From mountain to bedside: understanding the clinical relevance of human acclimatisation to high-altitude hypoxia

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1 Centre for Altitude, Spae and Extreme Environment Mediine (CASE Mediine), University College London, Institute of Human Health and Performane, London N19 5LW, UK Correspondene to: Dr D Martin, Centre for Altitude, Spae and Extreme Environment Mediine (CASE Mediine), University College London, Institute of Human Health and Performane, First Floor, Charterhouse Building, Arhway Campus, Highgate Hill, London N19 5LW, UK; dan.s.martin@ gmail.om Reeived 8 July 2008 Aepted 26 September 2008 From mountain to bedside: understanding the linial relevane of human alimatisation to high-altitude hypoxia D Martin, J Windsor ABSTRACT For enturies man has strived to reah the greatest heights on earth. In order to explain the physiologial hanges that are needed to ahieve this, physiologists have tended to fous on the improvements made in oxygen delivery to the body s tissues. Although this explains muh of the alimatisation proess, it has not been able to address the large interindividual variations seen in human performane at altitude. In reent years, attention has shifted and now fouses on mirovasular and ellular responses in an attempt to explain these differenes. Investigating these proesses not only helps to unravel the proess of alimatising to altitude, but it may also improve our understanding of the body s response to hypoxia in those with ritial illness. Lak of oxygen dulls the mind and judgement, slows the reflexes, weakens the musles, and takes away our higher faulties. The higher one goes, the more serious are these effets. Too many people forget this exatly at a time when they should be most responsive to the danger. 1 The World Health Organization estimates that approximately 35 million people travel to altitudes above 3000 m eah year. 2 Although this presents a variety of physial hardships, the single greatest hallenge faed is the fall in barometri pressure and the resulting deline in the partial pressure of oxygen. With time, humans an adapt to this harsh environment via a proess known as alimatisation. This review aims to summarise our understanding of the alimatisation proess to date by fousing on well-reognised mehanisms before going on to disuss new onepts in this field. By studying the way the human body responds to high altitude, we may also improve our understanding of the way hypoxia affets patients. ACCLIMATISATION TO ALTITUDE Hypobari hypoxia leads to a fall in the inspired partial pressure of oxygen (PIO 2 ), whih, in the absene of adaptive mehanisms, lowers alveolar partial pressure of oxygen (PAO 2 ), and results in a redution in the driving pressure needed for the diffusion of oxygen aross the alveolar apillary barrier. The result of these hanges is a fall in both the arterial partial pressure of oxygen (PaO 2 ) and the arterial oxygen saturation (SaO 2 ), leading to a redution in oxygen delivered to the tissues and the potential for ellular hypoxia and organ dysfuntion. A suessful period of alimatisation at high altitude ensures that humans are able to funtion in a similar way to that seen at sea level. Historially, we have understood this to involve restoring sea-level values of oxygen delivered to the body s tissues. Oxygen delivery (DO 2 ) is defined as the produt of ardia output (Q) and arterial oxygen ontent (CaO 2 ) (table 1). Here, Q is the produt of heart rate and stroke volume and CaO 2 is the sum of the oxygen bound to haemoglobin and that dissolved in the plasma. On asent to altitude, CaO 2 falls and DO 2 is therefore redued. In order to ounterat this, three prinipal physiologial hanges our as part of the alimatisation proess: (1) Q is inreased; (2) SaO 2 is restored; (3) haemoglobin onentration is inreased. (1) Inreased Q Within minutes of asending to altitude, Q inreases during both rest and submaximal exerise. This was first observed in resting volunteers by the physiologists C G Douglas and J S Haldane during their ground-breaking experiments on Pike s Peak (4300 m) in On the same mountain, some 60 years later, researhers were able to onfirm that Q was also raised for a given level of submaximal exerise. Using three different work settings on a yle ergometer, the team showed a 10 15% inrease in Q during exerise in the first 4 days at altitude. 