Articles in PresS. J Appl Physiol (December 24, 2014). doi:10.1152/japplphysiol.00955.

2014
Luks AM Advising the High Altitude Traveler

1 Physiology in Medicine: A Physiologic Approach To Prevention and Treatment of

2 Acute High Altitude Illnesses
3
4 Andrew M. Luks, MD
5 Associate Professor, Division of Pulmonary and Critical Care Medicine
6 University of Washington Seattle, WA USA
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8
9
10
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12 Word Count: 5679 (includes text in Key Points boxes)
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14 Abstract Word Count: 186
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16 Title Word Count: 9
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18 Running Title: Prevention and Treatment of Acute High Altitude Illnesses
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20 Tables: 3
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22 Figures: 3
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24 Disclosure: The author has no financial or other conflicts of interest to report regarding
25 the contents of this manuscript. There are no competing interests. No funding sources
26 were used in the preparation of this manuscript.
27
28 Key Words: Hypoxia, altitude illness, cerebral edema, pulmonary edema, hypoxic
29 ventilatory response, hypoxic pulmonary vasoconstriction
30
31 Correspondence:
32 Andrew M. Luks, MD
33 Associate Professor
34 Division of Pulmonary and Critical Care Medicine
35 Harborview Medical Center
36 325 Ninth Avenue Box 359762
37 Seattle, WA 98104
38 Email: aluks@u.washington.edu
39 Phone: 206-744-4161
40 Fax: 206-744-8584
41

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Copyright 2014 by the American Physiological Society.

 Luks AM Advising the High Altitude Traveler

42 Abstract
43
44 With the growing interest in adventure travel and the increasing ease and affordability

45 of air, rail and road-based transportation, increasing numbers of individuals are traveling

46 to high altitude. The decline in barometric pressure and ambient oxygen tensions in this

47 environment trigger a series of physiologic responses across organ systems and over a

48 varying time frame that help the individual acclimatize to the low oxygen conditions but

49 occasionally lead to maladaptive responses and one or several forms of acute altitude

50 illness. The goal of this Physiology in Medicine article is to provide information that

51 providers can use when counseling patients who present to primary care or travel

52 medicine clinics seeking advice about how to prevent these problems. After discussing

53 the primary physiologic responses to acute hypoxia from the organ to the molecular level

54 in normal individuals, the review describes the main forms of acute altitude illness --

55 acute mountain sickness, high altitude cerebral edema and high altitude pulmonary edema

56 and the basic approaches to their prevention and treatment of these problems, with an

57 emphasis throughout on the physiologic basis for the development of these illnesses and

58 their management.

59
60 Abbreviations
61 AMS: acute mountain sickness; CaO2: arterial oxygen content; EPO: erythropoietin;
62 HACE: high altitude cerebral edema; HAPE: high altitude pulmonary edema; PA:
63 pulmonary artery; PO2: partial pressure of oxygen; SaO2: oxygen saturation

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64 Introduction

65 Increasing numbers of people are traveling to high altitudes for work or pleasure. The

66 rewards of such travel can be high but do come at the risk of developing of one of several

67 forms of acute altitude illnesses and/or worsening of underlying medical problems. In

68 response to these risks, many individuals planning high altitude travel present to their

69 primary care providers or travel medicine clinic seeking advice about how to ensure a

70 successful sojourn. The purpose of this Physiology in Medicine article is to provide

71 physiologically-based information that can be used when counseling patients for these

72 purposes.

73 The review begins by describing the physiologic responses to acute hypoxia from the

74 organ to the molecular level and then uses this information to describe the main forms of

75 acute altitude illness, acute mountain sickness (AMS), high altitude cerebral edema

76 (HACE) and high altitude pulmonary edema (HAPE) with a particular emphasis on how

77 alterations in the normal physiologic responses to hypoxia contribute to their

78 development. The review then examines the main pharmacologic and non-pharmacologic

79 approaches to prevention and treatment of acute altitude illness, again emphasizing the

80 physiologic basis for these approaches. General approaches to altitude illness prevention

81 and treatment are described along with a brief discussion of how the standard approaches

82 for prevention no longer apply at the extremes of high altitude. The focus throughout the

83 review will be on healthy individuals traveling to high altitude rather than individuals

84 with underlying cardiopulmonary diseases. For further information on such patients, the

85 reader is referred to an earlier Physiology in Medicine article on that topic. (57)

86

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87 Physiologic Responses to Acute Hypoxia

88 With ascent to high altitude, there is a non-linear decrease in barometric pressure,

89 which leads to a decrease in the ambient partial pressure of oxygen (PO2) and,

90 subsequently, a decrease in the PO2 at every point along the oxygen transport cascade

91 from inspired air to the alveolar space, arterial blood, the tissues and venous blood. The

92 higher the elevation attained, the greater the drop in PO2 at each of these points.

