critical Care & Sleep Medicine, Harborview Medical Center, The University of Washington, Seattle, USA

Philip N. Ainslie Professor, School of Health & Exercise Sciences and Co-Director, Centre for Heart, Lung & Vascular Health, The University of British Columbia, Okanagan, Canada

Justin S. Lawley Professor, Institute for Sports Science, University of Innsbruck, Innsbruck, Austria

Robert C. Roach Associate Professor, Altitude Research Center, Division of Pulmonary Sciences & Critical Care, Anschutz Medical Campus, University of Colorado, Denver, USA

Tatum S. Simonson Assistant Professor, Division of Pulmonary, Critical Care & Sleep Medicine and Co-Director, Center for Physiological Genomics of Low Oxygen, University of California, San Diego School of Medicine, USA

Sixth edition published 2021 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487–2742 and by CRC Press 2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN © 2021 Taylor & Francis Group, LLC First edition published by Hodder Arnold 1998 Fifth edition published by CRC Press 2012 CRC Press is an imprint of Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors, or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific, or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions, and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures, or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions and their websites before administering or utilizing any of the drugs, devices, or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately, it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged, please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data [Insert LoC Data here when available] ISBN: [978-0-367-00135-3] (hbk) ISBN: [978-0-429-44433-3] (ebk) Typeset in Minion Pro by KnowledgeWorks Global Ltd.

Contents

Foreword

vii

Acknowledgments

ix

1

History of high altitude medicine and physiology

1

section 1 THE ENVIRONMENT AND ITS PEOPLE

23

2 3 4 5 6

25 37 51 75 91

The atmosphere Geography High altitude residents Travelers and workers at high altitude Genetics and genomics of exposure to high altitude

section 2  PHYSIOLOGIC RESPONSES TO HYPOXIA

109

7 8 9 10 11 12 13 14 15 16 17 18 19

111 123 143 163 181 203 225 243 263 281 309 325 351

Acclimatization Pulmonary gas exchange Control of breathing Oxygen affinity and acid–base balance Cardiovascular system Central nervous system Hematologic responses Peripheral tissues Energy balance and metabolism Endocrinology and renal function Sleep Exercise Physiology of extreme altitude

section 3 CLINICAL HIGH ALTITUDE MEDICINE

369

0 2 21 22 23 24 25 26 27

371 403 415 439 455 471 495 511

Acute mountain sickness High altitude cerebral edema High altitude pulmonary edema Other medical conditions that occur at high altitude Chronic altitude illness High altitude travel with preexisting medical conditions Children, the elderly, and women at high altitude Other environmental illnesses in the mountains

Index

529

v

Foreword

Three remarkable men, James Milledge, Michael Ward, and John West came together first while spending six months in a research camp at 5800 m in the Nepalese Himalayas as part of the 1960–61 Silver Hut Expedition. In the midst of a rich history of major contributions to the field of high altitude medicine and physiology during the last 40 years of the 20th century, the group collaborated once again to create the first edition of this textbook in 1989, with subsequent editions following in 1995 and 2000. On Ward’s death in 2005, Robert “Brownie” Schoene joined Milledge and West as a coauthor for the fourth edition in 2007. This team was then joined by Andrew Luks for the fifth edition in 2013. With this sixth edition, Jim Milledge, Brownie Schoene, and John West have passed the baton to a younger generation of experts in high altitude medicine and physiology. Led by Andrew Luks, who has been joined in the effort by Philip Ainslie from the University of British Columbia, Justin Lawley of the University of Innsbruck, Robert Roach from the University of Colorado, and Tatum Simonson from the University of California, San Diego, the team has worked hard to maintain the high standards set by the original authors. In addition to changes to the book’s organization, major updates have been made to nearly every part of the book to reflect the current state of the research in the field. As part of the effort to respect the traditions of the book, the new authors have made two symbolic, yet important changes. First, in recognition of the role Jim Milledge, Michael Ward, and John West have played through the years with not only the development of this landmark textbook

but also the entire field of high altitude medicine and physiology, the book will hence forth be published under the title “Ward, Milledge & West’s High Altitude Medicine and Physiology.” Second, with the exception of the second edition, the book cover has always included at least one image from the mountains. For this edition, we have chosen a photo of Ama Dablam. This decision is not simply because it is a beautiful mountain that lends itself to striking photos, but because Michael Ward, Jim Milledge, and John West spent considerable time in this mountain’s home region of Nepal, the Khumbu Valley, and much of the physiology and clinical research described in this book has been conducted within view of it. In addition, while much of the work on hypoxia in the 21st century is performed quite far from the high mountain ranges of the world, the photo of this iconic mountain serves as a reminder of the origin of this discipline and, in particular, how high altitude medicine and physiology was born out of a passion for the mountains and an interest in overcoming the physiologic challenges posed by this environment. Taking over the book from the original authors and carrying on the high standards they set has been a large and, at times, daunting undertaking. It is hoped that we have done justice to their pioneering contributions and have maintained the strong traditions of this book. Andrew M. Luks, MD Seattle, WA April 2020

vii

Acknowledgments

We would like to thank Drs. West, Milledge, and Schoene for the opportunity to carry on the work on this book as well as the following individuals for their time and effort in reviewing a great deal of the material in this new edition: Peter Bärtsch, Olivier Birot, Jay Carr, William Cornwell, Trevor Day, Jerry Dempsey, Ryan Hoiland, Carsten Lundby,

Jonathan Moore, Lorna Moore, Matt Rieger, Peter Robbins, Christoph Siebenmann, Michael Stembridge, Erik Swenson, Josh Tremblay, Francisco Villafuerte, and James Yu. We would also like to thank Richard Salisbury from the Himalayan Database for his work providing data to us that was used to create several new figures for this edition of the book.

ix

1 History of high altitude medicine and physiology

Introduction 1 Early descriptions of the effects of high altitude and altitude illness 1 Classical Greece and Rome 1 Chinese Headache Mountains 2 Possible early reference to high altitude pulmonary edema 2 Joseph de Acosta’s description of mountain sickness 2 Early scientific advances 3 Invention of the barometer 3 Invention of the air pump 3 Discovery of oxygen 4 First balloon ascents and the recognition of severe acute hypoxia 4 Mountain sickness in mountaineers 5 Paul Bert and the publication of La Pression Barométrique 5 Two new, permanent high altitude laboratories 6 Scientific expeditions and laboratory explorations: 1900–1950 7 Tenerife expedition 7

Anglo-American expedition to Pikes Peak 7 Mabel FitzGerald’s field work in Colorado 9 International high altitude expedition to Cerro de Pasco, Peru 9 International high altitude expedition to Chile 9 Operation Everest I 9 Human’s quest to climb Mount Everest: Scientific underpinnings 10 High altitude research in the latter half of the 20th century 10 1960s 10 1970s 11 1980–90s 11 Major research programs in the early 21st century 12 High altitude chambers 12 Caudwell Xtreme Everest Expedition 13 AltitudeOmics 13 University of British Columbia (UBC) Okanagan high altitude research program 13 Expanding frontiers in hypoxia research 13 Recent breakthroughs in high altitude genomics 13 References 15

INTRODUCTION

EARLY DESCRIPTIONS OF THE EFFECTS OF HIGH ALTITUDE AND ALTITUDE ILLNESS

While references to the effects of hypoxia on the human body can be traced as far back as the ancient Greeks, research into the physiological effects of hypoxia began in earnest in the latter part of the 19th century and continues to this day among several large and active research programs. Before examining the results of these extensive efforts in the pages and chapters that follow, this first chapter provides an overview of the history of high altitude medicine and physiology. Readers who desire more details can find these in perhaps the most comprehensive work on this rich and colorful history written by John West (1998).

Classical Greece and Rome It is perhaps surprising that there are so few references to the ill effects of high altitude in the extensive writings of classical Greece and Rome. The Greek epics and myths, in particular, are so rich in the accounts of travelers and the foibles of human nature that one might expect there to be a reference to the deleterious effects of high altitude, but this is generally not the case. However, 17th-century writers

1

2  History of high altitude medicine and physiology

believed that the ancient Greeks were aware of the thinness of the air at high altitude. For example, Robert Boyle (1627–91) claimed that Aristotle (384–322 BC) held this view when he wrote: That which some of those that treat of the height of Mountains, relate out of Aristotle, namely, That those that ascend to the top of the Mountain Olympus, could not keep themselves alive, without carrying with them wet Spunges, by whose assistance they could respire in that Air, otherwise too thin for Respiration: … (Boyle 1660) However, modern historians have not been able to find this statement in Aristotle’s extensive writings. Similar attributions to Aristotle can be found in the writings of Francis Bacon (1561–1626) and St. Augustine of Hippo (AD 354–430). See West (1998) for additional information.

Chinese Headache Mountains There is a tantalizing reference to what may have been acute mountain sickness (AMS) in the classical Chinese history, the Ch’ien Han Shu, which dates from about 30 BC. One of the Chinese officials warned about the dangers of traveling to the Western regions, probably part of present day Afghanistan, when he stated that travelers would not only be exposed to attacks from robbers but they would also become ill. One of the translations reads:

Joseph de Acosta’s description of mountain sickness Joseph de Acosta (1540–1600) was a Jesuit priest who traveled to Peru in about 1570. While he was there, he ascended the Andes and gave a very colorful account of illness associated with high altitude. This was first published in 1590 in Spanish (Acosta 1590) (Figure 1.1), and a new English translation entitled Natural and Moral History of the Indies appeared in 2002 (Acosta 2002). The following is from his account when the party crossed the Pariacaca mountain range: I have said all this in order to speak of a strange effect caused by the air or wind that prevails in certain lands in the Indies, which is that men become ill from it, not less but much more than at sea. Some think it a legend and others call it an exaggeration, but I will tell what happened to me. In Peru there is a very lofty mountain range that is called Pariacaca; I had heard of this alteration that it causes and went prepared as best I could according to the advice given me by those called vaquianos there, or experts; yet after all my preparation, when I climbed the Staircases, as they are called, the highest part of that range, almost in an instant I felt such mortal anguish that I thought I would have to throw

Again, on passing the Great Headache Mountain, the Little Headache Mountain, the Red Land, and the Fever Slope, men’s bodies become feverish, they lose colour, and are attacked with headache and vomiting; the asses and cattle being all in like condition … Several people have tried to identify the site of the Headache Mountains, suggesting for instance that it is the Kilik Pass (4827 m) in the Karakoram Range on the route from Kashgar to Gilgit (Gilbert 1983). However, there is not universal agreement on this.

Possible early reference to high altitude pulmonary edema Fâ-Hien was a Chinese Buddhist monk who made a remarkable journey through China and adjoining countries in about AD 400. He related that when crossing the “Little Snowy Mountains” (probably in Afghanistan) his companion became ill, “a white froth came from his mouth,” and he died. It is tempting to identify this as the first description of high altitude pulmonary edema.

Figure 1.1  Title page of the first edition of the book by Joseph de Acosta published in Seville in 1590. (Source: Acosta 1590.)

Early scientific advances  3

myself off my mount onto the ground. Although many of us were making the journey, each one was hurrying and not waiting for the others in order to get out of that bad situation. I was left with only one Indian, whom I begged to help hold me on my mount.... Finally, I will say that if it had continued I would have been certain of dying, but it lasted only a matter of three or four hours until we had gone a good way down the mountain and reached a more tolerable altitude, where I found all my companions, of whom there were some fourteen or fifteen, completely exhausted. Some had asked for Confession along the way, thinking that they were dying; others had dismounted and were in a wretched condition with vomiting and flux. Some told me that they were sure their end was at hand from that illness. I saw another who threw himself to the ground and screamed from the terrible pain that the transit of Pariacaca had cost him. But commonly it does not result in any great harm, apart from the feelings of nausea and extreme discomfort that it causes while it lasts. (Acosta 2002, pp. 119–120) Acosta’s book was widely read such that, for example, Robert Boyle was familiar with his description of mountain sickness. Various people including Gilbert (1991) have attempted to identify the site of Pariacaca but there is some disagreement over this.

EARLY SCIENTIFIC ADVANCES Invention of the barometer A key advance in high altitude science was the recognition that barometric pressure falls with increasing altitude. In 1644, Evangelista Torricelli (1608–47) wrote a letter to his friend Michelangelo Ricci in which he described how he had filled a glass tube with mercury and inverted it so that one end was immersed in a dish of the same liquid (Torricelli et al. 1644) (Figure 1.2). The mercury descended to form a column about 76-cm high, and Torricelli argued that the mercury was supported by the weight of the atmosphere acting on the dish. His letter included the striking sentence: “We live submerged at the bottom of an ocean of the element air, which by unquestioned experiments is known to have weight....” This was a conceptual breakthrough. Torricelli also speculated that on the tops of high mountains the pressure might be less because the air is “distinctly rare.” However, it was left to Blaise Pascal (1623–62) to prove that barometric pressure falls with increasing altitude. In 1648, he persuaded his brother-in-law, Florin Perier, to carry a mercury barometer up the Puy-de-Dôme in central France. This was an elaborate experiment with careful controls and he was successful in showing that on the summit

Figure 1.2  Torricelli’s drawing of his first mercury barometer, from his letter to Michelangelo Ricci of 1644. (Source: Torricelli et al. 1644.)

the pressure had fallen by approximately 12% of its value in the village of Clermont.

Invention of the air pump The first effective air pump was constructed by Otto von Guericke (1602–86), who was mayor of the city of Magdeburg in central Germany. In a famous experiment, he constructed two metal hemispheres which fitted together accurately when the air within them was pumped out. Two teams of horses were then unable to separate the two hemispheres, graphically demonstrating the enormous force that could be developed by the air pressure. However, Guericke’s pump was cumbersome to operate and it was impossible to place objects in the hemispheres to study the effects of the reduced air pressure. This was first done by Robert Boyle (1627–91) and his colleague Robert Hooke (1635–1703). Hooke was a mechanical genius who designed an air pump consisting of a piston inside a brass cylinder. Above this was a large glass receiver into which various objects and small animals could be placed (Figure 1.3). In his groundbreaking book, New Experiments Physico-Mechanicall, Touching the Spring of the Air, and Its Effects (Boyle 1660), he demonstrated the effects of a reduced

4  History of high altitude medicine and physiology

tenth part of the air (which he found by a gage suspended within the vessel) and had felt no inconvenience but that of some pain in his ears at the breaking out of the air included in them, and the like pain upon the readmission of the air pressing the ear inwards.

Discovery of oxygen Progress in the remainder of the 17th century and most of the 18th century was largely stymied until the nature of the respiratory gases was characterized. There is not space here to follow the interesting story of the work of Boyle, Hooke, Lower, and Mayow in the 17th century and the discovery of oxygen by Joseph Priestley (1733–1804), Carl Scheele (1742–86), and Antoine Lavoisier (1743–94). For more information see the excellent review by Severinghaus (2016). John Mayow (1641–79) was aware in 1674 of what he called “nitro-aerial spirit,” which we now recognize as oxygen, but his work was largely ignored for almost a century. Both Priestley and Scheele independently isolated oxygen but Priestley was confused about its nature, believing that it was “unphlogisticated air,” and Scheele’s report was delayed because of publication problems. It was left to the brilliant French chemist Lavoisier (Figure 1.4) to clearly describe the three respiratory gases. In 1777, he stated:

Figure 1.3  Air pump constructed by Robert Boyle and Robert Hooke. This enabled them to carry out the first experiments on hypobaric hypoxia. (Source: Boyle 1660.)

atmospheric pressure in a variety of experiments. In one of these a lark was placed in the receiver and Boyle wrote: the Lark was very lively, and did, being put into the Receiver, divers times spring up in it to a good height. The Vessel being hastily, but carefully clos’d, the Pump was diligently ply’d, and the Bird for a while appear’d lively enough; but upon a greater Exsuction of the Air, she began manifestly to droop and appear sick, and very soon after was taken with as violent and irregular Convulsions, as are wont to be observ’d in Poultry, when their heads are wrung off … Following these experiments Hooke made a chamber large enough for a man to sit in it while it was partially evacuated and he reported to the young Royal Society: that himself had been in it, and by the contrivance of bellows and valves blown out of it one

Eminently respirable air [he later called it oxygine] that enters the lung, leaves it in the form of chalky aeriform acids [carbon dioxide] … in almost equal volume. … Respiration acts only on the portion of pure air that is eminently respirable … the excess, that is its mephitic portion [nitrogen], is a purely passive medium which enters and leaves the lung … without change or alteration. The respirable portion of air has the property to combine with blood and its combination results in its red color. Carbon dioxide had been discovered earlier by Joseph Black (1728–99) while he was a medical student, although he used the term “fixed air.”

First balloon ascents and the recognition of severe acute hypoxia The Montgolfier brothers, Joseph (1740–1810) and Jacques (1745–99), invented the man-carrying balloon, first using heated air, and later hydrogen. The first free ascent of a manned balloon took place in Paris in 1783. It was not long before these adventurous balloonists became aware of the deleterious effects of high altitude on the body. For example, Alexandre Charles (1746–1823) (of Charles’ law) ascended in a hydrogen-filled balloon in December 1783 and reported, “In the midst of the inexpressible rapture of this contemplative ecstasy, I was recalled to myself by a very extraordinary

Early scientific advances  5

joy, as if it were an effect of the inundating flood of light. One becomes indifferent…. Soon I wanted to seize the oxygen tube, but could not raise my arm…. Suddenly I closed my eyes and fell inert, entirely losing consciousness. When the balloon ultimately reached the ground, Sivel and Crocé-Spinelli were dead, having perished as a result of the severe hypoxia. The disaster caused a sensation in France.

Mountain sickness in mountaineers During the 19th century, mountaineering became popular particularly in the European Alps. The result was many descriptions of AMS, some of which seem to us today to be greatly exaggerated. One of the first was from the great German naturalist Alexander von Humboldt (1769–1859) when he reached very high altitudes on two volcanoes in South America in 1799. On Chimborazo, at an altitude of about 5540 m, he stated that the whole party felt “a discomfort, a weakness, a desire to vomit, which certainly arises as much from the lack of oxygen in these regions as from the rarity of the air.” Another early account was by HoraceBénédict de Saussure (1740–99) on Mont Blanc (4807 m) in 1787. When he was near the summit he stated:

Figure 1.4  Antoine Lavoisier (1747–1794) with his wife Marie-Anne (1759–1836), who was his laboratory assistant. (From the painting by Jacques-Louis David, 1780.)

pain in the interior of my right ear….” He correctly attributed this to the effects of air pressure. However, more ominous effects were soon noted. Jean Blanchard (1753–1809) claimed to have ascended to an altitude of over 10,000 m in 1785 (although the altitude was contested) and reported that “Nature grew languid, I felt a numbness, prelude of a dangerous sleep….” However, much more dramatic were the events in 1862 when James Glaisher (1809–1903) and Henry Coxwell (1819–1900) rose to an altitude which was estimated to exceed 10,000 m. Glaisher became partly paralyzed and then unconscious, and Coxwell lost the use of his hands, and could only open the valve of the balloon by seizing the cord with his teeth. Glaisher also reported losing his sight before his partial paralysis. The most famous and tragic balloon ascent was by three French aeronauts, Gaston Tissandier (1843–99), Joseph Crocé-Spinelli (1843–75), and Theodore Sivel (1834–75), in their balloon Zénith in 1875. Paul Bert recommended that they take oxygen but they had too little and there were difficulties in inhaling it. Tissandier’s report (1875) is dramatic (De Oliveira 2019). Towards 7500 meters, the numbness one experiences is extraordinary…. One does not suffer at all; on the contrary. One experiences inner

I therefore hoped to reach the crest in less than three quarters of an hour; but the rarity of the air gave me more trouble than I could have believed. At last I was obliged to stop for breath every fifteen or sixteen steps.... This need of rest was absolutely unconquerable; if I tried to overcome it, my legs refused to move…. Numerous other reports of the deleterious effects of high altitude while climbing mountains are given in the first chapter of Paul Bert’s book, La Pression Barométrique (Bert 1878), which is discussed in the following section.

Paul Bert and the publication of La Pression Barométrique The French environmental physiologist Paul Bert (1833–86) is often cited as the father of modern high altitude physiology and medicine. The publication of his great book, La Pression Barométrique, in 1878 was certainly an important landmark. One of his principal findings was that the deleterious effects of exposure to low pressure could be attributed to the low PO2. He did this by exposing experimental animals to a low pressure of air on the one hand (hypobaric hypoxia), and to gas mixtures at normal pressure but with a low oxygen concentration (normobaric hypoxia) on the other. In this way, he showed that the critical variable was the PO2. La Pression Barométrique is essential reading for anybody with a serious interest in the history of high altitude medicine and physiology. For one thing, there is a long introductory section on the history as Bert saw it, and this makes fascinating reading

6  History of high altitude medicine and physiology

today. Bert wrote with a charming style and urbane wit. The book not only deals with the medical and physiological effects of low pressure but high pressure as well. Many of Bert’s studies were carried out at the Sorbonne in Paris, which was equipped with both low-pressure and high-pressure chambers (Figure 1.5). At one stage, he tested the three French balloonists Tissandier, Crocé-Spinelli, and Sivel who were referred to above and he actually warned them that they had insufficient oxygen but the warning letter arrived too late. La Pression Barométrique includes many interesting passages. For example, it contains the first graphs of the oxygen and carbon dioxide dissociation curves in blood. Bert also speculated that polycythemia might occur at high altitude and this was shown a short time later by compatriots, including Viault (Viault 1890). Bert speculated on the possible reduction of metabolism in frequent visitors to high altitude and people who live permanently there. This short section will be cited partly because it gives a good feel for the style of Bert. We see that very probably, in the habitual conditions of our life, we commit excesses of oxygenation as well as of nourishment, two kinds of excess, which are correlative. And just as peasants, who eat much less than we do, but utilizing all that they absorb, produce in heat and work a useful result equal, if not superior, to that of city dwellers; just as a Basque mountaineer furnished with a piece of bread and a few onions makes expeditions which require of the member of the Alpine Club who

accompanies him the absorption of a pound of meat, so it may be that the dwellers in high places finally lessen the consumption of oxygen in their organism, while keeping at their disposal the same quantity of vital force, either for the equilibrium of temperature, or the production of work. Thus, we could explain the acclimatization of individuals, of generations, of races. (Bert 1878)

Two new, permanent high altitude laboratories OBSERVATOIRE VALLOT

Toward the end of the 19th century, the pace of discoveries in high altitude medicine and physiology accelerated rapidly, partly as the result of the publication of La Pression Barométrique and partly due to the establishment of two high altitude laboratories. The first was the Observatoire Vallot on Mont Blanc, which was installed in 1890. Joseph Vallot (1854–1925) conceived the idea of placing a small building at an altitude of about 4350 m, which is about 460 m below the summit of Mont Blanc. With typical French panache, he was not satisfied with a simple hut, but in addition there were a comprehensive laboratory, a well-appointed kitchen, and attractive interior decorations including a French tapestry of courtly ladies in the 18th-century style. The laboratory was used for research in several of the physical sciences, including astronomy and glaciology, but physiological studies were also carried out including some of the first observations of periodic breathing at high altitude (Egli 1893). In 1891, a young physician, Dr. Jacottet, died in the Observatoire Vallot from what was almost certainly high altitude pulmonary edema (Simons and Oelz 2000). A description of the illness, including the postmortem findings, is in Mosso’s book, Life of Man on the High Alps (Mosso 1898), which is referred to in the next section. A description of more recent work at the Observatoire Vallot is provided later in this chapter, while an image of the modernized hut is shown in Figure 1.6. CAPANNA MARGHERITA

Figure 1.5  Low-pressure chambers used by Paul Bert at the Sorbonne. (Source: Bert 1878.)

Shortly after the construction of the Observatoire Vallot, an even higher structure was placed on the Punta Gnifetti of the Monte Rosa massif on the Swiss-Italian border at an altitude of 4559 m. The original hut was completed in 1893 and 10 years later it was enlarged by the influential Italian scientist Angelo Mosso (1846–1910) to include a laboratory for physiological and medical studies. The structure owes its name to Queen Margherita of Savoy who was a lover of alpinism and a generous patron of science. In fact, she visited the Capanna in 1893 and spent the night there. Mosso was a physiologist with very broad interests, particularly in the area of exercise and environmental physiology.

Scientific expeditions and laboratory explorations: 1900–1950  7

Figure 1.6  Contemporary photograph of the Observatoire Vallot at 4362 m on Mont Blanc. Major renovation work was completed by the Centre National de Recherche Scientifique (CNRS) in 2017. (Image courtesy of François Estève.)

Some of the early studies in the Capanna Margherita were reported in his book, Fisiologia dell’uomo sulle Alpi: Studii fatti sul Monte Rosa (Mosso 1897), and this was translated into English as Life of Man on the High Alps (Mosso 1898). Among the projects carried out at the Capanna were some on periodic breathing, and also total ventilation at high altitude. In fact, Mosso believed that the deleterious effects of high altitude were related to the low PCO2 in the blood rather than the reduced PO2 as previously proposed by Paul Bert. Mosso coined the term “acapnia” to describe this condition, which he thought was important in the development of AMS. An interesting event at the Capanna was the illness of an Italian soldier, Pietro Ramella, who developed what was thought to be a respiratory infection and from which he recovered. In retrospect, this may have been high altitude pulmonary edema, as was the case with Dr. Jacottet at the Observatoire Vallot. Work continues today at Capanna Margherita (Figure 1.7) and is described further below.

SCIENTIFIC EXPEDITIONS AND LABORATORY EXPLORATIONS: 1900–1950 In the early 1900s, the tradition continued of organizing expeditions to high altitude locations to carry out medical and physiological research, and scientists began to do experiments at simulated high altitude in hypobaric chambers on human subjects.

Tenerife expedition One of the first research expeditions was organized by Nathan Zuntz (1847–1920), who was the first author of an influential book on high altitude physiology published in 1906 (Zuntz et al. 1906). The expedition was to Tenerife in the Canary Islands and experiments were carried out at the Alta Vista hut at an altitude of 3350 m. Among the members of the expedition were Joseph Barcroft (1872–1947) and C.G. Douglas (1882–1963) and they made an interesting observation on the alveolar gases and acclimatization. Barcroft was the only member of the party who showed no significant fall in alveolar PCO2 at the Alta Vista hut; that is, he was the only person who did not exhibit an increase in ventilation, and he was also the only person who was incapacitated by AMS. By contrast, the alveolar PCO2 of Douglas fell from 41 to 32 mmHg, and that of Zuntz fell from 35 to 27 mmHg and both of these members had no mountain sickness. This was corroborative evidence that mountain sickness was caused by the low PO2 as suggested by Paul Bert, rather than the low PCO2 as proposed by Angelo Mosso.

Anglo-American expedition to Pikes Peak A very important expedition took place in 1911 when an Anglo-American group led by J.S. Haldane (1860–1936) went to Pikes Peak just outside Colorado Springs, where

8  History of high altitude medicine and physiology

Figure 1.7.  Contemporary photograph of the Capanna Margherita (4559 m) taken from a helicopter approaching the hut. It remains the site of an active research program on high altitude medicine and physiology. (Image courtesy of Peter Bärtsch.)

there was a hotel on the summit at an altitude of 4300 m (Figure 1.8). One of the advantages of Pikes Peak was a cog railway and road all the way to the summit. The 1911 expedition was carefully planned so that there were measurements at a lower altitude prior to the ascent. Then, a rapid ascent was made and the party stayed on the summit where extensive data were collected. Finally, measurements were made again when the participants returned to low altitude.

Figure 1.8  Members of the Anglo-American Pikes Peak Expedition of 1911. Left to right: Henderson taking samples of alveolar gas, Schneider sitting and recording his respiration, Haldane standing, and Douglas wearing a “Douglas bag” to collect expired gas during exercise. (Source: Henderson 1938.)

Many important observations were made. The hyperventilation that accompanies ascent to high altitude was documented with the alveolar PCO2 falling to about two-thirds of its sea level value over two weeks on the summit. Periodic breathing was confirmed. Polycythemia was studied with the percentage of hemoglobin in the blood increasing over several weeks on the summit to values between 115% and 154% of normal as measured by color changes in the blood. All the measurements were reported in a long paper by Douglas et al. (1913). The members of the expedition also believed that they had obtained evidence for oxygen secretion at high altitude. In fact, the report stated that the arterial PO2 at rest was as much as 35 mmHg above the alveolar value on the summit, whereas at or near sea level the two values were the same. The investigators proposed that oxygen secretion was the most important factor in acclimatization. To this day, it is not clear where this large error was made in the measurements. Oxygen secretion was an important controversy around this time and Haldane actually believed in it until his death in 1936. In fact, the second edition of his book on respiration has a whole chapter devoted to the evidence for oxygen secretion (Haldane 1935). Haldane had originally developed the notion after visiting Christian Bohr (1855–1911) in Copenhagen who was a great champion of oxygen secretion. However, the error was exposed in the view of most physiologists by August Krogh (1874–1949) and his wife Marie (1874–1943) in a series of papers published in 1910 (Krogh 1910a; 1910b; 1910c; 1910d; 1910e; Krogh and Krogh 1910a; 1910b).

Scientific expeditions and laboratory explorations: 1900–1950  9

Mabel FitzGerald’s field work in Colorado Mabel FitzGerald (1872–1973) was invited to join the Pikes Peak expedition, but did not spend any time in the laboratory for reasons that are not entirely clear. Instead, she visited various mining camps in Colorado at altitudes between 1500 and 4300 m, where she measured the alveolar PCO2 in acclimatized miners and produced data on acclimatization to moderate altitudes that are still cited (Fitzgerald and Haldane 1905; Fitzgerald and Haldane 1913). Although she studied at Oxford University for a number of years, it was not the custom then to give degrees to women. However, the university relented in 1972 when she was 100 years old and awarded her an honorary MA degree.

International high altitude expedition to Cerro de Pasco, Peru Another classical expedition to high altitude was the International High Altitude Expedition to Cerro de Pasco, Peru, which took place in 1921–22, led by Joseph Barcroft (1872–1947). An attractive feature of this location at an altitude of about 4330 m was that it could be reached by railway from Lima, and the expedition fitted out a railway baggage van as an efficient laboratory (Figure 1.9). Again, there was a very extensive scientific program (Barcroft et al. 1923). The topic of oxygen secretion was investigated but no support for it was found. In fact, the PO2 in arterial blood measured by a bubble equilibration method was about 3 mmHg lower than that in alveolar gas. There was an increase in red blood cell concentration by about 20–30% over the sea-level value. The arterial oxygen saturation fell during exercise at high altitude and this fall was correctly attributed to the failure of the PO2 to equilibrate between alveolar gas and pulmonary capillary blood because of diffusion limitation. Extensive measurements of neuropsychological function showed that

this was impaired at high altitude. In fact, Barcroft made the infamous statement “All dwellers at high altitude are persons of impaired physical and mental powers.” One of the novel features of this expedition was its studies of permanent residents of high altitude. Cerro de Pasco was a substantial mining town with a large permanent population. It was shown that the red cell concentrations in the permanent residents had values of 40–50% above what would be expected at sea level, that is substantially higher than the newcomers to high altitude. It was also found that the permanent residents of Cerro de Pasco tended to have lower arterial oxygen saturations of 80–85%, one of the first intimations that highlanders have lower ventilation than newcomers to high altitude.

International high altitude expedition to Chile In 1935, the International High Altitude Expedition to Chile took place, led by D.B. Dill (1891–1986). Many measurements were made at a mining camp, altitude 5334 m, and these resulted in a classical paper entitled “Blood as a physicochemical system. XII. Man at high altitudes” (Dill et al. 1937). Extensive measurements of exercise were carried out showing, for example, that in one of the members the maximal oxygen consumption fell from 3.72 to 1.80 L min−1 at the altitude of the high camp (compared with sea level), while the maximal heart rate fell from 190 to 132 beats min−1. A particularly interesting finding was that in wellacclimatized subjects the maximal levels of blood lactate were remarkably low, certainly much lower than in acute hypoxia or in subjects without acclimatization (Edwards 1936). This so-called “lactate paradox” has been observed on many occasions since and is still not fully understood. Indeed, some scientists disagree that the “lactate paradox” even exists and, as described in the section “Copenhagen Muscle Research Center High Altitude Expeditions,” research continues on this issue to this day.

Operation Everest I

Figure 1.9  Laboratory of the International High Altitude Expedition to Cerro de Pasco, Peru, 1921–22. This was set up in a railroad car. (Source: Barcroft et al. 1923.)

After decades of important field studies, by the 1940s it was time to bring the mountain to the laboratory. In 1944, renowned mountaineer and physician Charles Houston (1913–2009) and his Navy colleague Richard Riley (1911–2001) carried out a remarkable study known as Operation Everest I at the US Naval School of Aviation Medicine in Pensacola, Florida. Four volunteers lived continuously in a low-pressure chamber for 35 days and were gradually decompressed to the equivalent of the altitude of Mount Everest. The project was justified to the Navy on the grounds that it was relevant to improving the tolerance of aviators to high altitudes. Alveolar gas and arterial blood studies were carried out and the most striking finding was that it was possible for resting, partly acclimatized subjects to survive without supplemental oxygen for 20 minutes or so at a simulated altitude that actually exceeded the summit of Mount Everest (Houston et al. 1987). This came about because they

10  History of high altitude medicine and physiology

were using the Standard Atmosphere, which predicts a substantially lower pressure on the summit than actually exists.

1964). Blood-volume and respiratory regulation were also investigated (Michel and Milledge 1963; Pugh 1964a).

Human’s quest to climb Mount Everest: Scientific underpinnings

WHITE MOUNTAIN RESEARCH STATION (WMRS)

A major high-altitude physiologist at this time was L.C.G.E. Pugh (1909–94), who was a participant in the first expedition to make a successful ascent of Mount Everest in 1953. During 1952, Pugh and others conducted physiological studies on the nearby mountain Cho Oyu to clarify some of the logistics of tolerating extreme altitude, including ventilation rates, maximal oxygen consumptions, effects of oxygen breathing, hydration, food, and clothing. A recent biography of Pugh provides background and insight into many of these important studies (Tuckey 2013). Pugh’s contributions were a major factor in the ultimate success of the expedition when Edmund Hillary and Tenzing Norgay became the first people to reach the highest point in the world.

HIGH ALTITUDE RESEARCH IN THE LATTER HALF OF THE 20th CENTURY 1960s SILVER HUT EXPEDITION

The Himalayan Scientific and Mountaineering Expedition of 1960–61, led by Griffith Pugh, was the first party to winter high in the Himalayas, with the team spending eight and a half months at over at an altitude of >5800 m in a wooden structure painted silver (Figure 1.10). Even 60 years later, the physiological studies remain relevant and oft-quoted. The physiological program consisted mainly in a detailed investigation of the oxygen transport system (West et al. 1962), with studies of the blood (Gill and Pugh 1964) and respiratory gases (Gill et al. 1962), lung diffusion (West 1962), and cardiac output (Pugh 1964b), as well as oxygen intake and ventilation during bicycle ergometer exercise (Pugh et al.

Figure 1.10  Main laboratory of the Himalayan Scientific and Mountaineering Expedition, 1960–61. The Silver Hut was at an altitude of 5800 m about 16 km south of Mount Everest.

Founded by the University of California in 1950, and initially led by Nello Pace (Cook and Pace 1952), in the late 1950s and early 1960s the WMRS hosted many well-known high altitude researchers who contributed much to this mid-20th century period of exploration of the physiology of acclimatization. Some of the first studies of work capacity at high altitude were carried out by Per Olaf Åstrand, a pioneer in exercise physiology (Åstrand and Åstrand 1958). Ralph Kellogg and colleagues made important early observations regarding oxygen and carbon dioxide controlling ventilatory acclimatization at rest (Kellogg 1960; Kellogg et al. 1957). These investigations into the chemical control of ventilation led John Severinghaus to lead a number of studies including repeat lumbar and jugular vein punctures with Robert Mitchell, the discoverer of the medullary chemoreflexes (Severinghaus and Carcelen 1964; Severinghaus et al. 1963). With Thomas Hornbein, Severinghaus also completed some of the first studies documenting the changes in cerebral blood flow during acclimatization (Severinghaus et al. 1966). David Bruce Dill, one of the 20th-century’s preeminent environmental physiologists, completed the first study of the impact of aging on the ability to acclimatize by restudying the surviving members of the 1935 expedition to the Andes (Dill et al. 1966; Dill et al. 1967; Dill et al. 1964). Although the pace of work at WMRS has slowed in recent decades, some groups still make use of this excellent facility (Alsup et al. 2019; Burns et al. 2019; Kanaan et al. 2015; Lipman et al. 2012; Smith et al. 2017). 1968 OLYMPICS

In 1968, the Olympics were held for the first time at high altitude in Mexico City (2240 m). This occasioned a significant burst of research into the impact of high altitude on physical performance (Balke et al. 1965; Buskirk et al. 1967; Faulkner et al. 1967; Pugh 1967; Williams 1966). In sports where lower air density lent itself to better performance, world records were set. In contrast, oxygen demanding endurance events were performed at a much slower pace than in previous Olympics at lower altitudes. However, this Olympics was a preview of the coming dominance of East African (Kenyan and Ethiopian) runners, with winners in the 1500, 5000, and 10,000 m races, all from these countries. How East Africans do so well in endurance running events remains a mystery today in the early 21st century. The research undertaken to support athletes for the 1968 Olympics also was the foundation for current research on training at high altitude. In the late 1990s, this idea experienced a revival based on the work of Levine and colleagues using a model of living at high altitude and training at lower altitude (Levine and Stray-Gundersen 1997), which has since come into question (Siebenmann et al. 2011). Further information on this topic can be found in Chapter 18.

High altitude research in the latter half of the 20th century  11

INDIAN HIGH ALTITUDE RESEARCH

A scientific consequence of the 1962 Indo-China War was an intense effort by both countries in high altitude medicine and physiology in support of long-term deployment of troops to altitudes above 6000 m in the border areas between India and China. The classic paper “Acute Mountain Sickness,” by Inder Singh (Singh et al. 1969), formed the basis for our understanding of this field for decades by offering a detailed description of AMS, high altitude pulmonary edema, and high altitude cerebral edema, and exploring the pathophysiology of these problems. With the conflict persisting into the 21st century, Indian and Chinese research on these topics has continued. USARIEM MAHER MEMORIAL ALTITUDE LABORATORY ON PIKES PEAK

From 1969 to the present, a laboratory run by USARIEM (United States Army Research Institute of Environmental Medicine) has been serving the US Army’s research needs on the top of Pikes Peak (4300 m), just outside of Colorado Springs, Colorado. Very productive work on the role of autonomic nervous system control of cardiovascular function during acclimatization was carried out in the mid-1980s in collaboration with Jack Reeves and his team at the University of Colorado (Brooks et al. 1998; Grover et al. 1998; Mazzeo et al. 1991; Mazzeo et al. 1994a; Mazzeo et al. 1994b; Roberts et al. 1996; Wolfel et al. 1991). More recently, the USARIEMbased team has focused on the benefits of staging and preacclimatization strategies (Beidleman et al. 2017; Beidleman et al. 2019; Fulco et al. 2013; Staab et al. 2013).

1970s HIGH ALTITUDE PHYSIOLOGY STUDY, MT. LOGAN, CANADA

In between Operation Everest I and II, Charles Houston developed the High Altitude Physiology Study on Mt. Logan, in the far north of western Canada (5250 m). Starting in 1970 and lasting more than a decade, major studies focused on gas exchange in AMS (Sutton et al. 1976), on sleep periodic breathing and its amelioration with acetazolamide (Sutton et al. 1980; Sutton et al. 1979), as well as high altitude retinal hemorrhage (Frayser et al. 1974; Frayser et al. 1970; Frayser et al. 1971; Lubin et al. 1982; McFadden et al. 1981). In addition to studies of fluid and electrolyte balance (Frayser et al. 1975), endocrine system adaptations (Frayser et al. 1975; Sutton 1983) and blood coagulation (Gray et al. 1975) were also explored.

1980–90s AMERICAN MEDICAL RESEARCH EXPEDITION TO EVEREST (AMREE)

In 1981, the American Medical Research Expedition to Everest (AMREE), led by John West, set out to obtain the first data from the Everest summit itself (West 1984). Among the remarkable findings were alveolar PO2 and PCO2 values of 35 and 7–8 mmHg, respectively, and an arterial pH (based

on the measured alveolar PCO2 and blood base excess) of more than 7.7 mmHg (West et al. 1983b). The barometric pressure on the summit was determined to be 253 mmHg (West et al. 1983c) and the maximal oxygen consumption measured using the summit-inspired PO2 was just over 1 L min−1 (West et al. 1983a). In addition to these enduringly important findings, AMREE also explored in Everest climbers the control of ventilation (Schoene et al. 1984), red cell function (Winslow et al. 1984), and the effect of hemodilution on exercise (Sarnquist et al. 1986) and endocrine function (Milledge et al. 1983). DENALI MEDICAL RESEARCH PROJECT

Building on his experience with Charles Houston on Mt. Logan, at the Himalayan Rescue Association clinic in Nepal, and as a scientist and climber with John West on AMREE in 1981, Dr. Peter Hackett in 1982 began the Denali Medical Research Project at 4200 m on the West Buttress of Denali (Mt. McKinley) in one of the most austere environments on earth, with temperatures reaching −40°C at night, frequent high winds, and no resupply once camp was established every year at the beginning of the climbing season in May (Hackett and Roach 1986). Over the next decade, major advances were made in understanding the use of dexamethasone (Hackett et al. 1988b) and acetazolamide (Grissom et al. 1992) for the treatment and prevention of AMS, and the bronchoalveolar lavage characteristics of (Schoene et al. 1986; Schoene et al. 1988) and the control of ventilation in high altitude pulmonary edema (HAPE) (Hackett et al. 1988a), among many other topics. THE OBSERVATOIRE VALLOT

The Observatoire Vallot (4350 m) is still in use today, although it has been considerably modified (Richalet 2001) (Figure 1.6). Access is challenging because usually a night must be spent at the Grands Mulets (3050 m) followed by a climb over the snow and ice the next day. Alternatively, a helicopter ascent is possible. Richalet and colleagues conducted an extensive research program at the Observatoire Vallot between 1984 and 2003 and occasional work continues today. Highlights include a series of reports on adrenergic receptor modulation of cardiac function during acclimatization (Bouissou et al. 1989; Cornolo et al. 2004; Richalet et al. 1988; Richalet et al. 1989). Additionally, a collaboration with Danish scientists led to a series of important studies on the regulation of fluid balance (Bouchet et al. 1997; Hansen et al. 1996; Klausen et al. 1997; Olsen et al. 1993; Olsen et al. 1992; Poulsen et al. 1998). OPERATION EVEREST II

Charles Houston, John Sutton, and Jack Reeves carried out Operation Everest II at a US Army facility in Natick, Massachusetts, in the fall of 1986, which was basically similar to Operation Everest I in design, but much more sophisticated in the measurements that were made. Again, the volunteers were gradually decompressed to the barometric pressure on the Everest summit and a large series

12  History of high altitude medicine and physiology

of measurements that could not be made in the field were completed. Notable experiments included cardiac catheterization, which showed substantial increases in pulmonary artery pressures with ascent up to the simulated summit of Mount Everest, particularly on exercise (Groves et al. 1987). Other important information was obtained at extreme altitude on exercise performance (Reeves et al. 1987; Reeves et al. 1989; Reeves et al. 1992; Sutton et al. 1992; Sutton et al. 1988), nutrition (Rose et al. 1988), pulmonary gas exchange (Wagner et al. 1987), control of ventilation (Schoene et al. 1990), sleep at high altitude (Anholm et al. 1992), changes in skeletal muscle energetics by biopsy (Green et al. 1989), and neuropsychological changes (Hornbein et al. 1989).

acclimatized subjects for seven days at the Observatoire Vallot. The subjects then descended to sea level and were transported to the COMEX chamber in Marseille, France, where decompression from 422 to 253 mmHg (8848 m) started within 24 hours and lasted 31 days. All subjects made it to 8000 m, and seven achieved the simulated summit. During the chamber study, a series of noninvasive studies were conducted resulting in several papers on the impact of plasma volume on exercise performance (Robach et al. 2000), cardiac function (Boussuges et al. 2000), and appetite (Westerterp-Plantenga et al. 1999), among others.

THE CAPANNA REGINA MARGHERITA

Danish expeditions to Chacaltaya (1998) and El Alto, Bolivia (2002) led by Bengt Saltin (1998) and Carsten Lundby (2002) provided important advances in our understanding of cardiovascular regulation during acclimatization and exercise. The Danish High-Altitude Expedition to Chacaltaya in 1998 focused on mechanisms of acclimatization and alterations at various steps of oxygen transport in studies of Danish men and women acclimatizing for five weeks at 5200 m on Mt. Chacaltaya, Bolivia. Studies included measurements of mechanisms limiting maximal oxygen consumption (Calbet et al. 2003), pulmonary gas exchange (Wagner et al. 2002), and the initial paper refuting the theory of the lactate paradox (van Hall et al. 2001). Subsequent studies led by Lundby advanced the lactate paradox story (van Hall et al. 2009), extended the pulmonary gas exchange story (Lundby et al. 2004a), explored angiogenesis in skeletal muscle (Lundby et al. 2004b), and did pioneering work comparing adapting lowlanders to high altitude natives (Lundby and Calbet 2016; Lundby et al. 2006).

The Capanna Regina Margherita (CRM) (Figure 1.7) has been enlarged over the years. The updated, three-level building now provides sleeping accommodations for up to 80 mountaineers. The infrastructure, the possibility of transporting sophisticated equipment by helicopter, and the proximity to highly populated areas with communities interested in mountaineering allow researchers to perform prospective investigations in susceptible mountaineers as well as epidemiologic studies on visitors of the hut. In 1983, Oswald Oelz, Everest summiteer and physician to Reinhold Messner and Peter Habeler on their 1978 ascent of Mount Everest without supplemental oxygen, led the first team to make use of this unique opportunity. Joined by Peter Bartsch, and later Marco Maggiorini, they led many high-impact studies at the rejuvenated hut, which have transformed our understanding of the physiology of acclimatization and the pathophysiology and management of HAPE and AMS and served as a fertile training environment for a new generation of Swiss, Italian, German, American, and other researchers in high altitude medicine and physiology. One of the major advances made possible by their clinical studies of mountaineers with a history of HAPE in conjunction with portable radiography and echocardiography equipment was establishing the efficacy of nifedipine for treatment and prevention of HAPE (Bärtsch et al. 1991; Oelz et al. 1989). Right heart catheterization, bronchoalveolar lavage, and lung perfusion scanning in mountaineers with and without early HAPE allowed further insight into the pathophysiologic mechanisms underlying HAPE (Bailey et al. 2010; Duplain et al. 1999; Grünig et al. 2000; Mairbäurl et al. 2003; Sartori et al. 1999), as discussed in later chapters. These include the seminal findings providing insight into the underlying mechanisms of HAPE (Maggiorini et al. 2001; Swenson et al. 2002). Additionally, this group made major contributions to advancing our understanding of AMS pathophysiology (Bärtsch et al. 1993; Maggiorini et al. 1990; Schneider et al. 2002). Recent work continues this impressive history (Berger et al. 2018; Berger et al. 2019; Sareban et al. 2019). COMEX (EVEREST III)

In 1997, Richalet led a team of scientists and eight research subjects on a creative extreme altitude study. They first

COPENHAGEN MUSCLE RESEARCH CENTER HIGH ALTITUDE EXPEDITIONS

MAJOR RESEARCH PROGRAMS IN THE EARLY 21st CENTURY In addition to ongoing work at the CRM and the Observatoire Vallot, several new initiatives have led to very productive research projects around the world. There are many excellent additional research expeditions at high altitude by different groups across the world, including the growing contributions of Indian (e.g., Mishra et al. 2015; Rain et al. 2018) and Chinese scientists (Huang et al. 2017; Liu et al. 2018; Yuhong et al. 2018). What follows are just a few examples of larger scale research expeditions that reflect the ongoing growth in the field of high altitude medicine and physiology more than 30 years after the first edition of this book.