4 However, subsequent studies have shown that this inrease is short lived, and Q during rest and submaximal exerise returns to sealevel values within a few weeks. 5 Interestingly, the ontributions made by the heart rate and stroke volume differ dramatially during this time. In a review of 11 studies looking at the effet of altitude on the ardiovasular system, Wolfel and Levine 6 identified a 14 25% inrease in heart rate and an 8 32% fall in stroke volume during the first 4 weeks at 3800 m or higher. Although an inrease in sympatheti ativity an largely explain the persistent rise in heart rate, the reasons for a deline in stroke volume are poorly understood. This is partiularly onfusing beause stroke volume does not return to normal values when the irulating volume is artifiially restored to normal sea-level values. 7 However, as we will see later, the proess of alimatisation is a dynami one, and the ontribution made by the ardiovasular system may only be required during initial exposure to altitude. (2) Restoration of SaO 2 One oxygen moleules enter the body, they enounter a number of obstales before they finally reah the mitohondria for whih they are destined. Postgrad Med J: first published as /pgmj on 6 February Downloaded from on 7 June 2018 by guest. Proteted by opyright. 622 Postgrad Med J 2008;84: doi: /pgmj

2 At eah of these obstales, there is a step-like redution in the partial pressure of the oxygen. This is ommonly referred to as the oxygen asade and was first desribed at altitude by the pioneering physiologist Joseph Barroft more than 80 years ago. 8 The profound effet that altitude has on the oxygen asade an be seen in fig 1 using data from a simulated high-altitude asent of Mount Everest. 9 Although most of the steps in the oxygen asade are beyond human ontrol, the body an limit the fall in PO 2 in one key area. As oxygen enters the alveoli, the PO 2 falls as a result of the addition of the uptake of oxygen by the inoming mixed venous blood. PAO 2 an be alulated from the alveolar gas equation: PAO 2 =PIO 2 (PACO 2 /R) where R is the respiratory exhange ratio (the ratio of the volume of arbon dioxide produed by the tissues to the volume of oxygen onsumed per unit time, whih varies with the substrate being used, eg, 0.7 for fat and 1.0 for gluose). Aording to this equation, if R remains unhanged, any redution in PACO 2 leads to an inrease in PAO 2. As ventilation and PACO 2 are inversely proportional, any inrease in the rate or depth of breathing will therefore result in a fall in PACO 2 and an inrease in PAO 2. Over the ourse of several days at altitude, ventilation inreases involuntarily and results in a redution in PACO 2. This is largely due to the ombined effets of two physiologial responses: the hypoxi ventilatory response and the hyperapni ventilatory response. 10 As PAO 2 falls, peripheral hemoreeptors in the arotid and aorti bodies are stimulated, ausing ventilation to inrease. This is known as the hypoxi ventilatory response, and the magnitude of the response varies widely between individuals. 11 At sea level, any rise in ventilation lowers PACO 2 and results in the slowing of breathing and an inrease in PACO 2. However, at altitude, the response from the entral medullary hemoreeptors inreases, triggering high levels of ventilation and a rise in PAO This response, ommonly referred to as the hyperapni ventilatory response, is thought to be due largely to the redution in biarbonate ions (HCO 32 ) that is ommonly seen in the erebrospinal fluid on asent to altitude. 13 The fall in HCO 32 is the result of renal tubular ells failing to reabsorb HCO 32 and results in aidi erebrospinal fluid, whih enourages higher levels of ventilation. 