Accepted Manuscript

Altitude Training for Elite Endurance Athletes: A Review for the Travel Medicine
Practitioner

Gerard Flaherty, Rory O’Connor, Niall Johnston

PII: S1477-8939(16)30007-2
DOI: 10.1016/j.tmaid.2016.03.015
Reference: TMAID 974

To appear in: Travel Medicine and Infectious Disease

Received Date: 28 October 2015

Revised Date: 22 March 2016
Accepted Date: 23 March 2016

Please cite this article as: Flaherty G, O’Connor R, Johnston N, Altitude Training for Elite Endurance
Athletes: A Review for the Travel Medicine Practitioner, Travel Medicine and Infectious Disease (2016),
doi: 10.1016/j.tmaid.2016.03.015.

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1 Title page

2 TITLE Altitude Training for Elite Endurance Athletes: A Review for the Travel

3 Medicine Practitioner

4 RUNNING TITLE Altitude training

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5 AUTHORS AND AFFILIATIONS

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6 Gerard Flaherty (corresponding author)

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7 School of Medicine, National University of Ireland, Galway, Ireland

8 School of Medicine, International Medical University, Kuala Lumpur, Malaysia

9 Tel.: +353 91 495469

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10 Email: gerard.flaherty@nuigalway.ie

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13 Rory O’Connor
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14 School of Biomedical Science, National University of Ireland, Galway, Ireland

15 Email: r.oconnor38@nuigalway.ie
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17 Niall Johnston
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18 School of Medicine, National University of Ireland, Galway, Ireland

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19 Email: nijohnst@gmail.com

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21 KEYWORDS altitude; endurance; exercise; training; hypoxia; athletes

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23 WORD COUNT: 5061

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24 ABSTRACT

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26 High altitude training is regarded as an integral component of modern athletic

27 preparation, especially for endurance sports such as middle and long distance running.

28 It has rapidly achieved popularity among elite endurance athletes and their coaches.

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29 Increased hypoxic stress at altitude facilitates key physiological adaptations within the

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30 athlete, which in turn may lead to improvements in sea-level athletic performance.

31 Despite much research in this area to date, the exact mechanisms which underlie such

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32 improvements remain to be fully elucidated. This review describes the current

33 understanding of physiological adaptation to high altitude training and its implications

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for athletic performance. It also discusses the rationale and main effects of different
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35 training models currently employed to maximise performance. Athletes who travel to
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36 altitude for training purposes are at risk of suffering the detrimental effects of altitude.

37 Altitude illness, weight loss, immune suppression and sleep disturbance may serve to
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38 limit athletic performance. This review provides an overview of potential problems

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39 which an athlete may experience at altitude, and offers specific training

40 recommendations so that these detrimental effects are minimised.

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48 Literature search strategy

49 Medline and Pubmed databases were accessed to source relevant literature. The

50 following key words were used as search terms: altitude, exercise, training, hypoxia,

51 athletes, and endurance. Only articles published in the English language were

52 selected. Preference was given to articles published in the previous 5-10 years. The

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53 reference lists of published articles were also examined to ensure all relevant articles

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54 were included in the review. Textbooks also provided an additional source of

55 information and the grey literature was also consulted for relevant sources.

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56

57

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58 Introduction

59 In 1968, the results of the Mexico Olympic Games revealed the profound effect of
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60 high altitude on athletic performance [1]. Individuals who resided or trained at

61 altitude for significant periods of time prior to competition performed better than
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62 native lowlanders, who were subject to the negative effect of competing in an un-
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63 acclimatised state. While short distance events actually benefited from the reduced air
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64 density at altitude, performances in endurance events notably suffered. Later, it

65 became apparent that competing at high altitude was associated with improved
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66 athletic performance when the athlete returned to sea level. It became clear that
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67 hypoxic exposure at altitude was a key environmental stressor that initiated important

68 physiological adaptations in the athlete.

69 Even though these adaptations were poorly understood, high altitude training

70 rapidly achieved popularity amongst endurance athletes and their coaches. Today,

71 high altitude training is regarded by many as an indispensable factor in the success of

72 the elite endurance athlete. Such popularity may be due in part to the unrivaled
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73 success of native high-altitude athletes of African origin in middle- and long-distance

74 endurance events over many decades (Table 1). The most popular high altitude

75 training destinations are presented in Table 2. There is also a sound theoretical

76 rationale underlying high altitude training: various physiological adaptations which

77 occur at altitude may be exploited to yield significant improvements in sea-level

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78 athletic performance [2]. However, despite much scientific investigation, the exact

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79 mechanisms underpinning these adaptations remain to be fully elucidated.

80 This review describes the current understanding of the physiological

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81 adaptations which occur in response to training in a high altitude environment. In

82 addition, the paper provides an overview of the various training approaches employed

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by endurance athletes, and reviews the current literature pertaining to each approach.
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84 Finally, the potential harmful effects of high altitude training for the athlete are
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85 explored.

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87
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88 Physiological responses to altitude

89 The partial pressure exerted by oxygen in the arterial blood (PaO2) decreases directly
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90 with ascent, due to progressively falling barometric pressure. At 2,000 metres for
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91 example, the alveolar partial pressure of oxygen (PAO2) decreases from its sea-level
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92 value of 100 mmHg to 78 mmHg, which causes a reduced haemoglobin-oxygen

93 saturation and reduced total oxygen content of the blood. Therefore, a series of

94 physiological adaptations must be initiated to compensate for this hypoxic stress.