High altitude chambers In the late 20th century, many laboratories installed “hypoxic rooms” allowing easy and relatively inexpensive study of subjects and patients with varying degrees of low inspired oxygen. After it became apparent that there are significant differences between the physiologic responses seen with normobaric hypoxic chambers and those seen with

Major research programs in the early 21st century  13

exposure to simulated or terrestrial hypobaric hypoxia, there has been a resurgence of interest in hypobaric exposure since the beginning of the 21st century. Large new facilities in Europe (TerraXcube in Bolzano, Italy, and Envihab near Cologne, Germany) and existing facilities in the United States (Colorado Altitude Research Center in Denver, Institute for Exercise and Environmental Medicine in Dallas, and the Natick Lab chambers near Boston) are sites of significant work.

Caudwell Xtreme Everest Expedition In 2007, the Caudwell Xtreme Everest Expedition, led by Michael Grocott, conducted an extensive number of experiments on a cohort of 200 individuals who trekked into Everest base camp, as well as studies on climbers traveling to the summit of the mountain and other expedition support personnel who spent an extended period of time at base camp (Levett et al. 2010). Among the high impact reports from this expedition were the collection of arterial blood samples from four climbers at an altitude of 8400 m, which showed an arterial PO2 as low as 19.1 mmHg (Grocott et al. 2010). Other important new findings were reported on skeletal muscle energetics (Edwards et al. 2010; Levett et al. 2012), cerebral blood flow changes (Wilson et al. 2011), cardiac function (Holloway et al. 2011), and acute pulmonary vascular responses (Luks et al. 2017). The Xtreme Everest group has completed additional projects including Xtreme Everest 2 (Gilbert-Kawai et al. 2015), Xtreme Alps (Martin et al. 2013), and the Young Everest Study (Gavlak et al. 2013), in which studies have focused on metabolic (Horscroft et al. 2017) and circulatory (Gilbert-Kawai et al. 2017) differences in Sherpas as well as shifts in metabolomic signatures (O’Brien et al. 2019) and cognitive function (Griva et al. 2017) in travelers to altitude.

AltitudeOmics Led by Robert Roach of the University of Colorado Altitude Research Center and comprised an international team of 25 researchers, AltitudeOmics studied the integrated physiological and genomic responses during acclimatization to high altitude on Mt. Chacaltaya, Bolivia, at 5260 m (Subudhi et al. 2014). Lowland volunteers were taken rapidly to 5260 m, where they acclimatized for 16 days, and then descended to 1525 m for either 7 or 21 days, after which they returned quickly to 5260 m and were further examined. The reasoning behind this experimental design was that “memory” of altitude acclimatization was likely, and discovery of its mechanisms might lead to new insights into the physiology of acclimatization and pathophysiology of AMS. A surprise finding was that red blood cells retain through adenosine signaling their ability to rapidly adjust to hypoxia, even after days of deacclimatization (Song et al. 2017). Another important study was an “omics”-based evaluation of skeletal muscle energy metabolism that showed that integration of aerobic and anaerobic metabolism is required for

adaptation in skeletal muscle and highlighted the important role of protein catabolism and allosteric regulation (Chicco et al. 2018). Additional studies focused on mechanisms of fatigue (Amann et al. 2013; Goodall et al. 2014), cerebrovascular function (Fan et al. 2015; Fan et al. 2014; Subudhi et al. 2014a; Subudhi et al. 2014b) and cardiac function (Elliott et al. 2015; Petrassi et al. 2018).

University of British Columbia (UBC) Okanagan high altitude research program The University of British Columbia (UBC) Okanagan altitude research program, led by Phillip Ainslie, comprised a diverse international team of more than 40 researchers. It has conducted a wide variety of projects on hypoxia at sea level, in Nepal (around the Khumbu and at the Pyramid International Laboratory/Observatory; Figure 1.11), and in Peru (Cerro de Pasco and La Rinconada; Figure 1.12). (Willie et al. 2018). By frequently including lowlanders and high altitude natives in their study design, the UBC studies have made many important contributions to high altitude physiology over the past two decades. Among the many high impact findings are reports with a focus on cerebrovascular physiology (Hoiland et al. 2019; Willie et al. 2015), vascular function (Tremblay et al. 2018; Tremblay et al. 2019), cardiac mechanics (Stembridge et al. 2016; Williams et al. 2019), blood volume regulation (Stembridge et al. 2019), sleep (Burgess et al. 2013; 2014), and exercise (Smith et al. 2014; Stembridge et al. 2015).

Expanding frontiers in hypoxia research As will become apparent in subsequent chapters in this book, one of the burgeoning areas of hypoxia research in recent years has been the role of the hypoxia-inducible factor (HIF). The pathway mediated by this gene transcription factor, which was discovered and worked out by William Kaelin Jr, Sir Peter Ratcliffe, and Gregg Semenza (Figure 1.13), is active in every cell and controls hundreds of downstream genes and physiologic processes in animals and humans. Further detailed information can be found in subsequent chapters of this book and several recent reviews (Ivan and Kaelin 2017; Schödel and Ratcliffe 2019; Semenza 2014). The work by these and other investigators has provided researchers and clinicians new routes for treatment of anemia, cancer, heart disease, and many other conditions and, in the years to come, is likely to fundamentally transform our understanding of most topics explored in this book. In recognition of the significance of this work, Kaelin, Ratcliffe, and Semenza were awarded the Nobel Prize in Physiology or Medicine in 2019.

Recent breakthroughs in high altitude genomics After decades of broad interest in the performance of high altitude natives, hints of naturally selected genomic

14  History of high altitude medicine and physiology

Figure 1.11  The Pyramid International Research Laboratory and Observatory, located at 5050 m in the Khumbu Valley of Nepal. (Image courtesy of Philip Ainslie.)

Figure 1.12  Cerro de Pasco, Peru. Elevation 4330 m. (Image courtesy of Philip Ainslie.)

Major research programs in the early 21st century  15

Figure 1.13  Investigators who were awarded the 2019 Nobel Prize in Physiology or Medicine for their discovery of the hypoxiainducible factor pathway. From left to right, William G. Kaelin, Jr., MD, Sir Peter J. Ratcliffe, and Gregg L. Semenza, MD, PhD.

mechanisms have emerged in the last decade. For example, genomic scans for selection have revealed at least 40 candidate genes related to the HIF, such as EPAS1 in populations from Tibet, EGLN1 in Andeans and Tibetans, and BHLHE41, THRB, and ARNT2 in Ethiopians (Beall et al. 2010; Bigham et al. 2010; Scheinfeldt et al. 2012; Simonson et al. 2010; Xu et al. 2011). Of note is that one of the key genetic adaptations identified in Tibetans is contained within a region of DNA passed down from an archaic human population (HuertaSánchez et al. 2014). The significance of these advances is the subject of intense research and is discussed in detail in Chapter 6.

REFERENCES Acosta Jd. (1590). Historia natural y moral de las Indias. Seville. Acosta Jd. (2002). Natural and Moral History of the Indies. Duke University Press, Durham, NC USA. Alsup C, Lipman GS, Pomeranz D, Huang RW, Burns P, Juul N, Phillips C, Jurkiewicz C, Cheffers M, Evans K, Saraswathula A, Baumeister P, Lai L, Rainey J, Lobo V. (2019). Interstitial pulmonary edema assessed by lung ultrasound on ascent to high altitude and slight association with acute mountain sickness: a prospective observational study. High Alt Med Biol. 20:150–156. Amann M, Goodall S, Twomey R, Subudhi AW, Lovering AT, Roach RC. (2013). AltitudeOmics: on the consequences of high-altitude acclimatization for the development of fatigue during locomotor exercise in humans. J Appl Physiol. 115:634–642. Anholm JD, Powles AC, Downey R, 3rd, Houston CS, Sutton JR, Bonnet MH, Cymerman A. (1992). Operation Everest II: arterial oxygen saturation and sleep at extreme simulated altitude. Am Rev Respir Dis. 145:817–826. Åstrand P-O, Åstrand I. (1958). Heart rate during muscular work in man exposed to prolonged hypoxia. J Appl Physiol. 13:75–80.

Bailey DM, Dehnert C, Luks AM, Menold E, Castell C, Schendler G, Faoro V, Gutowski M, Evans KA, Taudorf S, James PE, McEneny J, Young IS, Swenson ER, Mairbäurl H, Bärtsch P, Berger MM. (2010). Highaltitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability. J Physiol. 588:4837–4847. Balke B, Nagle FJ, Daniels J. (1965). Altitude and maximum performance in work and sports activity. JAMA. 194:646–649. Barcroft J, Binger CA, Bock AV, Doggart JH, Forbes HS, Harrop G, Meakins JC, Redfield AC. (1923). Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lond B. 211:351–480. Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. (1991). Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med. 325:1284–1289. Bärtsch P, Merki B, Hofstetter D, Maggiorini M, Kayser B, Oelz O. (1993). Treatment of acute mountain sickness by simulated descent: a randomised controlled trial. BMJ. 306:1098–1101. Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT. (2010). Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci USA. 107:11459–11464. Beidleman BA, Fulco CS, Cadarette BS, Cymerman A, Buller MJ, Salgado RM, Posch AM, Staab JE, Sils IV, Yurkevicius BR, Luippold AJ, Welles AP, Muza SR. (2017). Is normobaric hypoxia an effective treatment for sustaining previously acquired altitude acclimatization? J Appl Physiol. 123:1214–1227.

16  History of high altitude medicine and physiology

Beidleman BA, Fulco CS, Cymerman A, Staab JE, Buller MJ, Muza SR. (2019). New metric of hypoxic dose predicts altitude acclimatization status following various ascent profiles. Physiol Rep. 7:e14263–e14263. Berger MM, Macholz F, Schmidt P, Fried S, Perz T, Dankl D, Niebauer J, Bärtsch P, Mairbäurl H, Sareban M. (2018). Inhaled budesonide does not affect hypoxic pulmonary vasoconstriction at 4559 meters of altitude. High Alt Med Biol. 19:52–59. Berger MM, Sareban M, Bärtsch P. (2020). Acute mountain sickness: do different time courses point to different pathophysiologic mechanisms? J Appl Physiol (1985). 128:952–959. Bert P. (1878). La Pression Barométrique. Masson, Paris. English translation by MA Hitchcock and FA Hitchcock, College Book Co., Columbus, OH, 1943. https:// archive.org/details/barometricpressu00bert. Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, López Herráez D, Brutsaert T, Parra EJ, Moore LG, Shriver MD. (2010). Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLOS Genet. 6:e1001116–e1001116. Bouchet P, Morlet D, Bertrand O, Fischer C, Richalet JP, Pernier J. (1997). Effects of altitude hypoxia on middle latency auditory evoked potentials in humans. Aviat Space Environ Med. 68:699–704. Bouissou P, Richalet JP, Galen FX, Lartigue M, Larmignat P, Devaux F, Dubray C, Keromes A. (1989). Effect of beta-adrenoceptor blockade on renin-aldosterone and alpha-ANF during exercise at altitude. J Appl Physiol. 67:141–146. Boussuges A, Molenat F, Burnet H, Cauchy E, Gardette B, Sainty JM, Jammes Y, Richalet JP. (2000). Operation Everest III (Comex ’97): modifications of cardiac function secondary to altitude-induced hypoxia. An echocardiographic and Doppler study. Am J Respir Crit Care Med. 161:264–270. Boyle R. (1660). New Experiments Physico-mechanical: Touching the Spring of the Air, and Its Effects. T Robinson, Oxford. Brooks GA, Wolfel EE, Butterfield GE, Cymerman A, Roberts AC, Mazzeo RS, Reeves JT. (1998). Poor relationship between arterial (lactate) and leg net release during exercise at 4,300 m altitude. Am J Physiol. 275:R1192–1201. Burgess KR, Lucas SJ, Shepherd K, Dawson A, Swart M, Thomas KN, Lucas RA, Donnelly J, Peebles KC, Basnyat R, Ainslie PN. (2013). Worsening of central sleep apnea at high altitude—a role for cerebrovascular function. J Appl Physiol (1985). 114:1021–1028. Burgess KR, Lucas SJ, Shepherd K, Dawson A, Swart M, Thomas KN, Lucas RA, Donnelly J, Peebles KC, Basnyat R, Ainslie PN. (2014). Influence of cerebral blood flow on central sleep apnea at high altitude. Sleep. 37:1679–1687.

Burns P, Lipman GS, Warner K, Jurkiewicz C, Phillips C, Sanders L, Soto M, Hackett P. (2019). Altitude sickness prevention with ibuprofen relative to acetazolamide. Am J Med. 132: 247–251. Buskirk ER, Kollias J, Akers RF, Prokop EK, Reategui EP. (1967). Maximal performance at altitude and on return from altitude in conditioned runners. J Appl Physiol (1985). 23:259–266. Calbet JAL, Boushel R, Radegran G, Sondergaard H, Wagner PD, Saltin B. (2003). Why is VO2 max after altitude acclimatization still reduced despite normalization of arterial O2 content? Am J Physiol Regul Integr Comp Physiol. 284:R304–R316. Chicco AJ, Le CH, Gnaiger E, Dreyer HC, Muyskens JB, D’Alessandro A, Nemkov T, Hocker AD, Prenni JE, Wolfe LM, Sindt NM, Lovering AT, Subudhi AW, Roach RC. (2018). Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: lessons from AltitudeOmics. J Biol Chem. 293:6659–6671. Cook SF, Pace N. (1952). White Mountain High Altitude Research Station. Science. 116:697–700. Cornolo J, Mollard P, Brugniaux JV, Robach P, Richalet J-P. (2004). Autonomic control of the cardiovascular system during acclimatization to high altitude: effects of sildenafil. J Appl Physiol (1985). 97:935–940. De Oliveira PLS. (2019). Martyrs made in the sky: the Zénith balloon tragedy and the construction of the French Third Republic’s first scientific heroes. Notes Rec R Soc Lond. https://doi.org/10.1098/ rsnr.2019.0022. Dill DB, Myhre G, Phillips EE, Brown DK. (1966). Work capacity in acute exposures to altitude. J Appl Physiol. 21:1168–1176. Dill DB, Myhre LG, Brown DK, Burrus K, Gehlsen G. (1967). Work capacity in chronic exposures to altitude. J Appl Physiol. 23:555–560. Dill DB, Robinson S, Balke B, Newton JL. (1964). Work Tolerance: age and altitude. J Appl Physiol. 19:483–488. Dill DB, Talbott JH, Consolazio WV. (1937). Blood as a physicochemical system XII. Man at high altitudes. J Biol Chem. 118:649–666. Douglas CG, Haldane JS, Henderson Y, Schneider EC. (1913). VI. Physiological observations made on Pike’s Peak, Colorado, with special reference to adaptation to low barometric pressures. Philos Trans R Soc Lond B. 203:185–318. Duplain H, Vollenweider L, Delabays A, Nicod P, Bärtsch P, Scherrer U. (1999). Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema. Circulation. 99:1713–1718. Edwards HT. (1936). Lactic acid in rest and work at high altitude. Am J Physiol. 116:367–375. Edwards LM, Murray AJ, Tyler DJ, Kemp GJ, Holloway CJ, Robbins PA, Neubauer S, Levett D, Montgomery HE, Grocott MP, Clarke K, Caudwell Xtreme Everest

Major research programs in the early 21st century  17

Research G. (2010). The effect of high-altitude on human skeletal muscle energetics: P-MRS results from the Caudwell Xtreme Everest expedition. PLOS ONE. 5:e10681–e10681. Egli S. (1893). Sur le mal de montagne. Annals de Observatoire Météorologique, Physique et Glaciaire du Mont Blanc. pp. 109–130. Elliott JE, Laurie SS, Kern JP, Beasley KM, Goodman RD, Kayser B, Subudhi AW, Roach RC, Lovering AT. (2015). AltitudeOmics: impaired pulmonary gas exchange efficiency and blunted ventilatory acclimatization in humans with patent foramen ovale after 16 days at 5,260 m. J Appl Physiol (1985). 118:1100–1112. Fan JL, Subudhi AW, Duffin J, Lovering AT, Roach RC, Kayser B. (2015). AltitudeOmics: resetting of cerebrovascular CO2 reactivity following acclimatization to high altitude. Front Physiol. 6:394. Fan JL, 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 acclimatization and reexposure. J Appl Physiol. 116:911–918. Faulkner JA, Daniels JT, Balke B. (1967). Effects of training at moderate altitude on physical performance capacity. J Appl Physiol (1985). 23:85–89. Fitzgerald MP, Haldane JS. (1905). The normal alveolar carbonic acid pressure in man. J Physiol. 32:486–494. Fitzgerald MP, Haldane JS. (1913). VIII. The changes in the breathing and the blood at various high altitudes. Philos Trans R Soc Lond B. 203:351–371. Frayser R, Gray GW, Houston CS. (1974). Control of the retinal circulation at altitude. J Appl Physiol (1985). 37:302–304. Frayser R, Houston CS, Bryan AC, Rennie ID, Gray G. (1970). Retinal hemorrhage at high altitude. N Engl J Med. 282:1183–1184. Frayser R, Houston CS, Gray GW, Bryan AC, Rennie ID. (1971). The response of the retinal circulation to altitude. Arch Intern Med. 127:708–711. Frayser R, Rennie ID, Gray GW, Houston CS. (1975). Hormonal and electrolyte response to exposure to 17,500 ft. J Appl Physiol (1985). 38:636–642. Fulco CS, Beidleman BA, Muza SR. (2013). Effectiveness of preacclimatization strategies for high-altitude exposure. Exerc Sport Sci Rev. 41:55–63. Gavlak JC, Stocks J, Laverty A, Fettes E, Bucks R, Sonnappa S, Cooper J, Grocott MP, Levett DZ, Martin DS, Imray CH, Kirkham FJ. (2013). The Young Everest Study: preliminary report of changes in sleep and cerebral blood flow velocity during slow ascent to altitude in unacclimatised children. Arch Dis Child. 98:356–362. Gilbert DL. (1983). The first documented report of mountain sickness: the China or Headache Mountain story. Respir Physiol. 52:315–326. Gilbert DL. (1991). The Pariacaca or Tullujoto story: political realism? Respir Physiol. 86:147–157.

Gilbert-Kawai E, Coppel J, Court J, van der Kaaij J, Vercueil A, Feelisch M, Levett D, Mythen M, Grocott MP, Martin D, Xtreme Everest 2 Research Group. (2017). Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude. J Appl Physiol (1985). 122:1011–1018. Gilbert-Kawai E, Sheperdigian A, Adams T, Mitchell K, Feelisch M, Murray A, Peters M, Gilbert-Kawai G, Montgomery H, Levett D, Kumar R, Mythen M, Grocott M, Martin D. (2015). Design and conduct of Xtreme Everest 2: an observational cohort study of Sherpa and lowlander responses to graduated hypobaric hypoxia. F1000Res. 4:90. Gill MB, Milledge JS, Pugh LG, West JB. (1962). Alveolar gas composition at 21,000 to 25,700 ft. (6400-7830 m). J Physiol. 163:373–377. Gill MB, Pugh LG. (1964). Basal metabolism and respiration in men living at 5,800 m (19,000 ft). J Appl Physiol (1985). 19:949–954. Goodall S, Twomey R, Amann M, Ross EZ, Lovering AT, Romer LM, Subudhi AW, Roach RC. (2014). AltitudeOmics: exercise-induced supraspinal fatigue is attenuated in healthy humans after acclimatization to high altitude. Acta Physiol (Oxf). 210:875–888. Gray GW, Bryan AC, Freedman MH, Houston CS, Lewis WF, McFadden DM, Newell G. (1975). Effect of altitude exposure on platelets. J Appl Physiol (1985). 39:648–652. Green HJ, Sutton JR, Cymerman A, Young PM, Houston CS. (1989). Operation Everest II: adaptations in human skeletal muscle. J Appl Physiol (1985). 66:2454–2461. Grissom CK, Roach RC, Sarnquist FH, Hackett PH. (1992). Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange. Ann Intern Med. 116:461–465. Griva K, Stygall J, Wilson MH, Martin D, Levett D, Mitchell K, Mythen M, Montgomery HE, Grocott MP, Aref-Adib G, Edsell M, Plant T, Imray C, Cooke D, Harrington J, Khosravi M, Newman SP, Caudwell Xtreme Everest Research Group. (2017). Caudwell Xtreme Everest: a prospective study of the effects of environmental hypoxia on cognitive functioning. PLOS ONE. 12:e0174277. Grocott MPW, Daniel SM, Levett DZH, McMorrow R, Windsor J, Montgomery HE, Caudwell Xtreme Everest Research Group. (2009). Arterial blood gases and oxygen content in climbers on Mount Everest. N Engl J Med. 360:140–149. Grover RF, Selland MA, McCullough RG, Dahms TE, Wolfel EE, Butterfield GE, Reeves JT, Greenleaf JE. (1998). Beta-adrenergic blockade does not prevent polycythemia or decrease in plasma volume in men at 4300 m altitude. Eur J Appl Physiol Occup Physiol. 77:264–270. Groves BM, Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Houston CS. (1987). Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol (1985). 63:521–530.

18  History of high altitude medicine and physiology

Grünig E, Mereles D, Hildebrandt W, Swenson ER, Kübler W, Kuecherer H, Bärtsch P. (2000). Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema. J Am Coll Cardiol. 35:980–987. Hackett PH, Roach RC. (1986). The Denali Medical Research Project, 1982-85. Am Alpine J. 129–137. Hackett PH, Roach RC, Schoene RB, Harrison GL, Mills WJ. (1988a). Abnormal control of ventilation in highaltitude pulmonary edema. J Appl Physiol (1985). 64:1268–1272. Hackett PH, Roach RC, Wood RA, Foutch RG, Meehan RT, Rennie D, Mills WJ. (1988b). Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space Environ Med. 59:950–954. Haldane JS. (1935). Respiration, New ed. Yale University Press, New Haven, CT. Hansen JM, Kanstrup IL, Richalet JP, Olsen NV. (1996). High altitude-induced albuminuria in normal man is enhanced by infusion of low-dose dopamine. Scand J Clin Lab Invest. 56:367–372. Henderson Y. (1938). Adventures in Respiration: Modes of Asphyxiation and Methods of Resuscitation. The Williams & Wilkins Company, Baltimore. Hoiland RL, Howe CA, Carter HH, Tremblay JC, Willie CK, Donnelly J, MacLeod DB, Gasho C, Stembridge M, Boulet LM, Niroula S, Ainslie PN. (2019). UBCNepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude. J Physiol. 597:2993–3008. Holloway CJ, Montgomery HE, Murray AJ, Cochlin LE, Codreanu I, Hopwood N, Johnson AW, Rider OJ, Levett DZH, Tyler DJ, Francis JM, Neubauer S, Grocott MPW, Clarke K, Caudwell Xtreme Everest Research Group. (2011). Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp. FASEB J. 25:792–796. Hornbein TF, Townes BD, Schoene RB, Sutton JR, Houston CS. (1989). The cost to the central nervous system of climbing to extremely high altitude. N Engl J Med. 321:1714–1719. Horscroft JA, Kotwica AO, Laner V, West JA, Hennis PJ, Levett DZH, Howard DJ, Fernandez BO, Burgess SL, Ament Z, Gilbert-Kawai ET, Vercueil A, Landis BD, Mitchell K, Mythen MG, Branco C, Johnson RS, Feelisch M, Montgomery HE, Griffin JL, Grocott MPW, Gnaiger E, Martin DS, Murray AJ. (2017). Metabolic basis to Sherpa altitude adaptation. Proc Natl Acad Sci USA. 114:6382–6387. Houston CS, Sutton JR, Cymerman A, Reeves JT. (1987). Operation Everest II: man at extreme altitude. J Appl Physiol (1985). 63:877–882. Huang H, Liu B, Wu G, Xu G, Sun B-D, Gao Y-Q. (2017). Hematological risk factors for High-altitude headache in Chinese men following acute exposure at 3,700 m. Front Physiol. 8:801.

Huerta-Sánchez E, Jin X, Asan, Bianba Z, Peter BM, Vinckenbosch N, Liang Y, Yi X, He M, Somel M, Ni P, Wang B, Ou X, Huasang, Luosang J, Cuo ZXP, Li K, Gao G, Yin Y, Wang W, Zhang X, Xu X, Yang H, Li Y, Wang J, Wang J, Nielsen R. (2014). Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature. 512:194–197. Ivan M, Kaelin WG, Jr. (2017). The EGLN-HIF O2-sensing system: multiple inputs and feedbacks. Mol Cell. 66:772–779. Kanaan NC, Lipman GS, Constance BB, Holck PS, Preuss JF, Williams SR, Group P. (2015). Optic nerve sheath diameter increase on ascent to high altitude: correlation with acute mountain sickness. J Ultrasound Med. 34:1677–1682. Kellogg RH. (1960). Acclimatization to carbon dioxide. Anesthesiology. 21:634–641. Kellogg RH, Pace N, Archibald ER, Vaughan BE. (1957). Respiratory response to inspired CO2 during acclimatization to an altitude of 12,470 feet. J Appl Physiol. 11:65–71. Klausen T, Olsen NV, Poulsen TD, Richalet JP, Pedersen BK. (1997). Hypoxemia increases serum interleukin-6 in humans. Eur J App Physiol Occup Physiol. 76:480–482. Krogh A. (1910a). On the combination of hæmoglobin with mixtures of oxygen and carbonic oxide. Skand Arch Physiol. 23:217–223. Krogh A. (1910b). On the mechanism of the gas-exchange in the lungs. Skand Arch Physiol. 23:248–278. Krogh A. (1910c). On the mechanism of the gas-exchange in the lungs of the tortoise. Skand Arch Physiol. 23:200–216. Krogh A. (1910d). On the oxygen-metabolism of the blood. Skand Arch Physiol. 23:193–199. Krogh A. (1910e). Some experiments on the invasion of oxygen and carbonic oxide into water. Skand Arch Physiol. 23:224–235. Krogh A, Krogh M. (1910a). On the rate of diffusion of carbonic oxide into the lungs of man. Skand Arch Physiol. 23:236–247. Krogh A, Krogh M. (1910b). On the tensions of gases in the arterial blood. Skand Arch Physiol. 23:179–192. Levett DZ, Radford EJ, Menassa DA, Graber EF, Morash AJ, Hoppeler H, Clarke K, Martin DS, Ferguson-Smith AC, Montgomery HE, Grocott MPW, Murray AJ, Caudwell Xtreme Everest Research Group. (2012). Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J. 26:1431–1441. Levett DZH, Martin DS, Wilson MH, Mitchell K, Dhillon S, Rigat F, Montgomery HE, Mythen MG, Grocott MPW, Caudwell Xtreme Everest Research Group. (2010). Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia. BMC Med Res Methodol. 10:98–98. Levine BD, Stray-Gundersen J. (1997). “Living high-training low”: effect of moderate-altitude acclimatization

Major research programs in the early 21st century  19

with low-altitude training on performance. J Appl Physiol (1985). 83:102–112. Lipman GS, Kanaan NC, Holck PS, Constance BB, Gertsch JH, Group P. (2012). Ibuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories. Ann Emerg Med. 59:484–490. Liu XS, Yang XR, Liu L, Qin XK, Gao Y-Q. (2018). A hypothesis study on a four-period prevention model for high altitude disease. Mil Med Res. 5:2. Lubin JR, Rennie D, Hackett P, Albert DM. (1982). High altitude retinal hemorrhage: a clinical and pathological case report. Ann Ophthalmol. 14:1071–1076. Luks AM, Swenson ER, Bärtsch P. (2017). Acute highaltitude sickness. Eur Respir Rev. 26:160096. Lundby C, Calbet JAL. (2016). Why are high-altitude natives so strong at altitude? Maximal oxygen transport to the muscle cell in altitude natives. Adv Exp Med Biol. 903:65–81. Lundby C, Calbet JAL, van Hall G, Saltin B, Sander M. (2004a). Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives. Am J Physiol Regul Integr Comp Physiol. 287:R1202–1208. Lundby C, Pilegaard H, Andersen JL, van Hall G, Sander M, Calbet JAL. (2004b). Acclimatization to 4100 m does not change capillary density or mRNA expression of potential angiogenesis regulatory factors in human skeletal muscle. J Exp Biol. 207:3865–3871. Lundby C, Sander M, van Hall G, Saltin B, Calbet JAL. (2006). Maximal exercise and muscle oxygen extraction in acclimatizing lowlanders and high altitude natives. J Physiol. 573:535–547. Maggiorini M, Bühler B, Walter M, Oelz O. (1990). Prevalence of acute mountain sickness in the Swiss Alps. BMJ. 301:853–855. Maggiorini M, Mélot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori M, Hauser M, Scherrer U, Naeije R. (2001). High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 103:2078–2083. Mairbäurl H, Weymann J, Möhrlein A, Swenson ER, Maggiorini M, Gibbs JSR, Bärtsch P. (2003). Nasal epithelium potential difference at high altitude (4,559 m): evidence for secretion. Am J Respir Crit Care Med. 167:862–867. Martin DS, Gilbert-Kawai ET, Meale PM, Fernandez BO, Cobb A, Khosravi M, Mitchell K, Grocott MPW, Levett DZH, Mythen MG, Feelisch M, Xtreme Alps Research Group. (2013). Design and conduct of ‘Xtreme Alps’: a double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude. Contemp Clin Trials. 36:450–459. Mazzeo RS, Bender PR, Brooks GA, Butterfield GE, Groves BM, Sutton JR, Wolfel EE, Reeves JT. (1991). Arterial catecholamine responses during exercise with acute and chronic high-altitude exposure. Am J Physiol. 261:E419–424.

Mazzeo RS, Brooks GA, Butterfield GE, Cymerman A, Roberts AC, Selland M, Wolfel EE, Reeves JT. (1994a). Beta-adrenergic blockade does not prevent the lactate response to exercise after acclimatization to high altitude. J Appl Physiol (1985). 76:610–615. Mazzeo RS, Wolfel EE, Butterfield GE, Reeves JT. (1994b). Sympathetic response during 21 days at high altitude (4,300 m) as determined by urinary and arterial catecholamines. Metabolism. 43:1226–1232. McFadden DM, Houston CS, Sutton JR, Powles AC, Gray GW, Roberts RS. (1981). High-altitude retinopathy. JAMA. 245:581–586. Michel CC, Milledge JS. (1963). Respiratory regulation in man during acclimatization to high altitude. J Physiol. 168:631–643. Milledge JS, Catley DM, Blume FD, West JB. (1983). Renin, angiotensin-converting enzyme, and aldosterone in humans on Mount Everest. J Appl Physiol (1985). 55:1109–1112. Mishra A, Kohli S, Dua S, Thinlas T, Mohammad G, Pasha MAQ. (2015). Genetic differences and aberrant methylation in the apelin system predict the risk of highaltitude pulmonary edema. Proc Natl Acad Sci U S A. 112:6134–6139. Mosso A. (1897). Fisiologia dell’uomo sulle Alpi: studii fatti sul Monte Rosa. Treves, Milan. Mosso A. (1898). Life of Man on the High Alps. T.F. Unwin, London, UK. O’Brien KA, Atkinson RA, Richardson L, Koulman A, Murray AJ, Harridge SDR, Martin DS, Levett DZH, Mitchell K, Mythen MG, Montgomery HE, Grocott MPW, Griffin JL, Edwards LM. (2019). Metabolomic and lipidomic plasma profile changes in human participants ascending to Everest Base Camp. Sci Rep. 9. https://doi.org/10.1038/s41598-019-38832-z. Oelz O, Maggiorini M, Ritter M, Waber U, Jenni R, Vock P, Bartsch P. (1989). Nifedipine for high altitude pulmonary oedema. Lancet. 2:1241–1244. Olsen NV, Hansen JM, Kanstrup IL, Richalet JP, Leyssac PP. (1993). Renal hemodynamics, tubular function, and response to low-dose dopamine during acute hypoxia in humans. J Appl Physiol (1985). 74:2166–2173. Olsen NV, Kanstrup IL, Richalet JP, Hansen JM, Plazen G, Galen FX. (1992). Effects of acute hypoxia on renal and endocrine function at rest and during graded exercise in hydrated subjects. J Appl Physiol (1985). 73:2036–2043. Petrassi FA, Davis JT, Beasley KM, Evero O, Elliott JE, Goodman RD, Futral JE, Subudhi A, Solano-Altamirano JM, Goldman S, Roach RC, Lovering AT. (2018). AltitudeOmics: effect of reduced barometric pressure on detection of intrapulmonary shunt, pulmonary gas exchange efficiency, and total pulmonary resistance. J Appl Physiol (1985). 124:1363–1376. Poulsen TD, Klausen T, Richalet JP, Kanstrup IL, Fogh-Andersen N, Olsen NV. (1998). Plasma volume in acute hypoxia: comparison of a carbon monoxide

20  History of high altitude medicine and physiology

rebreathing method and dye dilution with Evans’ blue. Eur J Appl Physiol Occup Physiol. 77:457–461. Pugh LG. (1964a). Blood volume and haemoglobin concentration at altitudes above 18,000 ft (5500 M). J Physiol. 170:344–354. Pugh LG. (1964b). Cardiac output in muscular exercise at 5,800 m (19,000 ft). J Appl Physiol (1985). 19:441–447. Pugh LG. (1967). Athletes at altitude. J Physiol. 192:619–646. Pugh LG, Gill MB, Lahiri S, Milledge JS, Ward MP, West JB. (1964). Muscular exercise at great altitudes. J Appl Physiol (1985). 19:431–440. Rain M, Chaudhary H, Kukreti R, Thinlas T, Mohammad G, Pasha Q. (2018). Elevated vasodilatory cyclases and shorter telomere length contribute to high-altitude pulmonary edema. High Alt Med Biol. 19:60–68. Reeves JT, Groves BM, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Alexander JK, Houston CS. (1987). Oxygen transport during exercise at extreme altitude: Operation Everest II. Ann Emerg Med. 16:993–998. Reeves JT, Houston CS, Sutton JR. (1989). Operation Everest II: resistance and susceptibility to chronic hypoxia in man. J R Soc Med. 82:513–514. Reeves JT, Wolfel EE, Green HJ, Mazzeo RS, Young AJ, Sutton JR, Brooks GA. (1992). Oxygen transport during exercise at altitude and the lactate paradox: lessons from Operation Everest II and Pikes Peak. Exerc Sport Sci Rev. 20:275–296. Richalet JP. (2001). The scientific observatories on Mont Blanc. High Alt Med Biol. 2:57–68. Richalet JP, Larmignat P, Rathat C, Kéromès A, Baud P, Lhoste F. (1988). Decreased cardiac response to isoproterenol infusion in acute and chronic hypoxia. J Appl Physiol (1985). 65:1957–1961. Richalet JP, Le-Trong JL, Rathat C, Merlet P, Bouissou P, Keromes A, Veyrac P. (1989). Reversal of hypoxiainduced decrease in human cardiac response to isoproterenol infusion. J Appl Physiol (1985). 67:523–527. Robach P, Déchaux M, Jarrot S, Vaysse J, Schneider JC, Mason NP, Herry JP, Gardette B, Richalet JP. (2000). Operation Everest III: role of plasma volume expansion on VO(2)(max) during prolonged high-altitude exposure. J Appl Physiol (1985). 89:29–37. Roberts AC, Butterfield GE, Cymerman A, Reeves JT, Wolfel EE, Brooks GA. (1996). Acclimatization to 4,300-m altitude decreases reliance on fat as a substrate. J Appl Physiol (1985). 81:1762–1771. Rose MS, Houston CS, Fulco CS, Coates G, Sutton JR, Cymerman A. (1988). Operation Everest. II: Nutrition and body composition. J Appl Physiol (1985). 65:2545–2551. Sareban M, Perz T, Macholz F, Reich B, Schmidt P, Fried S, Mairbäurl H, Berger MM, Niebauer J. (2019). Impairment of left atrial mechanics does not contribute to the reduction in stroke volume after active ascent to 4559 m. Scand J Med Sci Sports. 29:223–231.

Sarnquist FH, Schoene RB, Hackett PH, Townes BD. (1986). Hemodilution of polycythemic mountaineers: effects on exercise and mental function. Aviat Space Environ Med. 57: 313–317. Sartori C, Vollenweider L, Löffler BM, Delabays A, Nicod P, Bärtsch P, Scherrer U. (1999). Exaggerated endothelin release in high-altitude pulmonary edema. Circulation. 99:2665–2668. Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, Lambert C, Jarvis JP, Abate D, Belay G, Tishkoff SA. (2012). Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol. 13:R1–R1. Schneider M, Bernasch D, Weymann J, Holle R, Bartsch P. (2002). Acute mountain sickness: influence of susceptibility, preexposure, and ascent rate. Med Sci Sports Exerc. 34:1886–1891. Schödel J, Ratcliffe PJ. (2019). Mechanisms of hypoxia signalling: new implications for nephrology. Nat Rev Nephrol. 15:641–659. Schoene RB, Hackett PH, Henderson WR, Sage EH, Chow M, Roach RC, Mills WJ, Martin TR. (1986). High-altitude pulmonary edema characteristics of lung lavage fluid. JAMA. 256:63–69. Schoene RB, Lahiri S, Hackett PH, Peters RM, Jr., Milledge JS, Pizzo CJ, Sarnquist FH, Boyer SJ, Graber DJ, Maret KH. (1984). Relationship of hypoxic ventilatory response to exercise performance on Mount Everest. J Appl Physiol (1985). 56:1478–1483. Schoene RB, Roach RC, Hackett PH, Sutton JR, Cymerman A, Houston CS. (1990). Operation Everest II: ventilatory adaptation during gradual decompression to extreme altitude. Med Sci Sports Exerc. 22:804–810. Schoene RB, Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Mills WJ, Henderson WR, Martin TR. (1988). The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol (1985). 64:2605–2613. Semenza GL. (2014). Hypoxia-inducible factor 1 and cardiovascular disease. Ann Rev Physiol. 76:39–56. Severinghaus JW. (2016). Eight sages over five centuries share oxygen’s discovery. Adv Physiol Educ. 40:370–376. Severinghaus JW, Carcelen A. (1964). Cerebrospinal fluid in man native to high altitude. J Appl Physiol. 19:319–321. Severinghaus JW, Chiodi H, Eger EI, Brandstater B, Hornbein TF. (1966). Cerebral blood flow in man at high altitude Role of cerebrospinal fluid pH in normalization of flow in chronic hypocapnia. Circ Res. 19:274–282. Severinghaus JW, Mitchell RA, Richardson BW, Singer MM. (1963). Respiratory control at high altitude suggesting active transport regulation of CSF pH. J Appl Physiol. 18:1155–1166. Siebenmann C, Robach P, Jacobs RA, Rasmussen P, Nordsborg N, Diaz V, Christ A, Olsen NV, Maggiorini M, Lundby C. (2011). “Live high-train low” using

Major research programs in the early 21st century  21

normobaric hypoxia: a double-blinded, placebo-­ controlled study. J Appl Physiol (B1985). 112:106–117. Simons E, Oelz O. (2000). The mysterious death of Dr. Jacottet on Mont Blanc. High Alt Med Biol. 1:213–216. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R. (2010). Genetic evidence for high-altitude adaptation in Tibet. Science. 329:72–75. Singh I, Khanna PK, Srivastava MC, Lal M, Roy SB, Subramanyam CS. (1969). Acute mountain sickness. N Engl J Med. 280:175–184. Smith KJ, MacLeod D, Willie CK, Lewis NCS, Hoiland RL, Ikeda K, Tymko MM, Donnelly J, Day TA, MacLeod N, Lucas SJE, Ainslie PN. (2014). Influence of high altitude on cerebral blood flow and fuel utilization during exercise and recovery. J Physiol. 592:5507–5527. Smith ZM, Krizay E, Sá RC, Li ET, Scadeng M, Powell FL, Jr., Dubowitz DJ. (2017). Evidence from high-altitude acclimatization for an integrated cerebrovascular and ventilatory hypercapnic response but different responses to hypoxia. J Appl Physiol (1985). 123:1477–1486. Song A, Zhang Y, Han L, Yegutkin GG, Liu H, Sun K, D’Alessandro A, Li J, Karmouty-Quintana H, Iriyama T, Weng T, Zhao S, Wang W, Wu H, Nemkov T, Subudhi AW, Jameson-Van Houten S, Julian CG, Lovering AT, Hansen KC, Zhang H, Bogdanov M, Dowhan W, Jin J, Kellems RE, Eltzschig HK, Blackburn M, Roach RC, Xia Y. (2017). Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent. Nat Commun. 8:14108. Staab JE, Beidleman BA, Muza SR, Fulco CS, Rock PB, Cymerman A. (2013). Efficacy of residence at moderate versus low altitude on reducing acute mountain sickness in men following rapid ascent to 4300 m. High Alt Med Biol. 14:13–18. Stembridge M, Ainslie PN, Donnelly J, MacLeod NT, Joshi S, Hughes MG, Sherpa K, Shave R. (2016). Cardiac structure and function in adolescent Sherpa; effect of habitual altitude and developmental stage. Am J Physiol Heart Circ Physiol. 310:H740–H746. Stembridge M, Ainslie PN, Hughes MG, Stöhr EJ, Cotter JD, Tymko MM, Day TA, Bakker A, Shave R. (2015). Impaired myocardial function does not explain reduced left ventricular filling and stroke volume at rest or during exercise at high altitude. J Appl Physiol (1985). 119:1219–1227. Stembridge M, Williams AM, Gasho C, Dawkins TG, Drane A, Villafuerte FC, Levine BD, Shave R, Ainslie PN. (2019). The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives. Proc Natl Acad Sci USA. 116:16177–16179. Subudhi AW, Fan JL, 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 (1985). 116:724–729. Subudhi AW, Fan JL, 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. Sutton JR. (1983). The hormonal responses to exercise at sea level and at altitude. Prog Clin Biol Res. 136:325–341. Sutton JR, Bryan AC, Gray GW, Horton ES, Rebuck AS, Woodley W, Rennie ID, Houston CS. (1976). Pulmonary gas exchange in acute mountain sickness. Aviat Space Environ Med. 47:1032–1037. Sutton JR, Gray GW, Houston CS, Powles AC. (1980). Effects of duration at altitude and acetazolamide on ventilation and oxygenation during sleep. Sleep. 3:455–464. Sutton JR, Houston CS, Mansell AL, McFadden MD, Hackett PM, Rigg JR, Powles AC. (1979). Effect of acetazolamide on hypoxemia during sleep at high altitude. N Engl J Med. 301:1329–1331. Sutton JR, Reeves JT, Groves BM, Wagner PD, Alexander JK, Hultgren HN, Cymerman A, Houston CS. (1992). Oxygen transport and cardiovascular function at extreme altitude: lessons from Operation Everest II. Int J Sports Med. 13(Suppl 1):S13–S18. Sutton JR, Reeves JT, Wagner PD, Groves BM, Cymerman A, Malconian MK, Rock PB, Young PM, Walter SD, Houston CS. (1988). Operation Everest II: oxygen transport during exercise at extreme simulated altitude. J Appl Physiol (1985). 64:1309–1321. Swenson ER, Maggiorini M, Mongovin S, Gibbs JSR, Greve I, Mairbäurl H, Bärtsch P. (2002). Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor. JAMA. 287:2228–2235. Torricelli E, Masse A, Landis Ld. (1644). Opera geometrica Evangelistae Torricellii: De solidis sphaeralibus. De motu. De dimensione parabolae. De solido hyperbolico. Cum appendicibus de cycloide, & cochlea. [Typis Amatoris Masse & Laurentij de Landis], [Florentiae]. Tremblay JC, Hoiland RL, Carter HH, Howe CA, Stembridge M, Willie CK, Gasho C, MacLeod DB, Pyke KE, Ainslie PN. (2018). UBC-Nepal expedition: upper and lower limb conduit artery shear stress and flow-mediated dilation on ascent to 5,050 m in lowlanders and Sherpa. Am J Physiol Heart Circ Physiol. 315:H1532–H1543. Tremblay JC, Hoiland RL, Howe CA, Coombs GB, Vizcardo-Galindo GA, Figueroa-Mujíca RJ, Bermudez D, Gibbons TD, Stacey BS, Bailey DM, Tymko MM, MacLeod DB, Gasho C, Villafuerte FC, Pyke KE, Ainslie PN. (2019). Global REACH 2018: high blood viscosity and hemoglobin concentration contribute to reduced flow-mediated dilation in high-altitude excessive erythrocytosis. Hypertension. 73:1327–1335.

22  History of high altitude medicine and physiology

Tuckey H. (2013). Everest—The First Ascent: The Untold Story of Griffith Pugh, the Man Who Made It Possible. Rider Books, London. van Hall G, Calbet JA, Søndergaard H, Saltin B. (2001). The re-establishment of the normal blood lactate response to exercise in humans after prolonged acclimatization to altitude. J Physiol. 536:963–975. van Hall G, Lundby C, Araoz M, Calbet JAL, Sander M, Saltin B. (2009). The lactate paradox revisited in lowlanders during acclimatization to 4100 m and in highaltitude natives. J Physiol. 587:1117–1129. Viault F. (1890). Sur l’augmentation considerable de nombre des globules rouges dans le sang chez les habitants des haut plateaux de l’Amérique du Sud. Comptes Rendus, Hebdomaire Des Seances de l’Academie Des Sciences (Paris). III:917–918. Wagner PD, Araoz M, Boushel R, Calbet JAL, Jessen B, Rådegran G, Spielvogel H, Søndegaard H, Wagner H, Saltin B. (2002). Pulmonary gas exchange and acid-base state at 5,260 m in high-altitude Bolivians and acclimatized lowlanders. J Appl Physiol (1985). 92:1393–1400. Wagner PD, Sutton JR, Reeves JT, Cymerman A, Groves BM, Malconian MK. (1987). Operation Everest II: pulmonary gas exchange during a simulated ascent of Mt. Everest. J Appl Physiol (1985). 63:2348–2359. West JB. (1962). Diffusing capacity of the lung for carbon monoxide at high altitude. J Appl Physiol (1985). 17:421–426. West JB. (1984). Human physiology at extreme altitudes on Mount Everest. Science. 223:784–788. West JB. (1998). High Life: A History of High-Altitude Physiology and Medicine. Oxford University Press, Oxford, UK. West JB, Boyer SJ, Graber DJ, Hackett PH, Maret KH, Milledge JS, Peters RM, Jr., Pizzo CJ, Samaja M, Sarnquist FH. (1983a). Maximal exercise at extreme altitudes on Mount Everest. J Appl Physiol (1985). 55:688–698. West JB, Hackett PH, Maret KH, Milledge JS, Peters RM, Jr., Pizzo CJ, Winslow RM. (1983b). Pulmonary gas exchange on the summit of Mount Everest. J Appl Physiol (1985). 55:678–687. West JB, Lahiri S, Gill MB, Milledge JS, Pugh LGCE, Ward MP. (1962). Arterial oxygen saturation during exercise at high altitude. J Appl Physiol (1985). 17:617–621. West JB, Lahiri S, Maret KH, Peters RM, Jr., Pizzo CJ. (1983c). Barometric pressures at extreme altitudes on Mt. Everest: physiological significance. J Appl Physiol (1985). 54:1188–1194. Westerterp-Plantenga MS, Westerterp KR, Rubbens M, Verwegen CR, Richelet JP, Gardette B. (1999).