93 These declines in oxygen tensions trigger a variety of physiologic responses in

94 multiple organ systems (Figure 1) over a period of minutes to weeks following the initial

95 exposure (Figure 2) that are designed to help the individual adapt to or compensate for

96 the hypoxic conditions. Several important responses are described below.

97 Gas Exchange

98 Due to the decrease in barometric pressure and thus PAO2, the partial pressure

99 difference for oxygen between the alveolus and pulmonary capillary is decreased, thereby

100 slowing the rate of diffusion of oxygen across the alveolar-capillary membrane. The time

101 necessary to reach equilibration between the alveolar and capillary PO2 is further

102 increased because hypoxia results in gas exchange taking place on the steep part of the

103 hemoglobin-oxygen dissociation curve. As a result, more oxygen must be loaded onto

104 hemoglobin before the PO2 rises, delaying equilibration. At rest, however, red blood cell

105 capillary transit time in hypoxia is still sufficient for full equilibration of oxygen between

106 the alveolar gas and end-capillary blood, and the alveolar-arterial oxygen difference ([A-

107 a]O2) remains normal. However, during exercise, with reduced red cell transit time,

108 arterial PO2 drops substantially as pulmonary oxygen exchange now becomes diffusion

109 limitedeven in normal individuals.

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110 Ventilatory Responses

111 Arterial hypoxemia triggers an increase in minute ventilation known as the

112 ventilatory response to hypoxia. Mediated by the carotid bodies and determined by the

113 PO2 rather than the content (CaO2) of arterial blood, the magnitude of ventilatory

114 response to hypoxia varies between individuals and over time as the initial ventilatory

115 responses is blunted by the concurrent respiratory alkalosis before subsequent large

116 increases in ventilation occur due to further changes in acid-base status (described below)

117 and increased sensitivity of the peripheral chemoreceptors (16, 53).

118 Acid-Base Physiology

119 With the onset of the ventilatory response to hypoxia, individuals develop an

120 uncompensated respiratory alkalosis. This blunts the initial ventilatory responses, as the

121 increase in arterial pH decreases peripheral chemoreceptor output while a decrease in

122 diffusion of carbon dioxide across the blood-brain barrier causes a fall in CSF hydrogen

123 ion concentration that decreases central chemoreceptor responses. . Over a period of

124 several days, renal excretion of bicarbonate leads to a compensatory metabolic acidosis

125 and subsequent decrease in the pH toward normal, which contributes to later increases in

126 ventilation.

127 Cardiovascular Responses

128 Cardiac output increases in acute hypoxia to maintain tissue oxygen delivery in the

129 face of the lower PaO2. This increase is due largely to increases in heart rate (from

130 sympathetic activation) rather than stroke volume, as the latter actually declines

131 following exposure to high altitude due to decreases in plasma volume. Myocardial

132 contractility is preserved in hypoxia (45) while systemic blood pressure is increased to a

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133 variable extent in many individuals (34). The change in blood pressure is also a result of

134 augmented sympathetic nervous system activity (71), which increases continuously over

135 several weeks above 4000 m.

136 Pulmonary Vascular Responses

137 Exposure to environmental hypoxia also triggers hypoxic pulmonary

138 vasoconstriction, which, in conjunction with increased cardiac output, leads to a rise in

139 pulmonary artery (PA) pressure. Hypoxic pulmonary vasoconstriction occurs within

140 minutes of exposure to hypoxia (63) and is determined by primarily by the alveolar rather

141 than the arterial PO2, although the bronchial artery PO2 (40) and increased sympathetic

142 activity (15) may also play a role. As with the other responses described in this article,

143 there is considerable interindividual variability in the magnitude of hypoxic pulmonary

144 vasoconstriction (11, 20) that plays a key role in the development of one form of acute

145 altitude illness (HAPE, described below).