95 Central to these adaptations is hypoxia-inducible factor (HIF) which functions

96 as a transcription factor and master regulator of oxygen homeostasis [4,5]. In

97 normoxia, HIF1 is rapidly degraded by the ubiquitin-proteosome pathway and is

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98 undetectable [6]. Degradation is significantly slowed during hypoxia, allowing for an

99 increased half-life and transcriptional activation of its target genes, which encode for

100 erythropoietin (EPO) and other molecules [7]. The result is that tissue oxygenation is

101 improved, and hypoxic damage limited.

102 These adjustments provide the physiological rationale for altitude training,

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103 which has been used by endurance athletes for many years to enhance sea-level

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104 performance. For these athletes, hypoxia provides a key environmental stimulus

105 which initiates adaptations in ventilation, cardiovascular and haematological status,

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106 and muscle physiology. Each of these phenomena will now be considered in turn.

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109 Ventilatory effects
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110 In the early stages of altitude exposure, hypoxic drive from peripheral chemoreceptors

111 in the carotid sinus elevates respiratory rate [8,9]. Oxygen-sensitive potassium
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112 channels in glomic cells are inhibited by hypoxic conditions, causing calcium influx
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113 and the release of excitatory neurotransmitters from chemosensitive cells.

114 Acetylcholine, acting in concert with adenosine triphosphate (ATP), endothelin, and
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115 reactive oxygen species, alters afferent discharge from the carotid bodies, and effects
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116 a hypoxic ventilatory response (HVR) [9-11]. It has become clear that HIF-mediated
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117 changes within glial and neuronal cells in the brainstem also exert an influence on

118 respiratory motor output [9,12].

119 HVR is critical during exercise at high altitude. Hyperventilation increases

120 PaO2, and causes a respiratory alkalosis with a shift of the oxyhaemoglobin

121 dissociation curve (ODC) to the left. This allows for increased oxygen loading in the

122 lungs. Ventilatory adaptations ultimately fail to completely compensate for the effects
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123 of hypobaric hypoxia for two main reasons. Oxygen transfer from the atmosphere to

124 the lungs becomes diffusion-limited during exercise at altitude, due to a reduced PO2

125 diffusion gradient across the capillary wall, in addition to a reduced haemoglobin

126 transit time within the capillary [13]. During high intensity exercise at altitude, there

127 is an increasing influence of ventilation-perfusion (V/Q) mismatching, most likely

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128 attributable to hypoxia-induced pulmonary vasoconstriction [13] and interstitial

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129 pulmonary oedema [8]. As a consequence, athletic performance is reduced at altitude.

130 These ventilatory adaptations may have positive implications for athletic

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131 performance when the athlete returns to sea-level. Athletes demonstrate increased

132 PaO2 during exercise as a result of increased ventilation [14]. Rightward shift of the

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ODC caused by elevated 2,3-diphosphoglycerate (2,3-DPG) may also improve
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134 oxygen unloading in the tissues during exercise [15]. It is possible that both may have
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135 positive implications for sea-level performance.

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137 Cardiovascular effects

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138 At altitude, a sympathetic response is elicited to maintain oxygen perfusion to the

139 tissues in the face of hypoxaemia. Hypoxia directly influences catecholamine release
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140 in the adrenal medulla [13], and also reduces systemic vascular tone, causing
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141 baroreceptor stimulation of the brainstem, and increased sympathetic outflow [16,17].
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142 Athletes at altitude demonstrate significantly elevated epinephrine levels when

143 compared with those at sea-level performing at the same power output [7,13,16,18].

144 Following acclimatization maximal cardiac output (COmax) during exercise is

145 ultimately reduced [19]. Several mechanisms have been suggested for this observation

146 [1,7,18,20,21]: reduced sympathetic activity or reduced sensitivity to catecholamines,

147 increased parasympathetic stimulation of cardiac tissue, myocardial depression due to

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148 impaired oxygen delivery, loss of plasma volume resulting in reduced venous return,

149 increased blood viscosity, increased peripheral resistance, and exercise-induced

150 pulmonary hypertension. Reduced peak muscle blood flow also restricts oxygen

151 delivery, thereby reducing maximal oxygen uptake (VO2max) [1,7,18]. Reduced COmax

152 may also be the result of regulatory mechanisms which attempt to reduce hypoxic

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153 damage in the heart or brain [22]. Regardless of the exact cause, reduced cardiac

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154 output, and subsequent reduced VO2max significantly limit training intensity, and can

155 result in the detrimental ‘detraining’ effect [14,23].

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156

157 Haematological effects

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Haematological adaptation is regarded as an important component of altitude training.
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159 In response to hypoxia, HIF1 induces transcription of the EPO gene [5]. EPO, which
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160 is primarily produced in the kidneys, promotes erythropoiesis in the bone marrow and

161 improves oxygen carrying capacity in the blood [1,24]. Generally, serum EPO
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162 concentration peaks from day 1 to day 5 following hypoxic exposure: however this is
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163 highly variable amongst athletes. Most studies classify individual athletes into

164 ‘responder’ or ‘non-responder’ phenotypes [1,6,13] based on this individual

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165 variability. An athlete’s EPO response may be related to the presence of the specific
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166 EPO gene polymorphism D7S477 [6,25-27], and other polymorphisms which have
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167 yet to be identified.