Appetite at “high altitude” [Operation Everest III (Comex-’97)]: a simulated ascent of Mount Everest. J Appl Physiol (1985). 87:391–399. Williams AM, Ainslie PN, Anholm JD, Gasho C, Subedi P, Stembridge M. (2019). Left ventricular twist is augmented in hypoxia by β1-adrenergic-dependent and β1-adrenergic-independent factors, without evidence of endocardial dysfunction. Circ Cardiovasc Imaging. 12:e008455–e008455. Williams DA. (1966). Athletic performance at high altitude. Nature. 211:753–753. Willie CK, MacLeod DB, Smith KJ, Lewis NC, Foster GE, Ikeda K, Hoiland RL, Ainslie PN. (2015). The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude. J Cereb Blood Flow Metab. 35:873–881. Willie CK, Stembridge M, Hoiland RL, Tymko MM, Tremblay JC, Patrician A, Steinback C, Moore J, Anholm J, Subedi P, Niroula S, McNeil CJ, McManus A, MacLeod DB, Ainslie PN. (2018). UBC-Nepal Expedition: an experimental overview of the 2016 University of British Columbia Scientific Expedition to Nepal Himalaya. PLOS ONE. 13:e0204660. Wilson MH, Edsell MEG, Davagnanam I, Hirani SP, Martin DS, Levett DZH, Thornton JS, Golay X, Strycharczuk L, Newman SP, Montgomery HE, Grocott MPW, Imray CHE, Caudwell Xtreme Everest Research Group. (2011). Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia– an ultrasound and MRI study. J Cereb Blood Flow Metab. 31:2019–2029. Winslow RM, Samaja M, West JB. (1984). Red cell function at extreme altitude on Mount Everest. J Appl Physiol (1985). 56:109–116. Wolfel EE, Groves BM, Brooks GA, Butterfield GE, Mazzeo RS, Moore LG, Sutton JR, Bender PR, Dahms TE, McCullough RE. (1991). Oxygen transport during steady-state submaximal exercise in chronic hypoxia. J Appl Physiol (1985). 70:1129–1136. Xu S, Li S, Yang Y, Tan J, Lou H, Jin W, Yang L, Pan X, Wang J, Shen Y, Wu B, Wang H, Jin L. (2011). A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol. 28:1003–1011. Yuhong L, Tana W, Zhengzhong B, Feng T, Qin G, Yingzhong Y, Wei G, Yaping W, Langelier C, Rondina MT, Ge R-L. (2018). Transcriptomic profiling reveals gene expression kinetics in patients with hypoxia and high altitude pulmonary edema. Gene. 651:200–205. Zuntz N, Loewy A, Müller F, Caspari W. (1906). Höhenklima und Bergwanderungen in ihrer wirkung auf den Menschen. Bong and Company, Berlin.

1

Section     The Environment and Its People

2 The atmosphere 3 Geography 4 High altitude residents 5 Travelers and workers at high altitude 6 Genetics and genomics of exposure to high altitude

25 37 51 75 91

2 The atmosphere

Introduction Barometric pressure and altitude Historical Physical principles Standard atmosphere Variation of barometric pressure with latitude Variation of barometric pressure with season Barometric pressure–altitude relationship for locations of importance in high altitude medicine and physiology Model atmosphere equation Barometric pressure and inspired PO2

25 26 26 26 27 28 29

30 31 32

Physiological significance of barometric pressure at high altitude 32 Factors other than barometric pressure at high altitude 32 Temperature 32 Humidity 33 Atmospheric ozone 33 Solar radiation 33 Ionizing radiation 34 The future of the atmosphere and the implications of climatic change for high altitude 34 References 35

It has been known since the time of Paul Bert and the publication of La Pression Barométrique (Bert 1878) that most of the deleterious effects of high altitude on humans are caused by hypoxia. This, in turn, is a direct result of the reduction in atmospheric pressure. Yet in spite of the fact that Bert’s book appeared more than 130 years ago, there is still confusion in the minds of some physicians and physiologists about the relationship between barometric pressure and altitude, particularly at extreme heights. For example, some environmental physiologists are still surprised to learn that the barometric pressure at the summit of Mount Everest is considerably higher than that predicted by the standard pressure–altitude tables used by the aviation industry, and that humans can reach the summit without supplemental oxygen only because the tables are inapplicable. Although most of the undesirable effects of high altitude are due to hypoxia, under some circumstances, additional problems result from cold, dehydration, solar radiation, and perhaps ionizing radiation. However, most of these hazards of the environment can be avoided by proper clothing or shelter. Only hypoxia is unavoidable unless, of course, supplemental oxygen is available. The low barometric pressure in itself has no physiological sequelae unless

the decompression is rapid, for example, in the case of the explosive decompression that occurs when a window fails in a pressurized aircraft. Rapid decompression can cause barotrauma as a result of the very rapid enlargement of airspaces within the body, including the lungs and middle ear cavity. Such barotrauma can also occur during ascent from deep dives below the surface of the water, but is not considered here. That low pressure per se is innocuous was not always realized. Indeed, early theories of mountain sickness included a number of exotic explanations based on the reduced pressure itself (Bert 1878, pp. 342–347 in the 1943 translation). One was weakening of the coxofemoral articulation; it was thought that barometric pressure was an important factor in pressing the head of the femur into its socket and that, at high altitudes, the necessary increase in action of the neighboring muscles resulted in fatigue. Another hypothesis was that superficial blood vessels would dilate and rupture if the barometric pressure that normally supported them was reduced. A further theory was that distension of intestinal gas would interfere with the action of the diaphragm and also impede venous return to the heart. All these theories overlook the fact that, when humans ascend to high altitude, all the pressures in the body fall together. In other words, although the pressure outside the superficial blood

INTRODUCTION

25

26  The atmosphere

vessels falls, the pressure inside the vessels falls to the same extent and therefore the pressure differences across the vessels are unchanged.

BAROMETRIC PRESSURE AND ALTITUDE Historical A general historical introduction can be found in Chapter 1, but some additional background material related to the atmosphere is included here, while a more complete discussion is in West (1998). The notion that air has weight and therefore exerts a pressure at the surface of the earth eluded the ancient Greeks and had to wait until the Renaissance. Galileo (1981) was well aware of the force associated with a vacuum and therefore the effort required to “break” it, but he thought of this in the context of a force required to break a copper wire by stretching it, that is, the cohesive forces within the substance of the wire. It was left to Galileo’s pupil Torricelli to realize that the force of a vacuum is due to the weight of the atmosphere. In addition, he wondered whether the air pressure became less on the tops of high mountains where the air “begins to be distinctly rare” as he put it. Torricelli made the first mercury barometer, though barometers filled with other liquids had apparently been constructed previously, for example by Gaspar Berti in 1639. These had limitations because of the effect of the vapor pressure of the liquid. A landmark experiment took place in 1648 when the French philosopher and mathematician Blaise Pascal (1623–62) suggested that his brother-in-law, F. Périer, take a barometer to the top of the Puy-de-Dôme (1463 m) in central France to see whether the pressure fell (Pascal 1981). The results were communicated to Pascal in a delightful letter by Périer in which he described how the level of the mercury barometer fell some three pouces (about 75 mm) during the ascent of “500 fathoms” of altitude (probably about 900 m). The experiment had elaborate controls. For example, the Reverend Father Chastin, “a man as pious as he is capable,” stood guard over one barometer in the town of Clermont while Périer and a number of observers (including clerics, counselors, and a doctor of medicine) took another to the top of the mountain. On returning, it was found that the first barometer had not changed, and Périer even checked it again by filling it with the same mercury that he had taken up the mountain. Another observation was made the next day on the top of a high church tower in Clermont, and this also showed a fall in pressure, though of much smaller extent. A few years later, Robert Boyle carried out experiments with the newly invented air pump and wrote his influential book New Experiments Physico-Mechanicall Touching the Spring of the Air, and Its Effects. In the second edition of this book, published in 1662, he formulated his famous law, which states that at constant temperature, gas volume and pressure are inversely related (Boyle 1662). Recent commentaries on both the original book and Boyle’s law are available (West 1999b; West 2005).

An influential analysis of the relationships between altitude and barometric pressure was made by Zuntz et al. (1906). They pointed out the important effect of temperature on the pressure–altitude relationship noting that, on a fine warm day, the upcurrents carry air to high altitudes and thus increase the sea level barometric pressure. Indeed, this is the basis for weather prediction based on barometric pressure. Zuntz et al. (1906) gave the following logarithmic relationship for determining barometric pressure at any altitude:

log b = log B −

h 72 ( 256.4 + t )

where h is the altitude difference in meters, t is the mean temperature (°C) of the air column of height h, B is the barometric pressure (mmHg) at the lower altitude, and b is the barometric pressure at the higher altitude. Note that this expression implies that the higher the mean temperature, the slower the barometric pressure decrease with altitude. In addition, if temperature were constant, log b would be proportional to negative altitude, that is, the pressure would decrease exponentially as altitude increased. Zuntz et al. cite Hann’s Lehrbuch der Meteorologie, where the pressure– altitude relationship is given in a slightly different form (Hann 1901). The expression by Zuntz et al. was used by FitzGerald (1913) in her study of alveolar PCO2 and hemoglobin concentration in residents of various altitudes in the Colorado mountains during the Anglo-American Pikes Peak expedition of 1911. She showed that barometric pressures calculated from the Zuntz formula agreed closely with pressures observed in the mountains when a sea level pressure of 760 mmHg and a mean temperature of the air column of 115°C were assumed. Kellas (2001) used the same expression to predict barometric pressures in the Himalayan ranges, obtaining a value of 251 mmHg for the summit of Mount Everest (8848 m), assuming a mean temperature of 0°C. This was almost the same as the pressure of 248 mmHg given by Bert (Bert 1878) in contrast to the erroneously low values used 70 years after Bert because of the inappropriate application of the standard atmosphere. However, a major difficulty with the use of the Zuntz formula is the sensitivity of the calculated pressure to temperature and the fact that the mean temperature of the air column is not accurately known. For example, the barometric pressure on the summit of Mount Everest was calculated by Kellas to be 267 mmHg for a mean temperature of 115°C, but only 251 mmHg for a mean temperature of 0°C.

Physical principles Barometric pressure decreases with altitude because the higher we go, the less atmosphere there is above us pressing down by virtue of its weight. Various units for barometric pressure are available. In this book mmHg is used.

Barometric pressure and altitude  27

One mmHg is equal to 0.133 kPa. The barometric pressure at sea level for the standard atmosphere is 760 mmHg or torr (0.9999998575337 mmHg = 1 torr) or 101.325 kPa. Other units are 1013.25 millibars (mbar) or 14.696 pounds per square inch (psi). If the atmospheric air were incompressible, as is very nearly the case for a liquid, barometric pressure would decrease linearly with altitude, just as it does in a liquid. However, because the weight of the upper atmosphere compresses the lower gas, barometric pressure decreases more rapidly with height near the earth’s surface. If temperature were constant, the decrease in pressure would be exponential with respect to altitude, but because the temperature decreases as we go higher (at least, in the troposphere), the pressure falls more rapidly than the exponential law predicts. The relationships between pressure, volume, and temperature in a gas are governed by simple laws. These derive from the kinetic theory of gases that states that the molecules of a gas are in continuous random motion and are only deflected from their course by collision with other molecules, or with the walls of a container. When they strike the walls and rebound, the resulting bombardment results in a pressure. The magnitude of the pressure depends on the number of molecules present, their mass, and their speed: ●●

●●

●●

●●

Boyle’s law states that, at constant temperature, the pressure (P) of a given mass of gas is inversely proportional to its volume (V), or PV = constant (at constant temperature). This can be explained by the fact that as the molecules are brought closer together (smaller volume), the rate of bombardment on a unit surface increases (greater pressure). Charles’ law states that at constant pressure, the volume of a gas is proportional to its absolute temperature (T), or V/T = constant (at constant pressure). The explanation is that a rise in temperature increases the speed and therefore the momentum of the molecules, thus increasing their force of bombardment on the container. Another form of Charles’ law states that at constant volume, the pressure is proportional to absolute temperature. (Note that absolute temperature is obtained by adding 273 to the Celsius temperature. Thus 37°C = 310 K.) The ideal gas law combines the above laws; thus: PV = nRT, where n is the number of gram molecules of the gas and R is the “gas constant.” When the units employed are mmHg, liters, and Kelvin, then R = 62.4. Real gases deviate from ideal gas behavior to some extent at high pressures because of intermolecular forces, which are neglected in the derivation of the ideal gas law. Dalton’s law states that each gas in a mixture exerts a pressure according to its own concentration, independently of the other gases present. That is, each component behaves as though it were present alone. The pressure of each gas is referred to as its partial pressure.

●●

The total pressure is the sum of the partial pressures of all gases present. In symbols: Px = PFx, where Px is the partial pressure of gas x, P is the total pressure, and Fx is the fractional concentration of gas x. For example, if half the gas is oxygen, Fo2 = 0.5. The fractional concentration always refers to dry gas. The kinetic theory of gases explains their diffusion in the gas phase. Because of their random motion, gas molecules tend to distribute themselves uniformly throughout any available space until the partial pressure is the same everywhere. Light gases diffuse faster than heavy gases because the mean velocity of the molecules is higher. The kinetic theory of gases states that the kinetic energy (0.5 mv2) of all gases is the same at a given temperature and pressure. From this it follows that the rate of diffusion of a gas is inversely proportional to the square root of its density (Graham’s law).

Based on different rates of diffusion, one might expect that very light gases such as helium would separate and be lost from the upper atmosphere. This does happen to some extent at extreme altitudes. However, at the altitudes of interest to us, say up to 10 km, convective mixing maintains a constant composition of the atmosphere. Vertically, the atmosphere can be divided based on temperature variations into the troposphere, the stratosphere, and regions above that. The troposphere is the region where all the weather phenomena take place and is the only region of interest to high altitude medicine. Here, the temperature decreases approximately linearly with altitude until a low of about −60°C is reached. The troposphere extends to an altitude of about 19 km at the equator but only to about 9 km at the poles. The average upper limit is about 10 km. Above the troposphere is the stratosphere where the temperature remains nearly constant at about −60°C for some 10–12 km of altitude. The interface between the troposphere and stratosphere is known as the tropopause. Beyond the stratosphere, temperatures again vary with altitude. One of the important components of this region is the ionosphere where the degree of ionization of the molecules makes short-wave radio propagation possible.

Standard atmosphere With the development of the aviation industry in the 1920s, it became necessary to develop a barometric pressure–altitude relationship that could be universally accepted for calibrating altimeters, low pressure chambers, and other devices. Although it had been recognized for many years that the relationship between pressure and altitude was temperaturedependent and, as a result, latitude-dependent, there were clear advantages in having a model atmosphere that applied approximately to mean conditions over the surface of the earth. This is often referred to as the ICAO Standard Atmosphere (ICAO 1964) or the US Standard Atmosphere (NOAA 1976). These two are identical up to altitudes of interest to us.

28  The atmosphere

The assumptions of the standard atmosphere are a sea level pressure of 760 mmHg, sea level temperature of +15°C, and a linear decrease in temperature with altitude (lapse rate) of 6.5°C km−1 up to an altitude of 11 km (Table 2.1). Haldane and Priestley (1935, p. 323) gave the following expression for the pressure–altitude relationship of the standard atmosphere in the second edition of their textbook Respiration: 288 P0   =  P  288 − 1.98 H 



5.256

where P0 and P are the pressures in mmHg at sea level and high altitude, respectively, and H is the height in thousands of feet. A more rigorous description is given in the Manual of the ICAO Standard Atmosphere (ICAO 1964). It should be emphasized that this standard atmosphere was never meant to be used to predict the actual barometric pressure at a particular location. Rather, it was developed as a model of more or less average conditions within the troposphere with full recognition that there would be local variations caused by latitude and other factors. Nevertheless, the standard atmosphere has assumed some importance in respiratory physiology because it is universally used as the standard for altimeter calibrations, and it has frequently been inappropriately used to predict the pressure at various specific points of the earth’s surface, particularly on high mountains. Haldane and Priestley (1935) clearly understood that the standard atmosphere predicted barometric pressures considerably lower than those given by the expression of Zuntz et al. (1906), which had been shown by FitzGerald to predict accurately pressures in the Colorado mountains when a mean air column temperature of +15°C was assumed. Nevertheless, some physiologists have used the standard atmosphere for predicting the pressure at great altitudes,

for example on Mount Everest (Houston and Riley 1947; Houston et al. 1987; Rahn and Fenn 1955; Riley and Houston 1951). The barometric pressure calculated in this way for the Everest summit (8848 m) is 236 mmHg, which is far too low. In retrospect, one of the reasons for the indiscriminate use of the standard atmosphere was undoubtedly its very frequent employment in low pressure chambers during the very fertile period of research on respiratory physiology during World War II. Climbers using altimeters, including those on some wristwatches, should be aware that these use the standard atmosphere to convert barometric pressure to altitude. The difference between the readings given by these altimeters and the true altitude up to about 3000 m is unimportant for navigation in the mountains. From 4000 to 5000 m a climber should add 3% to the altimeter reading to get a truer altitude. From 5000 to 6000 m the change is 4%, from 6000 to 8000 m the change is about 5%, and above 8000 m it is 6% to 7%. Of course, if the altimeter also measures and reads pressure, the best solution is to relate this to altitude using the model atmosphere equation. Many modern-generation watches and navigation devices circumvent these issues by measuring altitude using GPS technology.

Variation of barometric pressure with latitude The limited applicability of the standard atmosphere is further clarified when we look at the relationship between barometric pressure and altitude for different latitudes (Figure 2.1). This shows that the barometric pressure at the earth’s surface and at an altitude of 24 km is essentially independent of latitude. However, in the altitude range of about 6–16 km, there is a pronounced bulge in the barometric pressure near the equator both in winter and summer. Since the latitude of

Table 2.1  Barometric pressures (in mmHg) from the standard atmosphere (ICAO 1964) and a model atmosphere (West 1996): The latter is a better fit for most sites where high altitude physiology and medicine are studied Altitude

Standard pressure

Model atmosphere

Kilometers

Feet

Barometric pressure

Inspired PO2a

Barometric pressure

Inspired PO2

0 1 2 3 4 5 6 7 8 9 10

0 3281 6562 9843 13,123 16,404 19,685 22,966 26,247 29,528 32,810

760 674 596 526 462 405 354 308 267 231 199

149 131 115 100 87 75 64 54 46 38 31

760 679 604 537 475 420 369 324 284 247 215

149 132 117 103 90 78 67 58 50 42 35

a

The PO2 of moist inspired gas is 0.2094 (PB − 47).

Barometric pressure and altitude  29

Figure 2.1  Increase of barometric pressure near the equator at various altitudes in both summer and winter. Vertical axis shows the pressure increasing upward according to the scale on the right. The numbers on the left show the barometric pressures at the poles for various altitudes; the altitude of Mount Everest is 8848 m. (Source: Brunt 1952.)

Mount Everest is 28°N, the pressure at its summit (8848 m) is considerably higher than would be the case for a hypothetical mountain of the same altitude near one of the poles. The cause of the bulge in barometric pressure near the equator is a very large mass of very cold air in the stratosphere above the equator (Brunt 1952). In fact, paradoxically, the coldest air in the atmosphere is above the equator. This is brought about by a combination of complex radiation and convective phenomena, which result in a large up-welling of air near the equator. Another corollary of the same phenomenon is that the height of the tropopause is much greater near the equator than near the poles. These latitudedependent variations of pressure are of great physiological significance for anyone attempting to climb Mount Everest without supplemental oxygen, because they result in a barometric pressure on the Everest summit which is considerably higher than that predicted from the model atmosphere. By the same token, a climber at a high latitude such as Denali (Mt. McKinley, 63°N latitude) is at a considerable disadvantage because of the low barometric pressure, especially in the winter months. It is for this reason that climbers feel that Denali behaves as a taller mountain than its true altitude.

Variation of barometric pressure with season Not only does barometric pressure change with latitude, there is also marked variation according to the month of

Figure 2.2  Mean monthly pressures for 8848 m altitude as obtained from weather balloons released from New Delhi, India. Note the increase during the summer months. The mean monthly standard deviation (SD) is also shown. The barometric pressure measured on the Everest summit on October 24, 1981 (*) was unusually high for that month. (Source: West et al. 1983.)

the year. For example, Figure 2.2 shows the mean monthly pressures for an altitude of 8848 m as obtained from radiosonde balloons released from New Delhi, India, which has about the same latitude as Everest, over a period of 15 years. Note that the mean pressures were lowest in the winter months of January and February (243.0 and 243.7 mmHg, respectively) and highest in the summer months of July and August (254.5 mmHg for both months). The monthly standard deviation showed a range of 0.65 mmHg (July) to 1.66 mmHg (December). The daily standard deviation was as low as 1.54 in the summer and as high as 2.92 in the winter. The standard deviation shown in Figure 2.2 is the mean of the monthly standard deviation for the 12 months of the year. Similar seasonal variation in barometric pressure was demonstrated in a more recent study in which in situ data on barometric pressure, as well as temperature and wind speed, were measured over a seven-month period by an automatic weather station installed at the South Col on Mount Everest (7896 m). Pressure was lowest in the pre- and postmonsoon period and varied significantly during passages of major weather systems (Figure 2.3) (Moore et al. 2012). Premonsoon data were limited in scope, however, because of a lack of data prior to the middle of May, likely due to the fact that this is the time period at which climbers first begin to access the South Col during the spring climbing season. The single measurement of barometric pressure (253.0 mmHg) made by Pizzo on the summit of Mount Everest on October 24, 1981, during the American Medical Research Expedition to Everest (AMREE) (West et al. 1983) is also shown in Figure 2.2. This was 4.3 mmHg higher than that predicted from the data shown in Figure 2.1, which is twice the daily standard deviation of barometric pressure

30  The atmosphere

390

Pressure (hPa)

385 380 375 370 365

May 15 Jun 15

Jul 15

Aug 15 Sep 15 Oct 15 Nov 15 Dec 15 Date

Figure 2.3  Daily mean time series of barometric pressure measured at the South Col of Mount Everest (7896 m) from midMay to mid-December 2008. Pressures are represented in hectopascals (hPA). The solid lines indicate the monthly mean pressures, while the dashed lines demonstrate the first and third quartiles. (Source: Moore et al. 2012.)

for the month of October. It should be added that Pizzo had an exceptionally fine day for his summit climb, the temperature on the summit being measured as −9°C, much higher than expected for that altitude. Figure 2.4 combines the effects of latitude and month of the year on the barometric pressure at an altitude of 8848 m. The data are for the northern hemisphere, and the pressures for the months of January (midwinter), July (midsummer), and October (preferred month for climbing in the postmonsoon period) are compared. The profile for the month of May, which is the usual month for reaching the summit in the premonsoon season, is almost the same as that for October.

The data are the means from all longitudes (Oort and Rasmusson 1971). The data clearly show the marked effects of both latitude and season on barometric pressure. It is interesting that in midsummer the pressure reaches a maximum near the latitude of Mount Everest (28°359N). Figure 2.4 shows that if Mount Everest was at the latitude of Denali (63°N), the pressure on the summit would be very much lower. Radiosonde balloons are released from meteorological stations all over the world twice a day, and the resulting data on the relationship between barometric pressure and altitude are available from constant pressure charts. Details on how to obtain these are given in West (1993). Using these data, it can be shown that the barometric pressure on the Everest summit was 251 mmHg when Messner and Habeler made their first ascent without supplemental oxygen in 1978. In August 1980, Messner made the first solo ascent without supplemental oxygen, and he was fortunate that the barometric pressure was unusually high at 256 mmHg. When Sherpa Ang Rita made the first winter ascent on December 22, 1987, the barometric pressure was only 247 mmHg.

Barometric pressure–altitude relationship for locations of importance in high altitude medicine and physiology

Figure 2.4  Barometric pressure at the altitude of Mount Everest plotted against latitude in the northern hemisphere for midsummer, midwinter, and the preferred month for climbing in the postmonsoon period (October). Note the considerably lower pressures in the winter. The arrows show the latitudes of Mount Everest and Mount McKinley. (Source: West et al. 1983.)

We have seen that the standard atmosphere generally underestimates the pressures on the high mountains that are of interest to people concerned with high altitude medicine and physiology. Recently, it has been possible to define the barometric pressure–altitude relationship in the Himalayan and Andean ranges with some accuracy, and it transpires that the relationship holds for many other locations where high altitude medicine and physiology are studied. In addition to obtaining a measurement of the barometric pressure on the summit of Mount Everest, careful measurements of barometric pressure were made during AMREE at two other locations on Mount Everest where the altitudes were accurately known, base camp (altitude 5400 m) and Camp 5,

Barometric pressure and altitude  31

just above the South Col (altitude 8050 m). These points lay very close to a straight line on a log pressure–altitude plot and therefore allowed the barometric pressure–altitude relationship at very high altitudes on Mount Everest to be accurately described for the first time (Figure 2 in West et al. 1983). This relationship is of great physiological interest because, as discussed in Chapter 19, the pressure near the summit is so low that the PO2 is very near the limit for human survival. More recently, additional measurements have been made at very high altitudes on Mount Everest (West 1999a). Another direct measurement was made on the summit in May 1997 and this agreed within 1 mmHg of Pizzo’s measurement of 253 mmHg. In addition, many measurements were reported from a barometer that telemetered information from the South Col (altitude 7986 m). Addition of these points to those obtained during the 1981 expedition (Figure 2.5), greatly increased the confidence in the barometric pressure–altitude relationship. Two other pieces of data provide further support for these relationships. Charles Corfield made a single measurement of the barometric pressure on the Everest summit at 10 a.m. on May 5, 1999. He used a Kollsman aneroid barometer and the value was 253 mmHg (personal communication). The air temperature was −18°C, and this had been shown not to affect the calibration of the barometer. The other data point comes from measurements made on the South Col by the Italian Ev-K2-CNR program. They reported 52 measurements of barometric pressure on 29 and 30 September and

Figure 2.5  Barometric pressure–altitude relationship for Mount Everest. The circles show data from the 1981 American Medical Research Expedition to Everest. The cross at the summit altitude (8848 m) is from the 1997 NOVA expedition. The cross at an altitude of 7986 m is from measurements made by the Massachusetts Institute of Technology in 1998. The standard deviations are too small to show on the graph. The line corresponds to the model atmosphere equation: PB = exp(6.63268 − 0.1112 h − 0.00149 h2) where h is in kilometers. (Source: West 1999a.)

1 October 1992 (personal communication). The mean value was 383.0 mbar (287 mmHg). This is the same pressure as that found by the MIT group in August 1997 (West 1999a).

Model atmosphere equation It is now possible to provide a barometric pressure–altitude relationship that accurately predicts the pressure at most locations of interest to high altitude medicine and physiology (West 1996). The data are shown in Figure 2.6. The prediction is particularly good if the locations lie within 30° of the equator, and especially if the pressure is measured in the summer months. Since many studies of high altitude medicine and physiology are carried out in locations and times that fulfill these criteria, the relationship is very useful in practice. The equation of the line is

(

PB = exp 6.63268 − 0.1112 h − 0.00149 h 2

)

where PB is the barometric pressure (in mmHg) and h is the altitude in kilometers. This has been called the model atmosphere equation and is useful for theoretical calculations in high altitude physiology such as predicting the effects

Figure 2.6  Barometric pressure–altitude relationship corresponding to the model atmosphere equation. Note that it predicts the altitudes of many locations of interest in high altitude medicine and physiology very well. The lower line shows the standard atmosphere, which predicts pressures that are too low. The locations and measured pressures are as follows: (1) Collahuasi mine, Chile, 438 mmHg; (2) Aucanquilcha mine, Chile, 372 mmHg; (3) Vallot observatory, France, 452 mmHg; (4) Capanna Margherita, Italy, 440 mmHg; (5) Mount Everest base camp, Nepal, 400 mmHg; (6) Mount Everest South Col, 284 mmHg; (7) Mount Everest summit, 253 mmHg; (8) Cerro de Pasco, Peru, 458 mmHg; (9) Morococha, Peru, 446 mmHg; (10) Lhasa, Tibet, 493 mmHg; (11) Crooked Creek, California, 530 mmHg; (12) Barcroft laboratory, California, 483 mmHg; (13) Pikes Peak, Colorado, 462 mmHg; (14) White Mountain summit, California, 455 mmHg. (Source: West 1996.)

32  The atmosphere

of oxygen enrichment at different altitudes. Procedures for both the standard and model atmospheres are available on the web at .

Barometric pressure and inspired PO2 As we have seen, the composition of the atmosphere is constant up to altitudes well above those of medical interest, so it is safe to assume that the concentration of oxygen in dry air is approximately 20.94%. However, the effects of water vapor on the inspired PO2 become increasingly important at higher altitudes. When air is inhaled into the upper bronchial tree, it is warmed and moistened and becomes saturated with vapor at the prevailing temperature. The water vapor pressure at 37°C is 47 mmHg and, of course, is independent of altitude. Thus, the PO2 of moist inspired gas is given by the expression

PIO2 = 0.2094 ( PB − 47 )

where PB is barometric pressure. This equation shows how much more important water vapor pressure becomes at very high altitudes. For example, at sea level, the water vapor pressure at 37°C is only 6% of the total barometric pressure. However, on the summit of Mount Everest, where the barometric pressure is about 250 mmHg, the water vapor pressure is nearly 19% of the total pressure, and the inspired PO2 is correspondingly further reduced (see Table 2.1). It has been pointed out from time to time that a relatively small reduction in body temperature at extreme altitude would confer a substantial increase in inspired PO2. For example, if the body temperature fell from 37 to 35°C where the water vapor is 42 mmHg, the PO2 of moist inspired gas would be increased from 42.5 to 43.5 mmHg. This increase of 1 mmHg would be beneficial because the arterial PO2 would increase by approximately the same extent, and since the oxygen dissociation curve is very steep at this point, there would be an appreciable gain in arterial oxygen content. However, there is no evidence that body temperature falls at extreme altitude. Nor is it reasonable to assume that the temperature in the alveoli where gas exchange takes place would be significantly less than the body core temperature.

Physiological significance of barometric pressure at high altitude Since the barometric pressure directly determines the inspired PO2, it is clear that the variations of barometric pressure with latitude and season affect the degree of hypoxemia in the body. For example, a climber on Denali in Alaska, which is situated at a latitude of 63°N, is exposed to a considerably lower barometric pressure on the summit than would be the case for a mountain of the same height located at lower latitudes (Figure 2.4). The reduction in inspired PO2 resulting from the lower barometric pressure not only reduces exercise performance

but may also increase the risk of altitude illness. In fact, there is some evidence that this may be the case at the comparatively modest altitudes of Summit County, Colorado (2650–2950 m) as reported by Reeves et al. (1994). They found that barometric pressure and environmental temperature averaged 8 mmHg and 23°C lower in winter compared with summer months. While the number of visits to the Summit Medical Center (2773 m) was nearly the same in the two periods, the proportion of patients with high altitude pulmonary edema was higher in winter, though interestingly there was no difference in the incidence of acute mountain sickness. Cold seemed to be more important than barometric pressure. The variations of barometric pressure with latitude and season become particularly significant from a physiological point of view at extreme altitudes such as near the summit of Mount Everest. For example, it has been argued that if the pressure on the Everest summit conformed to the standard atmosphere, it would be impossible to climb the mountain without supplemental oxygen (West 1983). In addition, the variation of barometric pressure with month of the year shown in Figure 2.2 indicates that it would be considerably more difficult to reach the summit without supplemental oxygen in the winter as a result of the reduced inspired PO2, quite apart from the obvious difficulties of lower temperatures and high winds. Although there have now been many ascents of Everest without supplemental oxygen in the pre- and postmonsoon seasons, only one person has made a winter ascent without supplemental oxygen. This was Sherpa Ang Rita on December 22, 1987, when the barometric pressure was 247 mmHg based on radiosonde balloon data for that date. Therefore, the pressure was much higher than it typically becomes in midwinter, for example in late January (Figure 2.2). As noted in The Himalayan Database (updated annually), by the end of 2018, a total of 15 climbers reached the Everest summit during the winter; supplemental oxygen was used by all of the climbers except Sherpa Ang Rita (Salisbury 2004). This topic is considered in more detail in Chapter 19.

FACTORS OTHER THAN BAROMETRIC PRESSURE AT HIGH ALTITUDE Temperature Temperature falls with increasing altitude at the rate of about 1°C for every 150 m. This lapse rate is essentially independent of latitude. The consequence is that on a very high mountain, such as Mount Everest, the average temperature near the summit is predicted to be about −40°C. Most climbers choose to climb during the warmer months of the year. In May, a temperature of −27°C was measured at an altitude of 8500 m on Everest (Pugh 1957), although Pizzo obtained a temperature of −9°C on the summit in October (West et al. 1983). In the winter, the temperatures are much lower. However, even then they do not approach the extremely low temperatures seen in northern Canada or Siberia during midwinter.

Factors other than barometric pressure at high altitude  33

More important than temperature per se is the wind chill factor that reflects the effect of wind speed as well as ambient temperature. Wind speed can be quite high at high elevations. Data collected from a weather station installed at the South Col (7896 m), for example, showed a mean daily wind speed of 11.9, 4.4, and 19.5 m sec−1 in May, July, and October, respectively (Moore et al. 2012). Moore and Semple (2011) have calculated two indices related to cold injury on Mount Everest using a meteorological dataset. They found that throughout the year the typical wind chill equivalent temperature on the summit is always less than −30°C, and the typical facial frostbite time is always less than 20 minutes. During the spring climbing season, typical values are −50°C and five minutes. The authors stated that the barometric pressure on the summit is a good predictor of these indices with a low pressure being associated with a low temperature and short frostbite time. Cold injury is common in the mountains and is discussed in Chapter 27.

Humidity Absolute humidity is the mass of water vapor per unit volume of gas at the prevailing temperature. This value is extremely low at high altitude because the water vapor pressure is so depressed at the reduced temperature. Thus, even if the air is fully saturated with water vapor, the actual amount will be very small. For example, the water vapor pressure at +20°C is 17 mmHg but only 1 mmHg at −20°C. Relative humidity is a measure of the amount of water vapor in the air as a percentage of the amount that could be contained at the prevailing temperature. This value may be low, normal, or high at high altitude. The disparity between absolute and relative humidities is explained by the fact that even saturated air is unable to contain much water vapor because of the very low temperature. If this air is warmed without allowing additional water vapor to form, its relative humidity falls. The very low absolute humidity at high altitude frequently causes dehydration. First, the insensible water loss caused by ventilation is great because of the dryness of the inspired air. In addition, the levels of ventilation may be extremely high, especially on exercise (Chapter 18), and this increases water loss. For example, near the summit of Mount Everest, the total ventilation is increased some five-fold compared with sea level for the same level of activity. Pugh (1964) calculated that during exercise at 5500 m altitude, the rate of fluid loss from the lungs alone was about 2.9 g water per 100 L of ventilation (body temperature and pressure, saturated with water vapor, or BTPS). This is equivalent to about 200 mL of water per hour for moderate exercise. However, it is likely that Pugh’s calculation gives erroneously high values because the temperature of expired gas is below body temperature, and the gas is probably not fully saturated with water even at this lower temperature (Burch 1945; Ferrus et al. 1980; Loewy and Gerhartz 1914; Webb 1951). Using an equation given by Ferrus et al. (1984), Milledge (1992) calculated that the water loss is only about

30% to 40% of that calculated assuming that the expired gas is fully saturated at body temperature in a climber at extreme altitude. Actual measurements during climbing at extreme altitude would be valuable. There is evidence that the dehydration resulting from these rapid fluid losses does not produce as strong a sensation of thirst as at sea level. As a result, it is necessary for climbers to drink large quantities of fluids at high altitude to remain hydrated even though they have little desire to do so. For people climbing seven hours a day at altitudes over 6000 m, 3–4 L of fluid are required to maintain a urine output of 1.5 L day−1 (Pugh 1964b). Even so, it appears that people living at very high altitude are in a state of chronic volume depletion (Blume et al. 1984). In a group of subjects living at an altitude of 6300 m during the American Medical Research Expedition to Everest, serum osmolality was significantly increased compared with sea level even though ample fluids were available and the lifestyle in terms of exercise and diet was not exceptional (Blume et al. 1984).

Atmospheric ozone Ozone (O3) is a potentially toxic gas and an important constituent of smog. Ozone can cause inflammation of mucous membranes and bronchi, cough, throat irritation, bronchoconstriction, and dyspnea. It is interesting, therefore, that increased concentrations have been recorded in the European Alps (Stohl et al. 2000) and at very high altitudes on Mount Everest (Bonasoni et al. 2008; Semple and Moore 2008; Zhu et al. 2006). Surface measurements in the Mount Everest region have exceeded 140 ppb during an eight-hour exposure (Semple and Moore 2009). These surface measurements increase with increasing altitude and are highest in the spring months (Semple et al. 2016). Two mechanisms for the increased concentrations have been identified on Mount Everest. One is ozone penetrating from the stratosphere in the premonsoon period, and the other is ozone from the troposphere during monsoon periods. The latter may be related to the so-called Asian Brown Clouds resulting from pollution in South East Asia and the Indo-Gangetic plain (Ramanathan et al. 2007; Semple et al. 2016).

Solar radiation The intensity of solar radiation increases markedly at high altitude for two reasons. First, the much thinner atmosphere absorbs fewer of the sun’s rays, especially those of short wavelength in the near ultraviolet region of the spectrum. Second, reflection of the sun from snow greatly increases radiation exposure. The reduced density of the air causes an increase in incident solar radiation of up to 100% at an altitude of 4000 m compared with sea level (Elterman 1964). The fact that mountain air is so dry is another important factor because water vapor in the atmosphere absorbs substantial amounts of solar radiation. The efficiency with which the ground reflects solar radiation is known as its albedo. This varies

34  The atmosphere

from less than 20% at sea level to up to 90% in the presence of snow at great altitudes (Buettner 1969). Mountaineers are familiar with the extreme intensity of solar radiation, especially on a glacier in a valley between two mountains. Here, the sunlight is reflected from both sides as well as from the snow or ice on the glacier and the heat can be very oppressive despite the great altitude. A consequence of this is the extreme diurnal variation in temperature that has been noted in mountaineering camps.

Ionizing radiation The intensity of cosmic radiation increases at high altitude because there is less of the earth’s atmosphere to absorb the rays as they enter from space. This is the reason why cosmic radiation laboratories are often located on high mountains. It has been shown that, at an altitude of 3000 m, the increased cosmic radiation results in an increased radiation dose to a human being of approximately 0.0007 Gy year−1 (70 mrad year−1). This should be considered in relation to the normal background radiation dose from all sources of 0.0005–0.004 Gy year−1 (50–400 mrad year−1). The increased ionizing radiation of high altitude has been cited as one of the factors causing acute mountain sickness (Bert 1878), but there is no scientific basis for this assertion.

THE FUTURE OF THE ATMOSPHERE AND THE IMPLICATIONS OF CLIMATIC CHANGE FOR HIGH ALTITUDE The potential effects of global climate change and the associated swings in environmental extremes will have an enormous influence on life on earth. These include serious adverse human health outcomes and socioeconomic implications on a worldwide scale. There are also clear

and present challenges to the high altitude environment. For example, the warming of the earth is also reflected in a further loss of the ozone layer and greater levels of pollution and radiation. Perhaps the greatest implication in the context of high altitude physiology and medicine, however, is the projected reductions in atmospheric O2. Figure 2.7a illustrates the temporal timeline for changes in atmospheric O2 over the last 5 billion years. Figure 2.7b illustrates the parabolic projection of the decline in future atmospheric O2 levels using a stochastic model (Livina et al. 2015) applied to original data obtained from recording stations in the Scripps Programme (Keeling 1988). This model predicts that in ∼3600 years, atmospheric O2 levels will be so low that hypoxia will be encountered even at sea level, equivalent to being exposed to a terrestrial altitude of ∼5340 m, an elevation which is very close to the highest elevation know to sustain lifelong human habitation. Complete oxygen depletion is predicted within ∼4.4 millennia (Martin et al. 2017). As mentioned and detailed in Chapter 19, even small alterations in barometric pressure and/or weather stability can have a remarkable influence on success or failure at extreme altitude. It is estimated, based on the published predictions of O2 decline, that even within 3000 years the barometric pressure on the summit of Everest will be reduced almost by ∼35 mmHg! In a closer time frame, over the next 1000 years, even a likely reduction of ∼8 mmHg in barometric pressure will pose a major challenge to oxygen-less ascents of Everest. These changes in atmospheric conditions are not only relevant for performance at extreme altitude, but also the achievement of optimal performance in everyday life, especially in those working at higher elevations. There are also obvious implications of changes in atmospheric O2 levels on the treatment and prevention of high altitude related illnesses.

Figure 2.7  Timeline for changes in atmospheric O2 over the last 5 billion years (a) and (b) the parabolic projection of the decline in future atmospheric O2 levels using a stochastic model (Livina et al. 2015) applied to original data obtained from recording stations in the Scripps Programme (Keeling 1988).

The future of the atmosphere and the implications of climatic change for high altitude  35

REFERENCES Bert P. (1878). La Pression Barométrique. Masson, Paris. English translation by MA Hitchcock and FA Hitchcock, College Book Co., Columbus, OH, 1943. Blume FD, Boyer SJ, Braverman LE, Cohen A, Dirkse J, Mordes JP. (1984). Impaired osmoregulation at high altitude. Studies on Mt Everest. JAMA 252:524–526. Bonasoni P, Laj P, Angelini F, Arduini J, Bonafè U, Calzolari F, Cristofanelli P, Decesari S, Facchini MC, Fuzzi S, Gobbi GP, Maione M, Marinoni A, Petzold A, Roccato F, Roger JC, Sellegri K, Sprenger M, Venzac H, Verza GP, Villani P, Vuillermoz E. (2008). The ABC-Pyramid Atmospheric Research Observatory in Himalaya for aerosol, ozone and halocarbon measurements. Sci Total Environ. 391:252–261. Boyle R. (1662). New Experiments Physico-mechanicall, Touching the Spring of the Air, and Its Effects. H. Hall for Tho. Robinson, Oxford. Brunt D. (1952). Physical and Dynamical Meteorology, 2nd ed. Cambridge University Press, Cambridge, p. 379. Buettner KJK. (1969). The Effects of Natural Sunlight on Human Skin. Pergamon Press, London, New York. Burch GE. (1945). The rate of water loss from the respiratory tract of man living in a subtropical climate. Science. 102:619–620. Elterman L. (1964). Atmospheric attenuation model, 1964, in the ultraviolet, visible, and infrared regions for altitudes to 50 km. Air Force Cambridge Research Labs Hanscom AFBMA. Ferrus L, Commenges D, Gire J, Varène P. (1984). Respiratory water loss as a function of ventilatory or environmental factors. Respir Physiol. 56:11–20. Ferrus L, Guenard H, Vardon G, Varene P. (1980). Respiratory water loss. Respir Physiol. 39:367–381. FitzGerald MP. (1913). VIII. The changes in the breathing and the blood at various high altitudes. Philos Trans R Soc Lond B. 203:351–371. Galileo G. (1981). Dialogues Concerning Two New Sciences. English translation of relevant pages in High Altitude Physiology (ed. JB West), Hutchinson Ross, Stroudsburg, PA. Haldane JS, Priestley JC. (1935). Respiration. Yale University Press, New Haven, CT. Hann J. (1901). Lehrbuch der Meteorologie. Verlag von Chr Herm Tauchnitz, p. 329. Houston CS, Riley RL. (1947). Respiratory and circulatory changes during acclimatization to high altitude. Am J Physiol. 149:565–588. Houston CS, Sutton JR, Cymerman A, Reeves JT. (1987). Operation Everest II: man at extreme altitude. J Appl Physiol. 63:877–882. Keeling FR. (1988). Development of an interferometric oxygen analyzer for precise measurement of the atmospheric O2 mole fraction. PhD thesis, Harvard University.

Kellas AM. (2001). A consideration of the possibility of ascending Mount Everest. High Alt Med Biol. 2:431–461. Livina VN, Martins TMV, Forbes AB. (2015). Tipping point analysis of atmospheric oxygen concentration. Chaos. 25:036403. Loewy A, Gerhartz H. (1914). Über die Temperatur der Exspirationsluft und der Lungenluft. Pflügers Arch. 155:231. Martin D, McKenna H, Livina V. (2017). The human physiological impact of global deoxygenation. J Physiol Sci. 67:97–106. Milledge JS. (1992). Respiratory water loss at altitude. The Newsletter of the International Society of Mountain Medicine 2:5–7. Moore GWK, Semple JL. (2011). Freezing and frostbite on Mount Everest: new insights into wind chill and freezing times at extreme altitude. High Alt Med Biol. 12:271–275. Moore K, Semple J, Cristofanelli P, Bonasoni P, Stocchi P. (2012). Environmental conditions at the South Col of Mount Everest and their impact on hypoxia and hypothermia experienced by mountaineers. Extrem Physiol Med. 1:2. Oort AH, Rasmusson EM. (1971). Atmospheric circulation statistics. US Gov. Printing Office, Washington, DC. Pascal B. (1981). Story of the Great Experiment on the Equilibrium of Fluids. English Translation of Relevant Pages in High Altitude Physiology (ed. JB West), Hutchinson Ross, Stroudsburg, PA. Pugh LG. (1957). Resting ventilation and alveolar air on Mount Everest: with remarks on the relation of barometric pressure to altitude in mountains. J Physiol. 135:590–610. Pugh LG. (1964). Man at high altitude: studies carried out in the Himalaya. Sci Basis Med Annu Rev. 32–54. Rahn H, Fenn WO. (1955). A Graphical Analysis of the Respiratory Gas Exchange: The Ob2-COb2 Diagram. American Physiological Society, Washington, DC. Ramanathan V, Li F, Ramana MV, Praveen PS, Kim D, Corrigan CE, Nguyen H, Stone EA, Schauer JJ, Carmichael GR, others. (2007). Atmospheric brown clouds: hemispherical and regional variations in longrange transport, absorption, and radiative forcing. J Geophys Res Atmos. 112:1–26 Reeves JT, Wagner J, Zafren K. (1994). Seasonal variation in barometric pressure and temperature: effect on altitude illness. In: Hypoxia and Molecular Medicine. JR Sutton, CS Houston, G Coates, eds. Queen City Printers, Burlington, VT, pp. 275–281. Riley RL, Houston CS. (1951). Composition of alveolar air and volume of pulmonary ventilation during long exposure to high altitude. J Appl Physiol. 3:526–534. Hawley E, Salisbury R. (2004). The Himalayan Database: The Expedition Archives of Elizabeth Hawley. The American Alpine Club, Golden, CO. Accessed March 2018.