146 Fluid Homeostasis

147 With acute hypoxia, individuals experience diuresis and natriuresis. This response,

148 which also shows significant interindividual variability, is mediated by the peripheral

149 chemoreceptors and does not appear to be related to changes in renin, angiotensin,

150 aldosterone or atrial natriuretic peptide levels (60). Together with the decrease in

151 humidity at high altitude and increased fluid losses via the respiratory tract due to

152 hyperventilation, the decrease in plasma volume increases the risk of dehydration in those

153 with inadequate fluid intake.

154 Hematologic Responses

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155 Hemoglobin concentrations increase within 24-48 hours of ascent and continue to rise

156 in the weeks that follow. The initial changes are due to the reduction in plasma volume

157 while later changes are related to increases in red cell mass resulting from early rises in

158 serum erythropoietin (EPO) concentrations (42). These responses are important for

159 maintaining tissue oxygen delivery in the setting arterial hypoxemia (69). The position of

160 the hemoglobin oxygen dissociation curve at high altitude is affected by the respiratory

161 alkalosis and changes in 2,3 diphosphoglycerate concentrations with the ultimate position

162 likely a function of the altitude attained and the duration of stay. Studies have

163 documented, for example, a rightwards shift in the curve at 2500-3000 m, (38) no change

164 in overall position at 4500 m (39) and a leftward shift at extremely high elevations (>

165 8000 m) in acclimatized individuals., likely due to the marked respiratory alkalosis (70).

166 Cellular Level Responses

167 Many of the physiologic responses to hypoxia occur at the cellular, molecular level

168 and genetic level, with the major driver of these responses being Hypoxia Inducible

169 Factor (HIF) 1- (58). Whereas this transcription factor is degraded in normoxia by

170 prolyl hydroxylases, it avoids degradation in hypoxia and enters the nucleus where it

171 binds to HIF 1- and co-activator proteins (Figure 3). These complexes then combine

172 with hypoxia response elements to activate transcription of genes related to mitochondrial

173 function, glycolytic pathways, angiogenesis (especially via vascular endothelial growth

174 factor), endothelial function via inducible nitric oxide synthetase, erythropoiesis via EPO

175 and tyrosine hydroxylases with subsequent downstream effects on a variety of processes

176 including energy utilization, angiogenesis, erythropoiesis, nitric oxide metabolism and

177 chemoreceptor function.

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178 Sleep

179 Sleep disturbances are common at high altitude with an increased incidence of poor

180 sleep quality, increased arousals and changes in sleep architecture (66). The most

181 noteworthy feature, however, is the increased incidence of central sleep apnea, similar to

182 that seen in heart failure patients as sea-level, that develops as a result of an interaction

183 between ventilatory response to hypoxia and the feedback-control system that governs

184 breathing during sleep when cortical influences on breathing are absent. Periodic

185 breathing may be more common in individuals with stronger ventilatory responses to

186 hypoxia (41) and can persist or worsen during long stays at high altitude as ventilatory

187 responses continue to increase (5).

188 Exercise

189 For any given submaximal work rate, heart rate, cardiac output, and minute

190 ventilation are higher at high altitude than at sea-level. For most normal individuals, and

191 in contrast to sea level exercise, PaO2 and oxygen saturation (SaO2) decline with

192 progressive exercise, (68) as the rise in cardiac output shortens red blood cell transit time

193 in the pulmonary capillaries, thereby preventing full equilibration of oxygen between the

194 alveolar and capillary spaces. Maximum exercise capacity is decreased and does not

195 return to sea-level values even with prolonged stays at high altitude (68) despite [Hb]

196 being increased to mitigate reduced SaO2. Multiple factors such as redistribution of blood

197 flow to non-exercising muscles, (6) increases in right ventricular afterload and impaired

198 right ventricular function (19) and others have been implicated in this phenomenon but

199 the precise mechanism remains unclear.

200 How Travelers to Altitude Experience The Physiologic Responses

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201 As a result of these and other physiologic responses, travelers often feel different at

202 high altitude than they do at sea level. It is useful to review these differences (Table 1) as

203 part of pre-travel counseling as it will prevent travelers from misinterpreting normal

204 responses as signs of illness and allow them to better recognize when they or fellow

205 travelers manifest abnormal responses.

206

Key Points

Ascent to high altitude leads to a decrease in the PO2 at all points along the
oxygen transport cascade.