168 Apart from polymorphic variation, factors such as illness or iron deficiency

169 may also affect the erythropoietic response of athletes [28]. It has become evident that

170 individuals returning from altitude adapt to their new sea-level environment by

171 reducing their red cell mass. This is achieved through EPO suppression, reduced iron

172 turnover, and neocytolysis, or the selective haemolysis of young circulating red blood
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173 cells [29]. Therefore, training must be timed appropriately so that loss of red cell mass

174 upon descent does not coincide with competitive performance [30].

175 Unfortunately, there is insufficient evidence to establish a cause-and-effect

176 relationship between erythropoiesis and enhanced athletic performance. Studies vary

177 greatly in terms of hypoxic exposure, training content, detection methods, and level of

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178 ability of subjects, which makes it difficult to compare haematological benefits

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179 recorded in different studies. The role of increased haemoglobin mass in enhanced

180 athletic performance is questioned further by the observation that high-altitude native

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181 Ethiopian athletes show no significant increases in EPO, haemoglobin or oxygen

182 saturation when compared with normal sea-level values [31]. It may be that their

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extraordinary performance capabilities arise instead from non-haematological
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184 adaptations of oxygen uptake or delivery [32].
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186 Skeletal muscle effects

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187 When intramuscular oxygen is reduced at altitude, specific changes may be seen in
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188 gene transcription, economy of muscle metabolism and buffering capacity. Elevated

189 GLUT-4 transporter mRNA has been recorded in skeletal muscle following 6 weeks
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190 of intermittent hypoxic training in athletes [33], which facilitates a longer-lasting

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191 uptake of glucose during exercise [34]. Similarly, upregulation of angiogenin,

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192 interleukin-8, and vascular endothelial growth factor production promotes the

193 formation of new capillaries, and improves muscle blood flow to exercising tissue

194 [35,36].

195 Improved economy of muscle metabolism may also result from training in

196 hypoxic conditions. Increases in mitochondrial density [37], and oxidative enzyme

197 concentration may lead to a greater muscle oxidative capacity. Slow-twitch muscle
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198 fibre protein expression may be increased, resulting in a slower contractile phenotype

199 [33,38,39], or there may be increased efficiency in the excitation-contraction coupling

200 process itself [32]. Together, these changes in muscle phenotype are likely to increase

201 economy of muscle metabolism, but it is not clear whether or not they yield

202 improvements in endurance performance [40].

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203 Muscle buffering capacity is enhanced following hypoxic exposure [33,34].

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204 This is related to upregulation of monocarboxylate transporters which handle lactate,

205 and carbonic anhydrase enzymes which influence hydrogen and bicarbonate ion

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206 transport. However, muscle acidosis is not thought to play a major role in the

207 development of muscle fatigue and therefore it is questionable whether or not

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increased buffering capacity improves endurance performance [41].
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209 These physiologic effects are seen when the athlete trains in a hypoxic
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210 environment, and later returns to normoxic conditions. In contrast, continuous

211 hypoxic exposure has well documented deleterious effects on muscle tissue [42,43].
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212 Even at moderate altitudes, muscle fibre atrophy occurs, perhaps to reduce oxygen
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213 diffusion distance and optimise tissue oxygenation in the hypoxic environment

214 [33].This loss of muscle mass is further compounded by the overall cachectic effects
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215 of altitude, and weight loss may ensue [13,44]. There is also a reduced myocyte
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216 oxidative capacity, which may arise from lipid peroxidation of mitochondrial
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217 membranes [45].

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220 High altitude training models

221 Scientific evidence supporting the use of high altitude training models tends to be

222 controversial, and the subject of intense debate amongst researchers. This reflects the
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223 difficulties associated with working in this field. Elite athletes may be required to

224 improve performance by as little as 1% to succeed in competition [46], and the small

225 sample sizes of athletes reported in these studies are inadequate for the purpose of

226 detecting these changes. When the typical error of measurement in these studies is

227 considered, it is clear that such studies are generally underpowered for statistical

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228 purposes. It has also been noted in these trials that endurance may be altered by

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229 placebo or training camp effects, fatigue or motivation [47,48]. Table 3 summarises

230 the three main models of altitude training, their rationale, and associated positive and

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231 negative effects. Each model will now be discussed in further detail.

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233 Live high-train high (LHTH) training model

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234 During LHTH training, athletes live at altitude to facilitate physiological adaptation,
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235 and train at the same altitude to provide an additional hypoxic stimulus. Despite its

236 popularity amongst endurance athletes [1], trials which investigate its effects on sea-
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237 level performance demonstrate mixed results. Some studies demonstrate improved
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238 endurance performance, while others demonstrate no benefit when compared to

239 similar sea-level training programmes.

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240 There are a number of reasons which may account for this apparent lack of
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241 benefit. Difficulties arise in relation to the issue of training intensity [24]. As a result
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242 of reduced VO2max and aerobic capacity at altitude, athletes must reduce their training

243 intensity to a variable extent in order to avoid overtraining, which negatively impacts

244 on race-specific fitness [6,41,49]. Conversely, overtraining or immune suppression

245 may occur if training intensity is maintained to equal that of sea-level training,

246 perhaps as a result of the additive effect of combined hypoxia and exercise [14, 24].