36  The atmosphere

Semple JL, Moore GWK. (2008). First observations of surface ozone concentration from the summit region of Mount Everest. Geophys Res Lett. 35. Semple JL, Moore GWK. (2009). Ozone exposure and mortality. N Engl J Med. 360:2786–2787; author reply 2788–2789. Semple JL, Moore GWK, Koutrakis P, Wolfson JM, Cristofanelli P, Bonasoni P. (2016). High concentrations of ozone air pollution on Mount Everest: health implications for Sherpa communities and mountaineers. High Alt Med Biol. 17:365–369. Stohl A, Spichtinger-Rakowsky N, Bonasoni P, Feldmann H, Memmesheimer M, Scheel HE, Trickl T, Hübener S, Ringer W, Mandl M. (2000). The influence of stratospheric intrusions on alpine ozone concentrations. Atmos Environ. 34:1323–1354. Webb P. (1951). Air temperatures in respiratory tracts of resting subjects in cold. J Appl Physiol. 4:378–382. West JB. (1983). Climbing Mt. Everest without oxygen: an analysis of maximal exercise during extreme hypoxia. Respir Physiol. 52:265–279. West JB. (1993). Acclimatization and tolerance to extreme altitude. J Wilderness Med. 4:17–26. West JB. (1996). Prediction of barometric pressures at high altitudes with the use of model atmospheres. J Appl Physiol. 81:1850–1854.

West JB. (1998). High Life: A History of High Altitude Physiology and Medicine. Oxford University Press, Oxford. West JB. (1999a). Barometric pressures on Mt. Everest: new data and physiological significance. J Appl Physiol. 86:1062–1066. West JB. (1999b). The original presentation of Boyle’s law. J Appl Physiol. 87:1543–1545. West JB. (2005). Robert Boyle’s landmark book of 1660 with the first experiments on rarified air. J Appl Physiol. 98:31–39. West JB, Lahiri S, Maret KH, Peters RM Jr, Pizzo CJ. (1983). Barometric pressures at extreme altitudes on Mt. Everest: physiological significance. J Appl Physiol. 54:1188–1194. Zhu T, Lin W, Song Y, Cai X, Zou H, Kang L, Zhou L, Akimoto H. (2006). Downward transport of ozone-rich air near Mt. Everest. Geophys Res Lett. 33:L23809. Zuntz N, Loewy A, Müller F, Caspari W. (1906s). Höhenklima und Bergwanderungen: in ihrer Wirkung auf den manschen. Deutsches verlagshaus bong & Company.

3 Geography

Introduction 37 Major high altitude regions of the world 37 Himalayas and Tibetan plateau 37 Andean Mountains of South America 38 Ethiopian highlands 39 Population 39 Terrain 40 Climate 40 Rainfall 41

Temperature 41 Solar and ultraviolet radiation 41 Economics 42 Load carrying 42 Porters’ health and welfare 44 Housing and shelter 46 Clothing 47 References47

INTRODUCTION

(as of 2019) located at an altitude of 5100 m in southern Peru (Figure 3.1) (West 2002). Although even high altitude residents are affected by the altitude, the limit of permanent habitation is probably dictated by economic, rather than physiological, factors. Above 5000 m—even in the tropics— crops cannot be grown and animals cannot be pastured all year round. Nomadic and seminomadic peoples regularly take their flocks to pastures higher than 5000 m but do not reside in these areas on a permanent basis. In addition to the European Alps and the Rocky Mountains of the United States and Canada, three of the major regions that support large populations are the Himalayas and Tibetan plateau, the Andes Mountains of South America, and the Ethiopian highlands. Each is considered in further detail below.

Although there is no precise definition of “high altitude,” the term is generally applied to elevations above 2500–3000 m, as this is the altitude range at which as most individuals manifest characteristic anatomic, biochemical, clinical, and physiological changes. There is considerable interindividual variation, however, and some people are affected at altitudes as low as 2000 m. The purpose of this chapter is to describe the geography of some of the major mountainous areas of the world. After a brief description of the primary high altitude regions in which people reside, the chapter considers the people, terrain, climate, and socioeconomic features of these regions with a focus primarily on two of the major high altitude regions of the world in which people reside on a permanent basis, the Himalaya and Andes Mountains.

MAJOR HIGH ALTITUDE REGIONS OF THE WORLD The primary areas where it is possible to ascend above 3000 m are listed in Table 3.1. For sea-level visitors, an altitude of 4600–4900 m represents the highest acceptable level for permanent habitation, whereas for high altitude residents, 5800–6000 m is the highest so far recorded (West 1986). Indeed, the highest permanent human habitation is probably the town of La Rinconada (https://vis.sciencemag.org/ hypoxia-city/), a mining city of close to 70,000 inhabitants

Himalayas and Tibetan plateau The Himalayas form a topographically extremely complex region, extending 1500 miles from Nanga Parbat (8125 m) in the west to Namcha Barwa (7756 m) in the east. At their western extremity, they are part of a confused mass of peaks, passes, and glaciers where the western Kun Lun, Karakoram, Pir Panjal, and Pamirs form an area the size of France. The Himalayas contain the world’s highest mountain, Mount Everest (8848 m), and many other peaks over 7500 m. The main range forms the watershed between Central Asia and India, and there are middle ranges at 37

38 Geography

Table 3.1  Regions of the world above 2500 m Alaska Range Andes Mountains of South America Atlas Mountains of North Africa European Alps Ethiopian Highlands Himalayan Range Hindu Kush of Central Asia Mountains and Plateaus of Antarctica Mountains of East and South Africa Parts of the Southern Island of New Zealand Parts of New Guinea Pyrenees Mountains of France and Spain Rocky Mountains of the USA and Canada Sierra Madre of Mexico Sierra Nevada of the USA Tien Shan and Pamir

intermediate altitudes. The outer Himalayas (up to 1500 m) form foothills rising from the plains of India. The Tibetan plateau is an area occupied by Tibetans, who have a well-defined culture. It extends in the south to the Himalayas and high Himalayan valleys. To the west, the plateau is demarcated by the northward curve of the Himalayas that continues into Kashmir, Baltistan, and then to Gilgit and the Karakoram. To the north, the peaks (up to 7700 m) of the Kun Lun range, 1500 miles long, mark off the plateau of Tibet from Xinjiang, a vast desert region. To the east, it extends to the Koko Nor or Qinghai Lake and, further south, the valleys of Qinghai and Sikiang and the gorge country of southeast Tibet. The area covers about 1.5 million square miles and is the largest and highest plateau in the world, much of it at an altitude of 4600–4900 m. It presents an enormous range of climate and topography. The major climatic contrast is between the southern side of the Himalayas and the high

valleys exposed to the summer Indian monsoon with very high rainfall, particularly in the east, and the aridity and low rainfall of the Tibetan plateau. The change is so abrupt that in some passes in the eastern Himalayas, vegetation may change from tropical to subarctic within a few yards. Tibetans have been subject to influences from China, India, Central Asia, and the Middle East for many centuries (Stein 1972). Permanent buildings are found up to 3500 m with nomadic populations at higher levels. Neolithic human remains have been found near Lhasa (Ward 1990; Ward 1991). Aldenderfer (2011) suggested, “Although the data are sparse, both archaeology and genetics suggest that the plateau was occupied in the Late Pleistocene, perhaps as early as 30,000 yr ago.” Recent studies indicate the earliest habitation of the Tibetan plateau occurred 30,000 to 40,000 years before present (Zhang et al. 2018). There were almost certainly later migrations, with evidence of permanent settlements dating from about 6500, 5900, and 3750 years ago. With increasing numbers of Han Chinese immigrants, there are more than three million people living at or above more than 3000 m. It is estimated that the amount of land available for agriculture is only 5% of the total. The 1100 km Golmud to Lhasa rail link, three quarters of which is at altitudes above 4000 m, opened in July 2006. By making it possible to travel from all parts of China to Lhasa by rail, the railway has facilitated large increases in the number of Han Chinese tourists and residents in Tibet. The tourist population faces a risk of acute altitude illness, described further in Chapters 20–22, while those who relocate to Tibet are at risk for chronic forms of altitude illness described in Chapter 24.

Andean Mountains of South America The highland zone of the Andes Mountains extends from Colombia in the north to central Chile in the south. It is flanked by an arid desert on its west with a deeply eroded escarpment to the east, which adjoins the Amazon basin. The central Andean region has three broadly defined areas

Figure 3.1  La Rinconada, Peru. At an elevation of 5100 m, it is likely the highest permanent habitation in the world. (Image courtesy of Axel Pittet and Sam Verges, Expédition 5300.)

Population 39

running parallel with the Pacific Ocean: The cordillera occidental, the altiplano (a broad undulating plain at 4000 m in the middle), and the cordillera oriental in the east. The earliest archeological evidence for human occupation dates back 12,000 years (MacNeish 1971) and has been found at Ayacucho, Peru, at 2900 m; other early finds are recorded in central Chile, Venezuela, and Argentina. However, this date and the evidence for it have been questioned by Lynch (1990), who suggests a maximum date of 12,000 years ago, which is supported by more recent studies indicating humans reached high altitude regions in the Andes shortly after the arrival of modern humans in South America (Rademaker et al. 2014). The skeleton of a man who lived 9500 years ago has been found at Lauricocha (4200 m) in Peru (Hurtado 1971). It is widely accepted that South American indigenous peoples migrated into the American continent from the Mongolian area via the Bering land bridge. The pre-Inca civilizations were situated mainly along the Pacific coast and the population subsisted mainly on seafood. Little is known of the highland population during this period. Both agriculture and stock raising dominate the subsistence economy, with the upper limit of agriculture at 4000 m and the upper limit of vegetation at 4600 m. Mining is carried out at even greater altitudes, as described in Chapter 5, and tourism is a major source of visitors and revenue for the region.

Ethiopian highlands No well-circumscribed highland zone exists in the Ethiopian highlands. The country is intersected by many rift valley systems, establishing a connection between the African Rift Valley in the south and the Red Sea. The valley systems divide the country into three reasonably well-defined regions: The western highlands, the eastern highlands, and the rift valley itself with the lowland area. Some of the earliest hominids occupied wooded habitats between the Main Ethiopian Rift (MER) and the Afar Rift between 5.54 and 5.77 million years ago, providing important clues into the impact of climate and savannah habitat on hominid origins (WoldeGabriel et al. 2001). It appears that modern human populations have migrated in and out of the Ethiopian highlands for possibly the past 70,000 years (Hassen 1990), with recent archaeological evidence suggesting high altitude human settlements (above 4000 m) dated to 47,000 to 31,000 years ago in the Bale Mountains (Ossendorf et al. 2019). The northern part of the western highlands, the Amhara highlands, attains the greatest altitude (2400–3700 m) and is the home to some species that are not located anywhere else in the world: Geladas, the Ethiopian wolf, and ibex. Much of Ethiopian history centers on this area, which has been settled for many centuries. It is inhabited by the largest of Ethiopia’s many population groups, the Amharas and Tigraeans, who are the descendants of people who came from southern Arabia prior to 1000 BC (Sellassie 1972). Much of the population of Ethiopia lives above 2000 m. Gondar (3000 m), in the Amhara highlands with a population of about 200,000, became the second largest city in

Africa, and it remained the capital of Ethiopia until the middle of the first century, when Addis Ababa was founded. Teff, a type of grass that produces a small seed, is grown up to 3000 m and is the mainstay of the agricultural economy. Ethiopian, as well as Kenyan, distance runners are among the most elite in the world (Wilber et al. 2012). Efforts to understand the environmental and genetic contributions to endurance running in these populations are under way (Georgiades et al. 2003). Numerous high altitude training centers in Ethiopia and those at moderate altitudes in Kenya (e.g., Iten and Eldoret, between 2100 and 2700 m) showcase the extraordinary performance of individuals in these populations and attract visitors from throughout the world interested in high altitude training.

POPULATION Most of the high altitude areas of the world are less-developed economically and for this reason population numbers in relation to altitude are difficult to obtain. Whereas, as of 2004, about 89.3 million people were living at altitudes above 2500 m, including 25.9 million and 5.4 million living more than 3500 m and 4500 m above sea level, respectively (Beall 2014), it is now estimated that over 200 million people live above 2500 m (Moore et al. 1998; WHO 2019). In South America, large populations have lived at high altitude since prehistory, and the Andean population at the time of the Spanish conquest was estimated between 4.5 and 7.5 million. In 1980, it was considered that between 10 and 17 million were living at more than 2500 m and, in Peru, 30% to 40% of the population of 4 million lived at or above this height, with 1.5% living at more than 4000 m. The highest capital city in the world, La Paz, Bolivia (3650 m), has a population of 2.7 million; other large cities such as El Alto (4150 m) and the constitutional capital of Bolivia, Sucre (2810 m), have populations of 970,000 and 300,000, respectively. In Asia and Africa, the estimates are less accurate. On the Tibetan plateau, which consists of the autonomous region of Tibet (Xizang) and Qinghai province, the population has been estimated between 4 and 5 million. Lhasa (3658 m) was estimated to have 130,000 inhabitants, most of whom were Tibetan in 1986, but recent immigration of Han Chinese has increased this number to roughly 900,000 people in 2015. Relatively small groups, nomads (at up to 5450 m) and miners (at up to 6000 m), live at higher levels. Fairly large numbers live at altitudes exceeding 3000 m in the upper valleys of eastern Tibet, and in Nepal about 60,000 live above this level, with a number of villages in Dolpo located at 5000 m (Snellgrove 1961). About 50% of the total Ethiopian population of 110 million live above 2000 m. Small populations in Mexico, the United States, and the former Soviet Union, for instance in Kyrgyzstan, live above 3000 m. In tropical latitudes, permanent settlements are usually placed where both pasture and timber can be used; the upper limit of habitation may fall between the two. Further from the equator, the upper limit falls below the timber line and variation in temperature becomes seasonal; the upper

40 Geography

pasturelands are thus used for a seminomadic economy. Permanently inhabited villages are found at lower levels, with isolated groups of buildings or shelters on the pastures occupied for the grazing season and evacuated during the winter. Considerable migration may occur and part of the population may always be on the move. One mine, now closed, was worked at 5950 m in South America; although the miners lived at rather lower altitudes, the caretakers lived there permanently (West 1986a). Individuals who travel between moderate and high altitude work sites are discussed in Chapter 5. Highland populations, being strategically placed between prosperous lowland centers, play a vital role in trade. Because they are physiologically well adapted, they have been historically capable of crossing high mountain passes with heavy loads and have also used their animals to carry goods. Major mountain passes, including the Silk Road (Lu et al. 2016), have for centuries been arteries for trade, the movement of people and ideas, and the dissemination of disease. Increasing road construction in the Himalaya and elsewhere is changing many of these dynamics and facilitating both easier migration, as well as trade and commerce.

Plateaus can support large populations and large towns, but they may be isolated by virtue of distance from lowland cities, which are usually the center of government, commerce, and industry. Extensive road construction in northern India and Nepal is an example of recent efforts to counteract this isolation. Increasing ease of air travel and railway has served a similar purpose. In mountain valleys, where flat ground is at a premium, populations tend to be smaller, with groups perched on slopes and ridges far from one another. The placing of houses in sunny positions is more difficult and isolation within the community is common. Communications, roadways, and trails are easily severed by landslides, avalanches, and other natural disasters, as evidenced by the damage suffered in mountainous areas during the large 2015 earthquake in Nepal. The funneling effect of valleys on wind may increase its velocity with an ensuing stunting effect on vegetation and trees. This also restricts the placement of houses, as does the availability of water and the possibility of natural disasters.

TERRAIN

The climate near the ground at high altitude has several basic features. At any given latitude, seasonal variation of monthly temperature is less at high altitude than at sea level and, as the equator is reached, seasonal variation virtually disappears. Diurnal variations are considerable, with temperatures varying as much as 30°C. This is because of high levels of long-wave radiation that occur in cloudless skies during the day and escape to clear skies at night. Diurnal variation decreases in overcast conditions. Climate change has become an increasing concern in high altitude regions. Reports from 2005 indicate that glaciers covered more than 100,000 km2 in Asia, mostly in the Himalayas, and more than 4000 km2 combined in Argentina, Bolivia, Chile, and Peru in South America (WHO 2005). These values have declined in many areas since the time of that report, although areas of glacial growth, such as in the Karakoram range, have been documented (Gardelle et al. 2012). Evidence for altitude amplification (increased rate of warming with increased elevation) suggests mountain regions may experience even faster temperature changes in the coming decades (Pepin et al. 2015; Urrutia and Vuille 2009). Such changes present various challenges to highland communities. For example, glacial melting due to climate change leads to increased accumulation of water in large glacial lakes. The frequency of glacial lake outburst floods, which lead to the sudden discharge of large volumes of water and debris, have increased in the Himalayas since the latter half of the 20th century and are of major concern for nearby communities. Changes in snow and vegetation cover due to increasing temperature also affect hydropower and agriculture, which can impact resources available to and the lifestyle of highland populations. In the Andes, most freshwater comes from glaciers, and glacial melt can expose minerals that contaminate water sources, thereby

Although mountain country varies widely, there are two distinct types: The high, flat, plateaus characteristic of Tibet and the altiplano of South America and the deep valleys seen in the Himalayas and Andes (Figure 3.2) as well as Ethiopia.

Figure 3.2  Contrasting terrain and climate at altitude. (A) Typical mountainous country on southern slopes of the Himalayas. (B) The volcanoes Pomerape (left) and Parinacota rising above the arid altiplano near the border of northern Chile and Bolivia. (Images courtesy of Andrew M. Luks.)

CLIMATE

Climate 41

further threatening surrounding populations. These issues are of increasing concern as temperatures are predicted to rise 2–5°C, for example, in the Andes by the end of the 21st century (Cabré et al. 2016; Hijmans et al. 2005). The Research Centre for Alpine Ecosystems reports the 2°C temperature increase in the European Alps during the 20th century is double that of the northern hemisphere. Glacier melt in the European Alps has accelerated in the past 40 years, with a 50-cm average loss per year of glacier mass recorded between 2006 and 2015. A “Call for Action” was made by the World Meteorological Organization at the High Mountain Summit in October 2019 to create changes necessary to mitigate the decline of glacial melting and impacts on the ecosystem and the security, economy, food, and water resources for highland communities.

Rainfall In Asia, the monsoon flows from east to west across India, cooling as it is forced to ascend by the Himalayas. Water vapor condenses and falls as rain, and as it passes to the west, the monsoon becomes depleted of water; the eastern Himalayas are thus very wet, while the western part of the range is dry. Whereas in Darjeeling, the annual rainfall is 2000–3000 mm a year, it is 1500 mm in the central Himalayas at Simla and only 75 mm in the west at Ladakh. The Karakoram is arid, whereas the eastern Himalayan region is tropical. There is also considerable north–south variation with subarctic species on the Tibetan plateau and tropical species often only a few hundred yards away to the south. This is particularly marked on some passes in the eastern Himalayas. On the plateau, although monsoon clouds are seen on the Tangulla range, about 700 km north of Lhasa, precipitation is small. In the deserts of the Tarim basin and Tsaidam to the north of the Tibetan plateau, annual rainfall may be less than 100 mm. In the Andes, the Pacific coastal strip is desert. The western slopes of the Andes are dry, cacti and eucalyptus trees flourish, and only a few high mountains are snow-covered. The eastern slopes, which descend to the Amazon basin, become progressively more humid and tree-covered as one moves down in elevation. The Ethiopian highlands tend to have temperatures much lower than surrounding regions. Highland residents more than 2000 m above sea level may experience average temperatures near 16°C, a stark contrast to neighboring areas only hundreds of miles away, such as the Danakil Depression (100 m below sea level), with temperatures that may reach 50°C. Despite proximity to the equator, tropical monsoons that are common from June through September are also much cooler due to increased elevation.

Temperature As noted in Chapter 2, temperature falls with increasing elevation. There is no uniform value for this decline,

but a rate of 1°C for every 150 m increase in elevation is often given. Mountain temperatures vary between ranges based on the location relative to the equator and other factors. Temperatures as low as –73°C have been recorded on Denali (Dixon 1938) and −88.2°C in Antarctica. Mountain ranges located at far lower elevations, however, can also have quite low temperatures depending on local weather patterns. For example, on the summit of Ben Nevis in Scotland, a peak of only 1300 m, the mean temperature over a 17-year period from 1884 to 1901 was –0.1°C with a range from −17°C to +19°C. At a given location on a particular mountain, temperatures can also vary significantly over the course of the year. For example, in Antarctica, the temperatures ranged from the low of –88.2°C, as noted previously, to as high as 15°C, whereas at the South Col on Mount Everest (7896 m), monthly median temperatures of –11.9°C in July to –26.3°C in December have been documented. When accounting for wind chill, these values fall to –18.7°C and –39.3°C, respectively (Moore et al. 2012). These low temperatures are of great clinical relevance as they significantly increase the risk of cold injuries including hypothermia and frostbite, which are described further in Chapter 27. As global temperatures rise, it is expected that temperatures in highland regions will increase as well. Climate-sensitive diseases are impacted by temperature, as is the case with malaria, whereby temperatures below a specific threshold prohibit survival of parasites (18°C for Plasmodium falciparum and 15°C for P. vivax) that underlie a majority of malaria cases in Ethiopia. A widerange of elevations have lost this protection in the past three decades due to warmer temperatures (Lyon et al. 2017). The impact of a wider range for parasites and vectors (e.g., mosquitos) could have various impacts on highland communities as a result of temperature change that permits survival at high altitudes (discussed further in Chapter 4).

Solar and ultraviolet radiation With ascent to high altitude, exposure to solar radiation increases significantly (Chapter 2), with the amount absorbed by the body varying as a function of posture and clothing; dark clothing absorbs more radiation than lightcolored clothing. Ultraviolet light exposure also increases considerably with ascent, but its effect can be minimized by covering the exposed area of the body and/or liberally applying sunscreen. For both types of radiation, the degree of exposure increases significantly with travel over snow-covered terrain, as snow reflects up to 90% of ultraviolet radiation, compared with 9% to 17% reflected from ground covered by grass (Buettner 1969). The altitude of the sun also plays an important role with greater exposures seen in the equatorial regions during the summer months (Chrenko and Pugh 1961). The complications associated with increased ultraviolet light exposure are discussed further in Chapter 27.

42 Geography

ECONOMICS Most mountain communities depend on animal husbandry and agriculture; mining is important in some regions while, more recently, tourism and adventure travel have assumed a greater significance. Animal husbandry predominates in regions above the limit of agriculture. On the Tibetan plateau, there are immense herds of yak, sheep, and goats herded by nomads. Similar nomadic culture was traditional in mountainous regions of central Asian countries, such as Kyrgyzstan, although now most herdsmen are seminomadic, living in town or village houses in the winter and in their traditional felt-covered tents (yurts) in the summer. In the bitter climate, nomadic pastoralism, which likely started between 9000 and 10,000 years ago, is the only viable and economic way of life. The survival of the animals depends exclusively on natural fodder, which creates problems as the sedges and grasses have only a short growing season between May and September. Because there are no areas on the plateau where grass grows in the winter, they cannot escape the climate and, as extensive migration would weaken the stock, only short distances, up to 40 miles, are traversed. Each family has a “home base,” which is sometimes a house, and migrates to set areas whose boundaries, though not fenced, are all well known. On the Tibetan plateau, tents made of yak and sheep’s wool are used as dwellings. Further north, camels are common (Goldstein and Beall 1989). In the upper Himalayan valleys, the pattern is similar, with flocks spending the summer on pastures up to 5000 m, but below the snow line; in the winter they return to more permanent and protected locations at 4000 m. The first signs of domestication of camelids, the llama, alpaca, and their hybrids (Wheeler et al. 2012), date from ∼6000 years ago in the Andes (Telarmachay; Junín, Peru) (Lavallee et al. 1985). The majority of South American camelids are found in the Altiplano (southern Peru, Bolivia,

northern Chile, and Argentina), and of these, the majority are kept by herders in Quechua and Aymara regions (Flores Ochoa 1988). Cattle, sheep, hogs, goats, horses, and poultry were brought by the Spaniards and provide tons of livestock output each year. The limiting factor in agriculture is the number of months that the soil is frost-free. The type of crop may influence the size of the population. Potatoes, which are indigenous to the Andes (Spooner et al. 2005), were introduced into the high Himalayan valleys of Nepal between 1850 and 1860 and contributed to an increase in the population of the Solo Khumbu in the Everest region from 169 households in 1836 to 596 in 1957 (Fuhrer-Haimendorf 1964). Immigrants came from Tibet over the Nangpa La, a glacier pass of 5800 m, and, because food was more abundant, were able to adopt the religious life and built many new monasteries. Level land may have to be manufactured in the form of terraces. This technique to produce land for agriculture from even steeply sloping hillsides is found in almost all mountainous areas, but especially in the Himalayas and Andes. The terraces range in size from a few square feet to a relatively large area, but which is usually too small for pasture (Figure 3.3). Irrigation may involve ingenious construction of water conduits from surrounding streams. The task of building and maintaining terraces is considerable, especially as manure must be carried up and placed manually. Despite this, terracing is a marked feature of populated mountain valleys and, as it involves ownership and maintenance by groups rather than individuals, the social implications are important. High grazing pasture (alps) is also communal pastureland and this too has social overtones.

Load carrying Due to the relative lack of roads and airstrips in many mountainous regions, loads have traditionally been carried by all

Figure 3.3  Typical terraces in Nepal after harvesting, late autumn. (Image courtesy of Andrew M. Luks.)

Economics 43

Figure 3.4  Load carrying by porters in the Himalayas. (A) A Nepalese porter using a wicker basket to carry supplies to a local teahouse. Note the T-shaped walking stick in his right hand used to support the load on short breaks; (B) a Nepalese porter carrying large duffel bags for trekkers on an expedition to Everest base camp; (C) Yaks carrying expedition equipment. (Images courtesy of Andrew M. Luks.)

who visit or reside in mountainous regions. In the valleys of the Himalayas, for example, much of the merchandise is carried by either professional porters or yak or mule transport (Figure 3.4), although increasing road construction in some regions is changing this dynamic. The loads carried by porters can be substantial. Observations by Pugh in 1952 and 1953 on the march into Everest (Pugh 1955) estimated that loads of 40–50 kg, with an addition of 10 kg personal baggage, were carried routinely by porters for 10–12 hours over 10–12 miles each day. Often ascents and descents of 1000–1200 m were made, with loads of tea or paper weighing over 60 kg occasionally being carried. In a more formal study of 635 porters moving goods along traditional trade routes in eastern Nepal, Malville (1999) found the adult males (average weight 49.7 ± 5 kg, average height 155.5 ± 6.5 cm) carried loads of 73 ± 15 kg, equivalent to 146% ± 30% of their body mass. The method of carriage depends on the goods being transported. Where possible, loads are carried in a conical, light but strong, wicker basket, 22 cm by 30 cm at the base and 50 cm by 70 cm at the top, with a height of 60 cm (Figure 3.4A). Larger sizes are available for carrying bulky loads, such as leaf mold. Loads are supported by a strap passing over the forehead and under the lower end of the basket. When in position the upper end of the basket is level with the top of the porter’s head. The center of gravity therefore is as close as possible to a vertical line passing through the center of the pelvis, thus reducing the torque on the spine. The advantage of the head band is that it allows direct transmission of the load to the vertebral column, with muscles being used for balancing rather than support, as when shoulder straps are used. This method of carrying must be learned as a child, and the neck muscles in all such Himalayan porters are extremely well developed. In East Africa, heavy loads are carried in this way or just balanced on the head. It has been suggested that this method of load carrying, if practiced from childhood, is more economic, in terms of oxygen

consumption, than the Western method in a rucksack (Maloiy et al. 1986). Minetti et al. (2006) found Nepalese porters to have greatly increased performance in load carrying compared with Caucasian mountaineers. This was especially true of uphill walking (+60% in speed and +39% in mechanical power), but they showed greater efficiency also in downhill walking when carrying a load. The porters’ superior performance was attributed, in part, to better balance control; they had less oscillation of the trunk than the mountaineers, due presumably to skill acquired over a lifetime of load carrying. Thus, they did not waste energy in the unproductive muscle contraction needed by the mountaineers to keep their balance. Porters supporting trekking and climbing expeditions typically forego the wicker baskets and instead carry several duffel bags strapped together with rope. The loads are still supported by a strap passing over the forehead and passing around the lower portion of the duffle bags (Figure 3.4B). Marching technique depends on the weight of the load and altitude. With loads of 50 kg, stops are made every 2–3 minutes, with rests lasting 0.5–1.0 minute after a distance of 70–250 m has been covered, depending on the gradient. With lighter loads, rests for 2–3 minutes every 10 minutes are normal. Longer pauses are made every hour. During rests, the loads are supported on a T-stick about 1 m long, and the porter does not sit down (Figure 3.4A). When longer rests are taken, loads are placed on the top of stone walls conveniently placed beside the track (Figure 3.5). With high altitude Sherpas who participate on climbing expeditions, load carrying ability is considerable. Without supplementary oxygen on Everest in 1933, eight porters carried loads weighing 10–15 kg to an altitude of 8300 m, as they did on the Swiss Everest Expedition in 1952. Today, the majority of loads transported as part of climbing expeditions to the summit of Mount Everest and other major Himalayan peaks are transported by high altitude porters (who are not always Sherpa), who generally have exceptional high altitude and exertional tolerance.

44 Geography

Figure 3.5  Platform on a stone wall providing a place for porters to rest their loads during longer rest breaks. (Image courtesy of Andrew M. Luks.)

Porters’ health and welfare In the early days of Himalayan climbing and trekking, Sherpas were employed as porters above an altitude of about 3000–3500 m. Sherpas had clothing appropriate to the cold and were physiologically adapted to high altitudes. With increasing wealth, Sherpas moved up the social scale, becoming guides and staff members of expeditions and treks, so low altitude porters were employed by expeditions to higher altitudes for which they had neither the appropriate clothing, foot wear and other gear, nor generational adaptation to hypoxia. Porters who carry loads

in support of the local economy rather than in support of climbing expeditions are also lacking in appropriate clothing or adaptation. To make matters worse, they are often employed as casual labor, and expedition and trek leaders, in many cases, feel little or no responsibility for their welfare. Porters must provide their own food, clothing, and shelter. Traditionally, most commercial portering was done at lower altitudes, going from one village to another where shelter could be found, but treks and expeditions often take routes where options for shelter are more limited, in which case porters might spend their nights in porter caves (Figure 3.6).

Figure 3.6  Two examples of caves used by porters for shelter when other options are unavailable. A stone wall is often constructed at the opening of a cavernous area under a large boulder or rock wall and serves as a break against the wind. (Images courtesy of Andrew M. Luks.)

Economics 45

Figure 3.7  Example of information posted along trekking circuits in Nepal to increase trekker awareness of porter welfare issues. (Image courtesy of Andrew M. Luks.)

In recent years, several nonprofit groups, including Porters Progress (https://www.portersprogressuk.org/), the International Porter Protection Group (IPPG; http://www. ippg.net/), and the Kilimanjaro Porters Assistance Project (https://kiliporters.org/), have been established and have effectively lobbied for improved standards and care of porters in mountain regions throughout the world (Figure 3.7) and increased efforts at porter education about the risks of altitude illness and other maladies. Clinics, such as those run by the Himalayan Rescue Association in Pheriche (Figure 3.8) and Manang, as well as the ones run by the IPPG in Machermo and Gokyo up until the fall of 2019, have included porters as one of their mission patient populations, providing care to

this group free of charge and, in the case of the IPPG facilities, porter shelters. Together, these organizations have significantly improved the welfare of porters, but adherence to guidelines is variable and difficult to ensure for those portering outside the realm of organized expeditions. Lowland porters are just as prone to altitude illness, as well as gastrointestinal and respiratory diseases, as all other lowlanders traveling to high altitude. Dawadi et al. (2020) and Basnyat and Litch (1997) collected data on porter illnesses from a 22-day trek in the Mansalu area of Nepal, at altitudes up to 5100 m. The illness rate was similar in the porter group as in Western trekkers (52% and 55%), but lower in the Sherpa trek staff (13%). Most of the illnesses

Figure 3.8  Himalayan Rescue Association clinic in Pheriche, Nepal (elevation 4370 m). The clinic is dedicated to the treatment of the local population from Pheriche and nearby villages, trekkers, and porters, with the latter group receiving care free of charge. The Himalayan Rescue Association also operates a clinic in Manang (elevation 3520 m) on the Annapurna trekking circuit in Nepal. The International Porter Protection group runs a similar clinic in the village of Machermo (elevation 4410 m), which includes a dormitory and kitchen for porters traveling into the Gokyo valley of Nepal. (Image courtesy of Andrew M. Luks.)

46 Geography

were not altitude diseases, but among the latter, the rate in porters was similar to the trekkers, and evacuation was required for 5% of the party, all from the porter group. In another comparison of the incidence and understanding of altitude illness between porters and trekkers in the Solo Khumbu region of Nepal, Newcomb et al. (2011) actually found a lower incidence of AMS among porters (8% vs. 21%), which they attributed to a difference in reporting of symptoms between the groups and the fact that porters often made repeated ascents over the course of the trekking season, which afforded them a higher degree of acclimatization than the trekkers. The issue of reporting symptoms by porters is particularly important. Because their earnings depend on continued ability to carry loads each day, many porters are reluctant to report symptoms out of concern that they will be sent down to lower elevation and, as a result, experience a loss of wages, which they use to support themselves during the non-trekking seasons. For this reason, many porters press on in the face of developing symptoms and often present with severe forms of altitude illness, including high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE).

HOUSING AND SHELTER Traditional housing strategies, which have generally focused on provision of a comfortable microclimate and reduction of heat loss, have been developed in all remote high altitude communities, with the specific approaches varying from region to region based on cultural practices. The ideal house is draft-free with a low ratio of surface area to volume, is well-constructed of material that diminishes the daily extremes of temperature, and has a well-insulated roof. In the Andes, the adobe (dried mud) building has the first meter or so of the walls made of stone, the roof is made of tile, grass, or tin, and walls are plastered with mud to provide an airtight structure; the roof is tightly fitted and

the floor may be wood or dirt. Because of the method of construction, the diurnal change is reduced (Baker 1966). In the Himalayas, the thermal protection of stone structures built for seminomadic occupation appears to be less (Figure 3.9A). Traditional Sherpa houses often have stone walls and wooden roofs held on with stones. The ground floor is without windows and provides quarters for animals; the floor above is for human habitation. Windows usually have no glass, but have wooden shutters, and an open fire is placed in the center of one side, but this provides only a transient increase in temperature. In north Bhutan, houses are similarly constructed, but animals are kept in a yard. Cracks between stones in both Bhutanese and Sherpa houses are filled with earth. Tibetan houses may be of more than one floor and are often in terraces. Glass is rare and the houses are heated by an open fire or stove. Nomads have tents with a loose wide weave that enables warm air to be entrapped, but allows egress of smoke from open fires and is waterproof. However, some seminomadic families have a stove with a chimney. In Central Asia, the nomads traditionally live in yurts, tent-like structures with a wooden frame, the tunduk, that is covered with felt. The floor and walls are covered with rugs. Yurts are circular with an opening in the center of the conical roof allowing smoke to escape. This opening can be covered or “cowled” against the prevailing wind. The yurt can be quickly dismantled and transported on pack animals, yaks, camels, or horses. Some of the most common housing throughout Ethiopia consists of wood structures with earth and straw filling and round houses (tukuls) with thatch roofs (Figure 3.9B); housing with stone masonry walls and earth mortar is more common in the north. As noted above, indoor fires for cooking and heating, fueled by wood or animal dung, are common features of many traditional houses. Inadequate means for ventilating smoke to the outside increase biomass exposure and have contributed to the development of chronic obstructive

Figure 3.9  Traditional dwellings of high altitude residents. (A): Two-story Sherpa houses surrounded by rock walls in the Khumbu Valley of Nepal. (Image courtesy of Andrew M. Luks.) (B): A tukul (round home) on the Bale Plateau in southeastern Ethiopia. (Image courtesy of Cynthia Beall.)

Clothing 47

pulmonary disease and other respiratory problems among inhabitants of these regions. This has prompted increased efforts to promote use of kerosene stoves and/or install chimneys to vent smoke to the outside (Soneja et al. 2017). Areas where tourism has increased significantly such as the Solo Khumbu and Annapuruna regions of Nepal have seen increased wealth and, as a result, significant improvements in the quality of housing with glass windows, indoor toilet facilities, electrical power, and internet access. In less popular regions of this and other countries, more traditional forms of housing remain common.

CLOTHING Because of the generally low temperature and loss of heat, particularly due to radiation and convection, clothing with good insulation has traditionally been necessary to provide a warm microclimate. Trapped, still air is the best insulation and wool is the best naturally available insulating material; it resists compacting and loses only 40% of its insulating value when wet. Garments that are loosely woven entrap more air than those that are tightly woven. A multiple-layered system for garments has traditionally been preferable to one thick layer because insulation can be varied at will, thus minimizing perspiration. The outer layer is as impermeable to wind as possible. A sheepskin coat is the best naturally available garment that has many of these characteristics and is usually worn with cotton or wool undergarments. In general, traditional Andean clothing conformed to the above model and natural clothing was adequate for the conditions encountered. The greatest increase in surface temperature occurred in the hands and feet. At night, Andean highlanders, who used a bedding of skins, could maintain their metabolic rate by light shivering that does not disturb sleep. In the high Himalayan valleys and Tibet, traditional clothing assemblies have had similar features. The main garment was a thick sheepskin “chupa” with long, wide sleeves that, when extended, keep the hands warm; gloves are never used. Normally the garment was gathered around the waist by a belt and hitched up to the knees so that there is a pocket for loose objects in front of the chest. When the belt was loosened, the garment extended to the ground and thus could be used as a sleeping robe; often in warm conditions one or both shoulders are left bare. Under this is a woolen shirt and often long woolen, cotton, or sheepskin trousers. Soft leather boots with decorative wool leggings extending to the knees were packed with grass, straw, or leaves, but a Tibetan often may walk in bare feet in the snow or through streams. Some wear a felt hat or balaclava and, to prevent snow blindness, yak hair would be put in front of the eyes if goggles were not available (Desideri 1712–27; Moorcroft and Trebeck 1841). Other traditional methods used by Tibetans included blackening the eyelids and wearing masks with tiny eye holes, the rims of which are blackened (MacDonald 1929). Cotton clothing is favored at high temperatures and low altitudes, but nomads wear wool or sheepskin. Many

now wear wool sweaters and leather boots. Tibetan nomads sleep resting on their elbows and knees with all their clothes piled on their backs (Duff 1999; Holditch 1907). This “fetal position” diminishes surface area and therefore heat loss; contact with the ground is also minimal. Some Tibetan lamas have developed the ability to “warm without fire.” The central core temperature is kept raised under cold conditions, both by increasing the metabolic rate, probably by continuous light shivering, and also by the practice of g-tum-mo yoga (an advanced form of Tibetan yoga), which appears to involve peripheral vasodilatation (Benson et al. 1982; Pugh 1963). Similar to the changes in housing patterns noted above, improvements in transportation systems, increasing tourism, and increasing ease of travel to larger urban centers have changed the pattern of dress in wealthier communities. Clothing and other garments commonly used by climbers and trekkers, such as down and fleece jackets and warm hats, are now more widespread in many areas. Such materials are often provided by expedition companies or trekkers to guides and high altitude porters who reside in these communities, while those with the means to travel to larger cities, such as Kathmandu, can purchase and return with relatively inexpensive versions of similar clothing.

REFERENCES Aldenderfer M. (2011). Peopling the Tibetan plateau: insights from archaeology. High Alt Med Biol. 12:141–147. Baker PT. (1966). Micro-environment cold in a high altitude Peruvian population. In: Human Adaptability and Its Methodology. Yoshimura H, Weiner JS, eds. Japan Society for the Promotion of Sciences, Tokyo. pp. 67–77. Basnyat B, Litch JA. (1997). Medical problems of porters and trekkers in the Nepal Himalaya. Wilderness Environ Med. 8:78–81. Benson H, Lehmann JW, Malhotra MS, Goldman RF, Hopkins J, Epstein MD. (1982). Body temperature changes during the practice of g Tum-mo yoga. Nature. 295:234–236. Buettner KJK. (1969). The Effects of Natural Sunlight on Human Skin. Pergamon Press, London, New York. Cabré MF, Solman S, Núñez M. (2016). Regional climate change scenarios over southern South America for future climate (2080–2099) using the MM5 Model. Mean, interannual variability and uncertainties. Atmósfera. 29:35–60. Chrenko FA, Pugh LGCE, Harington CR. (1961). The contribution of solar radiation to the thermal environment of man in Antarctica. Proc R Soc Lond B. 155:243–265. Dawadi S, Basnyat B, Adhikari S. (2020). A review of medical problems in Himalayan porters. High Alt Med Biol. 21:109–113. Dixon JS. (1938). Fauna of the National Parks of the United States: Birds & Mammals of Mount McKinley National Park, Alaska. US Government Printing Office.

48 Geography

Duff J. (1999). The “Tibetan tuck”: A dry land–cold conditions survival position equivalent to that used in cold water. Wilderness Environ Med. 10:206–207. Flores Ochoa J. (1988). Llamichos y paqocheros: pastores de llamas y alpacas. Centro de Estudios Andinos, Cusco. Gardelle J, Berthier E, Arnaud Y. (2012). Slight mass gain of Karakoram glaciers in the early twenty-first century, Nat Geosci. 5:322–325. Georgiades E, Scott RA, Wilson RH, Goodwin W, Wolde B, Pitsiladis YP. (2003). Demographic characteristics of elite Ethiopian endurance runners. Med Sci Sports Exerc. 35:S90. Goldstein MC, Beall CM. (1989). The impact of China’s reform policy on the Nomads of western Tibet. Asian Survey. 29:619–641. Hassen M. (1990). The Oromo of Ethiopia: A History, 1570–1860. Red Sea Press, NJ. Hijmans RJ, Cameron SE, Parra JL, Jones PG, Jarvis A. (2005). Very high resolution interpolated climate surfaces for global land areas. Int J Climatol. 25:1965–1978. Holditch TH. (1907). Tibet the Mysterious. Alston Rivers, London. Lavallée D, Julien M, Wheeler J, Karlin C, Clement G, Guillen S, Trichet J, Van Der Hammen T, Noldus GW, Vaughan P. (1985). Telarmachay. Chasseurs et pasteurs préhistoriques des Andes-I. (2 tomes). Recherche sur les civilisations, Synthèse. Lu H, Zhang J, Yang Y, Yang X, Xu B, Yang W, Tong T, Jin S, Shen C, Rao H, Li X, Lu H, Fuller DQ, Wang L, Wang C, Xu D, Wu N. (2016). Earliest tea as evidence for one branch of the Silk Road across the Tibetan Plateau. Sci Rep. 6:18955. Lynch TF. (1990). Glacial-age man in South America? A critical review. Am Antiq. 55:12–36. Lyon B, Dinku T, Raman A, Thomson MC. (2017). Temperature suitability for malaria climbing the Ethiopian Highlands. Environ Res Lett. 12:064015. Macdonald D. (1929). The Land of the Lama: A Description of a Country of Contrasts & of Its Cheerful, Happy-golucky People of Hardy Nature & Curious Customs; Their Religion, Ways of Living, Trade & Social Life. Seeley, Service & Company, limited. MacNeish RS. (1971). Early man in the Andes. Sci Am. 224:36–46. Maloiy GM, Heglund NC, Prager LM, Cavagna GA, Taylor CR. (1986). Energetic cost of carrying loads: have African women discovered an economic way? Nature. 319:668–669. Malville NJ. (1999). Porters of the eastern hills of Nepal: body size and load weight. Am J Hum Biol. 11:1–11. Minetti AE, Ardigó LP, Formenti F. (2006). Heavily loaded walking on steep paths in hypoxia: the power and economy of Nepalese porters. J Biomech. 39:S36. Moorcroft W, Trebeck G. (1841). Travels in the Himalayan Provinces of Hindustan and the Panjab. J. Murray, London.

Moore K, Semple J, Cristofanelli P, Bonasoni P, Stocchi P. (2012). Environmental conditions at the South Col of Mount Everest and their impact on hypoxia and hypothermia experienced by mountaineers. Extrem Physiol Med. 1:2. Moore LG, Niermeyer S, Zamudio S. (1998). Human adaptation to high altitude: regional and life-cycle perspectives. Am J Phys Anthropol. Suppl. 27:25–64. Newcomb L, Sherpa C, Nickol A, Windsor J. (2011). A comparison of the incidence and understanding of altitude illness between porters and trekkers in the Solu Khumbu Region of Nepal. Wilderness Environ Med. 22:197–201. Ossendorf G, Groos AR, Bromm T, Tekelemariam MG, Glaser B, Lesur J, Schmidt J, Akçar N, Bekele T, Beldados A, Demissew S, Kahsay TH, Nash BP, Nauss T, Negash A, Nemomissa S, Veit H, Vogelsang R, Woldu Z, Zech W, Opgenoorth L, Miehe G. (2019). Middle Stone Age foragers resided in high elevations of the glaciated Bale Mountains, Ethiopia. Science. 365:583–587. Pepin N, Bradley RS, Diaz HF, Baraer M, Caceres EB, Forsythe N, Fowler H, Greenwood G, Hashmi MZ, Liu XD, Miller JR, Ning L, Ohmura A, Palazzi E, Rangwala I, Schöner W, Severskiy I, Shahgedanova M, Wang MB, Williamson SN, Yang DQ, Mountain Research Initiative EDW Working Group. (2015). Elevation-dependent warming in mountain regions of the world. Nat Clim Chang. 5:424–430. Pugh LGCE. (1955). Report on Cho Oyu 1952 and Everest 1953 expeditions. Unpublished archival material held in the Archival Collection in High Altitude Medicine and Physiology at University of California, San Diego. Pugh LGCE. (1963). Tolerance to extreme cold at altitude in a Nepalese pilgrim. J App Physiol. 18:1234–1238. Rademaker K, Hodgins G, Moore K, Zarrillo S, Miller C, Bromley GRM, Leach P, Reid DA, Álvarez WY, Sandweiss DH. (2014). Paleoindian settlement of the high-altitude Peruvian Andes. Science. 346:466–469. Sellassie SH. (1972) Ancient and Medieval Ethiopian History to 1270. United Printers, Addis Ababa, Ethiopia. Snellgrove DL. (1961). Himalayan Pilgrimage: A Study of Tibetan Religion. Bruno Cassirer. Soneja SI, Tielsch JM, Khatry SK, Zaitchik B, Curriero FC, Breysse PN. (2017). Characterizing particulate matter exfiltration estimates for alternative cookstoves in a village-like household in rural Nepal. Environ Manag. 60:797–808. Spooner DM, McLean K, Ramsay G, Waugh R, Bryan GJ. (2005). A single domestication for potato based on multilocus amplified fragment length polymorphism genotyping. Proc Natl Acad Sci USA. 102:14694–14699. Stein RA. (1972). Tibetan Civilization. Stanford University Press.