Decreased alveolar and arterial oxygen tensions trigger physiologic responses

across multiple organ systems over varying time frames

The magnitude of the physiologic responses varies significantly between

individuals

Because of the physiologic responses, individuals feel different at high altitude

than at sea level and should be counseled about what to expect in this regard
207

208

209 Acute Altitude Illness: Clinical Features and Pathophysiology

210 The majority of individuals ascending to high altitude manifest the physiologic

211 responses noted above and complete their sojourn without significant health problems. In

212 other cases, maladaptive responses occur and individuals develop one of three forms of

213 acute altitude illness, acute mountain sickness(AMS), high altitude cerebral edema

214 (HACE) or high altitude pulmonary edema (HAPE). The clinical features of these

215 illnesses are described in Table 2 and have been reviewed extensively elsewhere (4, 22).

216 Of these entities, AMS is by far the most common with reported incidence rates varying

217 between 25 and 78% depending on the study population, location, altitude reached and

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218 rate of ascent. HACE and HAPE are far less common but are potentially fatal if not

219 recognized and addressed promptly, thereby making it important to counsel all high

220 altitude travelers about how to recognize these entities at an early stage of illness. A

221 variety of other problems have been described in travelers at high altitude such as

222 transient cortical blindness and other visual defects, global amnesia and cranial nerve

223 palsies but there is insufficient evidence to suggest these are distinct altitude-related

224 illnesses like AMS, HACE or HAPE.

225 General Pathophysiology Principles

226 In general, the main reason individuals become ill is they ascend too high too fast.

227 For example, an individual who ascends over only 3 days to 5000 m and remains at this

228 altitude is far more likely to develop acute altitude illness than an individual who ascends

229 to the same elevation over a period of 7 days. Overly rapid ascent essentially prevents

230 adequate acclimatization, the series of organ and cellular level responses mentioned

231 above that, in broad terms, serve to limit the fall in PO2 at every step along the oxygen

232 cascade and, as a result, decrease the risk of acute altitude illness.

233 In considering this issue, it is important to note, that there is significant

234 interindividual variability in the pace of acclimatization, such that some individuals

235 acclimatize quickly and tolerate fast ascent rates while others have difficulty even with

236 slower ascent profiles. This is likely a multi-genetic trait and many polymorphisms

237 contribute to this phenotype but the full array of polymorphisms have yet to be identified.

238 There is also an important interaction between altitude reached and the time spent at that

239 altitude that affects risk, whereby individuals who quickly ascend to very high elevations

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240 but descend soon thereafter may avoid altitude illness while individuals who remain

241 longer at the peak elevation following a similar ascent profile often become ill.

242 Disease-Specific Pathophysiology

243 Beyond the general issues noted above, more specific pathophysiologic issues

244 warrant consideration for each form of altitude illness.

245 AMS and HACE: Despite considerable research in this area, there is still no unified

246 explanation for why individuals develop these entities and whether they represent

247 different manifestations and severity of the same underlying process or result from

248 distinct pathophysiologic mechanisms. Some studies suggest that individuals with a

249 lower SaO2 following arrival at high altitude are at greater risk for developing AMS later

250 in their sojourn (48, 64) while others have noted a correlation between SaO2 and

251 simultaneously measured AMS scores (29, 44). Because the SaO2 can be related to the

252 PaO2 through the hemoglobin-oxygen dissociation curve, assuming equal hemoglobin-

253 oxygen affinity between healthy and sick individuals, this would imply that individuals

254 who become sick either have lower ventilation and, therefore, lower alveolar and arterial

255 PO2 than healthy individuals or have abnormal ventilation-perfusion matching leading to

256 a lower PaO2.

257 Blunted ventilatory responses might play a role in the development of AMS as the

258 lower PaO2 and higher PaCO2 may cause higher cerebral blood flow with subsequent

259 increases in intracranial volume and, potentially, intracranial pressure. According to the

260 Tight-Fit Hypothesis, which posits that individuals with a greater ratio of cerebrospinal

261 fluid to blood and brain tissue volume have increased ability to compensate for cerebral

262 swelling or increasing intracranial blood volume,, these effects might be magnified in

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263 individuals with less intracranial volume, further increasing the risk of altitude illness.

264 (28, 50) The fact that decreased ventilation during hypoxia at rest or with exercise is

265 associated with a greater risk of AMS (7, 43, 47) and the fact that medications that

266 increase ventilation such as acetazolamide (discussed further below) and theophylline

267 also decrease the incidence of the disorder would provide support for this argument.