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248 Live high-train low (LHTL) training model

249 To avoid the problems of training at altitude, the “live high-train low” model has been

250 devised. Living at altitude facilitates acclimatisation while high intensity training at

251 sea-level yields metabolic and neuromuscular benefits [6]. A recent meta-analysis of

252 LHTL studies has demonstrated such synergistic benefits to sea-level athletic

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253 performance in elite endurance athletes [48]. At present, it remains to be seen whether

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254 this is a result of haematological (i.e., accelerated erythropoiesis), non-haematological

255 adaptations (i.e., ventilatory adaptation, improved economy of muscle metabolism or

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256 enhanced buffering capacity), or both. Whatever the mechanisms, athletes should live

257 at 2,000-2,500 metres for a minimum of 4 weeks for greater than 22 hours per day to

258
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ensure adequate hypoxic exposure [6,14,24,25,50,51]. This recommendation is
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259 supported by a recent study of collegiate distance runners assigned to one of 4 living
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260 altitudes, which determined that a target altitude of 2,000 to 2,500 metres provides

261 optimal acclimatization as part of a 4-week LHTL altitude training model [52],
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262 although this finding has been disputed by other authors [53]. The use of pulse
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263 oximetry offers a convenient, non-invasive and more precise method of measuring the

264 “hypoxic dose”, instead of relying on the more old-fashioned approach of “metres
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265 above sea level versus duration of exposure” [54]. The literature is not entirely
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266 consistent on the effects of LHTL training on endurance performance, as evidenced

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267 by a double-blind placebo-controlled study of 16 endurance cyclists living for 4

268 weeks in conditions of normobaric hypoxia for 16 hours per day, which failed to

269 demonstrate an improvement in haemoglobin mass, maximal oxygen uptake and

270 mean power output [55]. There may be a more pronounced beneficial effect on

271 performance and physiological parameters of living in conditions of hypobaric

272 hypoxia rather than normobaric hypoxia [56].

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273

274 Intermittent hypoxic training (IHT)

275 Athletes living in normobaric, normoxic conditions may be subjected to short

276 intervals of hypoxic stress via inspiration of hypoxic gas during training sessions.

277 This is termed intermittent hypoxia training (IHT) or the “live low-train high (LLTH)

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278 model. While IHT has shown to have no significant haematological benefits, it is

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279 accepted that improvements in endurance performance might arise from muscle

280 adaptations which occur during training in hypoxic conditions [41].

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281

282 Combining altitude training programmes

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Endurance athletes may utilise a combination of LHTH, LHTL, and IHT models to
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284 ensure peak fitness at the time of main competition. Millet [41] proposes a triphasic
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285 training cycle for endurance athletes involving each training model at various time

286 points. In the preparation phase, two or three LHTH sojourns at 2,200-2,500 metres
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287 are recommended as “base training”, while in pre-competition training, similar

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288 training at lower altitudes of 1,800-2,000 metres may facilitate more intense interval

289 training. During the competitive phase, athletes benefit from a combination of IHT
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290 and LHTL training.

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292

293 Possible harmful consequences of altitude training

294 Altitude illnesses, which are directly attributable to hypobaric hypoxia, may be

295 divided into three broad categories: acute mountain sickness, high altitude cerebral

296 oedema and high altitude pulmonary oedema. Diagnostic criteria for these conditions

297 were established in 1991 at the International Hypoxia Symposium, held in Lake
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298 Louise in Alberta, Canada [57]. Table 4 summarises the risk factors, clinical features,

299 treatment and preventive strategies for each condition. An excellent recent review of

300 the literature on acute high altitude illnesses [58], and the practice guidelines

301 published by the Wilderness Medical Society [59] should also be consulted. Athletes

302 with pre-existing medical conditions who travel to high altitude destinations should be

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303 counselled on appropriate precautions relevant to their underlying illnesses [60,61].

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304

305

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306 Acute mountain sickness (AMS)

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AMS can occur in previously healthy athletes who ascend rapidly to high altitude of
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309 above 2,500 metres [62]. AMS may be challenging to diagnose for an inexperienced
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310 clinician because non-specific symptoms of AMS can mimic other common problems

311 which affect elite athletes, such as exhaustion, migraine, dehydration, lower
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312 respiratory tract infection, and hypothermia [63-65]. Clinical features include
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313 headache, and one or more of the following symptoms: anorexia, nausea, vomiting,

314 fatigue, dizziness, and sleep disturbance. Symptoms typically appear within 6 to 12
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315 hours after arrival at altitude [66]. A previous study of high-altitude travellers
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316 attending a travel health clinic demonstrated that female gender was a significant risk
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317 factor for development of AMS [67].

318 Once AMS has been identified, it is vital that further ascent is avoided until

319 symptoms have resolved. Early detection and management of AMS are vital to

320 prevent deterioration, and development of cerebral and pulmonary sequelae. Aspirin

321 and ibuprofen are commonly used to reduce headache [68]. Acetazolamide, a

322 carbonic anhydrase inhibitor, is used to accelerate the bicarbonate diuresis which
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323 stimulates respiration and aids acclimatisation [64]. In general, those affected by

324 AMS generally achieve a complete resolution of symptoms within a number of days,

325 and may return to training with caution, if deemed safe to do so by an experienced

326 physician. However, severe AMS may require descent, oxygen therapy or treatment

327 in a portable hyperbaric chamber [68].