Clothing 49

Urrutia R, Vuille M. (2009). Climate change projections for the tropical Andes using a regional climate model: Temperature and precipitation simulations for the end of the 21st century. J Geophys Res. 114. von Fuhrer-Haimendorf C. (1964) The Sherpas of Nepal: Bhuddist Highlanders. John Murray, London. Ward M. (1991). Medicine in Tibet. J Wilderness Med. 2:198–205. Ward MP. (1990). Tibet: human and medical geography. J Wilderness Med. 1:36–46. West JB. (1986). Highest inhabitants in the world. Nature. 324:517–517. West JB. (2002). Highest permanent human habitation. High Alt Med Biol. 3:401–407. Wheeler JC, others. (2012). South American camelids: past, present and future. J Camelid Sci. 5:1–24.

WHO. (2019). World Health Statistics 2019: monitoring health for the SDGs, sustainable development goals. World Health Organization, Geneva. Wilber RL, Pitsiladis YP. (2012). Kenyan and Ethiopian distance runners: what makes them so good? Int J Sports Physiol Perform. 7:92–102. WoldeGabriel G, Haile-Selassie Y, Renne PR, Hart WK, Ambrose SH, Asfaw B, Heiken G, White T. (2001). Geology and palaeontology of the Late Miocene Middle Awash valley, Afar rift, Ethiopia. Nature. 412:175–178. Zhang XL, Ha BB, Wang SJ, Chen ZJ, Ge JY, Long H, He W, Da W, Nian XM, Yi MJ, Zhou XY, Zhang PQ, Jin YS, Bar-Yosef O, Olsen JW, Gao X. (2018). The earliest human occupation of the high-altitude Tibetan Plateau 40 thousand to 30 thousand years ago. Science. 362:1049–1051.

4 High altitude residents

Introduction 51 Adaptation 51 Brief history of research on long-term residents of high altitude 51 Duration of exposure in high altitude residents 53 Differences in phenotype between highland populations 53 Hematological 53 Respiratory 55

Circulatory 57 Skeletal muscle and metabolism 58 Exercise 58 Other health issues in high altitude residents 58 Pregnancy and development 58 Noncommunicable diseases 59 Communicable diseases 63 References 65

INTRODUCTION

and communicable diseases and how this burden is changing over time.

Increasing numbers of people are living permanently at high altitude. Whereas, as of 2004, about 89.3 million people were living at altitudes above 2500 m, including 25.9 million and 5.4 million living more than 3500 m and 4500 m above sea level, respectively (Beall 2014), it is now estimated that over 200 million people live above 2500 m (Moore et al. 1998; WHO 2019). High-altitude residents of the South American Andes, the Tibetan plateau, and Ethiopia highlands who have existed at altitude for hundreds of generations have developed distinct adaptive and maladaptive strategies while living in their respective hypoxic environments. This chapter does not deal directly with habitation at altitude (Chapter 3) nor genetic differences among highland populations (Chapter 6) but a related fascinating topic. This is the fact that successful groups of humans who have adapted to high altitude, Himalayan highlanders (Tibetans and Sherpa), Andeans (Aymara and Quechua), and Ethiopians (Amhara and Oromo), exhibit very different phenotypes (Table 4.1), although substantial variation is noted for some traits within each continental population. After describing the concept of adaptation in greater detail, a brief historical perspective of research in these high altitude populations is provided. Differences and similarities in phenotypes between these groups are reviewed, including pregnancy and childhood development. The chapter concludes with a review of another important issue for residents of high altitude regions, the burden of non-communicable

ADAPTATION When referring to phenotypic traits that have been acted upon by natural selection, the term “adaptation” has a specific meaning; namely, any features of structure, function, or behavior that increase the ability to survive and/or reproduce in a given environment (Moore 2017). Adaptation is distinct from “acclimatization” or the time-dependent rise in ventilation, hemoglobin concentration, heart rate, and redistribution of blood flow that serve to restore arterial O2 content and preserve O2 delivery to vital organs. Acclimatization processes are summarized in Chapter 7 and will be referred to within this chapter for purposes of making comparisons between acclimatized newcomers and long-term resident groups.

BRIEF HISTORY OF RESEARCH ON LONGTERM RESIDENTS OF HIGH ALTITUDE Just as many people regard Paul Bert as the father of modern high altitude physiology, Carlos Monge Medrano (1884–1970) merits the title of father of the study of permanent high altitude residents. He started the influential Peruvian school in Lima, which was subsequently continued by Alberto Hurtado Abadilla (1901–83) and Monge’s son, Carlos Monge Cassinelli (1921–2006). 51

52  High altitude residents

Table 4.1  Summary of the key phenotypical differences between Tibetan, Andean, and Ethiopian high altitude populations when compared to acclimatized lowlanders Andean (EE−)

Andean (EE+)

Ethiopian

Lowlander (acclimatized to 4000 m)

7–11,000 Hematological 16–20 20–26 High High 14–16 18–20 48 54 High High High Low Respiratory High Low 88–92 92–94 Low High Low Normal Circulatory Normal Normal Low Normal Low Normal High Normal High (same as acclimatized High lowlanders) Normal/high? Low Normal Normal

7–11,000

500–70,000

0

>25 Very high >22 >58 Very high Low

20–21 Unknown 15–16 48 Unknown Unknown

20 Low 16 50 Low Low

Low 86–90 Very high Low

Normal 92–96 Unknown Low

High 90 High Increased

Normal Low High Normal Very high

Unknown Unknown Unknown Normal High

Normal Normal Normal High (vs. sea level) High

Low Normal

Unknown Unknown

Low (vs. sea level) Low (vs. sea level)

Variable

Tibetan

Years spent high altitude

7–40,000

Arterial O2 content (mL/dL) Blood volume Hb (g/dL) HCT (%) Pack cell volume Plasma volume HVR O2 saturation (%) SDB Ventilation Cardiac output Cerebral blood flow Cerebral oxygen delivery HR PASP Peripheral blood flow Stroke volume

Key: EE: excessive erythrocytosis; HVR: hypoxic ventilatory response; Hb: hemoglobin; HCT: hematocrit; HR: heart rate; PASP, pulmonary arterial systolic pressure; SDB, sleep disordered breathing. See text for supporting references.

Mention was made earlier of Barcroft’s unguarded statement that “All dwellers at high altitude are persons of impaired physical and mental powers” (Barcroft 1925). Monge took great exception to this and in his influential book Acclimatization in the Andes (Monge 1948) he referred to “the incredible statement of Professor Barcroft, the Cambridge physiologist, who after staying three months at Cerro de Pasco.” Monge made the point that because of the “climatic aggression” of high altitudes as he referred to it, Andean man should not be assessed using the same criteria as people who live near sea level. In fact, at one stage, Monge attributed Barcroft’s statement to the fact that the latter had mountain sickness at the time! Monge made extensive studies of the ability of permanent residents of the Andes to withstand the hypoxia and cold of the environment. Nevertheless, he is best known for his work on chronic mountain sickness, also known as Monge’s disease (discussed in Chapter 24), which he set out in his book La Enfermedad de los Andes (Monge 1928). In this book, he describes the condition associated with severe polycythemia, cyanosis, and a variety of neuropsychological complaints including headache, dizziness, somnolence and fatigue. Initially, the condition was thought to be polycythemia vera, but was later shown to be a distinct malady.

Alberto Hurtado (1901–83) was a physiologist who trained under Monge and who made extensive studies of the highaltitude residents of Morococha at an altitude of 4550 m. Typically, the arterial PaO2 was only 45 mmHg with a corresponding arterial oxygen saturation of 81%. However, interestingly, because of the polycythemia, which raised the hemoglobin concentration to nearly 20 g dL−1, the arterial oxygen concentration was actually above the normal sea level value. The son of Carlos Monge Medrano, Carlos Monge Cassinelli (1921–2006) was a biologist with broad interests in high altitude including comparative physiology. However, he was very interested in the relationships between high altitude, polycythemia, and chronic mountain sickness and many of his studies were reported in a classical book (Winslow and Monge 1987; reviewed more recently by Heggie 2019). The Peruvian school remains very active today with high altitude scientists such as Fabiola León-Velarde, Francisco Villafuerte, and others. Environmental physiology was a major line of human biology research as part of the Human Adaptability Project of the International Biological Programme, a worldwide study of human adaptability (Weiner 1964). A high altitude program was suggested, with plans to conduct coordinated, parallel, multidisciplinary studies on the indigenous

Differences in phenotype between highland populations  53

populations of the Andes, Himalayas, and Ethiopian highlands. A team of researchers from Pennsylvania State University, the Instituto de Biolgía Andina de Peru, and dozens of other institutions conducted comprehensive studies on the Quechua population of Nuñoa, Peru (∼4000 m) in the 1960s detailed in Man in the Andes: Multidisciplinary Study of High Altitude Quechua (Baker and Little 1977). Some of the general physiology-related questions of the expedition included: To which unique environmental stresses has the population adapted; how has the population adapted culturally and biologically to high altitude stresses; and how did these adaptations become established? The landmark textbook published in 1978 (Baker 1978) compiles and integrates the work on this topic. Although to a lesser extent than work in the Andeans, early studies in the Sherpa were performed as far back as 1925 (Pugh 1962; Pugh et al. 1964; Somervell 1925). The Kunde Hospital, funded by Sir Edmund Hillary, was founded in 1966 and has been a site of research on Sherpa physiology. Since 1990, the Ev-K2-CNR Pyramid Research Laboratory, located outside the village of Lobuje and near Everest base camp, has served as a hub for human physiology research, including many studies on the resident Sherpa population. Notably, the UBC-Nepal Expedition and Xtreme Everest teams have recently conducted comprehensive integrative physiology and metabolic investigations on Sherpa and lowlanders both here and in other areas of Sagamartha National Park. Fewer studies have examined the residents of the Ethiopian highlands when compared to those of the Andes and Himalayas. In the 1960s, a group from England and Ethiopia conducted a research expedition to the Ethiopian highlands and collected demographic and clinical information on residents (primarily Amhara) of the Simien Mountains (Harrison et al. 1969). Later work was conducted in the 1990s by Cynthia Beall with the Ethiopian physician Amha Gebremedhin, and subsequently a group led by Roger Hainsworth. As with the earlier studies, these investigations were also conducted in the Simien Mountains. More recently, high altitude populations in the Simien Mountains (largely Amhara) in Northern Ethiopia have been compared to high altitude populations of the Bale Mountains (largely Oromo) in Southern Ethiopia (Alkorta-Aranburu et al. 2012). As the Amhara have resided at high altitude for much longer than the Oromo (>5000 years versus ∼500 years), this has given scientists a natural model for studying high altitude adaptation. Other groups from Argentina, Bolivia, Chile, China, and Tibet continue to do extensive work on high altitude residents. The gold standard for investigating human adaptation to high altitude remains the multiple population–single stressor model; in other words, comparing how separate populations have adapted to life at high altitude. Despite the growing body of work in this area, few groups have accomplished what was proposed by the Human Adaptability Project of the International Biological Programme. As mentioned earlier, this program included some of the first large-scale insights on the physiology, hematology, growth and development, reproduction, and nutrition of peoples

living above 2500 m in the Andean, Ethiopian highlands, and Himalayan regions (Baker 1978; Weiner 1964). Studies by Robert Winslow and others have provided detailed support for phenotypic differences between Quechua and Sherpa high altitude groups (Bigham et al. 2013; Claydon et al. 2008; Ghosh et al. 2019; Stembridge et al. 2019). Other groups have compared two populations, but aside from a study by Beall (2006), simultaneous comparisons among three populations are generally lacking and more comprehensive investigations are required to expand our understanding of human adaptation to generational high altitude stress. The timing of this research is essential, as many of the high altitude populations are undergoing rapid acculturation, urbanization, and migration, which is changing diet, physical activity habits, and other traditional aspects of the lives of the indigenous communities (Alae-Carew et al. 2019; McCloskey et al. 2017; Peng et al. 2019; Smith 1999), with subsequent effects on the burden of noncommunicable disease (discussed later) and other issues.

DURATION OF EXPOSURE IN HIGH ALTITUDE RESIDENTS Although there is considerable debate regarding specific durations at altitude, the general consensus is that the Old World plateaux (Ethiopian and Tibetan) have been settled for longer than the Altiplano in the New World (Andes) (Aldenderfer 2019; Alkorta-Aranburu et al. 2012; Beall 2006 2007; Ossendorf et al. 2019; Zhang et al. 2018b) as outlined in Figure 4.1. These three populations have likely lived under the stress of high altitude for a sufficient duration for natural selection to have changed the frequency of adaptive alleles. The genetic differences between these populations are presented in Chapter 6. As noted earlier, highland populations in the Himalayas and South American Andes have been the most thoroughly studied, while less research has been focused on Ethiopian populations. Nevertheless, the fact that these groups of highlanders have such different physiological characteristics, including hematological, respiratory, circulatory, and metabolic traits and developmental aspects, is truly remarkable. It is these physiological characteristics that are the subject of the next section of this chapter. More detail about the physiological responses to hypoxia seen in unacclimatized lowlanders traveling to high altitude is provided in subsequent chapters.

DIFFERENCES IN PHENOTYPE BETWEEN HIGHLAND POPULATIONS Hematological HEMOGLOBIN CONCENTRATION

Hemoglobin concentration is a defining feature in the differential manifestations of adaptation between high altitude Andeans and Tibetans (Beall 2007) (Table 4.1). Tibetans demonstrate a hemoglobin concentration that is lower than

54  High altitude residents

Figure 4.1  Summary of the proposed duration of Ethiopian, Tibetan, and Andean highlander settlements. Historical records indicate that the Oromo tribe of Ethiopia has only been settled in the highlands for ∼500 years (Lewis 1966); however, the Amhara tribe has been living at altitude for potentially up to 70,000 years (Aldenderfer 2003; Lewis 1966; Pleurdeau 2005). Humans are thought to have occupied the Tibetan plateau ∼30,000–40,000 years ago (Zhang et al. 2018b) and eventually crossed a land bridge that once connected present day Russia and Alaska, which facilitated North and South American settlements such as the Andean highlanders ∼7000–11,000 years ago (Haas et al. 2017).

the Andeans and that would be comparable to sea level residents (Beall 2007); the lower concentration is associated with greater reproductive success (Jeong et al. 2018) and exercise capacity (Simonson et al. 2015). Although some Ethiopian populations, especially the Amharas, have also been reported to have low hemoglobin concentration (Beall 2006; Beall et al. 2002; Cheong et al. 2017), the relationships to greater reproductive success or exercise capacity has not been established. Figure 4.2 shows hemoglobin concentrations plotted as a function of altitude and nicely demonstrates the higher concentrations seen in the Andeans and relatively low concentrations in the Tibetans and Ethiopians.

It has been widely assumed that lower hemoglobin concentration in Tibetans is achieved via the absence of a significant erythropoietic response to hypoxemia. However, this oversimplification disregards the equally important contribution of plasma volume in the regulation of hematocrit (Donnelly 2003). As discussed in Chapter 13, a larger plasma volume would decrease hemoglobin concentration and could decrease heart rate by mediating a larger stroke volume, but the importance of these volumetric measures has only recently been explored. It has been found, for example, that hemoglobin mass is highest in Andeans, but also elevated in Sherpa compared to lowlanders (Stembridge et al. 2019; Figure 4.3). Sherpa, however, demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration (Figure 4.3). The implications of this phenomenon provide a mechanism that enables Tibetans to maximize total oxygen carrying capacity of the blood without the detrimental effect of a high viscosity on microcirculatory blood flow. Further discussion on this topic can be found in Chapter 13. OXYGEN AFFINITY

Figure 4.2  Hemoglobin concentration versus altitude for Tibetans (filled circles), Andeans (open circles), and Europeans (filled triangles). (Source: Beall 2000.)

Increased hemoglobin-oxygen binding affinity has typically been regarded as beneficial at altitude by enhancing the rate of equilibration across the alveolar-capillary barrier. Reports of hemoglobin-oxygen binding affinity differ widely across studies, although unrelated to exercise capacity, recent data indicate greater blood-oxygen binding affinity (i.e., a decreased P50) in both Tibetans and Han Chinese volunteers at 4200 m when compared to lowlanders at sea level (Simonson et al. 2014). Andean residents also exhibit

Differences in phenotype between highland populations  55

Figure 4.3  The relationship between hemoglobin mass and exercise capacity in lowlanders, Sherpa, and Andeans at sea level and high altitude. Note: there were no relationships between hemoglobin concentration and exercise capacity. (Modified from Stembridge et al. 2019.)

decreased P50 at high altitude when compared to lowlanders at sea level (Balaban et al. 2013). Any benefits of reductions in P50 at high altitude are unclear and likely require some adaptation at the tissue level to account for the higher affinity.

Respiratory VENTILATION

Beall (2000) reported a lower resting ventilation in Aymara compared with Tibetans as shown in Figure 4.4. Here, the resting ventilation in L min−1 is plotted against the age of the subjects over a large range from less than 20 to 90 years of age. Males are shown by the filled circles and females by the open circles. Note that the resting ventilations of the Aymara are uniformly low with females’ ventilation typically less than that of males. This is somewhat surprising because many measurements of resting ventilation at high altitude indicate that females have higher values. For example, in her early studies of alveolar PCO2 in the Colorado mountains, FitzGerald (1914) found that women had a lower alveolar PCO2 than men at the same altitude, indicating that they had higher ventilation. This finding is consistent with observations that Andean females at 4300 m have a higher ventilation during their luteal phase that is associated with higher concentrations of progesterone, a known respiratory stimulate (León-Velarde et al. 2001). A striking feature of Figure 4.4 is the large range of resting ventilations in Tibetans, and the corresponding fact

Figure 4.4  Comparison of resting ventilation in Tibetans and Aymara plotted against age. Males, filled circles; females, open circles. (Source: Beall 2000.)

56  High altitude residents

that many Tibetans have higher resting ventilations than Aymara. Additional analysis of these data, where Tibetans and Andeans are compared at the same altitude, indicate that there is a difference between the two populations for resting ventilation (Beall 2000). HYPOXIC VENTILATORY RESPONSE

The reason for these differences in ventilation is clarified when we look at the ventilatory responses to hypoxia (HVR) for the two populations, as shown in Figure 4.5. This looks similar to Figure 4.4 in that the Aymara have a fairly uniformly low HVR over the large age range, whereas there is much more variability for Tibetans. Furthermore, the relatively high response of the Tibetans may well be due to the genetic factors described earlier. Tibetans’ genomes exhibit an adaptive signal at EPAS1, a gene that codes for HIF-2α, and there is evidence that this transcription factor plays an important role in many potential mechanisms for adaptation, including the induction of tyrosine hydroxylase gene that increases the chemosensitivity of the carotid body. Early work by Severinghaus et al. (1966) in both healthy and polycythemic Andean highlanders found the HVR to be severely blunted in a limited number of highlanders, with a large range of hematocrit associated with a very small change in hypoxic chemosensitivity. The implication of alterations in these ventilatory patterns in these different populations on arterial blood gases and acid-base balance has yet to be reported.

Figure 4.5  Hypoxic ventilatory response (HVR) in Tibetans and Aymara plotted against age. Males, filled circles; females, open circles. (Source: Beall 2000.)

Figure 4.6  Arterial oxygen saturation (SaO2) plotted against altitude for Tibetans (filled circles), Andeans (open circles), and Europeans (filled triangles). (Source: Beall 2000.)

OXYGEN SATURATION

Figure 4.6 shows arterial oxygen saturation estimated by pulse oximetry plotted against altitude for Tibetans and Andeans in comparison to Europeans. Based on the higher ventilations and hypoxic ventilatory response of the Tibetans, we would expect a higher arterial oxygen saturation, and this seems to be true above 4000 m—but two open circles between 3000 m and 4000 m are not in agreement. The data show samples of 10 or more highlanders with a mean age from 10 to 50 years. Most studies indicate arterial oxygen saturation is lowest among Tibetans, is relatively higher in Andeans, and is highest in Amhara Ethiopians (reviewed in Simonson [2015]). As outlined later in this chapter, it has been proposed that a genetic factor underlies oxygen saturation differences observed among Tibetan mothers and is further associated with decreased infant mortality in this population (Beall et al. 2004). Additionally, oxygen saturation is higher in Tibetan relative to Han Chinese or Andean infants at comparable altitudes, and such differences are hypothesized to underlie susceptibility to high altitude pulmonary hypertension and chronic mountain sickness later in life in the latter populations (Niermeyer et al. 2015). The long-term effects of hypoxia and hypertension are further noted in a recent study that showed individuals with excessive erythrocytosis, when compared to controls, were more likely to have been born to mothers who exhibited hypertension and perinatal hypoxia (Julian et al. 2015). The data on the four traits shown in Figures 4.2–4.6, resting ventilation, hypoxic ventilatory response, oxygen saturation, and hemoglobin concentration, show considerable scatter. Beall (2000) carried out additional statistical analysis of the data and found that the first two traits were more than 0.5 standard deviation higher in Tibetans than the Aymara. In addition, the Tibetan means were more than one standard deviation lower than the Aymara means for the last two traits. Also, Beall calculated the “effect size” for the four traits, that is the difference in the mean values of

Differences in phenotype between highland populations  57

20- to 29-year-old males divided by their pooled standard deviation. The result showed that the effect sizes of resting ventilation and hypoxic ventilatory response are large and positive, that is, the Tibetan means are larger than Aymara means, and the effect sizes of arterial oxygen saturation and hemoglobin concentrations are large and negative; that is, Tibetan means are smaller than Aymara means. NOCTURNAL PERIODIC BREATHING

As detailed in Chapter 17, periodic breathing during sleep is almost universal in newcomers to high altitude and tends to intensify over time. For example, in lowlanders, periodic breathing was not altered or improved over 13 months at the Antarctic base Concordia, located at an equivalent altitude of 3800 m (Tellez et al. 2014). Likewise, Andean natives, especially those with chronic mountain sickness, present with marked periodic breathing (Bernardi et al. 2003; Guan et al. 2015; Julian et al. 2013; Moraga et al. 2014; Rexhaj et al. 2016; Sun et al. 1996). In contrast to both lowlanders and the Andeans, the Himalayan Sherpa tend to have little to no periodic breathing during sleep (Hackett et al. 1980; Lahiri et al. 1983). Lahiri et al. (1983) have argued that this represents an important feature of the true adaptation of the Sherpas to high altitude. It is unknown if sleep disordered breathing occurs in Ethiopian high altitude populations.

Circulatory SYSTEMIC CIRCULATION

A limited number of studies provide insight into the basis of cardiac adaptations in highland populations. Compared to lowlanders, Tibetans and Sherpas have a higher maximal heart rate at altitude (Pugh 1962; Pugh et al. 1964; Sun et al. 1990; Wu 1990), have no difference in resting cardiac output, but exhibit mechanical reserve similar to lowlanders at sea level (i.e., smaller relative left ventricle size and reduced systolic deformation and slower diastolic untwisting). Interestingly, it has recently been reported that directly measured sympathetic nervous activity is significantly lower in Sherpa when compared to lowlanders at the same high altitude, which may be advantageous for blood pressure homeostasis (Simpson et al. 2019). Although not a universal finding (Tremblay et al. 2018), lower sympathetic nervous activity in the Sherpa may explain the “high-flow” phenotype that has been reported in their peripheral circulation (Erzurum et al. 2007). However, it should be noted that this is not a universal finding, as more recent studies have reported comparable blood flow patterns in the peripheral circulation in Sherpa, Andeans, and lowlanders at ∼4300 m (Tremblay et al. 2018; Tremblay et al. 2019). CEREBRAL CIRCULATION

As outlined in Chapter 12, given the drop in arterial oxygen content at high altitude, increases in cerebral blood flow are necessary to maintain oxygen delivery to the brain. When lowland natives travel to high altitude, cerebral blood flow increases in proportion to the reduction in arterial oxygen content, leading to the maintenance of cerebral oxygen

delivery (Ainslie and Subudhi 2014). This physiological response is intact at low, moderate, and severe high altitude (Hoiland et al. 2018). This pattern of cerebral blood flow regulation in relation to changes in arterial oxygen content is driven primarily by changes in hemoglobin concentration during acclimatization to high altitude with the remaining influences including ventilatory acclimatization and, to a lesser extent, alterations in cerebral vascular reactivity to alterations in arterial blood gases (Hoiland et al. 2018). In recent years it has become apparent that there are unique physiological adaptations in cerebral blood flow regulation among the three high altitude native populations (Table 4.1). Although not consistently observed in the highaltitude native Tibetans and Sherpa (Huang et al. 1992), cerebral blood flow and oxygen delivery are lower than that of lowland natives in both adults (Hoiland et al. 2019) and children (Flück et al. 2017). Such adaptations may underscore the unique resistance to neurological damage exhibited by Tibetans and Sherpa following extreme high altitude climbing (>8000 m) (Garrido et al. 1993; 1996). Studies utilizing transcranial Doppler, which measures cerebral blood velocity as a surrogate of blood flow, have indicated that cerebral blood flow in Andeans is ∼20% lower (Appenzeller et al. 2006) than that which is commonly observed in lowland natives at a similar altitude (Lucas et al. 2011). This is in agreement with the first study suggesting cerebral blood flow was lower in eight Peruvian natives living at 4300 m altitude in Cerro de Pasco (Milledge and Sorensen 1972). The authors found the mean arteriovenous oxygen content difference across the brain was 7.9 ± 1 vol%, which is about 20% higher than the published sea level mean of 6.5 vol%. Assuming that brain metabolic rate was normal, they suggested cerebral blood flow was proportionately ∼20% below sea-level normal values and postulated that the mechanism might be high blood viscosity given the high hematocrit (58 ± 6%) in these subjects. However, it is important to consider the impact of methodology on these outcomes, as this synthesis of data are from multiple reports. A direct comparison of lowlander to Andean cerebral blood flow and oxygen delivery has never been made, with the current comparisons impacted by unmatched arterial blood gas stimuli, among other methodological issues. Whether or not the Ethiopians express a unique phenotype for cerebral blood flow regulation at high altitude remains unknown. The currently limited data that are available indicate that the cerebral circulation of Ethiopians is less sensitive to hypoxia but more sensitive to alterations in carbon dioxide than other high altitude native populations and lowlanders (Claydon et al. 2008). How these functional differences coalesce to determine overall cerebral blood flow and oxygen delivery remains an unresolved area of research. PULMONARY CIRCULATION

Groves et al. (1993) showed the relationship between mean pulmonary artery pressure and arterial PaO2 in Tibetans, Andeans, and North Americans. In general, the fall in alveolar PaO2 triggers hypoxic pulmonary vasoconstriction

58  High altitude residents

(HPV), which contributes to a rise in pulmonary artery pressure. There is a striking difference between Andeans and Tibetans, with the Andean response not differing much from that in North Americans, while the Tibetans have a strikingly reduced or “blunted” HPV (Groves et al. 1993). Although Tibetan residents at sea level further exhibit a minimal pulmonary vasoconstrictor response to hypoxia, which was attributed to hyporesponsiveness of the hypoxiainducible factor pathway (Petousi et al. 2014), many studies report that pulmonary artery systolic pressure values in Sherpa are similar to lowlanders at high altitude (Foster et al. 2014; Hoiland et al. 2015; Stembridge et al. 2015). The Amhara residents of Ethiopia at 3700 m have also been reported to have elevated pulmonary artery pressure, but without the elevated pulmonary vascular resistance characteristic of the classic model of the response to long-term hypoxia by the pulmonary vasculature (Hoit et al. 2011).

In-depth reviews regarding distinct traits exhibited by high altitude residents are available (Beall 2006; GilbertKawai et al. 2014; Moore 2017; Simonson 2015). Efforts to identify relationships among key phenotypes, fully examine developmental changes in a longitudinal context, and directly compare within and across Tibetan, Andean, and Ethiopians populations will be necessary to unravel the complexities of highlander adaptations and maladaptations to high altitude.

OTHER HEALTH ISSUES IN HIGH ALTITUDE RESIDENTS

Compared to lowlanders, Sherpas have a higher capillarydensity-to-muscle-fiber ratio and decreased mitochondrial density (Kayser 1991) and exhibit a metabolic shift toward glucose metabolism under conditions of acute hypoxia (Hochachka et al. 1996). Recent analysis of skeletal muscle biopsies provides evidence for improved oxygen utilization efficiency, decreased fatty acid oxidation, and increased antioxidant levels in Sherpa (Horscroft et al. 2017), although such data are lacking in other highland populations.

Beyond the phenotypic differences discussed in detail above, another area of attention in the literature has been the question of whether differences exist between high and low altitude populations with regard to other health issues, such as pregnancy and development and the burden of noncommunicable and communicable disease. These topics are discussed in this section. When considering such issues, one important challenge is identifying the underlying cause of any observed differences. While such differences may, in some cases, relate to the effect of long-term exposure to hypoxia, in other situations socioeconomic factors, such as access to medical care, differences in diet and activity levels, and other issues associated with residence in remote mountain communities may be the primary explanatory variable. As will become apparent in the discussion that follows, this can be difficult to sort out from the available literature.

Exercise

Pregnancy and development

Andeans and Tibetans do not exhibit the same significant decline in exercise capacity typically observed in acclimatized individuals at high altitude (Chapter 18; Fulco et al. 1998). A within-population examination of exercise capacity and oxygen transport showed that Tibetans with . lower hemoglobin concentration exhibit higher peak V O2/kg, which is attributed to variation in cardiac output, ventilation, and oxygen diffusional conductance in muscle (Simonson et al. 2015). As mentioned above, it has recently been reported that Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration (Stembridge et al. 2019). It was also found that hemoglobin mass, rather than hemoglobin concentration, was positively related to maximum exercise capacity in lowlanders at sea level and Sherpa at high altitude but not in Andean natives (Figure 4.3). These findings demonstrate a unique adaptation in Sherpa that moves attention away from hemoglobin concentration per se and toward a paradigm where both hemoglobin mass and plasma volume represent phenotypes with adaptive significance at high altitude (Stembridge et al. 2019). Finally, although the Ethiopian adaptation is not well understood, East African runners from high altitude regions in Ethiopia and Kenya are undoubtedly the best distance runners in the world (Wilber and Pitsiladis 2012).

In humans, the effect of altitude on pregnancy has been extensively studied in high altitude residents (>2500 m), with fewer studies of unacclimatized lowlanders traveling to altitude during pregnancy (Keyes et al. 2016) or lowlanders residing at high altitude for longer periods of time.

Skeletal muscle and metabolism

BIRTH WEIGHT

A major focus of many of these studies is the effect of chronic hypoxemia on birth weight. In general, birth weights are lower at altitudes >2500 m (Giussani and Davidge 2013; Giussani et al. 2001; Jensen and Moore 1997; Krampl et al. 2000; Levine et al. 2015), although direct comparisons between Tibetans and Andeans have not been conducted. It has been determined that there is a decrease in birth weight of approximately 102 g/1000 m elevation, which correlates with the decrease in atmospheric PaO2 of approximately 11% per 1000 m (Moore et al. 2011). Thus, the effect of hypoxia on the developing fetus is graded and proportional to the severity of the hypoxia (Jang et al. 2015). PLACENTAL DEVELOPMENT

The cause of birth weight reduction is multifactorial. Vessels within an at-term placenta obtained at high altitude are more dilated and less frequently associated with smooth muscle, compared with sea level (Espinoza et al. 2001;

Other health issues in high altitude residents  59

Zhang 2002). This together with higher uterine artery blood flow in normotensive women at high altitude buffers fetal demands (Jensen and Moore 1997; Keyes et al. 2003) such that the high altitude fetus of a normotensive mother is only modestly hypoxic with lower heart rate and birth weight (Browne et al. 2015). However, the combination of lower uterine artery blood flow and early-onset preeclampsia may exaggerate fetal hypoxia leading to further fetal hypoxia, slower heart rate, and intrauterine growth restriction (Tissot van Patot et al. 2003; Tissot van Patot et al. 2010; Yung et al. 2012). As noted previously, unlike many other phenotypes (Table 4.1), there do not seem to be any major differences in adaptation strategies during pregnancy between the high altitude populations of the Andes and Himalayas. The adverse effect of altitude on birth weight is independent of maternal age, parity, and prenatal care, but is heavily influenced by population ancestry. In particular, the magnitude of effect is lessened among multigenerational high altitude communities, suggesting a genetic component in the adaptation (reviewed in Moore et al. 2011). Genetic factors that vary between Andeans and Europeans include genes related to the HIF-1 pathway in placentae (Gundling et al. 2013), soluble Epo receptor (Wolfson et al. 2017), and increased antioxidant status (erythrocyte catalase and superoxide dismutase) activity (Julian et al. 2012).

were controlled (Dang et al. 2008). This finding, however, contrasts with another report that showed no association between stunting and altitude (Harris et al. 2001). It was, therefore, concluded that stunting was more related to malnutrition and illness between 12 and 24 months of age than altitude per se. Broadly consistent with this observation, a study from Ecuador found very little difference in rates of body weight increase in children at high altitude (>3000 m) compared with children from low altitude (Leonard et al. 1995). There were some minor differences in rates of height increase but the authors concluded that hypoxia plays a relatively small role in shaping growth in the first five years after birth (Leonard et al. 1995). Differences in population’s studies, experiential designs and challenges untangling socioeconomic and genetic factors as well as access to health care resources, are likely important explanations for the discrepancies between studies. For example, additional gene-by-environment interactions have been noted in terms of stature, as Native American ancestry is associated with short stature and limbs at high but not low altitude in Andeans (Pomeroy et al. 2015). Interestingly, however, early studies in Ethiopia reported that high altitude children were taller and heavier for their age than lowlanders (Frisancho 1978).

BIRTH DEFECTS

Menarche occurs one to two years later in girls living in the Andes, Himalayas and Tien Shan than in low altitude residents (Frisancho 1978), while adrenarche, the increase in serum androgens, also occurs one to two years later in children at altitude compared with sea level in Peru (Goñez et al. 1993; Gonzales and Ortiz 1994). Based on an earlier report, the Ethiopian highlanders at 3700 m appear to be the exception, as no difference was found when compared to neighboring populations at 1500 m (Harrison et al. 1969). The impact of high altitude on key determinants of reproductive health, including menarche and menopause, has been reviewed in detail elsewhere (Shaw et al. 2018).

An increased risk for certain forms of birth defects has been noted at high altitude. In a collaborative study, based on information from 1,668,722 consecutive births from three hospitals situated between 2600 m and 3600 m in Bogota (Colombia), La Paz (Bolivia), and Quito (Ecuador), Castilla et al. (1999) found increased risk of craniofacial defects, cleft lip, microtia, preauricular tag, brachial arch complex, constriction band complex, and anal atresia but a decreased risk of neural tube defects, anencephaly, and spina bifida. Later work by the same group provided further evidence that high altitude residence is a risk factor for cleft lip +/− cleft palate (Poletta et al. 2007). CHILDHOOD GROWTH AND DEVELOPMENT

The high altitude infant starts life smaller than the average low altitude baby does, and its early growth is slower. Milestones such as sitting and walking seem to be delayed, but the differences between high and low altitude residents of the same ethnic group are less than those between different ethnic groups or between urban and rural populations (Clegg 1978). In Quechua natives in Peru, throughout childhood the high altitude child lags behind his low altitude counterpart in height by about two years. The adolescent growth spurt is less pronounced in high altitude youths but their growth continues for about two years longer and their adult stature is not reached until 22 years of age (Frisancho 1978). A large cross-sectional survey (n = 1458) that examined the effect of altitude on early childhood growth in Tibet reported that children born and living above 3500 m had two to six times the risk of stunted growth compared with those at 3000 m when socioeconomic and other factors

MENARCHE

Noncommunicable diseases As is the case with lowland populations, highland residents are at a growing risk for a variety of noncommunicable diseases including various forms of cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes mellitus. Historically, high altitude regions have been associated with decreased access to medical resources, which can affect the burden of and outcomes from these and other noncommunicable diseases, although many of these access issues may be changing as a result of increasing levels of development, migration, and greater ease of travel to and from these regions. In this section, mortality from noncommunicable diseases specific to indigenous high altitude populations is reviewed followed by a discussion of several specific noncommunicable diseases. Chronic mountain sickness, a major form of noncommunicable disease in many high altitude regions, is discussed in Chapter 24.

60  High altitude residents

MORTALITY RELATED TO NONCOMMUNICABLE DISEASE

Frequently cited work on lowlanders suggests that living at “high altitude” is associated with a lower mortality rate, in particular morality due to cardiovascular causes; however, these studies have generally examined populations living at relatively low altitudes (< 2500 m) (Baibas et al. 2005; Fabsitz and Feinleib 1980; Voors and Johnson 1979), well below that of many of the populations considered in this chapter. In regions located >3000 m and primarily populated by high altitude indigenous residents, an inverse relationship between mortality rate and altitude has not been observed. Although life expectancy at birth has increased by 14.2 years from 1990 to 2013, Tibet still has the lowest life expectancy at birth compared to all provinces in China (Zhou et al. 2016), including higher rates of death from cerebrovascular and hypertensive heart disease (but not ischemic heart disease). A similar trend is apparent in the Andes. From 1996–2000, noncommunicable disease-related deaths increased in the Peruvian Andes with the mortality rate of 892.7/100,000 population in the Andes exceeding the national average of 670.7/100,000 (Huicho et al. 2009). In Bolivia, a shorter lifespan was identified in older adults living >1500 m compared to those living below 1500 m. Importantly, income level, housing standards, and medical care access were similar, suggesting differences in environmental and physiological stressors associated with high altitude, as opposed to socioeconomic status, may contribute to the observed differences in survival (Virues-Ortega et al. 2009). While this evidence suggests an increased mortality rate in high altitude indigenous populations compared to sealevel regions in the same country, it remains unclear whether this can be attributed to high altitude or the socioeconomic challenges faced in these regions. For instance, only 44.3% and 48.9% of households in the mountain and hill regions of Nepal, respectively, had access to health facilities within 30 minutes, with the highest density of poor individuals found in the midwestern hill and mountain regions (The Nepal NCDI Poverty Commission 2018: http://www.ncdipoverty. org/nepal). DIABETES MELLITUS

While an inverse association between altitude and the prevalence of diabetes has been documented in the United States (Woolcott et al. 2014) and a lower rate of diabetes has been noted in Indian soldiers stationed between 3692 m and 5538 m (Singh et al. 1977), there is considerable heterogeneity among indigenous high altitude populations. Andeans living at 3250 m have been shown to have a lower 12-hour continuous glucose levels compared to sea-level residents (Castillo et al. 2007), but there is no consistent evidence to suggest that those living at high altitude have a lower prevalence of diabetes. In the Andes the prevalence of metabolic syndrome was 24.2% in those living at 4100 m (primarily Quechuan) compared to 22.1% at 101 m (Baracco et al. 2007) with the highest prevalence seen in those with

excessive erythrocytosis (De Ferrari et al. 2014) and lower oxyhemoglobin saturation (Miele et al. 2016). HispanicMestizas women have an increased prevalence of obesity and diabetes compared to Quechua women in Cusco region (2577–3570 m) (Ojeda et al. 2014). Likewise, the prevalence of diabetes was higher in the coastal region (8.2%) compared to the highlands (Huarez 3000 m; 4.5%) in Peru (Seclen et al. 2015). An important contribution to this field was made by the CRONICAS Cohort study, which was conducted in four Peruvian sites with varying degrees of altitude and urbanization: Pampas de San Juan de Miraflores, in Lima, Latin America’s fourth largest city and a highly urbanized area located at sea level; Puno, located at 3825 m above sea level, which contributed one urban and one rural site; and Tumbes, a semiurban setting in the coastal North of Peru, also at sea level (Miranda et al. 2012). Here, it was found that those living in rural Puno (3825 m) had a lower prevalence of diabetes and median Homeostatic Model Assessment of Insulin Resistance (HOMA) compared to urban and sea level populations (Carrillo-Larco et al. 2018); however, Andeans in Puno had a higher incidence of diabetes compared to those living in Lima or Tumbes (Bernabé-Ortiz et al. 2016). In the same cohort, a more traditional diet was associated with a lower prevalence of diabetes (Alae-Carew et al. 2019), suggesting the rapid nutrition transition, which refers to changes in diet and physical activity patterns that are changing body composition at a population level, may pose a particular threat to rural high altitude populations (Chaparro and Estrada 2012). The findings reported in Tibetan and Sherpa populations are equally equivocal. Several studies demonstrate increased problems among these high altitude residents. For example, the prevalence of metabolic syndrome in Tibetan farmers and herdsmen ages 30–80 living at 3700 m was 8.2% (Sherpa et al. 2013) compared to a prevalence of just 3.6% was reported in Derong County (2060–3820 m (Huang et al. 2020). Similarly, the prevalence of fasting hyperglycemia is higher in Tibetans living >3500 m compared to those living 2500–3500 m, with prevalence varying as a function of the degree of hypoxemia and polycythemia (Okumiya et al. 2016). Polycythemia was also shown to be associated with increased hemoglobin A1c (HbA1c) in Kham Tibetans living at >3600 m when compared to those with a lower HbA1c (Zhang et al. 2018a). Other studies, however, have shown different results. For example, it has been shown that Tibetans in the Changdu region living at 5000 m) is associated with comparable central and supraspinal fatigue, as observed during exercise in normoxia (Amann et al. 2013; Goodall et al. 2014b; Ruggiero et al. 2018). This recovery of supraspinal fatigue to normoxic standards can be partially ascribed to increased PaO2, arterial oxygen content (CaO2), and increased cerebral oxygen delivery (CDO2) during the performance (Goodall et al. 2014a). Interestingly, the period of measurements of the above-mentioned studies in chronic hypoxia corresponds with the window (sixth to 18th day) of maximal sympathetic norepinephrine concentration following exposure to high altitude (Barnholt et al. 2006), suggesting norepinephrine acts as a neuromodulator, triggering increased motoneuron excitability at altitude (Ruggiero et al. 2018). In turn, this can diminish the supraspinal neural effort,

Motor cortex stimulation Supraspinal fatigue Corticospinal neurone Central fatigue Motorneurone

Peripheral fatigue

Motor nerve stimulation

Muscle

Figure 12.1  Division of muscle fatigue into central and peripheral components. Central fatigue represents a reduction in voluntary drive, resulting in decreased voluntary muscle activation during exercise (Gandevia 2001), and is due to mechanisms located above the neuromuscular junction. Supraspinal fatigue is a subset of central fatigue, and is defined as a decline in voluntary drive from the motor cortex. Supraspinal fatigue is exacerbated in acute hypoxia compared to normoxia, and recovers to normoxic standards in chronic hypoxia (Goodall et al. 2014b; Nicol and Komi 2011; Ruggiero et al. 2018). (Adapted from Taylor et al. 2008.)

decrease fatigability, and improve successful completion of the task. Importantly, the recovery of supraspinal fatigue to normoxic standard with chronic hypoxia has notable positive implications for performance.

CEREBRAL BLOOD FLOW AND OXYGEN DELIVERY Cerebral blood flow under normal physiologic conditions Under normal conditions, the cerebral vasculature is sensitive to changes in CaO2. This sensitivity occurs below a PaO2 of ∼55 mmHg, whereby further reductions in PaO2 lead to an accelerated reduction in arterial oxygen saturation (Figure 12.2). This response characteristic is due to the shape of the oxyhemoglobin dissociation curve and its impact on the relationship between PaO2 and CaO2. The

208  Central nervous system

800

800

Q (ml/min)

600 400 200 0

ICA VA n = 10

600 Q (ml/min)

ICA VA n = 12

400 200

0

20

40 60 PaCO2 (mmHg)

80

0

0

20

40 60 80 PaO2 (mmHg)

100

120

Figure 12.2  Blood flow (Q) through the internal carotid (ICA) and vertebral arteries (VA) during steady-state changes in arterial CO2 (left) and oxygen (right) in humans. Cerebrovascular reactivity to changes in CO2 and to hypoxia (%ΔCBF / mmHg CO2 and %ΔCBF / %SaO2) was found to be similar between vessels in the hypercapnic range, ∼10% greater for the VA than the ICA in the hypocapnic range, and 50% greater for the VA with extreme hypoxia. Note that in the hypoxia trial (right), the arterial PCO2 was maintained normal. (Adapted from Willie et al. 2012.)

cerebrovascular response to changes in CaO2 is dependent on the prevailing PaCO2; hypercapnia increases and hypocapnia decreases cerebrovascular sensitivity to hypoxia (Mardimae et al. 2012). The cerebral vasculature is also highly sensitive to small changes in PaCO2. Studies employing a range of different experimental techniques for the assessment of CBF, which have been reviewed elsewhere (Ainslie et al. 2016; Hoiland et al. 2014; Hoiland et al. 2016), all show an approximate 6–8% increase and/or 3–4% decrease in flow per millimeter of mercury change in PaCO2 above and below eupneic PaCO2, respectively. Studies of hypoxic cerebrovascular reactivity are thus confounded by the ventilatory response to hypoxia, which produces hypocapnia and elicits a cerebrovascular vasoconstrictive response (i.e., poikilocapnic). As reviewed elsewhere (Ainslie and Subudhi 2014; Hoiland et al. 2018), studies incorporating a range of techniques to assess the CBF response to isocapnic hypoxia have reported CBF reactivities ranging from a 0.5% to 2.5% increase in CBF per percentage point reduction in arterial oxygen saturation. For a given severity of isocapnic hypoxia, the percent increase in blood flow to the brainstem is greater than that to the middle and anterior regions, as assessed by flow through the vertebral and internal carotid arteries, respectively (Ogoh et al. 2013; Willie et al., 2012). Congruous positron emission tomography (PET) scan data collected during isocapnic hypoxia reveal that cortical blood flow is less responsive to hypoxia than phylogenetically older areas of the brain (Binks et al. 2008). In addition to dilation of the arteries throughout the cerebrovascular with hypoxia and hypercapnia, venous capacitance vessels also dilate (Lawley et al. 2014; Weinbrecht et al. 1986; Wilson et al. 2013), thus also increasing the volume of cerebral venous blood. Increased cerebral blood volume is important as it may mediate increases in intracranial pressure and play a role in the pathophysiology of high altitude headache and cerebral edema (Lawley et al. 2015), as discussed in Chapters 20 and 21. Unlike the response to PaCO2, however, the CBF response to oxygen appears to be determined by

the content rather than the partial pressure of oxygen per se (Ainslie et al. 2016; Hoiland et al. 2016 2018). It is unknown if the venous capacitance vessels are also regulated via oxygen content. However, in conscious animals and humans, the hyperventilation caused by hypoxemia causes a reduction in PaCO2 and an increase in pH, which elicits a cerebral vasoconstrictive stimulus. Therefore, the results shown in Figure 12.2 cannot be applied directly to the climber at extreme altitude, as discussed next.