14 These hanges result in an inrease in PaO 2 and a substantial rise in SaO 2 due to the steep slope of the oxygen haemoglobin dissoiation urve over the range of PaO 2 values seen at altitude. The rapid nature of ventilatory alimatisation allows time for slower hanges in the haematologial system to our. (3) Inreased haemoglobin onentration Alongside the hanges seen in Q and SaO 2, the alimatisation proess also results in an inrease in the onentration of irulating haemoglobin. This is a result of two proesses. Table 1 Formulae for the alulation of systemi oxygen delivery Calulation of oxygen delivery (DO 2 ) Example in a 70 kg man DO 2 =Q6CaO 2 DO 2 = = ml/min Q=HR6SV Q = = 4.9 l/min CaO 2 = ([Hb]6 SaO 2 6 H) + (PaO 2 6 S) CaO 2 = ( ) + ( ) = = 19.4 ml O 2 /100 ml blood = 194 ml O 2 /l CaO 2, arterial oxygen ontent; H, Hufners onstant (1.39); [Hb], haemoglobin onentration; HR, heart rate; PaO 2, arterial partial pressure of oxygen; Q, ardia output; S, solubility oeffiient of oxygen (0.0225); SaO 2, arterial oxygen saturation of haemoglobin; SV, stroke volume. a. Arrival at altitude oinides with a rapid fall in plasma volume. Over several days, healthy individuals experiene a fall by up to 20% in their plasma volume beause water is exreted as urine or instead shifts into either the interstitium or ells. This results in a rapid inrease in the onentration of irulating haemoglobin and subsequent rises in CaO 2 and DO Although this proess an persist for several weeks, over a prolonged stay at altitude, plasma volume slowly returns to normal. After 18 weeks above 4000 m, Pugh 16 found that plasma volume had fallen by 21%; however, 3 months later the differene was only 10%. b. Within minutes of arrival at altitude, inreased ellular onentrations of the protein, hypoxia induible fator 1a (HIF1a), stimulate the release of erythropoietin from the liver and kidney. 17 Erythropoietin subsequently binds to erythroid ell lines in the bone marrow, triggering the release of immature nuleated red blood ells (retiuloytes) into the irulation. In some ases, this an lead to a doubling in the number of irulating retiuloytes within 7 days of arrival at altitude. 18 Although the plasma onentration of erythropoietin tends to fall over the ourse of 3 weeks at altitude, red ell prodution remains raised for up to 8 months in those new to altitude and an result in a 50% inrease in red ell mass. 19 Changes in apillary density and mitohondrial volume and funtion at altitude There was a revelation in our understanding of human adaptation to hypoxia when the aepted hypotheses of hanges in skeletal musle apillary and mitohondrial density after hroni exposure to hypoxia were questioned. Historially, it was believed that a sustained redution in oxygen availability would lead to inreases in apillary density and aerobi metaboli ativity in order to restore ellular energy requirements. 20 However, early studies of apillary density, on whih these ideas were grounded, failed to take into aount the dramati derease in musle fibre ross-setional area and skeletal musle mass. Although overall apillary density appeared to inrease, the apillary to fibre ratio remained unhanged. Thus the apparent rise in apillary density simply represented the redution in musle ross-setional area. 23 Traditional ideas were questioned further when skeletal musle biopsy speimens taken from limbers returning from the Himalayas revealed a 30% redution in mitohondrial volume density. 21 In the same group of subjets, the ativity of itrate synthase and ytohrome oxidase enzymes loated within the mitohondria were redued by,20%. 24 As these two enzymes are involved in the itri aid yle and oxidative phosphorylation, respetively, this would result in redued oxidative apaity after prolonged exposure to hypoxia, whih has been further onfirmed in other studies This ombined body of evidene opposes preeding theories and suggests that musle apillarity is inreased, whereas ellular aerobi apaity and mitohondrial volume density are both redued at altitude. SHORTCOMINGS OF THE CLASSICAL ACCLIMATISATION EXPLANATION The lassial explanation of alimatisation to moderate altitude has evolved over many years through desription of physiologial proesses operating synergistially to inrease oxygen flux to ells when faed with environmental hypobari hypoxia. So effetive is this adaptation that CaO 2 tends to surpass sea-level values in most lowland people after an adequate period of alimatisation (fig 2) However, it has Postgrad Med J: first published as /pgmj on 6 February Downloaded from on 7 June 2018 by guest. Proteted by opyright. Postgrad Med J 2008;84: doi: /pgmj