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328 While the pathophysiological processes underlying AMS are incompletely

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329 understood, strong evidence points to several mechanisms which cause brain oedema

330 during ascent [64,68]. In addition, increased sympathetic activity is thought to be

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331 involved in the early development of AMS [68]. More recently, the role of oxidative

332 stress of cerebrovascular endothelium has emerged as a plausible contributing factor

333 [69].
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334 It is important to remember that sea-level fitness does not confer resistance
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335 against AMS [63,70]. Individuals who have experienced altitude illness previously,

336 who ascend rapidly, or who train excessively in the initial days of ascent at higher
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337 altitudes are at particular risk [71]. These athletes may benefit from
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338 chemoprophylaxis prior to altitude training, in the form of acetazolamide,

339 administered 1 day prior to ascent [64]. If acetazolamide is contraindicated, for

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340 example in an athlete with a sulpha allergy, dexamethasone is a safe and effective
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341 alternative prophylactic treatment. Ibuprofen has been found in a prospective, double-
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342 blind, placebo-controlled randomised trial to be as effective as acetazolamide in the

343 prophylaxis of high altitude headache and AMS [72], and this agent may be more

344 acceptable to a training athlete, in whom acral paraesthesiae may be problematic. The

345 reader is referred to a comprehensive review on prevention of high altitude illness for

346 detailed information regarding pharmacological prophylaxis [73].

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347 Preconditioning with normobaric hypoxia may be effective in reducing the

348 occurrence of AMS in susceptible athletes [6,68,74], while also improving their

349 training performance at altitude [74,75]. The susceptibility of athletes may be tested

350 by measuring capillary oxygen saturation values, heart rate or blood lactate following

351 30 minutes of exposure to an equivalent hypoxic environment [69,76]. Measurements

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352 of heart rate variability [77] and markers of lipid peroxidation in exhaled breath [78]

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353 may also have predictive value. The measurement of molecular markers, such as

354 vascular endothelial growth factor, during hypoxic exposure has emerged as a

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355 promising approach for the future [79]. At present, the observed response to previous

356 altitude exposure still remains the most reliable predictor of AMS.

357
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358 High altitude cerebral oedema
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360 In a small number of cases of AMS, the condition may progressively worsen and high
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361 altitude cerebral oedema (HACE) may develop [62]. HACE involves the presence of
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362 ataxia or a change in mental status in an individual who is suffering from AMS, or the

363 presence of both in an individual without AMS [57]. As brain oedema progressively
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364 worsens, athletes may demonstrate altered consciousness in addition to other

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365 neurological signs. The natural history of untreated HACE is rapid progression to
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366 death within hours or days, caused by coning [64]. Such a fatal outcome may be

367 prevented with immediate descent in conjunction with oxygen therapy, use of a

368 portable hyperbaric chamber [80] and intramuscular dexamethasone [68].

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370 High altitude pulmonary oedema

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372 High altitude pulmonary oedema (HAPE) is the most common cause of altitude-

373 related death [66]. It presents within the first number of days of ascent, and is not

374 always preceded by AMS. It occurs when patchy hypoxia-induced pulmonary

375 vasoconstriction gives rise to exaggerated pulmonary arterial hypertension, vascular

376 leakage, and eventual respiratory failure. Initially, there are at least two of the

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377 following symptoms: dyspnoea on exertion, cough productive of frothy, pink sputum,

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378 reduced exercise tolerance or chest tightness. These symptoms are accompanied by

379 two or more of the following signs: tachypnoea, tachycardia, central cyanosis and

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380 crackles on auscultation. It is known that individuals with a brisk hypoxic pulmonary

381 vasoconstrictor response are more susceptible, a risk that is increased by excessive

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physical exertion and cold ambient temperature at altitude [64]. Similarly, preexisting
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383 cardiopulmonary disease such as obstructive sleep apnoea also increases risk [70].
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384 Iron depletion [81] and certain HLA class II allelic variations may also play a role in

385 the development of HAPE [82]. Detecting susceptibility, however, still remains a
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386 difficult task.

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387 As with HACE, early recognition is critical in the management of HAPE.

388 Treatment involves supplementary oxygen in a hyperbaric chamber, and avoidance of

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389 exertion, the recumbent position, and cold ambient temperatures [64]. Positive end-
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390 expiratory pressure (PEEP) delivered via a face mask may provide a means of
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391 improving oxygenation if no hyperbaric chamber is available for use [83].

392 Administration of the calcium channel blocker nifedipine reduces pulmonary

393 vasoconstriction by antagonising calcium channels within the pulmonary vasculature.

394 Phosphodiesterase inhibitors such as sildenafil and tadalafil similarly reduce

395 pulmonary vascular tone. Inhaled long-acting beta-2 agonists such as salmeterol may
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396 also be of benefit in the clearance of alveolar fluid [64]. Prophylaxis for those athletes

397 at risk includes slow-release nifedipine, sildenafil or tadalafil, and salmeterol [68].

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399 Immune suppression

400 When exercise takes place at altitude, the additive hypoxic stress is associated with

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401 suppression of the immune system. Athletes consequently may suffer from infection

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402 at high altitude [84], especially if they are overtraining, experiencing psychological

403 stress, malnourished, or have poor personal hygiene [85]. Athletes exercising at

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404 altitude show increased levels of circulating stress hormones, such as cortisol, when

405 compared to athletes exercising at identical absolute workloads at sea level [86,87].