Cerebral blood flow at high altitude During ascent and initial stay at high altitude, increases in CBF are elicited via reductions in C aO2 and consequent hypoxic cerebral vasodilation (Hoiland et al. 2016). The magnitude of this increase in CBF is altitude dependent and contingent on the countervailing influences of hypoxemia, decreased C aO2 , and hypocapnia. The resulting cerebral vasodilation occurs throughout the cerebral vasculature from the large extracranial cerebral conduit arteries (i.e., internal carotid and vertebral arteries), large intracranial arteries (e.g., middle cerebral artery), through to pial vessels and is adequate to maintain CDO2 (Figure 12.3). While hyperventilation mitigates the drop in CaO2 at high altitude, it leads to concomitant reductions in PaCO2 resulting in an increased blood and CSF pH (Lahiri and Milledge 1967) as discussed in Chapter 9. As the cerebral vasculature is highly sensitive to alterations in pH (Kety and Schmidt 1948; Willie et al. 2012, 2015), decreased PaCO2 and increased pH produce a marked vasoconstrictor stimulus (Willie et al. 2014) that counteracts the hypoxic vasodilatory stimulus, although the hypoxic stimulus maintains a net vasodilatory outcome (Willie et al. 2015). Given the interplay of CaO2 and PaCO2 on CBF regulation at altitude, overall regulation appears to be dependent on four primary factors: 1) the hypoxic ventilatory response (HVR), 2) the ventilatory response to changes in CO2 (HCVR), 3) hypoxic cerebral vasodilation, and 4) hypocapnic cerebral

Cerebral blood flow and oxygen delivery  209

Figure 12.3  Changes in cerebral blood flow and oxygen delivery following ascent to altitude. Following initial exposure to high altitude, arterial oxygen content (CaO2) is reduced and cerebral blood flow (CBF) is commensurately increased. Increases and decreases in CaO2 and CBF, respectively, then mirror each other throughout acclimatization and maintain cerebral oxygen delivery (CDO2) constant. Alternating vertical bars represent individual days at altitude. Data are labeled based on their corresponding study. 1: Severinghaus et al. (1966), 2: Huang et al. (1987), 3: Jensen et al. (1990), 4: Baumgartner et al. (1994), 5: Lucas et al. (2011), 6: Willie et al. (2014a), 7: Willie et al. (2014b), 8: Subudhi et al. (2013).

vasoconstriction. The HVR and HCVR determine the prevailing arterial blood gas stimuli (see Chapter 9), while hypoxic cerebral vasodilation and hypocapnic vasoconstriction determine the magnitude by which the cerebral vasculature responds to the arterial blood gas stimuli. Hypoxic cerebral vasodilation notably occurs via several pathways but appears to be primarily regulated by deoxyhemoglobin-mediated release of ATP and nitric oxide (reviewed in Hoiland et al. 2018). These signaling processes alleviate cerebral hypoxemia by facilitating increased CBF (Doctor and Stamler 2011; Ellsworth et al. 2009; Gladwin et al. 2006; Hoiland et al. 2016). Another important consideration in the regulation of CBF at altitude is sympathetic nervous system activity (Brassard et al. 2017). However, a laboratory study demonstrates no influence of α1-adrenoceptor blockade on CBF during six hours of exposure to hypoxia (FIO2 0.11) (Lewis et al. 2014). Conversely, at high altitude, combined α1- and nonselective β-adrenoceptor blockade reduces CBF, although this is likely due to a marked drop in mean arterial pressure (∼25 mmHg) (Ainslie et al. 2012) and does not appear to have a direct influence on cerebrovascular tone. As time at high altitude progresses, CBF stabilizes and starts decreasing toward baseline values within two to three days after arrival (Figure 12.3) (Ainslie and Subudhi 2014). This is a result of both systemic adaptations affecting CaO2 and altered sensitivity of the cerebral vasculature (Lucas et al. 2011). Comprising the relevant systemic adaptations are three factors: 1) altitude-induced diuresis whereby HCO3− is excreted at an elevated rate in an attempt to compensate for respiratory alkalosis (Ge et al. 2006); 2) a substantial loss of

plasma volume, decreasing total blood volume but eliciting a significant increase in hematocrit and hemoglobin concentration within days of exposure to high altitude (Pugh 1964). This particular physiological response is a key factor, in addition to ventilatory acclimatization, that drives the early increase in CaO2 from initial hypoxic exposure and thus contributes to the progressive decrease in CBF); and 3) following ∼1 week at high altitude, erythropoiesis then increases hemoglobin mass leading to further increases in hematocrit (Ryan et al. 2014; Siebenmann et al. 2015, 2017). Another necessary consideration is the influence of the concentration of hemoglobin on blood viscosity and the potential implications of viscosity in regulating CBF at high altitude. To our knowledge, no data have specifically examined the influence of viscosity on CBF at high altitude; however, the existing data in humans at sea level indicates a likely negligible influence of viscosity on CBF in hypoxia (Hoiland et al. 2016). It should be noted, of course, that excessive polycythemia is extremely detrimental to physiological function and health at high altitude, especially in those with chronic mountain sickness (Dante and Javier 2007; Villafuerte and Corante 2016). Alterations in cerebral vascular reactivity to both oxygen and carbon dioxide may also be implicated in CBF regulation at high altitude (Lucas et al. 2011). Both increases (Lucas et al. 2011; Flück et al. 2015) and no change (Rupp et al. 2014; Willie et al. 2015) in hypocapnic cerebral vasoconstriction have been demonstrated upon ascent to and acclimatization at altitude. Therefore, given methodological (technical and logistical) differences between studies, physiological differences (e.g., acid–base balance) and the consequent inconsistency of results, it remains relatively

210  Central nervous system

unclear how altered hypocapnic vasoconstriction contributes to the progressively reduced CBF throughout acclimatization. Related to cerebral sensitivity to oxygen, one study to date has conducted repeated measures indicating that hypoxic cerebral vasodilation is increased at high altitude (Jensen et al. 1996), a result which has been corroborated by more well-controlled laboratory studies (Poulin et al. 2002). Yet, changes in hypoxic vasodilation with acclimatization have not been examined using volumetric measures of CBF, necessitating judicious interpretation of the currently available data. Nonetheless, the observed increase in hypoxic cerebral vasodilation may counteract the vasoconstrictor stimulus consequent to reduced PaCO2 and underscore the net vasodilatory stimulus and maintained CDO2 observed upon exposure to high altitude. Collectively, global CBF at high altitude mirrors changes in CaO2 and although PaCO2 is a very potent regulator of tone, following initial exposure to altitude, arterial pH is minimally altered. Therefore, it appears CaO2 is the primary factor governing the pattern by which CBF changes following initial exposure to high altitude. Potential alterations in reactivity at high altitude may further “fine tune” the observed changes in CBF. Although global changes in CBF have been shown to maintain CDO2 in hypobaric hypoxia throughout ascent and stay at high altitude, regional differences in the flow response to high altitude have been demonstrated (Hoiland et al. 2017; Subudhi et al. 2013). These high altitude studies and those conducted in well-controlled laboratory settings (Binks et al. 2008; Hoiland et al. 2017; Lawley et al. 2016; Subudhi et al. 2013) display preferential blood flow distribution to the posterior circulation, which perfuses brain regions such as the brainstem, hypothalamus, thalamus, and cerebellum (Binks et al. 2008). Despite no relationship between global CBF and AMS (Ainslie and Subudhi 2014) and failure of globally maintained CDO2 to explain cognitive deficits in hypoxia, the aforementioned regionalization of CBF is suggested to be responsible for AMS (Feddersen et al. 2015) as well as cognitive impairment (Lawley et al. 2016) at high altitude. However, given the number of inconsistent studies (Ainslie and Subudhi 2014; Liu et al. 2017), sufficient data are still lacking with regard to the intricacies of regionalized CBF regulation and its consequent impact(s). Nevertheless, regionally differential distribution of blood flow likely occurs as a survival mechanism to prioritize delivery to the posterior areas of the brain, including the brainstem, responsible for controlling functional and homeostatic processes while consequently reducing delivery to areas responsible for higher cognitive function. CEREBRAL VENOUS BLOOD FLOW

Although the focus in this chapter has been on inflow to the cerebral circulation, it should be noted that a mismatch between cerebral inflow and venous outflow may play a role in the pathophysiology of AMS (Chapter 20) (Wilson and Imray 2015) and potentially cerebral edema (Sagoo et al. 2016). In the latter landmark study, it was reported that

CDO2 was maintained via increased arterial inflow (i.e., CBF) and this preceded the development of cerebral edema, thus implicating venous outflow restriction as a key mechanism (Sagoo et al. 2016).

CENTRAL NERVOUS SYSTEM FUNCTION AT HIGH ALTITUDE Many professions rely on a thorough understanding of the effects of hypoxia on neurological function, as job performance and workplace safety are tightly linked to the oxygen availability of the local environment. In areas considered to have a high risk or consequence of fire, for example, oxygen concentration is often reduced in order to minimize the potential for fire outbreak. In specific areas of many nuclear plants, the ambient oxygen concentration is reduced to 15%, as this amount is thought to be a threshold for maintenance workers and inspectors to safely carry out their work unhindered by the cerebral effects of hypoxia (Küpper et al. 2011). If airplanes travelling at cruising altitude were not pressurized, pilots and passengers would certainly endure a rapid loss of consciousness, as was the case in the fatal Helios Airways Flight 522, where cabin pressure was lost at 10,365 m and all crew and passengers were rendered unconscious for almost three hours before the plane eventually ran out of fuel. While this is an extreme example, shorter unpressurized flights at lower altitudes would almost certainly have cognitive consequences; therefore, most commercial airlines are pressurized to simulate an “acceptable” altitude of 7300 m, no al. (1993) age: 35 ± 5 history of supplemental O2 years; 21 age ascents >7000 m and sex-matched controls Garrido et 7 elite Sherpa World class >8000 m MRI abnormalities (cortical atrophy, white al. (1996) climbers, 21 elite climbers (Sherpa matter hyperintensities) were present in 13 of lowland and lowlanders), 21 lowland climbers (66%), but only found in 1 climbers, 21 elite all with history of of 7 Sherpa climbers (14%). No abnormalities controls climbs >8000 m were observed in the controls. Hackett et 8 patients with Evacuated from 2700–3000 m HACE characterized by cytotoxic and vasogenic al. (2019) severe HACE Colorado edema, which progresses to microvascular mountain disruption and microbleeds. communities (Continued)

216  Central nervous system

Table 12.1  (Continued) MRI-based studies investigating brain changes after high altitude exposure

Study

Participants

Paola et al. (2008)

Mountaineers (9) and controls (19), age: 37.9 ± 7.2 years; all male 77 Tibetan natives (43f), age: 16 ± 1.2 years; 80 lowlander controls (46f), age: 16 ± 1.3 years 28 (16f) raised at high altitude, age: 20.4 ± 1.4 years; 28 lowland controls (16f), age: 20.9 ± 1.5 years 10 high altitude, 9 age-matched lowland controls

Wei et al. (2017)

Yan et al. (2011a)

Yan et al. (2011b)

Yan et al. (2011c)

28 high altitude, 30 age-matched lowland controls

Zhang et al. 14 (6f), age: 21 ± (2012) 1.9 years

Zhang et al. 16 male soldiers, (2013a) 16 age-matched controls (age: 21 ± 0.7 years)

Type of and duration of hypoxic exposure

Altitude

Main findings

High altitude Recently >7500 m; Extreme high altitude exposure causes gray and mountaineering, >15 days over white matter changes (reductions in volume/ pre/post 6500 m; plus density) in areas involved in motor activity. expedition history of high altitude exposure Adolescents born 2300–5300 m Reduced cortical thickness and increased and raised at cortical folding associated with increased high altitude altitude, predominantly in left hemisphere (superior/middle temporal gyrus, lingual gyrus, rostral middle frontal cortex, insular cortex). Students born and 2616–4200 m raised at high altitude (>18 years), relocated to sea level for 1 year

Common activation patterns during spatial working memory, increased activation in superior temporal gyrus and pyramid in high altitude, indicating increased attention levels as compensatory mechanism to maintain cognitive/behavioral performance.

Students born and raised at high altitude (>20 years), relocated to sea level for 1 year Students born and raised at high altitude (>18 years), relocated to sea level for 1 year Single short-term climbing, no prior high altitude exposure (26 days) Lowlanders garrisoned at high altitude for 2 years

2616–4200 m

In high altitude group, decreased activation in neural circuit for food craving, decreased activation in regions for cognitive control, increased activation in regions for emotional processing.

2616–4200 m

Impaired in reaction time and accuracy, verbal working memory in high altitude residents, and reduced activation in inferior and middle frontal gyrus, middle occipital lingual gyrus, pyramid of vermis, and thalamus.

6206 m

No changes in global or regional gray matter, white matter, or cerebral spinal fluid volumes. Compromised white mater fiber microstructural integrity.

2300–4400 m

Broad regional differences in cortical thickness, including decreased thickness in right superior frontal gyrus. No difference in total gray matter volume, but high altitude immigrants showed reduced gray matter volumes in right middle frontal gyrus, right parahippocampal gyrus, right inferior middle temporal gyri, bilateral inferior ventral pons, and right cerebellum crus.

In another study performed on climbers from four different expeditions (reaching heights ranging from 4810 m to 8848 m), cortical atrophy and enlargement in the perivascular Vichrow-Robin spaces were observed upon return to sea level, and additional subcortical lesions were observed predominantly in those determined to be insufficiently

acclimatized (Fayed et al. 2006). Further evidence is provided by the observation of reductions in both gray and white matter volume and density in the areas involved in motor control, in a group of elite mountaineers tested immediately after returning from an expedition where participants spent at least 15 days at an altitude >6500 m

Mitigating the effects of hypoxia on the brain  217

(Paola et al. 2008). Interestingly, MRI scans were performed on seven extreme-altitude Sherpa guides who had a similar climbing history to 21 non-Sherpa mountaineers, and MRI abnormalities were found in only one Sherpa compared to 13 of the lowland-born climbers (Garrido et al. 1996). These dramatically different findings provide evidence of an inherited or acquired resiliency against brain changes in response to extreme altitude exposure, likely a consequence of over 20,000 years of generational residence at high altitudes (see Chapter 4). The results for the structural brain changes following exposure to high altitude are summarized in Table 12.1. While suggestive of changes in brain structure, with the exception of one preliminary study (Foster et al. 2015), these studies were limited by the fact that they lacked preascent MRI imaging on any of the climbers, making it difficult to determine whether the observed abnormalities were related to a particular high altitude exposure.

Functional changes Another important limitation of the majority of the neuroimaging studies noted above, is that they did not correlate the observed structural problems with changes in cognitive function. Despite this issue with these particular studies, there is other evidence to suggest that such purported damage after repeated exposures to extreme altitude has clinical manifestations. For example, a persistent impairment in memory was observed in a group of 10 climbers tested 75 days after returning to sea level, after climbing to over 7000 m without supplemental oxygen (Cavaletti et al. 1990). In another group consisting of climbers who have each cumulatively spent between 48 and 358 hours at altitudes >8000 without oxygen, significant impairments were observed in concentration, short-term memory, and ability to shift concepts (Regard et al. 1989) despite the fact that tests were taken two to 10.5 months after their most recent exposures. Neuropsychological testing was included as part of AMREE in 1981, with 21 of the members undergoing a battery of tests before and after the expedition as well as at a postexpedition meeting one year following their return to the United States. Immediately following the expedition, subjects were noted to have deficits in verbal learning and memory, increased expressive language error, and decreased speed on a finger tapping test when compared to pre-­expedition testing. Of these deficits, only the decrease in finger tapping persisted at one-year follow-up (Townes et al. 1984). In a landmark publication on the topic (Hornbein et al. 1989), neuropsychological and physiologic testing was completed on 35 mountaineers before and one to 30 days after ascent to altitudes between 5488 m and 8848 m (from the AMREE), and on six subjects before and after simulation in an altitude chamber of a 40-day ascent to 8848 m (from the Operation Everest II chamber study). Neuropsychological testing revealed a decline in visual long-term memory after ascent as compared with before in both the simulated-ascent group and the mountaineers. Verbal long-term memory was also affected, but only in the simulated-ascent group. Of

particular note was the fact that the greatest decrements in neuropsychological function were seen in those individuals with the strongest hypoxic ventilatory response (Hornbein et al. 1989). It was hypothesized that those individuals with the strongest ventilatory response would have a lower PaCO2 and, as a result, greater cerebral vasoconstriction; however, cerebral blood flow was not assessed to confirm this concept.

MITIGATING THE EFFECTS OF HYPOXIA ON THE BRAIN Given concerns discussed above about the effects of acute hypoxic exposure on both short- and long-term cognitive function, an important question that arises is whether any such effects can be mitigated by the use of supplemental oxygen. Use of supplemental oxygen has become routine, for example, among climbers attempting Mount Everest and other peaks >8000 m. While this approach is associated with improved physical performance at such altitudes and anecdotal reports support the notion of improved cognitive function during the ascent, no systematic studies have examined whether those who use supplemental oxygen are more or less susceptible to residual effect on neuropsychiatric function months to years after an expedition to such high altitudes. One other area where supplemental oxygen may be of benefit for short-term purposes is with regard to the increasing numbers of people traveling to high altitude for commercial purposes including mining and work at high altitude observatories. Such individuals often have to perform highly technical tasks shortly following arrival and may lack sufficient time to acclimatize before doing so. One option considered to reduce neuropsychological impairment in such circumstances is through oxygen enrichment of room air, whereby every 1% increase in the oxygen concentration of the ambient environment reduces the equivalent altitude by 300 m. In one of the few studies to examine whether such an intervention improves neuropsychological function following acute ascent, Gerard et al. (2000) performed neuropsychological testing on 24 healthy subjects in a specially designed chamber at 3800 m that could simulate both 5000 m and an atmosphere of 6% oxygen enrichment at 5000 m. Compared with breathing air at the equivalent of 5000 m, oxygen enrichment improved arterial oxygen saturation and also improved reaction times, hand-eye coordination and the sense of well-being. Other aspects of neuropsychological function measured in the 16-test battery were not improved with supplemental oxygen, which the authors surmised could relate to the ability of individuals to concentrate for short periods of time and overcome true deficits. More recently, Heinrich et al. (2019) extended these findings and examined the influence of a night of supplemental oxygen versus no oxygen during acclimatization to 3800 m. The results revealed that administration of supplemental oxygen during sleep can reduce feelings of fatigue and confusion when compared to no treatment, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high

218  Central nervous system

altitude. This study also provided evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve, not worsen, with acclimatization to 3800 m (Heinrich et al. 2019). Further studies to examine the long-term implications of supplemental oxygen during mining and work at high altitude observatories have not been conducted. Since it has also been reported that high altitude impairs the neuropsychological function of school-age children when compared to similar control groups of children at low altitude, oxygenation in this context might be of particular importance to improve learning outcomes. This topic and the potential of “oxygen conditioning” at altitude have been reviewed in depth elsewhere (West 2015; West 2016).

REFERENCES Adam GE, Fulco CS, Muza SR. (2008). Multi-task performance at sea level and high altitude. Proceedings of the 26th Army Science Conference. Washington, DC: US Army. pp. 1–7. Ainslie PN, Fan JL, Thomas KN, Cotter JD, Tzeng YC, Burgess KR. (2012). Influence of sympathoexcitation at high altitude on cerebrovascular function and ventilatory control in humans. J Appl Physiol. 113:1058–1067. Ainslie PN, Hoiland RL, Bailey DM. (2016). Lessons from the laboratory; integrated regulation of cerebral blood flow during hypoxia. Exp Physiol. 101:1160–1166. Ainslie PN, Subudhi AW. (2014). Cerebral blood flow at high altitude. High Alt Med Biol. 15:133–140. Ainslie PN, Wilson M, Imray CH. (2014). The cerebral circulation and brain. In: High Altitude: Human Adaptation to Hypoxia. E Swenson and Pr Bartsch, eds. Springer, New York & Basel. 141–171. Amann M, Goodall S, Twomey R, Subudhi AW, Lovering AT, Roach RC. (2013). AltitudeOmics: on the consequences of high-altitude acclimatization for the development of fatigue during locomotor exercise in humans. J Appl Physiol. 115:634–642. Ballanyi K, Doutheil J, Brockhaus J. (1996). Membrane potentials and microenvironment of rat dorsal vagal cells in vitro during energy depletion. J Physiol. 495:769–784. Balldin U, Tutt R, Fischer J, Harrison R, Anderson E. (2007). The effects of 12 hours of low grade hypoxia at 10,000 ft at night in special operations forces aircraft operations on cognition, night vision goggle vision and subjective symptoms. Air Force Research Laboratory. San Antonio, TX. Report No: AFRL-HE-BR-TR-2007-0047. Barnholt KE, Hoffman AR, Rock PB, Muza SR, Fulco CS, Braun B, Holloway L, Mazzeo RS, Cymerman A, Friedlander AL. (2006). Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction. Am J Physiol Endocrinol Metab. 290:1078–1088. Bartholomew CJ, Jensen W, Petros T V, Richard F, Fire KM, Biberdorf D, Fraley E, Schalk J, Blumkin D. (1999).

The effect of moderate levels of simulated altitude on sustained cognitive performance. Int J Aviat Psychol. 9:351–359. Baumgartner RW, Bärtsch P, Maggiorini M, Waber U, Oelz O. (1994). Enhanced cerebral blood flow in acute mountain sickness. Aviat Space Environ Med. 65:726–729. Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR. (2000). Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol. 48:285–296. Bigland-Ritchie B, Johansson R, Lippold OC, Smith S, Woods JJ. (1983). Changes in motoneurone firing rates during sustained maximal voluntary contractions. J Physiol. 340:335–346. Binks AP, Cunningham VJ, Adams L, Banzett RB. (2008). Gray matter blood flow change is unevenly distributed during moderate isocapnic hypoxia in humans. J Appl Physiol. 104:212–217. Boero JA, Ascher J, Arregui A, Rovainen C, Woolsey TA. (1999). Increased brain capillaries in chronic hypoxia. J Appl Physiol. 86:1211–1219. Bonnon M, Noel-Jorand MC, Therme P. (1999). Criteria for psychological adaptation to high-altitude hypoxia. Percept Mot Skills. 89:3–18. Brassard P, Tymko MM, Ainslie PN. (2017). Sympathetic control of the brain circulation: appreciating the complexities to better understand the controversy. Auton Neurosci. 207:37–47. Bustamante-sánchez Á, Delgado-terán M, Javier V. (2018). Psychophysiological response of different aircrew in normobaric hypoxia training. Ergonomics. 0:1–9. Caldwell HG, Ainslie PN, Ellis LA, Phillips AA, Flück D. (2017). Stability in neurovascular function at 3800 m. Physiol Behav. 182:62–68. Caldwell HG, Coombs GB, Tymko MM, Nowak-Flück D, Ainslie PN. (2018). Severity-dependent influence of isocapnic hypoxia on reaction time is independent of neurovascular coupling. Physiol Behav. 188:262–269. Cavaletti G. (1993). Long-lasting neuro psychological changes after a single high altitude climb. Acta Neurol Scand. 87:103–105. Cavaletti G, Garavaglia P, Arrigoni G, Tredici G. (1990). Persistent memory impairment after high altitude climbing. Int J Sports Med. 11:76–178. Chavez JC, Agani F, Pichiule P, LaManna JC. (2000). Expression of hypoxia-inducible factor-1alpha in the brain of rats during chronic hypoxia. J Appl Physiol. 89:1937. Chen J, Fan C, Li J, Han Q, Lin J, Yang T, Zhang J. (2016a). Increased intraregional synchronized neural activity in adult brain after prolonged adaptation to high-altitude hypoxia: a resting-state fMRI study. High Alt Med Biol. 17:16–24. Chen J, Li J, Han Q, Lin J, Yang T, Chen Z, Zhang J. (2016b). Long-term acclimatization to high‐altitude hypoxia modifies interhemispheric functional and structural connectivity in the adult brain. Brain Behav. 6:e00512.

Mitigating the effects of hypoxia on the brain  219

Chen J, Luo W, Zhang Q, Li C, Zhao H, Aschner M, Li D, Liu J, Chen X, Meng S, Qi S, Li B, Xu H, Zhang W, Zhang J, Lu H, Yin H, Wang J. (2017a). Cognitive and neuroimaging changes in healthy immigrants upon relocation to a high altitude: a panel study. Hum Brain Mapp. 38:3865–3877. Chen L, Cai C, Yang T, Lin J, Cai S, Zhang J, Chen Z. (2017b). Changes in brain iron concentration after exposure to high-altitude hypoxia measured by quantitative susceptibility mapping. Neuroimage. 147:488–499. Curran T, Tanaka JW, Weiskopf DM. (2002). An electrophysiological comparison of visual categorization and recognition memory. Cogn Affect Behav Neurosci. 2:1–18. Dante P, Javier AS. (2007). The heart and pulmonary circulation at high altitudes. Circulation. 115:1132–1146. Davranche K, Casini L, Arnal PJ, Rupp T, Perrey S, Verges S. (2016). Cognitive functions and cerebral oxygenation changes during acute and prolonged hypoxic exposure. Physiol Behav. 164:189–197. De Aquino Lemos V, Antunes HKM, Dos Santos RVT, Lira FS, Tufik S, De Mello MT. (2012). High altitude exposure impairs sleep patterns, mood, and cognitive functions. Psychophysiology. 49:1298–1306 Decroix L, De Pauw K, Van Cutsem J, Pattyn N, Heyman E, Meeusen R. (2018). Acute cocoa flavanols intake improves cerebral hemodynamics while maintaining brain activity and cognitive performance in moderate hypoxia. Psychopharmacology. 235:2597–2608. Department of the Army. (2014). Aviation Flight Regulations. AR 95-1. Washington, DC. Di Russo F, Spinelli D, Morrone MC. (2001) Automatic gain control contrast mechanisms are modulated by attention in humans: evidence from visual evoked potentials. Vision Res. 41:2435–2447. Diarra A, Sheldon C, Brett CL, Baimbridge KG, Church J. (1999). Anoxia-evoked intracellular pH and Ca2+ concentration changes in cultured postnatal rat hippocampal neurons. Neurosci. 93:1003–1016. Doctor A, Stamler JS. (2011). Nitric oxide transport in blood: a third gas in the respiratory cycle. Compr Physiol. 1:541. Doherty MJ. (2003). James Glaisher’s 1862 account of balloon sickness. Neurology. 60:1016–1018. Dor Y, Porat R, Keshet E. (2001). Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol Cell Physiol. 280:1367–1374. Dykiert D, Hall D, van Gemeren N, Benson R, Der G, Starr JM, Deary IJ. (2010). The effects of high altitude on choice reaction time mean and intra-individual variability: results of the Edinburgh Altitude Research Expedition of 2008. Neuropsychology. 24:391–401. Ellsworth ML, Ellis CG, Goldman D, Stephenson AH, Dietrich HH, Sprague RS. (2009). Erythrocytes: oxygen sensors and modulators of vascular tone. Physiol. 24:107–116.

Erdemli G, Xu YZ, Krnjevic K. (1998). Potassium conductance causing hyperpolarization of ca1 hippocampal neurons during hypoxia. J Neurophysiol. 80:2378–2390. Ernsting J, Byford G, Denison D, Freyer D. (1973). Hypoxia induced by rapid decompression from 8000 feet to 40,000 feet — the influence of rate of decompression. Personal Flying Research Comittee Report No. 1324. Ministry of Defense (Air). London. Fan C, Zhao Y, Yu Q, Yin W, Liu H, Lin J, Yang T, Fan M, Gesang L, Zhang J. (2016). Reversible brain abnormalities in people without signs of mountain sickness during high-altitude exposure. Sci Rep. 16:33596. Faraci FM, Fedde MR. (1986). Regional circulatory responses to hypocapnia and hypercapnia in barheaded geese. Am J Physiol Integr Comp Physiol. 250:R499–R504. Fayed N, Modrego PJ, Morales H. (2006). Evidence of brain damage after high-altitude climbing by means of magnetic resonance imaging. Am J Med. 119:168. e1–168.e6. Feddersen B, Neupane P, Thanbichler F, Hadolt I, Sattelmeyer V, Pfefferkorn T, Waanders R, Noachtar S, Ausserer H. (2015). Regional differences in the cerebral blood flow velocity response to hypobaric hypoxia at high altitudes. J Cereb Blood Flow Metab. 35:1846–1851. Fischer S, Clauss M, Wiesnet M, Renz D, Schaper W, Karliczek GF. (1999). Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO. Am J Physiol Cell Physiol. 276:812–820. Flück D, Siebenmann C, Keiser S, Cathomen A, Lundby C. (2015). Cerebrovascular reactivity is increased with acclimatization to 3,454 m altitude. J Cereb Blood Flow Metab. 35:1323–1330. Forster H V, Soto RJ, Dempsey JA, Hosko MJ. (1975). Effect of sojourn at 4,300 m altitude on electroencephalogram and visual evoked response. J Appl Physiol. 39:109. Foster GE, Davies-Thompson J, Dominelli PB, Heran MKS, Donnelly J, duManoir GR, Ainslie PN, Rauscher A, Sheel AW. (2015). Changes in cerebral vascular reactivity and structure following prolonged exposure to high altitude in humans. Physiol Rep. 3:e12647. Fujimura N, Tanaka E, Yamamoto S, Shigemori M, Higashi H. (1997). Contribution of ATP-sensitive potassium channels to hypoxic hyperpolarization in rat hippocampal CA1 neurons in vitro. J Neurophysiol. 77:378–385. Gandevia SC. (2001). Spinal and supraspinal factors in human muscle fatigue. Physiol Rev 81:1725–1789. Gao Y, Li P, Jiang C, Liu C, Chen Y, Chen L, Ruan H. (2015). Psychological and cognitive impairment of long-term migrators to high altitudes and the relationship to physiological and biochemical changes. Eur J Neurol. 22:1363–1369. Garrido E, Castelló A, Ventura J, Capdevila A, Rodriguez F. (1993). Cortical atrophy and other brain magnetic

220  Central nervous system

resonance imaging (MRI) changes after extremely high-altitude climbs without oxygen. Int J Sport Med. 14:232–234. Garrido E, Segura R, Capdevila A, Pujol J, Javierre C, Ventura JL. (1996). Are Himalayan Sherpas better protected against brain damage associated with extreme altitude climbs? Clin Sci (London, Engl 1979). 90:81–85. Ge RL, Babb TG, Sivieri M, Resaland GK, Karlsen T, Stray-Gundersen J, Levine BD. (2006). Urine acid-base compensation at simulated moderate altitude. High Alt Med Biol. 7:64–71. Gerard AB, Mcelroy MK, Taylor MJ, Grant I, Powell FL, Holverda S, Sentse N, West JB. (2000). Six percent oxygen enrichment of room air at 5,000 m altitude improves neuropsychological function. High Alt Med Biol. 1(1):51–61. Gladwin MT, Shiva S, Dezfulian C, Hogg N, Kim-Shapiro DB, Patel RP. (2006). Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol. 291:2026–2035. Glaisher J, Flammarion C, de Fonvielle W, Tissandier G. (1871). Travels in the Air. J. B. Lippincott Company, Philadelphia, PA. Goodall S, Twomey R, Amann M. (2014a). Acute and chronic hypoxia: implications for cerebral function and exercise tolerance. Fatigue Biomed Heal Behav. 2:73–92. Goodall S, Twomey R, Amann M, Ross EZ, Lovering AT, Romer LM, Subudhi AW, Roach RC. (2014b). AltitudeOmics: exercise-induced supraspinal fatigue is attenuated in healthy humans after acclimatization to high altitude. Acta Physiol. 210:875–888. Gritti I, Martignoni M, Calcaterra R, Roi GS. (2012). Electroencephalographic changes after a marathon at 4300 m of altitude. J Behav Brain Sci. 2:380–386. Hackett PH, Yarnell PR, Weiland DA, Reynard KB. (2019). Acute and evolving MRI of high-altitude cerebral edema: microbleeds, edema, and pathophysiology. Am J Neuroradiol. 40:464–469. Haddad GG, Donnelly DF. (1990). O2 deprivation induces a major depolarization in brain stem neurons in the adult but not in the neonatal rat. J Physiol. 429:411–428. Haddad GG, Jiang C. (1993). O2 deprivation in the central nervous system: on mechanisms of neuronal response, differential sensitivity and injury. Prog Neurobiol. 40:277–318. Hampson NB, Kregenow DA, Mahoney AM, Kirtland SH, Horan KL, Holm JR, Gerbino AJ. (2013). Altitude exposures during commercial flight: a reappraisal. Aviat Space Environ Med. 84(1):27–31. Harris GA, Hons M, Cleland J, Collie A, Mccrory P. (2009). Cognitive assessment of a trekking expedition to 5100 m: a comparison of computerized and written testing methods. Wilderness Environ Med. 20:261–268. Hayashi R, Matsuzawa Y, Kubo K, Kobayashi T. (2005). Effects of simulated high altitude on event-related

potential (P300) and auditory brain-stem responses. Clin Neurophysiol. 116:1471–1476. Heinrich EC, Djokic MA, Gilbertson D, DeYoung PN, Bosompra N-O, Wu L, Anza-Ramirez C, Orr JE, Powell FL, Malhotra A, Simonson TS. (2019). Cognitive function and mood at high altitude following acclimatization and use of supplemental oxygen and adaptive servo ventilation sleep treatments. PLOS ONE. 14:e0217089. Hoiland RL, Ainslie PN, Wildfong KW, Smith KJ, Bain AR, Willie CK, Foster G, Monteleone B, Day TA. (2014). Indomethacin-induced impairment of regional cerebrovascular reactivity: implications for respiratory control. J Physiol. 593:1291–1306. Hoiland RL, Bain AR, Rieger MG, Bailey DM, Ainslie PN. (2016). Hypoxemia, oxygen content, and the regulation of cerebral blood flow. Am J Physiol Regul Integr Comp Physiol. 310:R398–R413. Hoiland RL, Bain AR, Tymko MM, Rieger MG, Howe CA, Willie CK, Hansen AB, Fluck D, Wildfong KW, Stembridge M, Subedi P, Anholm J, Ainslie PN. (2017). Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans. J Appl Physiol. 122:795–808. Hoiland RL, Howe CA, Coombs GB, Ainslie PN. (2018). Ventilatory and cerebrovascular regulation and integration at high-altitude. Clin Auton Res. 28:423–435. Horbein TF, Townes BD, Schoene RB, Sutton JR, Houston CS. (1989). The cost to the central nervous-system of climbing to extremely high altitude. N Engl J Med. 321:1714–1719. Hossmann KA. (1999). The hypoxic brain. Insights from ischemia research. Adv Exp Med Biol. 474:155. Hu SL, Xiong W, Dai ZQ, Zhao HL, Feng H. (2016). Cognitive changes during prolonged stay at high altitude and its correlation with c reactive protein. PLOS ONE. 11:e0146290. Huang L, Li W, Li B, Zou F. (2006). Activation of ATPsensitive K channels protects hippocampal CA1 neurons from hypoxia by suppressing p53 expression. Neurosci Lett. 398:34–38. Huang SY, Moore LG, McCullough RE, McCullough RG, Micco AJ, Fulco C, Cymerman A, Manco-Johnson M, Weil J V, Reeves JT. (1987). Internal carotid and vertebral arterial flow velocity in men at high altitude. J Appl Physiol. 63:395–400. Issa AN, Herman NM, Wentz RJ, Taylor BJ, Summer DC, Johnson BD. (2016). Association of cognitive performance with time at altitude, sleep quality, and acute mountain sickness symptoms. Wilderness Environ Med. 27(3):371–378. Jensen JB, Sperling B, Severinghaus JW, Lassen NA. (1996). Augmented hypoxic cerebral vasodilation in men during 5 days at 3,810 m altitude. J Appl Physiol. 80:1214–1218. Jensen JB, Wright AD, Lassen NA, Harvey TC, Winterborn MH, Raichle ME, Bradwell AR. (1990). Cerebral blood flow in acute mountain sickness. J Appl Physiol. 69:430–433.

Mitigating the effects of hypoxia on the brain  221

Jubeau M, Rupp T, Temesi J, Perrey S, Wuyam B, Millet G, Verges S. (2017). Neuromuscular fatigue during prolonged exercise in hypoxia. Med Sci Sport Exerc. 49:430–439. Kerem D, Elsner R. (1973). Cerebral tolerance to asphyxial hypoxia in the harbor seal. Respir Physiol. 19:188–200. Kety SS, Schmidt CF. (1948). The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest. 27:484–492. Kida M, Imai A. (1993). Cognitive performance and eventrelated brain potentials under simulated high altitudes. J Appl Physiol. 74:1735–1741. Kim C, Ryan EJ, Seo Y, Peacock C, Gunstad J, Muller MD, Ridgel AL, Glickman EL. (2015). Low intensity exercise does not impact cognitive function during exposure to normobaric hypoxia. Physiol Behav. 151:24–28. Kraaier V, Van Huffelen AC, Wieneke GH. (1988). Quantitative EEG changes due to hypobaric hypoxia in normal subjects. Electroencephalogr Clin Neurophysiol. 69:303–312. Küpper T, Milledge JS, Hillebrandt D, Kubalová J, Hefti U, Basnyat B, Gieseler U, Pullan R, Schöffl V. (2011). Work in hypoxic conditions-consensus statement of the medical commission of the Union Internationale des Associations d’Alpinisme (UIAA MedCom). Ann Occup Hyg. 55:369–386. Laguë SL. (2017). High-altitude champions: birds that live and migrate at altitude. J Appl Physiol. 123:942–950. Lahiri S, Milledge JS. (1967). Acid-base in Sherpa altitude residents and lowlanders at 4880 m. Respir Physiol. 2:323–334. LaManna JC, Chavez JC, Pichiule P. (2004). Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol. 207:3163–3169. Lawley JS, Alperin N, Bagci AM, Lee SH, Mullins PG, Oliver SJ, Macdonald JH. (2014). Normobaric hypoxia and symptoms of acute mountain sickness: elevated brain volume and intracranial hypertension. Ann Neurol. 75:890–898. Lawley JS, Levine BD, Williams MA, Malm J, Eklund A, Polaner DM, Subudhi AW, Hackett PH, Roach RC. (2015). Cerebral spinal fluid dynamics: effect of hypoxia and implications for high-altitude illness. J Appl Physiol. 120:251–262. Lawley JS, Macdonald JH, Oliver SJ, Mullins PG. (2016). Unexpected reductions in regional cerebral perfusion during prolonged hypoxia. J Physiol. 595:935–947. Legg SJ, Gilbey A, Hill S, Raman A, Dubray A, Iremonger G, Mündel T. (2018). Effects of mild hypoxia in aviation on mood and complex cognition. Appl Ergon. 53 Pt B:357–63. Lemos VDA, Moreira K. (2012). High altitude exposure impairs sleep patterns, mood, and cognitive functions. Psychophysiology. 49:1298–1306. Lewis NCS, Messinger L, Monteleone B, Ainslie PN. (2014). Effect of acute hypoxia on regional cerebral

blood flow: effect of sympathetic nerve activity. J Appl Physiol. 116:1189–1196. Liu W, Liu J, Lou X, Zheng D, Wu B, Wang DJJ, Ma L. (2017). A longitudinal study of cerebral blood flow under hypoxia at high altitude using 3D pseudo-continuous arterial spin labeling. Sci Rep. 7:43246. Lucas SJE, Burgess KR, Thomas KN, Donnelly J, Peebles KC, Lucas RAI, Fan J, Cotter JD, Basnyat R, Ainslie PN. (2011). Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m. J Physiol. 589:741–753. Lukyanetz EA, Shkryl VM, Kravchuk OV, Kostyuk PG. (2003). Action of hypoxia on different types of calcium channels in hippocampal neurons. Biochim Biophys Acta. 1618:33–38. Malle C, Quinette P, Laisney M, Bourrilhon C, Boissin J, Desgranges B, Eustache F, Piérard C. (2013). Working memory impairment in pilots exposed to acute hypobaric hypoxia. Aviat Sp Environ Med. 84:773–779. Mardimae A, Balaban DY, Machina MA, Han JS, Katznelson R, Minkovich LL, Fedorko L, Murphy PM, Wasowicz M, Naughton F, Meineri M, Fisher JA, Duffin J. (2012). The interaction of carbon dioxide and hypoxia in the control of cerebral blood flow. Pflügers Arch—Eur J Physiol. 464:345–351. Marina N, Ang R, Machhada A, Kasymov V, Karagiannis A, Hosford PS, Mosienko V, Teschemacher AG, Vihko P, Paton JFR, Kasparov S, Gourine AV. (2015). Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat. Hypertens. 65:775–783. Marti HJH, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W. (2000). Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol. 156:965–976. McAnally KI, Watson DB, Martin RL, Singh B. (2003). Effect of hypobaric hypoxia on auditory sensitivity. Aviat Space Environ Med. 74:1251–1255. McMorris T, Hale BJ, Barwood M, Costello J, Corbett J. (2017). Effect of acute hypoxia on cognition: a systematic review and meta-regression analysis. Neurosci Biobehav Rev. 74:225–232. Merz TM, Bosch MM, Barthelmes D, Pichler J. (2013). Cognitive performance in high-altitude climbers: a comparative study of saccadic eye movements and neuropsychological tests. Eur J Appl Physiol. 113:2025–2037. Mukhopadhyay S, Thakur L, Anand JP, Selvamurthy W. (2000). Effect of sojourn at altitude of 3,500 m on auditory evoked potential in man. Indian J Physiol Pharmacol. 44:211. Nakata H, Miyamoto T, Ogoh S, Kakigi R, Shibasaki M. (2017). Effects of acute hypoxia on human cognitive processing: a study using ERPs and SEPs. J Appl Physiol. 123:1246–1255. Nation DA, Bondi MW, Gayles E, Delis DC. (2017). Mechanisms of memory dysfunction during high

222  Central nervous system

altitude hypoxia training in military aircrew. J Int Neuropsychol Soc. 23:1–10. Nelson M. (1982). Psychological testing at high altitudes. Aviat Sp Environ Med. 53:122–126. Nelson TO, Dunlosky J, White DM, Steinberg J, Townes BD, Anderson D, Al NET. (1990). Cognition and metacognition at extreme altitudes on Mount Everest. J Exp Psychol Gen. 119:367–374. Nicol C, Komi P. (2011). Stretch-shortening cycle fatigue. In: Neuromuscular Aspects of Sport Performance. P Komi, ed. Blackwell Publishing Ltd: Chichester, UK, pp. 1–14. Ogoh S, Nakahara H, Okazaki K, Bailey DM, Miyamoto T. (2013). Cerebral hypoperfusion modifies the respiratory chemoreflex during orthostatic stress. Clin Sci. 125:37–44. Ozaki H, Watanabe S, Suzuki H. (1995). Topographic EEG changes due to hypobaric hypoxia at simulated high altitude. Electroencephalogr Clin Neurophysiol. 94:349–356. Pagani M, Ravagnan G, Salmaso D. (1998). Effect of acclimatisation to altitude on learning. Cortex. 34:243–251. Paola MD, Bozzali M, Fadda L, Musicco M, Sabatini U, Caltagirone C. (2008). Reduced oxygen due to highaltitude exposure relates to atrophy in motor-function brain areas. Eur J Neurol. 15:1050–1057. Papadelis C, Kourtidou-Papadeli C, Bamidis PD, Maglaveras N, Pappas K. (2007). The effect of hypobaric hypoxia on multichannel EEG signal complexity. Clin Neurophysiol. 118:31–52. Pavlicek V, Schirlo C, Nebel A, Regard M, Koller EA, Brugger P. (2005). Cognitive and emotional processing at high altitude. Aviat Space Environ Med. 76:28–33. Pelamatti G, Pascotto M, Semenza C. (2003). Verbal free recall in high altitude: proper names vs common names. Cortex. 39:97–103. Perez-Pinzon MA, Chan CY, Rosenthal M, Sick TJ. (1992). Membrane and synaptic activity during anoxia in the isolated turtle cerebellum. Am J Physiol. 263:1057–1063. Petiet CA, Townes BD, Brooks RJ, Kramer JH. (1988). Neurobehavioral and psychosocial functioning of women exposed to high altitude in mountaineering. Percept Mot Skills. 67:443–452. Pichiule P, LaManna JC. (2002). Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia. J Appl Physiol. 93:1131–1139. Pincus SM. (1994). Greater signal regularity may indicate increased system isolation. Math Biosci. 122:161–181. Poulin MJ, Fatemian M, Tansley JG, O’Connor DF, Robbins PA. (2002). Changes in cerebral blood flow during and after 48 h of both isocapnic and poikilocapnic hypoxia in humans. Exp Physiol. 87(5):633–642. Pramsohler S, Wimmer S, Kopp M, Gatterer H, Faulhaber M, Burtscher M, Netzer NC. (2017). Normobaric hypoxia overnight impairs cognitive reaction time. BMC Neurosci. 18(1):43.