268 However, because the ventilatory response to hypoxia is highly variable between

269 individuals and is just one of several factors contributing to the development of AMS,

270 measurement of this response has limited utility for assessing risk in a particular

271 individual. It should also be noted that while the Tight Fit Hypothesis is appealing from a

272 theoretical standpoint, supportive data are lacking. Studies using brain MRI, for example,

273 have not shown a relationship between changes in brain volume in acute hypoxia and

274 subsequent development of AMS (14, 51).

275 Ventilation-perfusion mismatch could possibly arise from subclinical pulmonary

276 edema but while a study of changes in closing volume in climbers ascending to 4559 m

277 suggested there was a high incidence of subclinical edema, (9) other studies examining

278 changes in diffusion capacity for carbon monoxide, a marker of the surface area for gas

279 exchange, and the development of AMS following ascent have yielded conflicting

280 evidence regarding this phenomenon (12, 18, 59).

281 Alterations in fluid balance have also been invoked as a potential mediator of AMS.

282 Clinical observations and controlled studies suggest, for example, that individuals who

283 develop AMS develop expanded plasma and extracellular volume in contrast to the mild

284 diuresis that occurs in individuals who remain healthy (21, 31). Studies have examined

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285 the role of anti-diuretic hormone, the renin-angiotensin system and atrial natriuretic

286 peptide levels in this phenomenon but the precise mechanism remains unclear.

287 Beyond these derangements in organ-level physiologic responses noted earlier, other

288 molecular-level mechanisms promoting inflammation, reactive oxygen species

289 generation, vascular endothelial growth factor upregulation have been examined for a

290 role in AMS and/or HACE pathophysiology but this work has not sufficiently clarified

291 the pathophysiology of these disorders to translate into clinical management.

292 HAPE: In contrast to AMS and HACE, the pathophysiology of HAPE is well

293 understood. Multiple studies have established that when compared to healthy controls

294 HAPE-susceptible individuals have abnormal pulmonary vascular responses to hypoxia

295 as well as exercise in both normoxia and hypoxia (11, 20, 37). At high altitude,

296 exaggerated hypoxic pulmonary vasoconstriction leads to elevated pulmonary artery

297 pressure and subsequent edema formation. High pulmonary artery pressure alone is not

298 sufficient to cause HAPE, however. Instead, the key feature of this process is the fact that

299 hypoxic pulmonary vasoconstriction occurs unevenly throughout the lung. As a result of

300 this heterogeneity, regions of the pulmonary vasculature where vasoconstriction does not

301 occur experience both increased pressure and increased blood flow, leading to capillary

302 stress failure and subsequent leakage of fluid and protein from the vascular space to the

303 interstitial and alveolar spaces. (3, 25) This concept, which is supported by the patchy

304 radiographic opacities in many HAPE patients and MRI studies demonstrating that

305 HAPE susceptible individuals develop increased heterogeneity of pulmonary blood flow

306 during hypoxic breathing (13, 24) helps account for the observation that edema is seen

307 with very high PA pressure at altitude but is not a feature of other forms of pulmonary

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308 arterial hypertension, where pathophysiologic changes are more even throughout the

309 lung, even in patients with severe forms of the disease. Heavy exercise contributes further

310 to the risk of edema formation at altitude by increasing pulmonary blood flow and

311 worsening over-perfusion in the unprotected regions.

312 At the molecular level, exaggerated hypoxic pulmonary vasoconstriction appears to

313 be the result of impaired endothelial function and decreased bioavailability of nitric oxide

314 but additional factors, including increased sympathetic activity and altered levels of other

315 vasoactive mediators such as endothelin and angiontensin II may also play a role (3).

316 Beyond these hemodynamic factors, alterations in alveolar fluid clearance also

317 contribute to edema formation. By decreasing the activity and expression of apical and

318 basolateral membrane sodium channels and sodium-potassium (Na+-K+) ATPases,

319 hypoxia decreases sodium transport across the alveolar wall and reduces reabsorption of

320 fluid that accumulates in the alveolar space (52, 65). While earlier studies suggested

321 inflammatory responses might effect edema formation, (55) more recent studies using

322 bronchoalveolar lavage in the early stages of HAPE demonstrated that edema formation

323 is driven by imbalances in hydrostatic forces rather than inflammation (61).