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Autonomic activation causes sympatho-adrenal impairment of T-cell activation,
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407 proliferation, and cytokine release, which together are likely to weaken host defences,
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408 particularly against viral infection [82,88-91]. Sympathetic overactivity has also been

409 linked to reduced secretory immunoglobulin production, and reduced mucosal

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410 immunity [92]. Elevated inflammatory markers suggest that immunosuppression may
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411 also result from the effects of local tissue hypoxia [93,94]. Elevated hypoxic stress

412 within the gut wall may facilitate the penetration of endotoxin into the circulation
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413 [92,95].
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414 It is recommended that athletes must be illness-free prior to training at altitude

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415 [1]. Athletes must also reduce their contact with airborne microbes, or other infected

416 individuals, and maintain adequate personal hygiene and nutrition [96]. Athletes

417 should avoid maximal exercise especially in the initial days at altitude, and may need

418 to reduce interval workout training intensity or increase recovery time between

419 interval sessions [97]. Altitude sessions should last for no longer than 8 weeks at any
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420 one time, and short blocks of altitude training throughout the year can prevent

421 excessive fatigue [1].

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423 Sleep disturbance

424 Athletes report abbreviated, restless sleep at altitude which is related to periodic

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425 breathing, or irregular respiratory oscillations [98,99]. Such periodic breathing arises

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426 when hypoxia-induced hyperventilation causes respiratory alkalosis and reduced

427 hypoxia during sleep. This subsequently lowers respiratory drive, resulting in apnoeic

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428 periods. Sleep disturbance may result in increased daytime somnolence, reduced

429 intellectual functioning, low mood [100], reduced reaction speeds and early morning

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clumsiness, which has practical implications for morning training sessions [101].
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431 Sleep disturbance could result in inadequate recovery, symptoms of overtraining, and
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432 athletic underperformance.

433 Staged, gradual ascent is of paramount importance in order to aid

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434 acclimatisation and reduce sleep-related symptoms. A prospective observational study

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435 performed on 16 healthy mountaineers sleeping in a mountain hut at 4559 metres

436 demonstrated that sleep quality improves with acclimatization along with increases in
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437 oxygen saturation, while periodic breathing persists [102]. The authors conclude that
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438 sleep disturbances at altitude result mostly from hypoxaemia than periodic breathing.
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439 Nocturnal capillary oxygen saturation monitoring [103,104] may be useful to

440 determine the extent of sleep disturbance. There is strong evidence to support the use

441 of acetazolamide in improving sleep quality at altitude [105].

442

443 Nutritional and hydration issues

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444 Weight loss is commonly reported at altitude [13]. Apart from muscle atrophy, weight

445 loss may be attributed to reduced appetite and food intake. This observation is

446 probably related to alterations in appetite regulatory peptides such as leptin,

447 cholecystokinin, or other mechanisms [106-109]. When these effects are combined

448 with an overall increased total energy output during exercise, athletes are at

PT
449 significant risk of loss of body mass. In general, endurance athletes should be advised

RI
450 to eat a diet high in carbohydrate or fat, but low in protein. Low protein diets are

451 associated with reduced dietary thermogenesis and reduced satiety, and therefore help

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452 to maximise calorific intake and appetite [110]. Increasing meal frequency and

453 regular monitoring of body mass and composition is also important. [82] Athletes

454
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training at altitude should be made aware that reduced energy intake after rapid ascent
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455 to high altitude correlates with severity of AMS [111].
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456 Respiratory and urinary fluid losses at altitude must be addressed by careful

457 monitoring of water balance [68], especially in athletes exposed to several weeks of
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458 high altitude. Athletes should aim to increase fluid intake to 4 or 5 litres per day.
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459 Dehydration causes headache, has been linked with the development of AMS, and

460 also negatively impacts on training performance.

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461 Rapid mobilisation of iron stores occurs at altitude so that erythropoietic

C

462 requirements may be met in the bone marrow. Athletes are at risk of iron deficiency
AC

463 as a consequence of this [1]. Frequent ferritin monitoring and oral iron

464 supplementation is recommended in cases where altitude training periods are

465 prolonged. Govus and co-workers used linear regression to investigate the effect of

466 daily oral iron supplementation on haemoglobin mass and serum ferritin in 178

467 athletes exposed to moderate altitude of 1,350-3,000 metres for 2-4 weeks, and
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468 concluded that iron supplementation may help to restore iron balance to athletes with

469 low pre-altitude exposure iron levels [112].

470

471 Environmental injury

472 Cold may become a problem in exposed, mountainous areas, particularly in wet,

PT
473 windy weather [62]. Athletes are at risk of developing hypothermia following

RI
474 endurance races, as a consequence of low blood glucose, reduced intravascular

475 volume, and peripheral vasodilatation [70]. Most vulnerable to injury are older,

SC
476 exhausted or malnourished athletes who may have impaired thermoregulatory

477 mechanisms [70]. Prevention of cold-related injuries in these athletes is achieved by

478
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use of appropriate clothing, limiting exposure to cold conditions, and monitoring of
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479 wind chill [66]. When mild hypothermia does occur, the athlete should be protected
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480 from further cold exposure, have wet clothing replaced with dry, be insulated with

481 blankets, and given warm beverages [70]. The International Olympic Committee
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482 Medical Commission has published an evidence-based consensus statement on the

TE

483 environment-related health risks of athletic training and competition at altitude [113].

484 UV exposure is an important risk factor in the development of skin cancer.

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485 Therefore, athletes who train or compete at altitude are at considerable risk [66] and
C

486 must be encouraged to use sun-cream with a high sun protection factor, wear
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487 sunglasses, cover high-risk areas of the body appropriately, and minimise training

488 during times of peak sun exposure. Athletes who wear soft contact lenses during

489 training and competition should be aware of the challenges of using contact lenses in

490 high altitude environments where low relative humidity, high winds, and dust may be

491 challenging factors [114]. The negative effects of altitude training for the athlete, and

492 recommendations to minimise these effects are summarised in Table 5. The reader is
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493 directed to excellent recent reviews on the non-altitude related general health risks

494 associated with international travel, such as travellers’ diarrhoea [115] and insect-

495 borne infectious diseases, including malaria [116].