Pugh LGCE. (1964). Blood volume and haemoglobin concentration at altitudes above 18,000 ft. (5500 m). J Physiol. 170:344–354. Pulsinelli WA. (1985). Selective neuronal vulnerability: morphological and molecular characteristics. Prog Brain Res. 63:29. Raichle ME, Hornbein TF. (2001). The high-altitude brain. In: High Altitude: An Exploration of Human Adaptation. TF Hornbein and RB Schoen, eds. Marcel Dekker: New York, pp. 377–423. Raley-Susman KM, Kass IS, Cottrell JE, Newman RB, Chambers G, Wang J. (2001). Sodium influx blockade and hypoxic damage to CA1 pyramidal neurons in rat hippocampal slices. J Neurophysiol. 86:2715–2726. Regard M, Brugger P, Biol D, Landis T. (1989). Persistent cognitive impairment in climbers after repeated exposure to extreme altitude. Neurology. 39:210–214. Rimoldi SF, Rexhaj E, Duplain H, Urben S, Billieux J, Allemann Y, Romero C, Ayaviri A, Salinas C, Villena M, Scherrer U, Sartori C. (2016). Acute and chronic altitude-induced cognitive dysfunction in children and adolescents. J Pediatr. 169:238–243. Rozhkov VP, Soroko SI, Trifonov MI, Bekshaev SS, Burykh EA, Sergeeva EG. (2009). Cortical-subcortical interactions and the regulation of the functional state of the brain in acute hypoxia in humans. Neurosci Behav Physiol. 39:417–428. Ruggiero L, Yacyshyn AF, Nettleton J, McNeil CJ. (2018). UBC-Nepal expedition: acclimatization to high-altitude increases spinal motoneurone excitability during fatigue in humans—increased motoneurone excitability during fatigue in chronic hypoxia. J Physiol. 596:3327–3339. Rupp T, Esteve F, Bouzat P, Lundby C, Perrey S, Levy P, Robach P, Verges S. (2014). Cerebral hemodynamic and ventilatory responses to hypoxia, hypercapnia, and hypocapnia during 5 days at 4,350 m. J Cereb Blood Flow Metab. 34:52–60. Ruttledge H. (1934). The Mount Everest Expedition, 1933. Geogr J. 83:1–9. Ryan BJ, Wachsmuth NB, Schmidt WF, Byrnes WC, Julian CG, Lovering AT, Subudhi AW, Roach RC. (2014). AltitudeOmics: rapid hemoglobin mass alterations with early acclimatization to and de-acclimatization from 5260 m in healthy humans. PLOS ONE. 9(10):e108788. Ryn Z. (1971). Psychopathology in alpinism. Acta Med Pol. 12:453–67. Sagoo RS, Hutchinson CE, Wright A, Handford C, Parsons H, Sherwood V, Wayte S, Nagaraja S, Ng’Andwe E, Wilson MH, Imray CHE. (2016). Magnetic resonance investigation into the mechanisms involved in the development of high-altitude cerebral edema. J Cereb Blood Flow Metab. 37:319–331. Schoch HJ, Fischer S, Marti HH. (2002). Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain J Neurol. 125:2549–2557.

Mitigating the effects of hypoxia on the brain  223

Scott GR, Hawkes LA, Frappell PB, Butler PJ, Bishop CM, Milsom WK. (2015). How bar-headed geese fly over the Himalayas. Physiology. 30:107–115. Semenza GL. (2019). Pharmacologic targeting of hypoxiainducible factors. Annu Rev Pharmacol Toxicol. 59:379–403. Semenza GL. (2000). Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest. 106:809–812. Seo Y, Burns K, Fennell C, Kim J-H, Gunstad J, Glickman E, McDaniel J. (2015). The influence of exercise on cognitive performance in normobaric hypoxia. High Alt Med Biol. 16:298–305. Severinghaus JW, Chiodi H, Eger II EI, Brandstater B, Hornbein TF. (1966). Cerebral blood flow in man at high altitude: role of cerebrospinal fluid pH in normalization of flow in chronic hypocapnia. Circ Res. 19:274–282. Sharma VM, Malhotra MS. (1976). Ethnic variations in psychological performance under altitude stress. Aviat Sp Environ Med. 47:248–251. Sharma VM, Malhotra MS, Baskaran AS. (1975). Variations in psychomotor efficiency during prolonged stay at high altitude. Ergon. 18:511. Shimoda LA, Polak J. (2010). Hypoxia. 4. Hypoxia and ion channel function. Am J Physiol Physiol. 300:C951–C967. Shipton E. (1943). Upon That Mountain. Hodder and Stoughton: London. Shukitt-hale B, Banderet LE, Lieberman HR, Banderet LE, Lieberman HR, Shukitt-hale B, Banderet LE, Lieberman HR. (1998). Elevation-dependent symptom, mood, and performance changes produced by exposure to hypobaric hypoxia. Int J Aviat Psychol. 8:319–334. Siebenmann C, Cathomen A, Hug M, Keiser S, Lundby AK, Hilty MP, Goetze JP, Rasmussen P, Lundby C. (2015). Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454-m altitude. J Appl Physiol (1985). 119:1194–1201. Siebenmann C, Robach P, Lundby C. (2017). Regulation of blood volume in lowlanders exposed to high altitude. J Appl Physiol. 123:957–966. Siesjö BK. (1992a). Pathophysiology and treatment of focal cerebral ischemia. Part I: pathophysiology. J Neurosurg. 77:169–184. Siesjö BK. (1992b). Pathophysiology and treatment of focal cerebral ischemia. Part II: mechanisms of damage and treatment. J Neurosurg. 77:337–354. Silver IA, Erecińska M. (1990). Intracellular and extracellular changes of [Ca2+] in hypoxia and ischemia in rat brain in vivo. J Gen Physiol. 95:837–866. Singh SB, Thakur L, Anand JP, Yadav D, Amitabh, Banerjee PK, Selvamurthy W. (2004). Changes in visual evoked potentials on acute induction to high altitude. Indian J Med Res. 120:472. Subudhi AW, Bourdillon N, Bucher J, Davis C, Elliott JE, Eutermoster M, Evero O, Fan J, Houten SJ, Julian CG,

Kark J, Kark S, Kayser B, Kern JP, Kim SE, Lathan C, Laurie SS, Lovering AT, Paterson R, Polaner DM, Ryan BJ, Spira JL, Tsao JW, Wachsmuth NB, Roach RC. (2014). AltitudeOmics: the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent. PLOS ONE. 9:e92191. Subudhi AW, Fan JL, Evero O, Bourdillon N, Kayser B, Julian CG, Lovering AT, Roach RC. (2013). AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery. Exp Physiol. 99:772–781. Subudhi AW, Miramon BR, Granger ME, Roach RC. (2009). Frontal and motor cortex oxygenation during maximal exercise in normoxia and hypoxia. J Appl Physiol. 106:1153–1158. Taylor J, Komi P, Nicol C. (2008). Central and neuromuscular fatigue. In: Physiological Bases of Human Performance during Work and Exercise. Taylor NAS, Groeller H, eds. Elsevier: Churchill Livingstone, pp. 91–113. Temme LA, Still DL, Acromite MT. (2010). Hypoxia and flight performance of military instructor pilots in a flight simulator. Aviat Sp Environ Med. 81:654–659. Thakur L, Ray K, Anand JP, Panjwani U. (2011). Event related potential (ERP) P300 after 6 months residence at 4115 meter. Indian J Med Res. 134:113–117. Tissandier G. (1875). Le voyage à grande hauteur du ballon “Le Zenith.” La Nat Paris 3:337–344. Tjong YW, Jian K, Li M, Chen M, Gao TM, Fung ML. (2007). Elevated endogenous nitric oxide increases Ca2+ flux via L-type Ca2+ channels by S-nitrosylation in rat hippocampal neurons during severe hypoxia and in vitro ischemia. Free Radic Biol Med. 42:52–63. Townes BD, Hornbein TF, Schoene RB. (1984). Human cerebral function at extreme altitude. In: High Altitude and Man. JB West and S Lahiri, eds. American Physiological Society: Bethesda, Md. pp. 32–36. Trapp S, Ballanyi K. (1995). KATP channel mediation of anoxia-induced outward current in rat dorsal vagal neurons in vitro. J Physiol. 487:37–50. Tsarouchas N, Benedek K, Bezerianos A, Benedek G, Keri S. (2008). Effects of moderate hypobaric hypoxia on evoked categorical visuocognitive responses. Clin Neurophysiol. 119:1475–1485. Turner CE, Barker-collo SL, Connell CJW, Gant N. (2015). Physiology & behavior acute hypoxic gas breathing severely impairs cognition and task learning in humans. Physiol Behav. 142:104–110. Vestergaard MB, Lindberg U, Aachmann-Andersen NJ, Lisbjerg K, Christensen SJ, Law I, Rasmussen P, Olsen N V, Larsson HBW. (2016). Acute hypoxia increases the cerebral metabolic rate – a magnetic resonance imaging study. J Cereb Blood Flow Metab. 36:1046–1058. Villafuerte FC, Corante N. (2016). Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High Alt Med Biol. 17:61–69.

224  Central nervous system

Virués-Ortega J, Buela-Casal G, Garrido E, Alcázar B. (2004). Neuropsychological functioning associated with high-altitude exposure. Neuropsychol Rev. 4:197–224. Wang J, Ke T, Zhang X, Chen Y, Liu M, Chen J, Luo W. (2013). Neurotoxicology and Teratology Effects of acetazolamide on cognitive performance during highaltitude exposure. Neurotoxicol Teratol. 35:28–33. Watson DB, Martin RL, McAnally KI, Smith SE, Emonson DL. (2000). Effect of normobaric hypoxia on auditory sensitivity. Aviat Space Environ Med. 71:791–797. Wei W, Wang X, Gong Q, Fan M, Zhang J. (2017). Cortical thickness of Native Tibetans in the Qinghai-Tibetan Plateau. Am J Neuroradiol. 38:553–560. Weinbrecht PT, Johnson LC, Longmuir IS, Knopp JA. (1986). Influence of PaO2 on cerebral macro- and microcirculation as observed by light reflection: time course of changes. Adv Exp Med Biol. 200:131. West JB. (2015). A strategy for oxygen conditioning at high altitude: comparison with air conditioning. J Appl Physiol. 119:719–723. West JB. (2016). Oxygen conditioning: a new technique for improving living and working at high altitude. Physiology. 31:216–222. 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, MacLeod DB, Smith KJ, Lewis NC, Foster GE, Ikeda K, Hoiland RL, Ainslie PN. (2015). The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude. J Cereb Blood Flow Metab. 35:873–881. Willie CK, Tzeng Y, Fisher JA, Ainslie PN. (2014a). Integrative regulation of human brain blood flow. J Physiol. 592:841–859. Willie CK, Smith KJ, Day TA, Ray LA, Bakker A, Macleod DB, Ainslie PN. (2014b). Regional cerebral blood flow in humans at high altitude: gradual ascent and 2 wk at 5,050 m. J Appl Physiol. 116:905–910. Wilson MH, Davagnanam I, Holland G, Dattani RS, Tamm A, Hirani SP, Kolfschoten N, Strycharczuk L, Green C, Thornton JS, Wright A, Edsell M, Kitchen ND, Sharp DJ, Ham TE, Murray A, Holloway CJ, Clarke K, Grocott MPW, Montgomery H, Imray C, Birmingham Medical Research Expeditionary Society, Caudwell Xtreme

Everest Research Group. (2013). Cerebral venous system and anatomical predisposition to high-altitude headache. Ann Neurol. 73:381–389. Wilson MH, Imray CHE. (2015). The cerebral venous system and hypoxia. J Appl Physiol. 120:244–250. Wohns RN, Colpitts M, Colpitts Y, Clement T, Blackett WB. (1987). Effect of high altitude on the visual evoked responses in humans on Mt. Everest. Neurosurgery. 21:352–356. Xu K, LaManna JC. (2006). Chronic hypoxia and the cerebral circulation. J Appl Physiol. 100:725–730. Yamamoto S, Tanaka E, Higashi H. (1997). Mediation by intracellular calcium-dependent signals of hypoxic hyperpolarization in rat hippocampal CA1 neurons in vitro. J Neurophysiol. 77:386–392. Yan X, Zhang J, Gong Q, Weng X. (2011a). Adaptive influence of long term high altitude residence on spatial working memory: an fMRI study. Brain Cogn. 77:53–59. Yan X, Zhang J, Gong Q, Weng X. (2011b). Appetite at high altitude: an fMRI study on the impact of prolonged high-altitude residence on gustatory neural processing. Exp Brain Res. 209:495–499. Yan X, Zhang J, Gong Q, Weng X. (2011c). Prolonged high-altitude residence impacts verbal working memory: an fMRI study. Exp Brain Res. 208:437–445. Yao H, Haddad GG. (2004). Calcium and pH homeostasis in neurons during hypoxia and ischemia. Cell Calcium. 36:247–255. Zhang H, Sun Y, Lin J, Ye H, Zhang J, Jiang X, Wang X, Huang Y, Yang T. (2012). Compromised white matter microstructural integrity after mountain climbing: evidence from diffusion tensor imaging. High Alt Med Biol. 13:118–125. Zhang J, Chen J, Lin J, Yang T, Zhang H, Han Q, Fan M, Li J. (2013a). Adaptive modulation of adult brain gray and white matter to high altitude: structural MRI studies. PLOS ONE. 8:e68621. Zhang J, Liu H, Yan X, Weng X. (2011). Minimal effects on human memory following long-term living at moderate altitude. High Alt Med Biol. 12:37–43. Zhang J, Zhang H, Chen J, Fan M, Gong Q. (2013b). Structural modulation of brain development by oxygen: evidence on adolescents migrating from high altitude to sea level environment. PLOS ONE. 8:1–10. Zhao J, Zhang R, Yu Q, Zhang J. (2016). Characteristics of EEG activity during high altitude hypoxia and lowland reoxygenation. Brain Res. 1648:243–249.

13 Hematologic responses

Introduction 225 Effect of high altitude on plasma volume 225 Regulation of plasma volume 226 The effect of posture on plasma volume 227 Exercise and plasma volume 227 Effect of acute hypoxia on plasma volume 228 Effect of chronic hypoxia on plasma volume 228 Plasma volume on return to sea level 229 Erythropoiesis 229 EPO and its regulation 229 Erythropoietin, HIF, and other stimuli to production 230 High altitude and serum EPO concentration 230 Intermittent hypoxia and EPO concentration 231 High altitude and red cell mass 231

Hemoglobin concentration 232 Lowlanders going from sea level to high altitude 232 Long-term high altitude residents 232 Polycythemia of high altitude 233 Optimum hemoglobin concentration 233 Effect of blood boosting on performance at sea level and high altitude 234 Erythropoietin and hemoglobin concentration on descent from high altitude 235 Iron and hematologic responses to high altitude 235 Platelet function at high altitude 236 The coagulation system at high altitude 237 White blood cells 237 References 237

INTRODUCTION

and other variables, and how these responses may vary between high altitude populations. The chapter concludes with consideration of other aspects of hematologic function at high altitude including platelet function, the clotting cascade, and white blood cell function.

Following ascent to high altitude, barometric pressure decreases, thereby leading to a decrease in the arterial partial pressure of oxygen and, as a result, a decrease in hemoglobin-oxygen saturation. Acutely, cardiac output increases and helps maintain oxygen delivery in the face of these changes, but over time, the primary compensatory mechanism is a rise in blood hemoglobin concentration and the subsequent increase in oxygen-carrying capacity and arterial oxygen content. This chapter examines the primary factors responsible for changes in plasma volume (PV), which play a large role in the initial increase in hemoglobin concentration (Hb), and changes in red cell mass (RCM), the factor responsible for the continuing rise in oxygen carrying capacity over the following weeks to months at high altitude. The regulation of each of these factors is discussed, as well as how the observed responses are altered by acute and chronic hypoxic exposure, exercise,

EFFECT OF HIGH ALTITUDE ON PLASMA VOLUME As noted above, the initial increase in hemoglobin concentration following ascent occurs as a result of a reduction in plasma volume rather than erythropoiesis itself, as the latter requires several days to weeks to take place. As a result, it is necessary to begin a discussion of hematologic responses to acute hypoxia with a discussion of how plasma volume changes at high altitude and in response to other factors such as changes in posture and exercise.

225

226  Hematologic responses

Regulation of plasma volume Plasma volume is primarily controlled by a feedback loop involving atrial natriuretic peptide (ANP). This hormone is released in response to increased right atrial stretch (Laragh 1985), which occurs as a result of redistribution of blood volume from the periphery or by an increase in the total blood volume. ANP causes sodium and water loss from the kidneys, which, in turn, reduces PV. The regulation of this system is described in Figure 13.1, although the precise mechanisms by which PV is controlled in acute hypoxia has not yet been elucidated. The endocrine response to high altitude, including ANP, is described in further detail in Chapter 16. HYDRATION STATUS

Hydration and dehydration obviously affect PV, along with all other body fluid compartments. Depending on whether dehydration occurs by decreased fluid intake or fluid loss via increased diuresis and sweating with its associated salt and electrolyte losses, it may affect the balance of water loss from various body compartments. VASCULAR CAPACITY

The vascular capacity is determined by the tone of the vessels, especially the venous capacitance vessels and vessels in the skin. Vascular tone, in turn, depends on a number of

factors, such as temperature and catecholamine levels, as well as hydration status. Peripheral vasoconstriction shifts blood from the periphery to the central circulation, raising right atrial pressure, stretching the atria, and stimulating ANP release, while vasodilatation has the opposite effect. A change in vascular capacity also has a more direct effect on PV by shifting the balance of forces in the Starling equation. Vasodilatation tends to reduce the intravascular pressure, favoring inward movement of fluid to the circulation, while vasoconstriction has the opposite effect. ANTIDIURETIC HORMONE

Secretion of antidiuretic hormone (ADH) in response to increased plasma osmolality raises PV by decreasing free water loss in the kidney. Increases in vascular volume caused by hydration cause a fall in plasma osmolality that inhibits ADH secretion. This leads to a water diuresis, which leads to an increase in plasma osmolality and a subsequent rise in ADH levels. SODIUM STATUS

High sodium intake can cause water retention and increased PV, particularly when intake exceeds the individual’s ability to excrete sodium via the urine and sweat. Similar changes can be seen with sodium retention caused by stimulation of the renin-angiotensin-aldosterone system as a result of exercise or assumption of an upright posture. Exercise and

Figure 13.1  Factors affecting plasma volume (PV) and its regulation by atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), aldosterone (Aldo), and vascular capacity. Na, sodium.

Effect of high altitude on plasma volume  227

postural changes affect PV via other mechanisms that are discussed further below. These effects are mitigated to some extent by the rise in ANP that follows the increase in PV and the increase in right atrial stretch. OTHER FACTORS

Other factors that shift blood volume to the central circulation causing increased atrial stretch and ANP secretion include splanchnic vasoconstriction, assumption of the supine posture, lower body immersion, G-suits, and microgravity experienced by astronauts. Conversely, the upright position tends to shift volume to the lower extremities, reducing right atrial pressure and inhibiting ANP release.

The effect of posture on plasma volume The effect of posture must be taken into account when considering the effect of other variables such as hypoxia or exercise on PV. Seventy percent of the blood volume is below the heart in the upright position and, of this volume, 75% is in the distensible veins. Upon standing, 500 mL of additional blood enters the legs. In individuals with intact autonomic function, this leads to a reflex tachycardia and vasoconstriction that are essential to maintain cerebral perfusion and prevent fainting. Vasoconstriction maintains the blood pressure and reduces flow, especially to the skin, muscles, kidneys, and abdominal viscera. The capillaries are exposed to the hydrostatic pressure of the column of venous blood. Upon standing, the height of the venous column is increased, leading to higher hydrostatic pressure, increased filtration of f luid out of the vascular compartment, and, as a result, hemoconcentration. Numerous investigators from Thompson et al. (1928) onward have confirmed these theoretical expectations. Thompson et al., for example, found a reduction of plasma volume of 15% on assuming the upright position, but the magnitude of this effect is variable and is inf luenced by many factors, including the temperature of the environment and the subject, the state of hydration, etc.

particularly through the respiratory tract, as a result of the increased minute ventilation. These factors play a significant role at high altitude where humidity falls and minute ventilation is higher for any given level of work than at sea level. Harrison (1985) reviewed the literature and, with a number of reservations, came to the conclusion that, for bicycle ergometer exercise, there is a reduction in PV soon after starting exercise. This reduction is proportional to the intensity of exercise or, more precisely, to the rise in atrial pressure. Thereafter, there is little change with continued exercise at normal room temperature, but in high temperatures, there is a further reduction in PV with time due to sweating. However, these laboratory studies tend to look at fairly high intensity exercise (greater than 50% V.O2max) for periods of up to an hour or two. Exercise in the mountains, on the other hand, is typically done over many hours and may go on day after day. Exercise of eight hours or more at normal climbing rates (i.e., up to about 50% V.O2max but often averaging much less) is associated with an increase in PV. Pugh (1969), for example, found an increase in blood volume of 7% after a 28-mile hill walk, while Williams et al. (1979) found PV increased progressively for five days of strenuous daily hill walking, eventually reaching a value 22% above the baseline value. Both these studies were carried out under cold conditions and subjects avoided both overheating and cold stress. The changes in PV, interstitial, and intracellular volumes documented in the study by Williams et al. are shown in Figure 13.2. The reason for the expanded PV after sea-level mountaineering is predominantly due to the effect of exercise. The mechanism for these exercise-induced changes in PV is due, in part, to activation of the renin-angiotensin-aldosterone system (Milledge and Catley 1982), although multiple other factors play a role as well (Montero and Lundby 2018).

Exercise and plasma volume Exercise has an important effect on plasma volume and, therefore, hemoglobin concentration, with the effect varying according to the intensity, duration, and type of exercise, the temperatures of the environment, and the posture assumed during exercise. This is because temperature and posture affect the skin blood flow and hence the distribution of cardiac output to the working muscles and other vascular beds. This, in turn, affects the capillary and venous pressures in these areas and hence the balance of forces in the Starling equation. Many studies on the effect of exercise have ignored the effect of posture and have taken control samples in a different posture from exercise samples. Another important factor that may affect PV is the high insensible fluid losses,

Figure 13.2  The effect of five consecutive days of strenuous hill walking on body fluid compartments. The changes are calculated from changes in packed cell volume and sodium and water balances. (Source: Williams et al. 1979.)

228  Hematologic responses

It should also be noted that prolonged, continuous climbing increases the risk of dehydration and reduction in PV. In many cases, however, adequate fluid supplies are available and the risk of dehydration and heat illness remains low as long as the individual is conscientious about maintaining adequate fluid intake.

Effect of acute hypoxia on plasma volume Within one to two hours of exposure, mild-moderate degrees of acute hypoxia trigger diuretic and natriuretic responses in the kidney that can last for one to two days, while more severe levels of acute hypoxia (FIO2 6000 m) may cause a reduction in the activity of certain enzymes. The effect of extreme altitude exposure on muscle enzyme systems has been studied by taking muscle biopsies from climbers before and after the Swiss expeditions to Lhotse Shar in 1981 (Cerretelli 1987) and Mount Everest in 1986 (Howald et al. 1990) and also from experimental subjects before and after prolonged decompression during Operation Everest II (Green et al. 1989). All of these studies reported decreased activities of oxidative enzymes. Results on three subjects from the Lhotse Shar expedition suggest that extreme altitude reduces the activity of both Krebs cycle (succinate dehydrogenase) and glycolytic (phosphofructokinase and lactate dehydrogenase) enzymes (Cerretelli 1987). In a more comprehensive study of seven climbers from the Swiss 1986 expedition, reduced activity of Krebs cycle enzymes (citrate synthase, malate dehydrogenase) and the electron transport chain (cytochrome oxidase) were reported (Howald et al. 1990). In contrast to the Lhotse Shar study, this study found increased activity of glycolytic enzymes. In Operation Everest II, significant reductions were found in succinate dehydrogenase (21%), citrate synthase (37%), and hexokinase (53%) at extreme altitudes (Green et al. 1989). In one of the most involved and sophisticated studies to date (Horscroft et al. 2017), muscle biopsies were obtained at sea level or Kathmandu in lowlanders and Sherpa, respectively, 15 to 20 days after departure (five to 10 days at 5300 m), and again 54 to 59 days after departure (44 to 49 days at 5300 m). During ascent and acclimatization to high altitude, lowlanders accumulated potentially harmful lipid intermediates in muscle as a result of incomplete β-oxidation, alongside depletion of TCA cycle intermediates (including 6- and 5-carbon), accumulation of glycolytic intermediates, a loss of phosphocreatine despite improved mitochondrial coupling, and a transient increase in oxidative stress markers. In Sherpas, however, there were remarkably few changes in intermediary metabolism at altitude, but increased TCA cycle intermediates and PCr and ATP levels, with no sign of oxidative stress (Horscroft et al. 2017). The replete TCA cycle of Sherpas at altitude contrasts sharply with the depletion of TCA cycle intermediates in lowlanders and suggests a coupling of the TCA cycle in Sherpa muscle to its distinct intermediary substrate metabolism. These findings are highlighted in Figure 14.12 The impact of high altitude hypoxia on skeletal muscle metabolism has been and remains an intense and controversial area of research. Although no clear consensus has been reached, it seems that high altitude hypoxia decreases oxidative capacity in skeletal muscle, including a decrease in several markers of β-oxidation, Krebs cycle, and electron transport chain, as well as a metabolic substrate shift away from fatty acids oxidation toward glucose, amino acids, and ketone bodies. Conversely, hypoxia seems to have only a very minor impact on glycolytic enzymes, with glucose uptake well maintained, possibly to counterbalance the decrease in oxidative capacity and maintain sufficient

Intracellular enzymes, mitochondrial function, and metabolic activity  255

Figure 14.12  Tricarboxylic acid (TCA) cycle intermediates and activity in muscle. Citrate synthase (CS) activity (A) and TCA cycle intermediates (B–I) in lowlanders and Sherpas are shown. Metabolite levels are expressed relative to lowlanders at baseline. Mean ± SEM (n = 7–14). *P ≤0.05, **P ≤0.01, ***P ≤0.001 in lowlanders vs. Sherpas at baseline. †P ≤ 0.05, ††P ≤ 0.01 at baseline vs. altitude within cohort. (Source: Horscroft et al. 2017.)

energy production. Several excellent and thorough reviews are available on this topic (Hoppeler et al. 2003; Horscroft et al. 2017; Horscroft and Murray 2014).

Myoglobin concentration Myoglobin is a monomeric globin protein that facilitates diffusion of oxygen into and storage within skeletal and heart

muscle, where it is normally expressed at high levels in most vertebrates (Wittenberg and Wittenberg 2003). Because it has a higher affinity for oxygen than hemoglobin, myoglobin efficiently extracts oxygen from the blood by creating a steep pressure gradient at the sarcoplasmic membrane that increases the rate of diffusion, while also delivering it to the mitochondria through its role as an intracellular oxygen carrier (Wittenberg and Wittenberg 2003). When expressed

256  Peripheral tissues

at high concentrations, myoglobin also functions as an oxygen store, making oxygen available for respiration during muscle contractions when gas exchange with the peripheral capillaries is impaired (Fago 2017). Early studies by Hurtado et al. (1937) showed increased concentrations of myoglobin in the diaphragm, adductor muscles of the leg, pectoral muscles of the chest, and the myocardium of dogs born and raised in Morococha, Peru (4550 m), when compared to dogs at sea level in Lima. Other studies that have shown an increase in myoglobin as a result of acclimatization to hypoxia include those of hamster heart muscle (Clark 1952), rat heart muscle and diaphragm (Vaughan and Pace 1956), and various guinea pig tissues (Tappan and Reynafarje 1957). In many other species, elevations in myoglobin expression have been reported at high altitude (reviewed in [Fago 2017]), albeit with marked variation between different organs In contrast to the animal studies, results from human analyses remain equivocal. Reynafarje (1962) measured myoglobin concentrations in the sartorius muscle of healthy humans native to Cerro de Pasco (4400 m) and in other Peruvians native to sea level and found higher concentrations of myoglobin in the high altitude natives tissue (7.03 mg g−1) than in the sea-level controls (6.07 mg g−1). These results occurred in the absence of changes in lean body mass and body water content and, as a result, were likely not an artifact due to dehydration. Likewise, in humans who exercise in normobaric hypoxia, it has been reported that circulating erythropoietin (Guadalupe-Grau et al. 2015) and HIF-1α stabilization (Vogt et al. 2001) enhance myoglobin expression in exercising skeletal muscle, and possibly in other species as well (reviewed in [Fago 2017]). In contrast to these reports of elevated myoglobin concentration, others have shown that myoglobin expression in human is unaltered after return from the summit of Mount Everest (Levett et al. 2012) or decreased following a seven-to-nineday stay at 4559 m (Robach et al. 2007). Therefore, apart from one earlier study at 4440 m (Reynafarje 1962) and one that involved exercise training in normobaric hypoxia (Vogt et al. 2001), there is little consistent evidence in humans for elevations in myoglobin expression at high altitude.

EFFECTS OF PHYSICAL ACTIVITY AND OTHER FACTORS While hypoxia may directly account for many of the peripheral adaptations described above, several confounding factors should be taken into account when interpreting the literature on this topic, including the potential for both negative energy balance and dehydration at high altitude as well as changes in physical activity. The direction and magnitude that each of these confounding factors have on the studied variables are difficult to identify. For example, in the general sedentary population, a sojourn to high altitude is often associated with a strong exercise training stimulus due to multiple long days of trekking. Alternatively, in the mountaineering as well as

the scientific community interested in the physiology of high altitude, spending a substantial amount of time at a reduced level of physical activity at base camp and/or collecting scientific data may be associated with substantial detraining effects. Indeed, Tilman (1952) once remarked that a hazard of Himalayan expeditions was bedsores! Thus, the effect of physical activity or lack thereof, must be accounted for when interpreting the literature on changes in the peripheral tissues at high altitude.

Exercise training and detraining All of the changes in peripheral tissue outlined in this chapter are intimately influenced by the extent of exercise training or detraining while at high altitude. For example, exercise training at sea level increases muscle capillarity including both the capillary/fiber ratio and number of capillaries per square millimeter within several weeks (Andersen and Henriksson 1977; Brodal et al. 1977; Ingjer and Brodal 1978). Furthermore, the increase in number of capillaries is found in all fiber types that are recruited during training (Andersen and Henriksson 1977; Nygaard and Nielsen 1978), and the increased capillary supply is proportional to the increased maximum oxygen uptake (Andersen and Henriksson 1977). Endurance exercise training also increases mitochondrial volume (Meinild Lundby et al. 2018) and respiratory capacity through enzymes involved in β-oxidation, the Krebs cycle, and the electron transport chain (Holloszy and Coyle 1984; Lundby and Jacobs 2016). Myoglobin concentrations may also be affected by training status. In experimental animals, myoglobin content increases with exercise (Lawrie 1953; Pattengale and Holloszy 1967), with animals, such as seals who have large amounts of myoglobin, exhibiting high oxygen uptake in conditions of reduced oxygen availability (Castellini and Somero 1981). However, a study comparing trained and untrained human subjects (Jansson et al. 1982) and another study of short-term training in humans (Svedenhag et al. 1983) both failed to show any effect of training on muscle myoglobin concentration. Interestingly, when exercise training was performed under hypoxic conditions, muscle myoglobin concentrations were increased (Terrados et al. 1990). Detraining or inactivity, a common phenomenon during high altitude expeditions, can also lead to profound deconditioning within the peripheral tissues. For example, bed rest typically results in a loss of skeletal muscle mass, capillary density, skeletal muscle oxidative function, mitochondrial biogenesis, and remodeling (Buso et al. 2019; Standley et al. 2020; Trevino et al. 2019). Interestingly, the addition of hypoxia seems to aggravate inactivity-induced muscle wasting, but has little effect on mitochondrial and oxidative function (Debevec et al. 2018; Salvadego et al. 2016; Salvadego et al. 2018). While these data highlight that exercise or lack thereof may augment or counteract adaptations to hypoxia, changes in physical activity are unlikely to be the whole story as evidenced by the experience of

Effects of physical activity and other factors  257

Table 14.1  Comparison of tissue changes caused by endurance training and exposure to high altitude Tissue changes

Endurance training

High altitude

Capillary density in skeletal muscle

Increased mainly due to formation of new capillaries (angiogenesis)

Increased mainly due to a size reduction of muscle fibers

Capillary perfusion Angiogenic activity Fiber diameter of skeletal muscle Myoglobin concentration Muscle enzymes

Increased Increased May be increased

Increased ? Decreased

No change in humans

Increased in skeletal, heart muscle

No change in glycolytic, increase in oxidative

Mitochondria

Increased volume density

Similar changes at moderate altitudes; at extreme altitudes, increase in glycolytic and decrease in oxidative Increased volume density in some animals at moderate altitude but reduced density in humans at extreme altitude Different intracellular distribution, e.g., loss of subsarcolemmal mitochondria in comparison to training

the investigators on the 1960–61 Himalayan Scientific and Mountaineering Expedition. During several months at 5800 m, the level of physical activity was well maintained with opportunities for daily skiing, yet the expedition members suffered a relentless and progressive loss of weight that averaged 0.5–1.5 kg per week (Pugh 1964) (discussed further in Chapter 15). Moreover, one study directly compared active versus passive ascent to 5250 m and found that the loss in muscle fiber area was independent of the method of ascent (Mizuno et al. 2008). Nevertheless, the influence of well-controlled and comparable (e.g., intensity and duration) exercise training studies at both sea level and high altitude on peripheral tissue adaptations have not been conducted. It must be stressed, however, that it is difficult to maintain the same level of physical activity during exposure to chronic hypoxia and difficult to match sea level residents with residents at altitude with respect to physical activity Future research that accounts for the effects of exercise and inactivity may yield further insights into the peripheral tissue adaptations to hypoxia. Table 14.1 compares some of the tissue changes caused by training with those resulting from exposure to high altitude.

REFERENCES Aiken J, Roudier E, Ciccone J, Drouin G, Stromberg A, Vojnovic J, Olfert IM, Haas T, Gustafsson T, Grenier G, others. (2016). Phosphorylation of murine double minute-2 on Ser166 is downstream of VEGF-A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression. FASEB J 30:120–134.

Amadio M, Scapagnini G, Lupo G, Drago F, Govoni S, Pascale A. (2008). PKCbetaII/HuR/VEGF: a new molecular cascade in retinal pericytes for the regulation of VEGF gene expression. Pharmacol Res. 57:60–66. Andersen P, Henriksson J. (1977). Capillary supply of the quadriceps femoris muscle of man: adaptive response to exercise. J Physiol. 270:677–690. Angleys H, Ostergaard L. (2020). Krogh’s capillary recruitment hypothesis, 100 years on: is the opening of previously closed capillaries necessary to ensure muscle oxygenation during exercise? Am J Physiol Heart Circ Physiol. 318:H425–H447. Appell HJ. (1978). Capillary density and patterns in skeletal muscle. III. Changes of the capillary pattern after hypoxia. Pflügers Arch. 377:R53 (abstract). Banchero N. (1982). Long term adaptation of skeletal muscle capillarity. Physiologist. 25:385–389. Banchero N. (1987). Cardiovascular responses to chronic hypoxia. Annu Rev Physiol. 49:465–476. Berryman CE, Karl JP, Cole RE, Kenefick RW, Margolis LM, Carbone JW, Ferrando AA, Lieberman HR, Young AJ, Pasiakos SM. (2017). Prolonged high altitude exposure exacerbates fat‐free mass and fat mass loss during negative energy balance regardless of dietary protein intake. FASEB J. https://doi.org/10.1096/ fasebj.31.1_supplement.841.17. Birot OJ, Koulmann N, Peinnequin A, Bigard XA. (2003). Exercise-induced expression of vascular endothelial growth factor mRNA in rat skeletal muscle is dependent on fibre type. J Physiol. 552:213–221.

258  Peripheral tissues

Birot OJ, Peinnequin A, Simler N, van Cuyck-Gandre H, Hamel R, Bigard XA. (2004). Vascular endothelial growth factor expression in heart of rats exposed to hypobaric hypoxia: differential response between mRNA and protein. J Cell Physiol. 200:107–115. Bourdillon N, Mollard P, Letournel M, Beaudry M, Richalet JP. (2009). Non-invasive evaluation of capillary recruitment in the human muscle during exercise in hypoxia. Respir Physiol Neurobiol. 165:237–244. Boutellier U, Howald H, di Prampero PE, Giezendanner D, Cerretelli P. (1983). Human muscle adaptations to chronic hypoxia. Prog Clin Biol Res. 136:273–285. Breen E, Tang K, Olfert M, Knapp A, Wagner P. (2008). Skeletal muscle capillarity during hypoxia: VEGF and its activation. High Alt Med Biol. 9:158–166. Breen EC, Johnson EC, Wagner H, Tseng HM, Sung LA, Wagner PD. (1996). Angiogenic growth factor mRNA responses in muscle to a single bout of exercise. J Appl Physiol (1985). 81:355–361. Brodal P, Ingjer F, Hermansen L. (1977). Capillary supply of skeletal muscle fibers in untrained and endurancetrained men. Am J Physiol. 232:H705–712. Buso A, Comelli M, Picco R, Isola M, Magnesa B, Pisot R, Rittweger J, Salvadego D, Simunic B, Grassi B, others. (2019). Mitochondrial adaptations in elderly and young men skeletal muscle following 2 weeks of bed rest and rehabilitation. Front Physiol. 10:474. Cassin S, Gilbert RD, Bunnell CE, Johnson EM. (1971). Capillary development during exposure to chronic hypoxia. Am J Physiol. 220:448–451. Castellini MA, Somero GN. (1981). Buffering capacity of vertebrate muscle: correlations with potentials for anaerobic function. J Comp Physiol. 143:191–198. Cerretelli P. (1987). Extreme hypoxia in air breathers: some problems. In Comparative Physiology of Environmental Adaptations, Vol. 2: Adaptations to Extreme Environments. Dejours P, ed. Karger, Basel. Cerretelli P, Marconi C, Deriaz O, Giezendanner D. (1984). After effects of chronic hypoxia on cardiac output and muscle blood flow at rest and exercise. Eur J Appl Physiol Occup Physiol. 53:92–96. Chaillou T. (2018). Skeletal muscle fiber type in hypoxia: adaptation to high-altitude exposure and under conditions of pathological hypoxia. Front Physiol. 9:1450. Chaillou T, Koulmann N, Meunier A, Pugniere P, McCarthy JJ, Beaudry M, Bigard X. (2014). Ambient hypoxia enhances the loss of muscle mass after extensive injury. Pflugers Arch. 466:587–598. Chance B. (1957). Cellular oxygen requirements. Fed Proc. 16:671–680. Chance B, Cohen P, Jobsis F, Schoener B. (1962). Intracellular oxidation-reduction states in vivo. Science. 137:499–508. Clark RT, Criscuolo, D, Coulson, DK. (1952). Effects of 20,000 feet simulated altitude on myoglobin content of animals with and without exercise. Fed Proc. 11:25.

D’Hulst G, Deldicque L. (2017). Human skeletal muscle wasting in hypoxia: a matter of hypoxic dose? J Appl Physiol (1985). 122:406–408. D’Hulst G, Ferri A, Naslain D, Bertrand L, Horman S, Francaux M, Bishop DJ, Deldicque L. (2016). Fifteen days of 3,200 m simulated hypoxia marginally regulates markers for protein synthesis and degradation in human skeletal muscle. Hypoxia (Auckl). 4:1–14. de Theije CC, Langen RC, Lamers WH, Gosker HR, Schols AM, Kohler SE. (2015). Differential sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy. J Appl Physiol (1985). 118:200–211. Debevec T, Ganse B, Mittag U, Eiken O, Mekjavic IB, Rittweger J. (2018). Hypoxia aggravates inactivityrelated muscle wasting. Front Physiol. 9:494. Deveci D, Egginton S. (2002). Differing mechanisms of cold-induced changes in capillary supply in m. tibialis anterior of rats and hamsters. J Exp Biol. 205:829–840. Deveci D, Marshall JM, Egginton S. (2001). Relationship between capillary angiogenesis, fiber type, and fiber size in chronic systemic hypoxia. Am J Physiol Heart Circ Physiol. 281:H241–252. Deveci D, Marshall JM, Egginton S. (2002). Chronic hypoxia induces prolonged angiogenesis in skeletal muscles of rats. Exp Physiol. 87:287–291. Doria C, Toniolo L, Verratti V, Cancellara P, Pietrangelo T, Marconi V, Paoli A, Pogliaghi S, Fano G, Reggiani C, others. (2011). Improved VO2 uptake kinetics and shift in muscle fiber type in high-altitude trekkers. J Appl Physiol (1985). 111:1597–1605. Ellis CG, Wrigley SM, Groom AC. (1994). Heterogeneity of red blood cell perfusion in capillary networks supplied by a single arteriole in resting skeletal muscle. Circ Res. 75:357–368. Etheridge T, Atherton PJ, Wilkinson D, Selby A, Rankin D, Webborn N, Smith K, Watt PW. (2011). Effects of hypoxia on muscle protein synthesis and anabolic signaling at rest and in response to acute resistance exercise. Am J Physiol Endocrinol Metab. 301:E697–E702. Fago A. (2017). Functional roles of globin proteins in hypoxia-tolerant ectothermic vertebrates. J Appl Physiol (1985). 123:926–934. Favier FB, Britto FA, Freyssenet DG, Bigard XA, Benoit H. (2015). HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology. Cell Mol Life Sci. 72:4681–4696. Favier FB, Costes F, Defour A, Bonnefoy R, Lefai E, Bauge S, Peinnequin A, Benoit H, Freyssenet D. (2010). Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia. Am J Physiol Regul Integr Comp Physiol. 298:R1659–1666. Ferrara N. (2001). Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 280:C1358–1366.

Effects of physical activity and other factors  259

Folkman J, Shing Y. (1992). Angiogenesis. J Biol Chem. 267:10931–10934. Gamboa JL, Andrade FH. (2010). Mitochondrial content and distribution changes specific to mouse diaphragm after chronic normobaric hypoxia. Am J Physiol Regul Integr Comp Physiol. 298:R575–583. Gavin TP, Wagner PD. (2001). Effect of short-term exercise training on angiogenic growth factor gene responses in rats. J Appl Physiol (1985). 90:1219–1226. Gerber HP, Condorelli F, Park J, Ferrara N. (1997). Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem. 272:23659–23667. Golub AS, Pittman RN. (2013). Bang-bang model for regulation of local blood flow. Microcirculation. 20:455–483. Green H, Roy B, Grant S, Burnett M, Tupling R, Otto C, Pipe A, McKenzie D. (2000). Downregulation in muscle Na(+)-K(+)-ATPase following a 21-day expedition to 6,194 m. J Appl Physiol (1985). 88:634–640. Green HJ, Sutton JR, Cymerman A, Young PM, Houston CS. (1989). Operation Everest II: adaptations in human skeletal muscle. J Appl Physiol (1985). 66:2454–2461. Guadalupe-Grau A, Plenge U, Helbo S, Kristensen M, Andersen PR, Fago A, Belhage B, Dela F, Helge JW. (2015). Effects of an 8-weeks erythropoietin treatment on mitochondrial and whole body fat oxidation capacity during exercise in healthy males. J Sports Sci. 33:570–578. Gustafsson T, Puntschart A, Kaijser L, Jansson E, Sundberg CJ. (1999). Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle. Am J Physiol. 276:H679–685. Harris P, Castillo Y, Gibson K, and others. (1970). Succinic and lactic dehydrogenase activity in myocardial homogenates from animals at high and low altitude. J Mol Cell Cardiol. 1:189–193. Hepple RT, Agey PJ, Hazelwood L, Szewczak JM, MacMillen RE, Mathieu-Costello O. (1998). Increased capillarity in leg muscle of finches living at altitude. J Appl Physiol (1985). 85:1871–1876. Hill AV. (1928). The diffusion of oxygen and lactic acid through tissues. Proc R Soc Lond B. 104:39–96. Hochachka PW, Stanley C, Merkt J, Sumar-Kalinowski J. (1983). Metabolic meaning of elevated levels of oxidative enzymes in high altitude adapted animals: an interpretive hypothesis. Respir Physiol. 52:303–313. Holloszy JO, Coyle EF. (1984). Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol Respir Environ Exerc Physiol. 56:831–838. Holm L, Haslund ML, Robach P, van Hall G, Calbet JA, Saltin B, Lundby C. (2010). Skeletal muscle myofibrillar and sarcoplasmic protein synthesis rates are affected

differently by altitude-induced hypoxia in native lowlanders. PLOS ONE. 5:e15606. Honig CR, Gayeski TEJ, Groebe K. (1991). Myoglobin and oxygen gradients. In The Lung: Scientific Foundations. Crystal RG, West JB, eds. Raven Press, New York. pp. 1489–1496. Hoppeler H. (1990). The different relationship of VO2max to muscle mitochondria in humans and quadrupedal animals. Respir Physiol. 80:137–145. Hoppeler H. (1999). Vascular growth in hypoxic skeletal muscle. Adv Exp Med Biol 474:277–286. Hoppeler H, Howald H, Cerretelli P. (1990a). Human muscle structure after exposure to extreme altitude. Experientia. 46:1185–1187. Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P. (1990b). Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 11:S3–9. Hoppeler H, Vogt M, Weibel ER, Fluck M. (2003). Response of skeletal muscle mitochondria to hypoxia. Exp Physiol. 88:109–119. Horscroft JA, Kotwica AO, Laner V, West JA, Hennis PJ, Levett DZH, Howard DJ, Fernandez BO, Burgess SL, Ament Z, others. (2017). Metabolic basis to Sherpa altitude adaptation. Proc Natl Acad Sci U S A. 114:6382–6387. Horscroft JA, Murray AJ. (2014). Skeletal muscle energy metabolism in environmental hypoxia: climbing towards consensus. Extrem Physiol Med. 3:19. Howald H, Hoppeler H. (2003). Performing at extreme altitude: muscle cellular and subcellular adaptations. Eur J Appl Physiol. 90:360–364. Howald H, Pette D, Simoneau, JA, and others. (1990). Effect of chronic hypoxia on muscle enzyme activities. Int J Sports Med. 11(Suppl. 1):S10–S14. Huez I, Creancier L, Audigier S, Gensac MC, Prats AC, Prats H. (1998). Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol Cell Biol. 18:6178–6190. Hurtado A, Rotta A, Merino C, Pons J. (1937). Studies of myohemoglobin at high altitude. Am J Med Sci. 194:708–713. Hutter J, Habler O, Kleen M, Tiede M, Podtschaske A, Kemming G, Corso C, Batra S, Keipert P, Faithfull S, others. (1999). Effect of acute normovolemic hemodilution on distribution of blood flow and tissue oxygenation in dog skeletal muscle. J Appl Physiol (1985). 86:860–866. Imoberdorf R, Garlick PJ, McNurlan MA, Casella GA, Marini JC, Turgay M, Bartsch P, Ballmer PE. (2006). Skeletal muscle protein synthesis after active or passive ascent to high altitude. Med Sci Sports Exerc 38:1082–1087. Ingjer F, Brodal P. (1978). Capillary supply of skeletal muscle fibers in untrained and endurance-trained women. Eur J Appl Physiol Occup Physiol. 38:291–299.