324

Key Points

There is significant inter-individual variability in susceptibility to acute altitude

illness

Overly rapid ascent is the main reason that individuals develop acute altitude
illness

The pathophysiology of acute mountain sickness and high altitude cerebral edema
is not well understood but may be related to alterations in ventilation, gas
exchange, cerebral blood flow, fluid homeostasis and a varitety of molecular-level
processes

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High altitude pulmonary edema occurs as a result of excessive hypoxic

pulmonary vasoconstriction that occurs unevenly throughout the lung and leads to
leakage of fluid from the vascular into the alveolar and interstitial spaces of the
lung

325

326

327 A Physiologic Perspective on Preventing Acute Altitude Illness

328 A variety of non-pharmacologic and pharmacologic measures are available for

329 preventing acute altitude illness following ascent. The basis for many of these

330 interventions can be understood in light of the physiologic and pathophysiologic

331 responses described above.

332 Non-Pharmacologic Measures for Altitude Illness Prevention

333 Because overly rapid ascent is a critical risk factor for acute altitude illness, the best

334 preventive measure is to undertake a slow ascent to the target altitude, where the term

335 slow refers to the rate at which one increases their sleeping elevation rather than the

336 walking or climbing pace at any given time (35). Although the molecular level details of

337 what happens with slow, compared to fast, ascent remain unclear, slow ascent essentially

338 provides more time for protective physiologic responses while blunting pathophysiologic

339 responses that contribute to illness, a concept is demonstrated nicely by data showing that

340 PA pressure at 4300 m is lower when ascent is interrupted by a 7-day stay at an

341 intermediate altitude compared to immediate exposure to this altitude in a hypobaric

342 chamber (1).

343 Avoiding overexertion at altitude is another common recommendation for preventing

344 altitude illness, although the evidence supporting this is mixed (49, 56). The mechanism

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345 by which overexertion affects risk is not clear but may relate to decreases in PaO2 that

346 occur with progressive exercise at altitude and subsequent downstream consequences of

347 increased hypoxemia or to increases in cerebral and pulmonary blood flow, with the latter

348 being an important contributor to the development of HAPE. Overexertion also increases

349 the risk of dehydration, whose symptoms mimic those of AMS. Forced hydration is often

350 recommended in lay publications as a means to decrease the risk of altitude illness but the

351 available evidence does not support a relationship between hydration status and AMS (8)

352 and forced hydration might actually increase the risk of problems such as hyponatremia

353 or, when combined with heavy sodium intake, pulmonary edema (32).

354

355 Pharmacologic Measures for Altitude Illness Prevention

356 Several medications have an established benefit in prevention of AMS, HACE and

357 HAPE. The appropriate doses are listed in Table 3 and their physiologic rationale is

358 described below.

359 Acetazolamide: The mainstay of pharmacologic prophylaxis, acetazolamide,

360 decreases the risk of AMS by initiating a renal bicarbonate loss and causing a metabolic

361 acidosis. This counteracts the dampening effect of hypocapnia on the full ventilatory

362 response upon initial exposure to hypoxia. With the decrease in pH, peripheral

363 chemoreceptor output increases, leading to a rise in minute ventilation. Renal

364 bicarbonate losses also lead to increased efflux of bicarbonate from the CSF leading to a

365 decrease in CSF pH and further stimulation to ventilation via the central chemoreceptors.

366 Beyond these primary effects, acetazolamide may also play a role through direct effects

367 on the cerebrovascular endothelium, peripheral chemoreceptors and central

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368 chemoreceptors with subsequent downstream effects on minute ventilation (62). Some

369 animal studies suggest it may also blunt hypoxic pulmonary vasoconstriction (23) and

370 potentially have a role in HAPE prevention but this has not been confirmed in human

371 studies and acetazolamide is not used for HAPE prophylaxis at present.

372 Dexamethasone: Although its role in AMS prevention has been established in

373 research studies (26) and clinical experience, the mechanism by which it plays this role

374 remains unexplained. In a study of HAPE-susceptible individuals ascending to 4559 m,

375 dexamethasone was also shown to decrease PA pressure and prevent HAPE (36). The

376 mechanism underlying this surprising finding is unclear but may relate to effects on

377 endothelial nitric oxide synthetase activity and nitric oxide availability as well as effects

378 on sympathetic activity, pulmonary capillary permeability and epithelial sodium transport

379 (3).