496

497

PT
498 Athlete Biological Passport

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499 The World Anti-Doping Agency (WADA) administers the Athlete Biological

500 Passport (ABP) to monitor key biological parameters over time in an effort to detect

SC
501 violations of its doping code for elite athletes. The WADA guidelines for operation of

502 the ABP came into effect on December 1st, 2009 [117]. The effect of altitude training

U
AN
503 on selected haematological indices such as the haemoglobin concentration has been

504 studied. Bonne and colleagues compared the effects of a group of swimmers
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505 following the LHTH training model with a sea-level control group and determined

506 that training at altitude confounded the interpretation of the ABP for up to 4 weeks
D

507 after altitude exposure [118]. Not all athletes were similarly affected but the majority
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508 exceeded the threshold for an abnormal ABP. A study by Schumacher and co-workers

509 of highly trained cyclists participating in a 14-day stage race at an average altitude of
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510 2496 metres above sea level concluded that the observed abnormalities in the ABP of
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511 cyclists competing at altitude were limited and consistent with anticipated
AC

512 physiological changes [119].

513

514

515 Conclusions

516 The hypoxic stress imposed on physiological systems during altitude training

517 promotes overall favourable adaptations for the elite athlete. Numerous altitude
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518 training paradigms exist, but most recently, the live high-train low model to altitude

519 training has achieved significant popularity. This approach combines the

520 advantageous changes which occur at altitude, with an undiminished exercise

521 intensity stimulus at sea level. Current research supports its efficacy in improving sea-

522 level athletic performance. Altitude training models may be combined to maximise

PT
523 endurance performance in competitive events. Athletes must take measures to

RI
524 minimise the detrimental effects of travel to altitude, in order to benefit maximally

525 from altitude training programs. The possible effects of altitude training on the

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526 Athlete Biological Passport in elite athletic participants must also be considered.

527

528 Funding
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529
530 None received.
531
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532
533 Conflict of interest
534
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535 The authors state that they have no conflict of interest to declare.
536
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537

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862

863 TABLE LEGENDS

864 Table 1 Dominance of high altitude native athletes in long distance track events [3].

865 Table 2 Popular high altitude training destinations.

866 Table 3 Description, rationale, and main effects of altitude training models.

PT
867 Table 4 Comparison of high altitude illnesses.

RI
868 Table 5 Negative effects of altitude training.

869

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Table 1 Dominance of high altitude native athletes in long distance track events [3].
Rank Name Time Nationality Year
Marathon
1 Dennis Kipruto Kimetto 2:02:57 Kenyan 2014
2 Emmanuel Kipchirchir Mutai 2:03:13 Kenyan 2014
3 Wilson Kipsang Kiprotich 2:03:23 Kenyan 2013
4 Patrick Makau Musyoki 2:03:38 Kenyan 2011
5 Wilson Kipsang Kiprotich 2:03:42 Kenyan 2011
6 Dennis Kipruto Kimetto 2:03:45 Kenyan 2013

PT
7 Emmanuel Kipchirchir Mutai 2:03:52 Kenyan 2013
8 Haile Gebrselassie 2:03:59 Ethiopian 2008
9 Eliud Kipchoge 2:04:00 Kenyan 2015
10 Eliud Kipchoge 2:04:05 Kenyan 2013

RI
10000 Metres
1 Kenenisa Bekele 26:17.53 Ethiopian 2005
2 Kenenisa Bekele 26:20.31 Ethiopian 2004

SC
3 Haile Gebrselassie 26:22.75 Ethiopian 1998
4 Kenenisa Bekele 26:25.97 Ethiopian 2008
5 Paul Tergat 26:27.85 Kenyan 1997
6 Kenenisa Bekele 26:28.72 Ethiopian 2005

U
7 Haile Gebrselassie 26:29.22 Ethiopian 2003
8 Nicholas Kemboi 26:30.03 Kenyan 2003
AN
9 Abebe Dinkesa 26:30.74 Ethiopian 2005
10 Haile Gebrselassie 26:31.32 Ethiopian 1997
5000 Metres
1 Kenenisa Bekele 12:37.35 Ethiopian 2004
M

2 Haile Gebrselassie 12:39.36 Ethiopian 1998

3 Daniel Komen 12:39.74 Kenyan 1997
4 Kenenisa Bekele 12:40.18 Ethiopian 2005
D

5 Haile Gebrselassie 12:41.86 Ethiopian 1997

6 Haile Gebrselassie 12:44.39 Ethiopian 1995
TE

7 Daniel Komen 12:44.90 Kenyan 1997

8 Daniel Komen 12:45.09 Kenyan 1996
9 Eliud Kipchoge 12:46.53 Kenyan 2004
10 Dejen Gebremeskel 12:46.81 Ethiopian 2012
C EP
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Table 2 Popular high altitude training destinations.

Country Location Altitude (above sea level)

Africa
Ethiopia Addis Ababa 2300m
Kenya Iten 2400m
Morocco Ifrane 1660m
South Africa Dullstroom 2100m

PT
South Africa Potchefstroom 1378m
South America
Mexico St Louis Potosi 1850m
Mexico Mexico City 2240m

RI
North America
USA Albuquerque 1619m
USA Mammoth Lakes 2400m

SC
USA Boulder, Colorado 1655m
USA Flagstaff 2106m
Oceania
Australia Falls Creek 1600m

U
Europe
Spain Sierra Nevada 2320m
AN
France Font Romeu 1850m
Switzerland St Moritz 1856m
M
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Table 3 Description, rationale, and main effects of altitude training models.