260  Peripheral tissues

Jacobs RA, Lundby AK, Fenk S, Gehrig S, Siebenmann C, Fluck D, Kirk N, Hilty MP, Lundby C. (2016). Twentyeight days of exposure to 3454 m increases mitochondrial volume density in human skeletal muscle. J Physiol. 594:1151–1166. Jansson E, Sylven C, Nordevang E. (1982). Myoglobin in the quadriceps femoris muscle of competitive cyclists and untrained men. Acta Physiol Scand. 114:627–629. Johnson PC, Vandegriff K, Tsai AG, Intaglietta M. (2005). Effect of acute hypoxia on microcirculatory and tissue oxygen levels in rat cremaster muscle. J Appl Physiol (1985). 98:1177–1184. Juel C, Lundby C, Sander M, Calbet JA, Hall G. (2003). Human skeletal muscle and erythrocyte proteins involved in acid-base homeostasis: adaptations to chronic hypoxia. J Physiol. 548:639–648. Jung F, Kessler H, Pindur G, Sternitzky R, Franke RP. (1999). Intramuscular oxygen partial pressure in the healthy during exercise. Clin Hemorheol Microcirc. 21:25–33. Kayser B, Hoppeler H, Claassen H, Cerretelli P. (1991). Muscle structure and performance capacity of Himalayan Sherpas. J Appl Physiol (1985). 70:1938–1942. Kayser B, Hoppeler H, Desplanches D, Marconi C, Broers B, Cerretelli P. (1996). Muscle ultrastructure and biochemistry of lowland Tibetans. J Appl Physiol (1985). 81:419–425. Kearney MS. (1973). Ultrastructural changes in the heart at high altitude. Pathol Microbiol (Basel). 39:258–265. Krogh A. (1919). The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J Physiol. 52:409–415. Lawrie RA. (1953). Effect of enforced exercise on myoglobin concentration in muscle. Nature. 171:1069–1070. Levett DZ, Radford EJ, Menassa DA, Graber EF, Morash AJ, Hoppeler H, Clarke K, Martin DS, Ferguson-Smith AC, Montgomery HE, others. (2012). Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J. 26:1431–1441. Lui MA, Mahalingam S, Patel P, Connaty AD, Ivy CM, Cheviron ZA, Storz JF, McClelland GB, Scott GR. (2015). High-altitude ancestry and hypoxia acclimation have distinct effects on exercise capacity and muscle phenotype in deer mice. Am J Physiol Regul Integr Comp Physiol. 308:R779–791. Lundby C, Jacobs RA. (2016). Adaptations of skeletal muscle mitochondria to exercise training. Exp Physiol. 101:17–22. Lundby C, Pilegaard H, Andersen JL, van Hall G, Sander M, Calbet JA. (2004). Acclimatization to 4100 m does not change capillary density or mRNA expression of potential angiogenesis regulatory factors in human skeletal muscle. J Exp Biol. 207:3865–3871. MacDougall JD, Green HJ, Sutton JR, Coates G, Cymerman A, Young P, Houston CS. (1991). Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand. 142:421–427.

Masschelein E, Van Thienen R, D’Hulst G, Hespel P, Thomis M, Deldicque L. (2014). Acute environmental hypoxia induces LC3 lipidation in a genotype-dependent manner. FASEB J. 28:1022–1034. Mathieu-Costello O. (1987). Capillary tortuosity and degree of contraction or extension of skeletal muscles. Microvasc Res. 33:98–117. Mathieu-Costello O. (1989). Muscle capillary tortuosity in high altitude mice depends on sarcomere length. Respir Physiol. 76:289–302. Meinild Lundby AK, Jacobs RA, Gehrig S, de Leur J, Hauser M, Bonne TC, Fluck D, Dandanell S, Kirk N, Kaech A, others. (2018). Exercise training increases skeletal muscle mitochondrial volume density by enlargement of existing mitochondria and not de novo biogenesis. Acta Physiol (Oxf). 222:e12976. Menzies RA, Gold PH. (1971). The turnover of mitochondria in a variety of tissues of young adult and aged rats. J Biol Chem. 246:2425–2429. Mercker H, Schneider M. (1949). Uber capillarveranderungen des gehirns bei hohenanpassung. Pflügers Arch. 251:49–55. Millet GP, Brocherie F, Girard O, Wehrlin JP, Troesch S, Hauser A, Steiner T, Peltonen JE, Rusko HK, Constantini K, others. (2016). Commentaries on viewpoint: time for a new metric for hypoxic dose? J Appl Physiol. (1985) 121:356–358. Millet GP, Debevec T, Brocherie F, Girard O, Pialoux V, Wust RC, Degens H, Zuo L, He F, Chaillou T, others. (2017). Commentaries on viewpoint: human skeletal muscle wasting in hypoxia: a matter of hypoxic dose? J Appl Physiol (1985). 122:409–411. Mizuno M, Savard GK, Areskog NH, Lundby C, Saltin B. (2008). Skeletal muscle adaptations to prolonged exposure to extreme altitude: a role of physical activity? High Alt Med Biol. 9:311–317. Morfoisse F, Renaud E, Hantelys F, Prats AC, Garmy-Susini B. (2015). Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis. Mol Cell Oncol. 2:e1024821. Murray AJ, Horscroft JA. (2016). Mitochondrial function at extreme high altitude. J Physiol. 594:1137–1149. Nygaard E, Nielsen E. (1978). Skeletal muscle fibre capillarization with extreme endurance training in man. In Swimming Medicine IV. Eriksson B, Furberg B, eds. University Park Press, Baltimore, MD. Olfert IM, Birot O. (2011). Importance of anti-angiogenic factors in the regulation of skeletal muscle angiogenesis. Microcirculation. 18:316–330. Olfert IM, Breen EC, Mathieu-Costello O, Wagner PD. (2001). Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia. J Appl Physiol. (1985) 91:1176–1184. Opitz E. (1951). Increased vascularization of the tissue due to acclimatization to high altitude and its significance for the oxygen transport. Exp Med Surg. 9:389–403.

Effects of physical activity and other factors  261

Osera C, Martindale JL, Amadio M, Kim J, Yang X, Moad CA, Indig FE, Govoni S, Abdelmohsen K, Gorospe M, others. (2015). Induction of VEGFA mRNA translation by CoCl2 mediated by HuR. RNA Biol. 12:1121–1130. Ou LC, Tenney SM. (1970). Properties of mitochondria from hearts of cattle acclimatized to high altitude. Respir Physiol. 8:151–159. Ozawa K, Kondo T, Hori O, Kitao Y, Stern DM, Eisenmenger W, Ogawa S, Ohshima T. (2001a). Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. J Clin Invest. 108:41–50. Ozawa K, Tsukamoto Y, Hori O, Kitao Y, Yanagi H, Stern DM, Ogawa S. (2001b). Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmic reticulum chaperone. Cancer Res. 61:4206–4213. Pattengale PK, Holloszy JO. (1967). Augmentation of skeletal muscle myoglobin by a program of treadmill running. Am J Physiol. 213:783–785. Piiper J, Scheid P. (1986). Cross-sectional PO2 distributions in Krogh cylinder and solid cylinder models. Respir Physiol. 64:241–251. Poole DC, Copp SW, Hirai DM, Musch TI. (2011). Dynamics of muscle microcirculatory and blood-myocyte O(2) flux during contractions. Acta Physiol (Oxf). 202:293–310. Poole DC, Mathieu-Costello O. (1990). Effects of hypoxia on capillary orientation in anterior tibialis muscle of highly active mice. Respir Physiol. 82:1–10. Poole DC, Mathieu-Costello O, West JB. (1989). Capillary tortuosity in rat soleus muscle is not affected by endurance training. Am J Physiol. 256:H1110–1116. Potter RF, Groom AC. (1983). Capillary diameter and geometry in cardiac and skeletal muscle studied by means of corrosion casts. Microvasc Res. 25:68–84. Pugh LGCE. (1964). Man at high altitude. Sci Basis Med Annual Rev. 32–54. Reynafarje B. (1962). Myoglobin content and enzymatic activity of muscle and altitude adaptation. J Appl Physiol. 17:301–305. Richardson RS. (2000). Intracellular PO2 and bioenergetic measurements in skeletal muscle: the role of exercise paradigm. Am J Physiol Regul Integr Comp Physiol. 278:R1111–1113. Richardson RS, Duteil S, Wary C, Wray DW, Hoff J, Carlier PG. (2006). Human skeletal muscle intracellular oxygenation: the impact of ambient oxygen availability. J Physiol. 571:415–424. Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. (1995). Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J Clin Invest. 96:1916–1926. Richmond KN, Burnite S, Lynch RM. (1997). Oxygen sensitivity of mitochondrial metabolic state in isolated skeletal and cardiac myocytes. Am J Physiol. 273:C1613–1622. Robach P, Cairo G, Gelfi C, Bernuzzi F, Pilegaard H, Vigano A, Santambrogio P, Cerretelli P, Calbet JA, Moutereau S, others. (2007). Strong iron demand

during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle. Blood. 109:4724–4731. Roughton FJW. (1964). Transport of oxygen and carbon dioxide. In Handbook of Physiology, Section 3, Respiration. Fenn WO, Rahn H, eds. American Physiological Society, Washington, DC. pp. 767–825. Salvadego D, Keramidas ME, Brocca L, Domenis R, Mavelli I, Rittweger J, Eiken O, Mekjavic IB, Grassi B. (2016). Separate and combined effects of a 10-d exposure to hypoxia and inactivity on oxidative function in vivo and mitochondrial respiration ex vivo in humans. J Appl Physiol. (1985) 121:154–163. Salvadego D, Keramidas ME, Kolegard R, Brocca L, Lazzer S, Mavelli I, Rittweger J, Eiken O, Mekjavic IB, Grassi B. (2018). PlanHab(*): hypoxia does not worsen the impairment of skeletal muscle oxidative function induced by bed rest alone. J Physiol. 596:3341–3355. Scholander PF. (1960). Oxygen transport through hemoglobin solutions. Science. 131:585–590. Semenza GL. (2001). Regulation of hypoxia-induced angiogenesis: a chaperone escorts VEGF to the dance. J Clin Invest. 108:39–40. Sillau AH, Banchero N. (1977). Effects of hypoxia on capillary density and fiber composition in rat skeletal muscle. Pflugers Arch. 370:227–232. Standley RA, Distefano G, Trevino MB, Chen E, Narain NR, Greenwood B, Kondakci G, Tolstikov VV, Kiebish MA, Yu G, others. (2020). Skeletal muscle energetics and mitochondrial function are impaired following 10 days of bed rest in older adults. J Gerontol A Biol Sci Med Sci. Glaa001. Svedenhag J, Henriksson J, Sylven C. (1983). Dissociation of training effects on skeletal muscle mitochondrial enzymes and myoglobin in man. Acta Physiol Scand. 117:213–218. Tang K, Breen EC, Wagner PD. (2002). Hu protein R-mediated posttranscriptional regulation of VEGF expression in rat gastrocnemius muscle. Am J Physiol Heart Circ Physiol. 283:H1497–504. Tappan DV, Reynafarje B. (1957). Tissue pigment manifestations of adaptation to high altitudes. Am J Physiol. 190:99–103. Taylor CR, Karas RH, Weibel ER, Hoppeler H. (1987). Adaptive variation in the mammalian respiratory system in relation to energetic demand. Respir Physiol. 69:1–127. Tilman HW. (1952) Nepal Himalaya: The Most Mountainous of a Singularly Mountainous. Verebrate Publishing. Terrados N, Jansson E, Sylven C, Kaijser L. (1990). Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? J Appl Physiol (1985). 68:2369–2372. Trevino MB, Zhang X, Standley RA, Wang M, Han X, Reis FCG, Periasamy M, Yu G, Kelly DP, Goodpaster BH, others. (2019). Loss of mitochondrial energetics

262  Peripheral tissues

is associated with poor recovery of muscle function but not mass following disuse atrophy. Am J Physiol Endocrinol Metab. 317:E899–E910. Valdivia E. (1958). Total capillary bed in striated muscles of guinea pigs native to the Peruvian mountains. Am J Physiol. 194:585–589. Vaughan BE, Pace N. (1956). Changes in myoglobin content of the high altitude acclimatized rat. Am J Physiol. 185:549–556. Vigano A, Ripamonti M, De Palma S, Capitanio D, Vasso M, Wait R, Lundby C, Cerretelli P, Gelfi C. (2008). Proteins modulation in human skeletal muscle in the early phase of adaptation to hypobaric hypoxia. Proteomics. 8:4668–4679.

Vogt M, Puntschart A, Geiser J, Zuleger C, Billeter R, Hoppeler H. (2001). Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol. (1985) 91:173–182. West JB. (1985). Best and Taylor’s Physiological Basis of Medical Practice. Williams and Wilkins, Baltimore, MD. Wilson DF, Erecinska M, Drown C, Silver IA. (1977). Effect of oxygen tension on cellular energetics. Am J Physiol. 233:C135–140. Wittenberg JB. (1959). Oxygen transport: a new function proposed for myoglobin. Biol Bull. 117:402–403. Wittenberg JB, Wittenberg BA. (2003). Myoglobin function reassessed. J Exp Biol. 206:2011–2020.

15 Energy balance and metabolism

Introduction 263 Magnitude of weight loss at high altitude 263 Moderate altitude (1500–3500 m) 264 High altitude (3500–5300 m) 264 Extreme altitude (>5300 m) 264 Sex differences in weight loss at high altitude 265 Weight loss in chamber experiments 265 Body composition during weight loss at high altitude 265 Changes in body composition during chamber studies 266 Energy deficit at high altitude 266 Determinants of energy balance 266 Total daily energy expenditure 266 Diet-induced energy expenditure 267 Activity-induced energy expenditure 267

Mechanisms for the energy deficit and weight loss 268 Neuroendocrine control of appetite at high altitude 269 Other factors affecting weight loss at high altitude 270 Diet for high altitude 272 High carbohydrate diet 272 High fat diet 273 High protein diet 273 Other dietary constituents 273 Nutrition and metabolism in high altitude residents 274 Water balance at high altitude 274 Respiratory water loss 274 References 275

INTRODUCTION

an overview of strategies for mitigating weight loss through alterations in dietary intake, the chapter considers alterations in energy balance and metabolism in long-term residence as well as the influence of high altitude on water balance.

Weight loss is a very common phenomenon associated with travel to high altitude, particularly with long exposures to the extremes of elevation. The mechanisms for this phenomenon, which is nearly universal with travel above 5000 m, vary significantly in magnitude between individuals and have remained unclear. Anorexia and decreased energy intake have long been suspected of playing a large role and may, in turn, be related to changes in neuroendocrine function and subsequent effects on taste, hunger, and satiety, as well as altitude illness and alterations in gastrointestinal function or protein metabolism. The goal of this chapter is to explore these issues in greater detail. This chapter begins by describing the extent of weight loss at high altitude and the consequences for body composition. It then reviews the changes in energy balance following ascent and considers the mechanisms responsible for these changes and the observed weight loss. After providing

MAGNITUDE OF WEIGHT LOSS AT HIGH ALTITUDE It is generally well established that chronic exposure to high altitude is associated with a decrease in body mass as a result of a chronic energy imbalance or deficiency. The results of a recent meta-analysis on the topic of weight loss at high altitude (Dünnwald et al. 2019) are illustrated in Figure 15.1 and reveal a progressive decrease in mean body weight, fat-free mass, and fat mass in proportion to the subgroups of high altitude exposure: moderate (1500–3500 m), high (3500–5300 m), and extreme altitude (>5300 m). Changes reported in each of these altitude ranges are described below.

263

264  Energy balance and metabolism

Figure 15.1  Forest plot from random-effects meta-analysis of mean body weight changes (95% confidence intervals) in the subgroups of moderate (1500–3500 m), high (3500–5300 m), and extreme (>5300 m) altitude. As noted in the overall averages, there is a progressive increase in average weight loss from moderate (–1.7 kg) to extreme (–4.9 kg) altitude. Plots B and C denote the corresponding losses (mean [95% CI]), where available, in fat-free mass and fat mass. Data redrawn and modified from previous work (Dünnwald et al. 2019) and comprise >30 published studies. For full references, see: Dünnwald et al. (2019).

Moderate altitude (1500–3500 m) Most members of climbing and trekking groups experience weight loss in the initial first three weeks of an expedition, even when walking below 3000 m. This is probably due to the change in lifestyle for most subjects from an urban semisedentary existence to the more active lifestyle of walking four to eight hours a day with some considerable ascents and descents. In addition to reduced food availability and frequency of meals while trekking, gastrointestinal infections, including traveler’s diarrhea and gastroenteritis, are common. Boyer and Blume (1984) found that 13 members of the American Medical Research Expedition to Everest (AMREE), during the trek into the Everest region (i.e., from 2800 to 5300 m), lost an average of 2 kg (range 0–6 kg). Those with the highest percentage of body fat to start were reported to lose the most weight. Two subjects with less than 13% of body fat lost no weight. Dinmore et al. (1994) similarly found an average loss of 1.3 kg during the first week of trekking but only a further 0.5 kg in the next week. These early studies are consistent with a meta-analysis (Dünnwald et al. 2019) of reductions in mean body weight of 1.7 kg as illustrated in Figure 15.1a.

High altitude (3500–5300 m) Although some studies have demonstrated that it is possible to attenuate high altitude induced weight loss by increasing caloric intake (Butterfield et al. 1992; Rai et al. 1975), the bulk of studies to date demonstrate that modest weight loss (2.3 kg; Dünnwald et al. 2019) is common during the typical trekking profiles (Figure 15.1a).

Extreme altitude (>5300 m) After partial acclimatization, weight loss is usually seen with travel to elevations above 5300 m with an average

loss of about 4.9 kg (Dünnwald et al. 2019) (Figure 15.1a). Figure 15.2 shows the extreme effect of altitude on body weight on one well-acclimatized subject during the 1960–61 Silver Hut expedition. Following an initial decline of 5.3 kg during the trek into the location of the hut, the individual steadily lost weight at a weekly rate of just under 400 g week−1 but, on two occasions, on descent to altitudes of 4000–4500 m, began to gain weight. Most subjects in the Silver Hut expedition lost between 0.5 and 1.5 kg week−1 (Pugh 1962). These early observations from the Silver Hut expedition are broadly consistent with Dinmore et al. (1994) who observed an average weight loss of 3.9 kg during two weeks of climbing above 5000 m. On the 1992 British Winter Everest Expedition, a mean weight loss of 5 kg was observed above 5400 m out of a total loss of 7.8 kg for the entire expedition (Travis et al. 1993). Exposure to cold temperatures is an unavoidable aspect of most high altitude expeditions; however, the execution of an Everest expedition during winter can only have compounded the effects of cold exposure on body weight and composition. At advanced base camp (6300 m) during AMREE, most subjects lost weight. Boyer and Blume (1984) documented an average loss of 4 kg (range 0–8 kg) over a mean of 47 days in 13 subjects, with considerable interindividual variation based on the initial percentage of body fat. Interestingly, Boyer and Blume also found that Sherpas, who averaged only half as much body fat as the Western climbers, lost no weight during the time spent above base camp, mostly at or above 6300 m. A possible reason for differences in weight loss in response to high altitude is the athletic fitness of subjects and the extent of fat mass at sea level. It is well known that the Sherpas and Nepali porters are well accustomed to long-term activities with high energy expenditure (and also have very low fat mass) and, as such, have likely evolved mechanisms to maintain appropriate energy balance.

Body composition during weight loss at high altitude  265

Figure 15.2  Record of body weight of one subject during the Silver Hut Expedition 1960–61. After the march out from Kathmandu (K) and the initial period of preparation, he was in residence at 5800 m (hatched areas) or at base camp at 4500 m. Note the loss of weight at 5800 m but weight gain during two breaks at 4500 m.

Sex differences in weight loss at high altitude There is some evidence that females may lose less weight than males at high altitude. Hannon et al. (1976) found their female subjects lost an average of only 1.8% of body weight during seven days at 4300 m, whereas previously reported data from males at this altitude found losses of 3.5–5.0% (Fulco et al. 1985). Collier et al. (1997) observed changes in body mass index at Everest base camp (5340 m) over a median of 15 days: 22 males lost 110 g m−2 day−1 compared with 20 g m−2 day−1 in eight females, a significant difference (p = 0.03). The seven male climbers who climbed to between 7100 m and 8848 m, using oxygen at extreme altitude, all lost weight, averaging 150 g m−2 day−1. The one female climber who spent four nights above 8000 m without supplementary oxygen lost no weight between leaving and arriving back at base camp. These initial studies and observations needed to be confirmed in larger sample sizes. The mechanism(s) explaining this stability of body mass in females were not explained but likely involve less muscle and/or fat mass, lower total daily energy expenditure (TDEE) and/or basal metabolic rate (BMR), and some protective influences of female sex hormones.

Weight loss in chamber experiments It could be argued that some of the weight loss on expeditions is due to cold, limited food supplies, and the increased energy expenditure of trekking and/or climbing. Chamber studies avoid this potential criticism and provide a means to isolate the effects of hypoxia per se from these other aforementioned factors. Although most chamber studies are of too short a duration to be relevant, Operation Everest I and II, studies of 40 days’ duration each, showed that despite stable environmental conditions of temperature and humidity, and diet ad libitum, subjects still lost weight (Rose et al. 1988). In Operation Everest II, six subjects lost an average of 7.4 kg

during the 38 days of observations as they ascended the simulated height of the summit of Everest. Energy intake fell by 43% and, interestingly, the subjects chose a diet that resulted in a reduction of carbohydrate from 62% to 53% of the total diet. The authors considered that the weight loss could not be accounted for solely by the reduction in intake and that malabsorption of nutrients or increase in energy expenditure due to increased BMR must be invoked. The exercise taken in this chamber study would probably be much less than on a climbing expedition; and while exercise equipment was available, only 20% of estimated basal energy expenditure was added to the subject’s routine activity, which would seem to have unlikely compensated for the confinement-induced reductions in normal daily activity. On Operation Everest III (Comex ’97) there was a similar loss of weight, averaging 5 kg during the 31-day chamber study taking eight subjects to the simulated height of the Everest summit. Intake was reduced by 4.2 MJ day−1 due to subjects feeling satiated sooner (Westerterp-Plantenga et al. 1999).

BODY COMPOSITION DURING WEIGHT LOSS AT HIGH ALTITUDE Assuming much of the weight loss is due to negative energy balance (see the “Energy Deficit at High Altitude” section later in this chapter), a simplistic view is that the body would use up fat stores along with skeletal muscle proteins. More realistically, however, the body uses concurrent stores of fat, glycogen, and, to a lesser extent, muscle mass, with the contribution from each varying based on the intensity of the activity (i.e., fat during rest to mostly glycogen during higher intensity exercise) and the level of protein intake, which helps to preserve muscle mass. Although this does not seem to be the case at high altitude as detailed in later sections, several studies at sea level using high protein intake with or without resistance training have been able to limit or even preserve muscle mass reduction during weight loss (reviewed in: Cava et al. 2017; Liao et al. 2017).

266  Energy balance and metabolism

The results of a recent meta-analysis on the topic of body composition at high altitude (Dünnwald et al. 2019) are illustrated in Figure 15.1 and show clear reductions in body mass, including both fat-free mass (FFM; Figure 15.1b) and fat mass (FM; Figure 15.1c), with larger changes occurring at higher altitudes. At high altitude, diet (21%) and expedition duration (20%) explain most of the heterogeneity in these changes in body composition between studies (Dünnwald et al. 2019). Physiological sex and diet explain 66% and 42% of the between-study heterogeneity in FFM changes, respectively, whereas diet and type of exposure (active [trekking/climbing, etc]/passive [simulated altitude or low level activity]) explain 25% and 30% of between-study heterogeneity in changes in FM, respectively. At high altitude, as at moderate altitude, the pooled mean decreases in body weight were higher with active exposure and when diet was not manipulated or when the diet was hypocaloric. However, even when the caloric intake is matched or increased relative to energy output, body weight is still significantly decreased by –2.5 to –0.4 kg, indicating hypoxia to be a possible trigger for body composition changes in these studies (Barnholt et al. 2006; Bharadwaj and Malhotra 1974; Butterfield et al. 1992; Consolazio et al. 1972; Holm et al. 2010; Surks et al. 1966). Perhaps not surprisingly, studies that revealed the highest mean reductions in body weight at high altitude were those associated with more prolonged durations of exposure. In these studies, on average, FFM and FM affected the pooled mean body weight changes to a similar extent. At extreme altitude, as proposed earlier, baseline body weight accounts for most of the heterogeneity in body weight changes between studies (84%), whereas the duration of exposure accounts for 14%.

Changes in body composition during chamber studies In the Operation Everest II study (Rose et al. 1988), there was a loss of 2.5 kg of FM (1.6% body weight) and 4.9 kg of FFM. Computed tomographic examination of the thigh showed a 17% loss of muscle and a 34% loss of subcutaneous fat. These results of reductions in both FM and FFM were confirmed in a very recent study that showed that there is muscle wasting even during short simulated exposures (21 days) to an altitude of only 4000 m under strictly controlled and standardized environmental, dietary, and activity conditions (Debevec et al. 2018).

ENERGY DEFICIT AT HIGH ALTITUDE An important driver of weight loss and changes in body composition seen with travel to very high elevation is the emergence of an energy deficit.

Determinants of energy balance The widely accepted view is that energy balance in humans is determined via the interplay between energy intake and energy expenditure. However, this view is limited because

it considers energy intake and expenditure to be independent parameters that can be adjusted at will and thereafter remain static without being influenced by homeostatic signals related to weight loss (Hall and Chow 2013). It is more appropriate to conceptualize energy intake and expenditure as interdependent variables that are dynamically influenced by each other and body weight (Hall et al. 2012). Ascent to, and life at, high altitude provide examples of such complex challenges to energy balance. While recognizing the complexities of energy balance, it is useful to define the main components of energy expenditure and energy intake. Total daily energy expenditure (TDEE) consists of three components: (1) expenditure for maintenance processes, usually called resting energy expenditure or basal metabolic rate (BMR); (2) thermogenesis from the processing of ingested food, referred to as diet-induced thermogenesis; and (3) energy cost of physical activity or activity-induced energy expenditure (AEE). Energy intake is influenced by appetite, including the palatability of food, gastrointestinal function, and the availability of food. The main determinants of energy balance are illustrated in Figure 15.3, while the alterations and modifying factors at high altitude are outlined in the following sections.

Total daily energy expenditure BASAL METABOLIC RATE IN LOWLANDERS ASCENDING TO HIGH ALTITUDE

Nair et al. (1971) found that after a week at 3300 m, the BMR was elevated by about 12% versus sea level. Exposure to cold and hypoxia in a second group of subjects made no difference in this effect compared with hypoxia alone. BMR returned to sea level values by week 2 and even fell below these values by week 3. With additional cold exposure in these hypoxic conditions, BMR rose above sea level values by week five and remained elevated a week after return to sea level. In seven healthy males, Butterfield et al. (1992) found BMR to be elevated by 27% on day 2 at Pikes Peak (4300 m) in Colorado; this increase in BMR was attenuated to 17% above baseline on day 10 and remained stable at this level for the next 11 days. In 16 females, also studied at 4300 m and while controlling for menstrual phase, it was found that BMR was elevated by 7% after three days but had returned to sea-level values by day six (Mawson et al. 2000). Although it was speculated that the high levels of fitness of the subjects could explain the temporal changes in BMR, the energy requirements to assure weight maintenance and composition remained 6% elevated above sea-level values giving rise to an apparent “energy requirement excess” of about 670 kJ/day; therefore, it is possible that this excess in energy could also influence the changes in BMR. After 82 to 113 days of acclimatization, BMR measured at 5800 m was elevated, on average, by about 10% (Gill and Pugh 1964). It is likely that BMR rises even more if subjects climb to very high altitudes without acclimatization. Although there are currently no data on BMR at altitudes above 6000 m, it is plausible that ascent to such elevations is a factor in the more pronounced weight loss that has been reported.

Energy deficit at high altitude  267

Figure 15.3  Potential factors involved in the regulation of energy balance during ascent and stay at high altitude EE, energy expenditure.. FFM, fat-free mass. FM, fat mass. MM, muscle mass. BW, body weight.

Sympathetic activity is increased at high altitude (Chapter 16) and the finding that ß-blocker administration blunts the increase in metabolic rate (Moore et al. 1987) suggests it is a likely important factor in driving these aforementioned elevations in BMR. Increased thyroid activity may also play a part, especially in the longer-term elevation of BMR (see Chapter 16). Finally, it should be noted that any periods of intense activity are usually of short duration so that under normal conditions it is the BMR that is the largest contributor to TDEE. Given that much of acclimatization is a passive progress, and the obvious dangers of ascending too high too fast, the contribution of BMR to overall energy balance is particularly important. BASAL METABOLIC RATE IN LONG-TERM HIGH ALTITUDE RESIDENTS

The BMR was found to be elevated in highland residents (Ladakhis and Sherpas) at high altitude compared with lowlanders (Gill and Pugh 1964; Nair et al. 1971), a result which persisted even when allowance was made for differences in body fat composition between the two groups. Picon-Reategui (1961) also reported elevated BMR in Andean miners at 4540 m. The mechanism for this difference in BMR between lowlanders and highlanders is uncertain but it would seem likely that, similar to lowlanders at high altitude, elevated sympathetic nervous and/or thyroid activity would likely play a key role for highlanders.

Diet-induced energy expenditure The smallest component of TDEE in humans is foodinduced thermogenesis, which is defined as the increase in metabolic rate observed for several hours following the ingestion of a meal (de Jonee and Bray 1997; Westerterp 2004). The thermic effect of food is believed to represent the energy cost of digestion, absorption, storage, and metabolic fate of dietary macronutrients (Westerterp 2004). While the precise mechanisms underlying the thermic effect of food are not fully understood, there is a clear macronutrient hierarchy, with protein causing a greater energy expenditure increment than carbohydrates, which is greater than that of fat (Westerterp 2004). For typical diet compositions, the thermic effect of food is approximately 10% of energy intake. Because energy and macronutrient intake are not particularly high at high altitude (see below), this expenditure likely accounts for less than 10% of the TDEE.

Activity-induced energy expenditure Although maximum work rate is reduced following ascent (Chapter 18; Levett et al. 2011; Pugh 1964; West et al. 1983; Wolfel et al. 1991) and all activity is associated with increased breathlessness and perceived level of exertion compared to sea level, the daily energy expenditure is almost twice of that of normal daily expenditures at sea

268  Energy balance and metabolism

Figure 15.4  Daily energy expenditures (bars) and distances covered (circles) during a range of prolonged expeditions measured via doubly labeled water. Examples, from left to right, include climbing Mount Everest, unsupported crossing of the Antarctic, and elite endurance athletes racing or training. See references in text for further details.

level (Figure 15.4) due to increased activity (e.g., multiple days trekking, etc.), increased work of breathing, and elevations in BMR. Even at altitudes of 2500–4500 m, it has been reported that the overall energy intake to maintain body weight increased from 13.22 MJ at sea level to 15.64 MJ a day at 4300 m due to the increase in BMR (Butterfield et al. 1992). Before about 1990, it was impossible to measure energy expenditure over long periods, but a water labeling technique using both deuterium and 18O was developed that made this possible, though expensive. The deuterium is eliminated as water while the oxygen is eliminated as both water and carbon dioxide. Thus carbon dioxide production can be calculated from the different elimination rates (Coward 1991; Schoeller and van Santen 1982) and the daily energy expenditure can be estimated. Using this technique, Westerterp et al. (1992) found average daily energy expenditure in the Alps (2500–4800 m) and on Mount Everest (5300–8848 m) to be 15.7 MJ and 13.6 MJ, respectively. Very similar results were obtained in the 1992 British Winter Everest Expedition with values ranging from 11.7 to 15.4 MJ (Travis et al. 1993). Pulfrey and Jones (1996), using the same technique at altitudes of 5900–8046 m, found the very high mean values of 19.4 MJ day−1 and a negative energy balance of 5.1 MJ day−1. Reynolds et al. (1999) found the same high mean value of 20.6 MJ day−1 above base camp with a dietary intake of only 10.5 MJ, giving a deficit of 10 MJ day−1! Based on a chamber experiment simulating an ascent of Everest over 31 days (Operation Everest III), it was found that energy expenditure and BMR were more or less unaltered (Westerterp et al. 2000); therefore, it seems that the high altitude environment, that is to say, the combination of hypoxia, cold exposure, associated trekking, and food availability and palatability, rather than merely hypoxia per se, is necessary to induce the elevations in BMR and higher energy outputs found in field studies.

Although the implications of a negative energy deficit are considered later in this chapter, the question arises: Are the energy expenditures while operating at very high altitude markedly higher than those seen with other extreme endurance activities? As illustrated in Figure 15.4, such energy expenditures, while almost double that of normal daily expenditures at sea level, are well below that of other pursuits such as the ski-crossing of the Antarctic (Halsey and Stroud 2012), ultra-endurance running (Eden and Abernethy 1994), cycling in the Tour de France (Westerterp et al. 1986), or cross-country ski training (Sjodin et al. 1994). Part of the difference may be attributable to the duration of time per 24 hours spent engaged in these activities. Time spent following safe ascent profiles and periods of acclimatization to attain moderate to high altitudes may be extended, but time spent at extreme altitudes is often short. Given the dangers of rapidly ascending to and climbing at extreme altitude, the distances covered are, by necessity, considerably less compared to these other activities at sea level.

MECHANISMS FOR THE ENERGY DEFICIT AND WEIGHT LOSS To this point in this chapter, we have established that body weight is reduced with prolonged exposure to high altitude, largely as a result of an accumulation of an energy deficit. A key question that remains is: Why does this deficit develop? Over the last 20 years or so, at least on commercial expeditions, food is generally in abundant supply. As a result, the well reported weight loss at altitude is most likely not due to the availability of food per se but rather due to other factors that cause decreased appetite and increased energy expenditures including neuroendocrine control of appetite, altitude illness, malabsorption, and/or impaired intestinal function. These factors are outlined next.

Mechanisms for the energy deficit and weight loss  269

Appetite is regulated, in part, by the neuroendocrine system (Murphy and Bloom 2006), and multiple hormones have been implicated as mediators of hunger and satiety in hypoxia (Bailey et al. 2000, 2004, 2015; Debevec et al. 2014, 2016; Matu et al. 2017; Shukla et al. 2005; Sierra-Johnson et al. 2008a; Tschöp et al. 1998), including glucagon-like peptide-1 (Bailey et al. 2004; Bailey et al. 2015), pancreatic polypeptide (Matu et al. 2017), peptide YY (Bailey et al. 2015; Wasse et al. 2012), neuropeptide Y (Vats et al. 2004), cholecystokinin (Aeberli et al. 2013; Riepl et al. 2012), adiponectin (Trayhurn, 2014), leptin (Tschöp et al. 1998), ghrelin (Benso et al. 2007; Mekjavic et al. 2016; Riedl et al. 2012; Riepl et al. 2012; Shukla et al. 2005), and insulin (Debevec et al. 2014; Matu et al. 2017; Mekjavic et al. 2016). The majority of research has focused on the latter three hormones and is discussed in more detail below. More detailed information can be found in several comprehensive reviews on this topic, including Debevec (2017) and Matu et al. (2018).

and the magnitude of increases in insulin, and suggested that extreme altitude may account for the larger increases in insulin seen in some studies. To the extent that they do occur, increases in insulin concentration may contribute to the observed reductions in hunger during hypoxic exposure but could also represent a reduction in insulin sensitivity (Karl et al. 2018; Woolcott et al. 2015). An increase in fasting, but not postprandial insulin concentrations, suggests that hepatic insulin sensitivity is more heavily influenced by hypoxia than peripheral insulin sensitivity (Radziuk 2014). The use of a hyperinsulinemic, euglycemic clamp in humans has demonstrated that an acute 30-minute hypoxic exposure (resulting in a blood oxygen saturation of ∼75%) rapidly reduces whole-body insulin sensitivity by ∼15% (Oltmanns et al. 2004). The reduction in insulin sensitivity could be due to catecholamine responses, adipose tissue inflammation, and/or HIF signaling (Murphy et al. 2017; Oltmanns et al. 2004). However, further work is required to establish whether chronic, sustained hypoxia reduces tissue insulin sensitivity and has any neuroendocrine role in appetite control.

LEPTIN

GHRELIN

The role of circulating leptin concentrations as a mediator of appetite and energy intake changes at altitude has been a topic of great interest and controversy. Leptin is an adipocytokine that has been proposed to express regulatory physiological effects on appetite and metabolism (Klok et al. 2007). It is well known that exposure to high altitude stimulates hypoxia-inducible factor 1 (HIF-1) and this can transactivate the human leptin gene promoter, potentially increasing circulating leptin concentrations (Grosfeld et al. 2002). On the contrary, altitude exposure is often associated with a significant loss of adiposity due to increased energy expenditure and/or decreased energy intake (see below), which would reduce leptin expression in adipose tissue. Consequently, the effects of high altitude exposure on leptin remain ambiguous (Sierra-Johnson et al. 2008b) with studies reporting increased (Tschöp et al. 1998), decreased (Bailey et al. 2004; Karl et al. 2018; Vats et al. 2004; Zaccaria et al. 2004), and unchanged (Smith et al. 2011) concentrations. It is now known that leptin release is influenced by several factors other than hypoxia (e.g., sleep, exercise, cold, adipose, and smoking status) and these may be confounding factors in some field studies. As highlighted in these studies and in a recent meta-analysis on the topic (Matu et al. 2018), it seems that leptin concentrations are not consistently affected by hypoxic exposure.

Acylated ghrelin has been hypothesized to act physiologically to signal hunger and initiate eating and has received growing attention in hypoxic research during recent years (Bailey et al. 2015; Goto and Morishima 2016; Karl et al. 2018; Matu et al. 2017; Wasse et al. 2012). Current evidence suggests that appetite and acylated ghrelin are concomitantly suppressed during exposure to high (>3500 m), but not moderate, simulated altitude. Based on these data and those outlined below, a potential mediating role of acylated ghrelin in high altitudeinduced anorexia has been proposed (Karl et al. 2018; Matu et al. 2017). However, due to the complex chemical preparation required for accurate acylated ghrelin measurements, total ghrelin concentrations have been more commonly measured in response to hypoxic exposure. A recent meta-analysis on the topic found a positive association between hypoxic severity and the decrease in acylated ghrelin concentrations. Specifically, it was demonstrated that acylated ghrelin is suppressed in hypoxia compared with normoxia but that total ghrelin concentrations remain unchanged. Such findings are consistent with those of Matu et al. (2017), who found that acylated ghrelin was suppressed with high but not moderate simulated altitude exposure. Total ghrelin consists of the combined levels of des-acyl ghrelin and acylated ghrelin, and recent research has found that des-acyl ghrelin can inhibit the orexigenic effects of acylated ghrelin by targeting the arcuate nucleus, independently of the growth hormone secretagogue receptors (Fernandez et al. 2016). The opposing effects of these hormones suggest that physiologically relevant changes in ghrelin constituents may be masked by the measurement of total ghrelin. It would therefore be beneficial for further research in this area to differentiate between the ghrelin constituents. Overall, it seems that postprandial acylated ghrelin concentrations are generally decreased during hypoxic exposure

Neuroendocrine control of appetite at high altitude

INSULIN

As outlined in depth in Chapter 16, the effect of prolonged high altitude on plasma insulin concentration is variable, with studies finding reductions (Stock et al. 1978), no change (Bailey et al. 2004; Blume and Pace 1967; Debevec et al. 2014; Riedl et al. 2012), or elevations (Bosco et al. 2019; Siervo et al. 2014; Williams 1975; Young et al. 1989) in insulin concentrations. A recent meta-analysis (Matu et al. 2018) found a positive association between severity of hypoxic exposure

270  Energy balance and metabolism

compared with normoxia. The observed reductions in hunger and energy intake are in accord with the hypothesized orexigenic effects of acylated ghrelin (Monteiro and Batterham 2017). In part due to a lack of research, the influence of high altitude on other hormones related to appetite suppression is less clear.

Other factors affecting weight loss at high altitude ALTITUDE ILLNESS

On first arrival at high altitude, acute mountain sickness (AMS) may cause anorexia and vomiting with resultant weight loss. However, fluid can often be retained, causing those suffering AMS to gain weight (Hackett et al. 1982). Consolazio et al. (1972) found a small gain in weight on the first day at high altitude in those with mild AMS followed by a loss of weight of about 1 kg over the next five days at 4300 m. The mechanism(s) of the anorexia as a symptom of AMS is not clear (Debevec 2017). Loss of appetite due to AMS is unlikely to be the sole cause of weight loss, as symptoms of anorexia persist even after AMS has subsided (Tschöp and Morrison 2001) and others have found appetite suppression in individuals without symptoms of AMS (Matu et al. 2017). In addition to AMS, other forms of illness seen among high altitude travelers, including gastrointestinal and upper respiratory tract infection, are important factors that can directly and indirectly lead to weight loss while at high altitude. GASTROINTESTINAL BLOOD FLOW

Anorexia might occur if exposure to hypoxia at high altitude blunts the normal increase in gastrointestinal blood flow. This possibility was tested in a study by Kalson et al. (2010) who used ultrasound to measure velocity and vessel diameter of the hepatic portal vein (as an index of flow from the gut to the liver) in 12 subjects before and after a meal at sea level and various altitudes up to 3767 m. They found increased flow at altitude but the increase in postprandial blood flow was still maintained. Although this finding suggests that inadequate increase in blood flow from the gut is not a cause of altitude anorexia, other indirect evidence suggests that gut mucosal blood flow may be altered in hypobaric hypoxia. For example, a study of Qinghai railroad construction workers showed a 0.5% incidence of life-threatening gastrointestinal bleeding due to ulcer formation (Wu et al. 2007). Broadly consistent with this observation, in 14 of 23 (61%) healthy mountaineers staying their fourth night at 4559 m, the presence of peptic mucosal lesions such as erosions, ulcers, and hemorrhagic gastritis/duodenitis was observed (Fruehauf et al. 2019). Such lesions may be the result of alterations in gut mucosal blood flow, as can be seen in patients with critical illness and impaired tissue oxygen delivery. GASTROINTESTINAL ABSORPTION

Given that weight loss occurs at altitudes above 5000 m with, in some cases, adequate intake and reduced energy output, the possibility of malabsorption of food must also be considered.

In this context, malabsorption is defined as a situation in which the small intestine is unable to absorb appropriate amounts of delivered nutrients and/or fluids. Pugh (1962) reported that members of the Silver Hut expedition reported greasy and bulky stools, suggesting possible steatorrhea due to malabsorption of fat. There seems to be little work carried out on this topic, perhaps because the methods involved are either too sophisticated for easy use in the field (e.g., absorption of radioactive materials) or are unattractive to investigators (e.g., fecal collection, liquidization and aliquot sampling, etc.) or because few altitude physiologists have a background or training in gastroenterology. The following sections review the limited number of studies that have assessed carbohydrate, fat, and protein absorption at high altitude.

Carbohydrate absorption In a field study, Chesner et al. (1987) found no malabsorption of xylose in 11 subjects up to 4846 m. However, 60-minute plasma xylose (5-carbon monosaccharide) concentrations were reduced in subjects who ascended to 5600 m, suggesting that absorption is not affected until hypoxia is severe. Boyer and Blume (1984), who studied subjects at 6300 m, found xylose absorption decreased by 24% in six out of seven subjects, compared with sea-level controls. However, absorption measured by xylose has the drawback that the result is influenced by factors such as gastric emptying time, absorption area, intestinal transit, and renal function. Dinmore et al. (1994) used a double carbohydrate test; the two nonmetabolized carbohydrates used undergo different forms of mediated absorption but are otherwise subject to the same external influences, which cancel out when results are expressed as a ratio (Menzies 1984). D-xylose is absorbed by passive mediated transport, whereas 3-O-methyl-d-glucose is absorbed by active mediated, sodium-dependent transport. Dinmore et al. (1994) found that at 6300 m there was a 34% decrease in d-xylose (Figure 15.5) and a 15% decrease in 3-O-methyld-glucose absorption. The ratio was consistently decreased at altitude, and in a subsequent study, the 60-minute serum xylose/3-O-methyl-d-glucose ratio was 17% lower at 5400 m than at sea level (Travis et al. 1993). These more sophisticated studies therefore support the hypothesis that at these high altitudes carbohydrate absorption is impaired (reviewed in: Hamad and Travis 2006).

Fat absorption The majority of studies have not found evidence of fat malabsorption at high altitude. For example, Rai et al. (1975) found no evidence of fat malabsorption at 4700 m, as did Chesner et al. (1987) at 3100 m and 4800 m. Imray et al. (1992) used the 14C-triolein breath test and found no malabsorption of fat at 5500 m on Aconcagua, while Butterfield et al. (1992) found no increase in fecal excretion of volatile fatty acids at 4300 m. In contrast to these studies, Boyer and Blume (1984) found that fat absorption decreased by 49% at 6300 m compared with sea level in three acclimatized subjects. Differences in altitudes and the techniques to measure fat absorption likely explain these contradictory findings.

Mechanisms for the energy deficit and weight loss  271

In summary, there is little evidence of malabsorption up to an altitude of about 5000 m. This has been confirmed by measurements of fecal energy excretion, which have shown that 96% of energy intake is assimilated (Kayser et al. 1992), a normal sea-level value for subjects on a Western low residue diet. There is always the possibility that intestinal infections, at the time of the study or in the previous few days or weeks, may have caused some malabsorption since many of these field studies were undertaken in countries where such infections are all too common. CHANGES IN PROTEIN METABOLISM

Figure 15.5  d -xylose absorption tested in a group of climbers at sea level (UK), at altitudes indicated in Nepal, and after return to the UK (with mean and SD values at each location). (Data from Dinmore et al. 1994.)

Protein absorption Kayser et al. (1992) measured protein absorption using urinary and fecal 15N excretion after ingestion of 15N-labeled soya protein and found no reduction in absorption in subjects after three weeks at 5000 m. The observation is consistent with a more recent report showing that a high protein diet did not influence weight loss over 22 days at high altitude when compared with an isoenergetic standard diet (Berryman et al. 2017; see Figure 15.6).

The obvious muscle wasting seen especially in climbers returning from extreme altitude prompts the question of whether hypoxia affects protein turnover directly. There are very few data on this topic in humans. Consolazio et al. (1968) first studied protein balance at high altitude and found no difference between subjects there and at sea level, but the altitude station was Pikes Peak (4300 m), below the crucial height at which continued weight loss is observed. Rennie et al. (1983) studied the effect of acute hypoxia in a chamber (equivalent altitude 4550 m) on leucine metabolism in forearm muscles and found that acute hypoxia resulted in a net loss of amino acids from the muscles, probably due to a fall in muscle protein synthesis. If this finding can be extrapolated to the situation of chronic hypoxia at altitudes of above 5000–6000 m, then it provides a further contributing factor to the loss of muscle mass described above. As such, at least at sea level, higher protein (>1.2 g of protein per kg of body weight per day) diets preserve fat-free mass during weight loss (Leidy et al. 2015; Pasiakos et al. 2014; Wycherley et al. 2012), which may be beneficial for maintaining physical function and health. These benefits underpin recommendations supporting higher protein diets for athletes (Thomas et al. 2016) and military personnel (Pasiakos et al. 2017, 2013, 2014, 2015) and have stimulated recent interest in studying the effectiveness of higher protein diets for mitigating fat-free mass loss during high altitude sojourn (Pasiakos et al. 2017). However, protein increases fullness (Dhillon et al. 2016) and is more satiating than carbohydrate or fat (Leidy et al. 2015). These effects may

Figure 15.6  Mean change in body mass with consumption of an isoenergetic standard protein (SP: n = 8) vs. a high protein (HP: n = 9) diet during energy deficit at 4300m. *P