380 Nifedipine: Based on a single, small, randomized study, (2) nifedipine has been the

381 primary option for preventing HAPE in known susceptible individuals. By inhibiting

382 calcium channels on the surface of vascular smooth muscle cells, the medication limits

383 the rise in intracellular calcium concentrations necessary for smooth muscle contraction,

384 thereby interfering with hypoxic pulmonary vasoconstriction and decreasing PA pressure,

385 the key issues driving edema formation in HAPE. Nifedipine has no known role in AMS

386 prevention.

387 Phosphodiesterase-5 (PDE-5) Inhibitors: Sildenafil and tadalafil can be used as

388 alternatives to nifedipine for HAPE prevention (36). These agents enhance the role of

389 nitric oxide by blocking the degradation of cyclic GMP in vascular smooth muscle.

390 Higher cGMP concentrations, in turn, decrease influx and increase efflux of calcium from

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391 smooth muscle cells, promoting vasodilation and decreasing PA pressure. These

392 medications may also improve gas exchange at altitude and partially mitigate the altitude-

393 induced decrease in maximum exercise capacity (19, 46). The mechanism for the former

394 effect is unclear while the latter is the result of diminished pulmonary artery pressure

395 responses to hypoxia and improvements in right ventricular function.

396 Salmeterol: This long acting -agonist increases sodium and fluid transport out of the

397 alveolar space by stimulating amiloride-sensitive sodium channels on the apical

398 membrane and possibly increasing Na+-K+-ATPase activity on the basolateral membrane.

399 Although it has been shown in a randomized, controlled trial to reduce the incidence of

400 HAPE in susceptible individuals (52), nifedipine or the PDE-5 inhibitors remain the

401 preferred first-line agents for HAPE prevention, (35) as lowering pulmonary artery

402 pressure appears to be a more effective prophylaxis strategy.

403 Ibuprofen: Recent data suggest ibuprofen may also be effective in the prevention of

404 AMS. (30) However, a clear mechanism of action has not been elucidated and the agent

405 has not yet supplanted acetazolamide or dexamethasone in prevention guidelines.

406 General Approach to Altitude Illness Prevention

407 All individuals ascending to high altitude should adhere to the non-pharmacologic

408 measures mentioned above. To limit the rate of ascent, once above 3000 m individuals

409 should not increase their sleeping elevation by more than 300-500 m per night and should

410 include a rest day every 3-4 days or before or following any very large gains in elevation

411 mandated by local terrain factors. Pharmacologic prophylaxis is not warranted in all high

412 altitude travelers and, instead, should be used based on the individuals prior history of

413 performance at altitude, if known, and the planned ascent profile as specified in published

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414 guidelines on this topic (35). Those individuals with a prior history of altitude illness,

415 very high sleeping elevations on the first night of the trip, or planned fast ascent rate

416 above 3000 m should strongly consider pharmacologic prophylaxis for AMS, with

417 acetazolamide being the first-line agent for this purpose. Because it is an uncommon

418 entity, pharmacologic prophylaxis for HAPE is reserved for those with a prior history of

419 the disorder. Because of genetic differences in susceptibility, individuals making repeated

420 ascents to high altitude over time can adapt these recommendations as they learn more

421 about their personal tolerance of hypoxia.

422

Key Points

Undertaking a gradual ascent is the primary non-pharmacologic means of

preventing acute altitude illness

The decision to initiate pharmacologic prophylaxis should be based on the

individuals planned ascent profile and prior history of illness at high altitude

Acetazolamide is the standard medication for preventing acute altitude illness and
works primarily by increasing ventilation through effects on acid-base balance

By blunting hypoxic pulmonary vasoconstriction, pulmonary vasodilators such as

nifedipine can be used to prevent HAPE in known susceptible individuals
423

424 Extreme Altitude: Where the Standard Approach No Longer Applies

425 The majority of individuals who travel to altitude for work or pleasure do not ascend

426 higher than 5500-6000 m, an altitude range that encompasses the highest altitude of

427 permanent human habitation and common trekking destinations such as Mt. Kilimanjaro

428 (5895 m) and Everest Base Camp (5350 m). Most of the discussion of physiologic

429 responses and prevention acute altitude illness described above largely applies to travel

430 up to such elevations. Select individuals, most commonly as part of climbing expeditions,

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431 however, do travel above these elevations and enter an environment of profound hypoxia

432 where many of the physiologic responses are pushed to the extremes (67).