3 Figure 1 The oxygen asade during rest at sea level and at an altitude of 8100 m. Data taken from a simulated asent of Mount Everest, Operation Everest II. 9 beome lear that, despite this remarkable adaptive phenomenon, exerise performane at altitude and suseptibility to altitude-related illnesses, suh as aute mountain sikness, high altitude pulmonary oedema, and high altitude erebral oedema, differs markedly between individuals. Our previous understanding of alimatisation fails to explain these signifiant interindividual differenes. High-altitude heroes are rarely athletes at sea level Interindividual variability in exerise performane at altitude is onsiderable. Aomplished high-altitude mountaineers are an example of those who adapt well to extreme degrees of hypoxia. Shortly after the first suessful summit of Mount Everest by Reinhold Messner and Peter Habeler without the aid of supplemental oxygen, an investigation was performed with the aim of eluidating the traits that permit human survival at suh heights. 28 At sea level, Messner, Habeler and a number of their limbing olleagues were studied alongside a group of sedentary ontrol subjets. Measures of aerobi performane, inluding stati and dynami lung volumes, ehoardiography, skeletal musle mitohondrial volume density and maximal oxygen onsumption, were performed. With no signifiant differenes noted between the two groups of subjets, the authors were fored to onlude that at sea level elite highaltitude limbers do not have physiologial adaptations to high altitude that justify their unique performane. 28 Sea-level performane fails to predit altitude performane Exeptional high-altitude athletes fail to display any remarkable physiologial features at sea level, but those who ope poorly with hypobari hypoxia are equally diffiult to identify. 29 No single test has the ability to differentiate those who fare well at altitude from those who do not. Early hypobari hamber studies suggested an assoiation between a blunted hypoxi ventilatory response and the development of aute mountain sikness However, these findings have not been onfirmed in the field. Despite many deades of investigation, the only reliable indiator of well-being at altitude is a previous history of suessful asent to a similar elevation. This diffiulty in prediting individual suess or failure on exposure to hypoxia Figure 2 Change in arterial oxygen ontent after alimatisation to 5260 m. Arterial oxygen ontent at altitude alulated with figures taken from Calbet et al. 26 is seen in linial pratie when managing hypoxi patients, partiularly those ategorised as ritially ill. Despite advanements in medial tehnology and a learer understanding of the pathophysiologial proesses underlying ritial illness, liniians still struggle to aurately differentiate survivors from non-survivors among a population of profoundly hypoxi patients. Exerise apaity remains limited after alimatisation to high altitude Anyone who has travelled to high altitude will report that exerise is severely limited, and this has been well doumented in reports over many enturies. 34 As alimatisation results in a return to sea-level values for systemi DO 2, it is unlear why exerise apaity, measured by a redution in maximum oxygen uptake (VO 2 max), remains signifiantly limited at altitude after adequate alimatisation Aute exposure to hypoxia leads to a preditable redution in VO 2 max, whih is proportional to the redution in CaO This diret relationship between CaO 2 and VO 2 max is lost after alimatisation, suggesting that other proesses are ontributing to the exerise derement. Debate over the underlying mehanism of this phenomenon has been ongoing for a number of deades. It has been suggested that the peripheral miroirulation may play an important role in the persistent limitation of exerise apaity at altitude. 35 However, this distal omponent of the oxygen-transportation system has not been diretly studied in lowland subjets asending to altitude. A reent study has ompared the resting forearm blood flow of high-altitude-dwelling (4200 m) Tibetans and a group of lowland ontrol subjets at sea level (206 m). 38 The forearm blood flow of the Tibetans was double that of the Amerian Postgrad Med J: first published as /pgmj on 6 February Downloaded from on 7 June 2018 by guest. Proteted by opyright. 624 Postgrad Med J 2008;84: doi: /pgmj