Model Description Rationale Effects on Performance

Positive Negative

LHTH Living and training at Live high: facilitate Increased endurance Reduced training intensity:
moderate altitude physiological adaptation performance (six to eight -Loss of race specific
(1800-2500m) for 2-3 weeks after training) fitness
weeks Train high: additional -Increased hypoxic stress

PT
hypoxic stimulus for -Overtraining
adaptation -Immune suppression

RI
LHTL Living at 2000-2500m Live high: facilitate Increases in endurance Requires significant travel

SC
for four weeks for physiological adaptation performance: between training sessions
greater than 22 hours
per day, and training at Train low: Haematological:
lower altitudes metabolic and -Increased Hb mass

U
neuromuscular benefits
of high intensity Non-haematological:
AN
training -Increased economy
-Increased buffering
-Increased ventilation
M

IHT Live in normobaric, Increased hypoxic Increased endurance Reduced training intensity:
normoxic condtions stress during training performance: -Loss of race specific fitness
yields increased muscle -Increased O2 utilisation
Train with short
D

adaptation -Increased buffering

intervals of hypoxic
stress using:
TE

- nitrogen dilution
-oxygen filtration
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-inspiration of hypoxic
gas
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Table 4 Comparison of high altitude illnesses.

Condition Risk Factors Clinical Features Treatment Prevention

AMS Previous altitude Presence of headache and one or more of Mild: Ascent rate

PT
sickness the following: -Stop ascent (<300m per day with rest
-Gastrointestinal e.g. anorexia, nausea, -Paracetamol (1g QDS) day every 1000m)

RI
Rapid ascent vomiting -Ibuprofen (400mg TDS)

SC
-Fatigue or weakness -Acetazolamide (125-500mg BD) Avoid ascent with symptoms
Excessive training -Dizziness or lightheadedness Moderate/Severe:

U
early in -Difficulty sleeping -Descent Preconditioning with

AN
acclimatisation -Acetazolamide (125-500mg BD) hypoxia
period Normal physical -Dexamethasone (4mg QDS PO, IM, IV)

M
examination -Oxygen (1-2 L/min) Acetazolamide (125-500mg
-Portable hyperbaric chamber BD 1 day prior to ascent)

D
TE
HACE Previous altitude Change in mental status or ataxia in Immediate descent Early recognition
sickness person with AMS Oxygen (2-4 L/min) and management
EP
or Dexamethasone: 8mg initial dose of symptoms of AMS
Rapid ascent Change in mental status plus 4mg every 6 hours thereafter
C

and ataxia in person without AMS Portable hyperbaric chamber

AC

Excessive training Other features: (if victim able to protect airway)

early in Irrationality, diplopia, hallucinations,
acclimatisation papilloedema, retinal haemorrhage,
period tachycardia, tachypnoea, cyanosis
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HAPE Underlying Presence of two of the Oxygen therapy (4-6L/min) Ascent rate (<300m
cardiopulmonary following signs: per day with rest day every
disease: -Crackles/wheeze in at least 1 lung field Descent 1000m)

PT
-Central cyanosis
Pulmonary -Tachypnoea Portable hyperbaric Avoid overexertion

RI
hypertension -Tachycardia chamber: sitting at 45° and in warm clothes

SC
Congestive heart Prophylaxis for
failure and Nifedipine (20-30mg susceptible

U
Chronic obstructive sustained release every individuals:
pulmonary disease Presence of two of the following 12 hours)

AN
Absence of single symptoms: Nifedipine
pulmonary artery Salmeterol (125mg BD) (20-30mg sustained

M
-Dyspnoea at rest release every 12 hours)

D
Brisk hypoxic -Cough (dry/productive) PEEP face mask

TE
pulmonary -Reduced exercise tolerance or fatigue Salmeterol (125mg BD
vasoconstrictor -Chest tightness 1 day prior to ascent)
EP
response
Other features: Tadalafil
C

Excessive physical -ECG: Right ventricular strain (10mg PO BD

AC

exertion and cold -CXR: Prominent pulmonary vessels and or Sildenafil 50mg PO every
patchy infiltrate 8 hours)
Respiratory tract
infection
ECG: electrocardiogram; CXR: chest radiograph; PEEP: positive end-expiratory pressure.
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Table 5 Negative effects of altitude training.

Negative effect Recommendations to reduce harm to athlete

Immune suppression Illness free prior to training

Reduce microbial exposure
Adequate nutrition
Reduce interval training intensity and increase recovery

PT
periods
Avoid training schedules which exceed 8 weeks in length

RI
Sleep disturbance Gradual ascent

SC
Acetazolamide

Weight loss Increase meal frequency and calorific intake

U
Low protein diet
AN
Monitor body mass and composition

Iron deficiency Monitor serum ferritin levels

M

Iron supplementation
D

Dehydration Increase fluid intake to 4-5 litres per day

TE

Avoid caffeinated beverages

Cold injury Appropriate clothing (warm and dry)

EP

Limit exposure to excess cold

C

Ultraviolet injury Sun-cream and sunglasses

Covering of high-risk areas of body
AC

Limit training during hours of peak sun exposure