4 omparison group and was assoiated with a.10-fold inrease in irulating onentrations of bioative nitri oxide produts. 38 Despite having lower systemi CaO 2 than the Amerian lowlanders, the Tibetans had higher regional levels of forearm DO 2, perhaps beause of inreased peripheral generation of nitri oxide. This finding is beginning to draw attention away from entral ardiorespiratory proesses, and investigators are now starting to study the peripheral irulation to gain a better understanding of hypoxi adaptation. PROPOSED HYPOXIA SURVIVAL STRATEGIES Faed with a redued availability of oxygen, humans must redress the supply-and-demand balane to avoid ellular dysfuntion and death. The lassi desription of alimatisation depends on a strategy of improving systemi DO 2 ; other methods of restoring oxygen balane inlude redued ellular oxygen onsumption and improved effiieny of energy generation. Redued ellular oxygen onsumption In mammalian speies, it is possible to redue global oxygen onsumption by lowering metaboli ativity, as is ommonly seen in hibernating animals and the developing fetus. At the ellular level, ells from anoxia-tolerant animals suh as turtles show a redution in metaboli rate of,25% after exposure to 30 min of anoxia After the reintrodution of oxygen, this proess is rapidly reversed. This anoxia-indued hypometaboli state is mainly brought about by downregulation of ATPonsuming membrane ion hannels 41 and permits neutral ellular energy balane during oxygen deprivation. Improved effiieny of energy prodution An alternative strategy for surviving prolonged and extreme hypoxia is a more effiient use of oxygen during the proess of aerobi energy prodution. 42 Although hard to imagine, the latter hypothesis has been demonstrated in isolated mitohondria in whih oxidative phosphorylation beame more effiient during exposure to hypoxia. 43 This may explain the redution in oxidative apaity desribed in limbers returning from a prolonged period at altitude. Alteration of unoupling protein funtion may be one mehanism that failitates improved effiieny of oxygen use during aerobi metabolism. Unoupling proteins allow protons to re-enter the mitohondria in the final stages of oxidative phosphorylation, thereby bypassing ATP synthase and effetively generating an energy leak. 44 Finetuning of this energy leak in the ell s favour may permit improved metaboli effiieny. THE RELEVANCE OF HIGH-ALTITUDE PHYSIOLOGY TO CLINICAL MEDICINE The study of healthy volunteers asending to altitude may help to define and improve our understanding of the limits of human tolerane to hypoxia. Hypoxaemia and ellular hypoxia are ommon in ritially ill patients, but it is unlear whether these patients are able to adapt to hypoxia in a similar manner to those healthy individuals who alimatise to altitude. Underlying pathology, infetion and the development of ritial illness in these patients may prevent a omparable alimatisation proess. Cellular mehanisms that determine systemi response to hypoxia are being unravelled at an inredible rate. Perhaps the most important of these in reent years has been the disovery of HIF1a and its role in oxygen homoeostasis by regulation of multiple gene loi. In the future, the role of HIF1a in the pathophysiology of aner, myoardial ishaemia and erebral hypoxia may be manipulated benefiially. The role of HIF1a in apoptosis and ishaemi preonditioning hold partiularly exiting potential High-altitude studies may suggest novel adaptive mehanisms in people who demonstrate tolerane to environmental hypoxia, leading to translational researh in hypoxi patients. Climbers making a brief trip to great altitude mount an impressive polyythaemia in order to inrease systemi oxygen flux. Tibetans, who have lived at altitude for ountless generations, do not show this possibly ounterprodutive adaptation, but demonstrate marked hanges in the peripheral irulation. 38 In the latter situation, hanges in the miroirulatory mitohondrial unit may aount for long-term hypoxi tolerane. Changes suh as this may be mirrored in ritial illness. 50 Evidene suggests that, early in ritial illness, restoration of normal levels of oxygen delivery is benefiial to outome, 51 whereas following the same line of management in established ritial illness an be harmful to patients These studies relied on measurements of systemi DO 2, and their results may be explained by the fat that persistent disruption of the miroirulation is assoiated with poor outome in septi ritially ill patients. Furthermore, exessive use of oxygen may lead to inflammatory hanges followed by irreversible damage in the pulmonary trat through the release of oxygen free radials. Common themes between hypoxi ritial illness and adaptation to the high-altitude environment are inspiring researh into this field. Investigators are now looking beyond the oxygen flux proess to explore the hypothesis that relative hanges in oxygen onsumption may explain differenes in aerobi performane at altitude. 58 CONCLUSIONS Our understanding of how humans adapt to hypoxia at high altitude ontinues to develop. Over the last entury, researh has revealed hanges in the ardiorespiratory and haematologial systems that allow exursions to altitude through augmentation of systemi oxygen delivery. More reently, fous has turned to the peripheral miroirulation and the proess of ATP prodution that ours within the mitohondria. Although different arenas, high-altitude physiology and ritial illness have interesting parallels whih ould be exploited in order to benefit hypoxi patients. Continuing work in the field of highaltitude mediine and physiology may help to unravel the omplex mehanisms that underlie the reasons for survival in a hypoxi environment. The assoiation of geneti markers with Key learning points The lassial explanation of alimatisation to moderate altitude is restoration of systemi oxygen delivery. The redued exerise apaity and marked interindividual variation in performane at altitude are diffiult to explain in the fae of normal systemi oxygen delivery. Changes in the peripheral miroirulation and mitohondrial enzymati pathways may profoundly alter the balane between oxygen supply and demand at a ellular level on asent to altitude. Lessons learnt from healthy volunteers exposed to the hypobari hypoxia enountered at altitude may benefit patients with hypoxia resulting from disease. Postgrad Med J: first published as /pgmj on 6 February Downloaded from on 7 June 2018 by guest. Proteted by opyright. Postgrad Med J 2008;84: doi: /pgmj

5 Current researh questions Do hanges in the peripheral irulation affet the diffusion of oxygen into tissues at altitude? Do humans possess ellular strategies for oping with prolonged hypoxia? Will mehanisms that identify performane at high altitude translate into tools for prediting survival of hypoxia in the linial setting? benefiial adaptations in the miroirulatory mitohondrial unit may one day provide liniians with the tools that they require to aurately predit tolerane to hypoxia and therefore inrease a patient s likelihood of survival. MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F); ANSWERS AFTER THE REFERENCES) 1. After 1 week at altitude, the following physiologial parameters have returned to normal: (A) Heart rate (B) Stroke volume (C) Cardia output (D) Amount of biarbonate exreted in the urine (E) Plasma volume 2. On return from an expedition to the Himalayas: (A) Mitohondrial volume density in skeletal musle is dereased (B) Cellular aerobi apaity is inreased (C) Capillary density is inreased in skeletal musle (D) Haemoglobin onentration remains raised for several months (E) Heart rate and stroke volume rapidly return to normal 3. The following inrease within hours of asending to altitude: (A) Serum onentrations of hypoxia-induible fator and erythropoietin (B) Sympatheti outflow (C) Plasma volume (D) Heart rate and ardia output (E) Red ell prodution 4. On asent to altitude, the following inrease: (A) Barometri pressure (B) Fration of inspired oxygen (C) Partial pressure of inspired oxygen (D) Saturated vapour pressure of water (E) Partial pressure of alveolar arbon dioxide 5. The following physiologial proesses inrease the partial pressure of alveolar oxygen: (A) An inrease in respiratory rate and tidal volume (B) A high-arbohydrate diet (C) The use of supplemental oxygen (D) A derease in plasma volume (E) An inrease in the onentration of irulating haemoglobin Competing interests: None. REFERENCES 1. Houston CS. What prie a summit? Wilderness Environ Med 1996;7: Dumont L, Lysakowski C, Tramer MR, et al. Controversies in altitude mediine. Travel Med Infet Dis 2005;3: Douglas CG, Haldane JS. The regulation of the general irulation rate in man. J Physiol 1922;56: Vogel JA, Hansen JE, Harris CW. Cardiovasular responses in man during exhaustive work at sea level and high altitude. J Appl Physiol 1967;23: Vogel JA, Harris CW. Cardiopulmonary responses of resting man during early exposure to high altitude. J Appl Physiol 1967;22: Wolfel EE, Levine BD. The ardiovasular system at high altitude. In: Hornbein TF, Shoene RB, eds. 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