433 Importantly, individuals cannot tolerate acute exposure to these marked degrees of

434 hypoxemia and can only do so if they take the appropriate amount of time to acclimatize

435 and allow for adaptive responses at the organ and molecular levels. The bulk of the

436 acclimatization work must take place at more modest elevations and through short

437 duration trips to higher elevations, however, because above about 7000 m (~23,000 ft),

438 acclimatization does not occur and stays of more than just a few days in succession are

439 associated with physical deterioration and impaired physical performance. It is for this

440 reason that with climbing at the extremes of high altitude, the commonly held notion of

441 ensuring a slow ascent to decrease the risk of altitude illness ceases to apply. Climbers

442 must do the bulk of their acclimatizing at more moderate elevations and minimize the

443 time spent in the death zone above ~7000 m by making a fast move to and from the

444 summit when conditions permit. Medications used for prophylaxis against the acute

445 altitude illnesses have also never been studied at these extreme elevations and it remains

446 unclear if they provide a benefit in this environment, although anecdotal reports suggest

447 some climbers use them for this purpose (10).

448

449

Key Points

Individuals do not tolerate acute exposure to to the extremes of high altitude

(>7000) and can only do so if they take the appropriate time to acclimatize at
more moderate elevations

Above about 7000 m, acclimatization is no longer feasible and prolonged stays

are associated with physical deterioration

Page 20
 Luks AM Advising the High Altitude Traveler

The usual rules of ensuring slow ascent and pharmacologic prophylaxis no longer
apply at elevations above 7,000 m
450

451 A Physiologic Perspective on Treating Acute Altitude Illness

452 As with altitude illness prevention, treatment involves a combination of both non-

453 pharmacologic and pharmacologic measures.

454 Non-Pharmacologic Measures for Treatment of Altitude Illness

455 Descent: With descent, barometric pressure increases leading to an increase in the

456 PO2 at every step along the oxygen transport cascade that effectively shuts off the

457 pathophysiologic processes contributing to acute altitude illness. Although beneficial

458 responses to hypoxia, such as hyperventilation, are eliminated over time following

459 descent, these effects are far outweighed by the increase in the ambient PO2. How far an

460 individual must descend is unclear and varies between individuals and with the severity

461 of illness. While it is the definitive form of treatment, it is not necessary in mild AMS

462 and is reserved for HACE, HAPE or those with AMS who are not responding to

463 appropriate treatment.

464 Portable Hyperbaric Chambers: When descent is not feasible due to weather or other

465 logistical factors, patients with severe illness can be treated in a tight-sealing fabric

466 pressure bag, often called a Gamow bag in reference to its inventor. With inflation by

467 manual air pump, the barometric pressure inside the bag rises and effectively brings the

468 ill individual to a lower elevation, with the magnitude of simulated descent a function of

469 the inflation pressure and altitude at which it is used. Following initial inflation, the bag

470 must be pumped on a continual basis to maintain pressure and ensure adequate

471 ventilation and removal of exhaled CO2. When patients are removed from the bag, they

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 Luks AM Advising the High Altitude Traveler

472 are, of course, immediately back at the original altitude but symptoms do not return

473 immediately, providing time for the patient to descend under their own power or by other

474 means.

475 Supplemental Oxygen: When available, administration of supplemental oxygen can

476 facilitate resolution of altitude illness and may be used in lieu of immediate descent in

477 cases where individuals have adequate access to medical resources such as a health

478 facility near a ski resort. Oxygen should be administered to raise the SpO2 to at least 90%

479 as this correlates with alveolar and arterial oxygen tensions above which adverse

480 physiologic responses, such as hypoxic pulmonary vasoconstriction, are essentially

481 turned off. The major challenge is ensuring adequate supply of oxygen in the event the

482 patient requires a long course of treatment, a problem that can be solved by using

483 portable oxygen concentrators when electrical power is available.

484 Expiratory Positive Airway Pressure (EPAP): Application of EPAP via a tight fitting

485 mask has been shown to be effective in improving oxygenation and managing HAPE in a

486 small case series from Denali (54) and may provide benefit in other forms of altitude

487 illness but has not been studied systematically in these other situations. From a theoretical

488 standpoint, EPAP works by increasing end-expiratory alveolar volume and improving

489 ventilation-perfusion matching but this mechanism has not been specifically studied at

490 high altitude. Individuals can recreate the physiologic benefit of EPAP through pursed lip

491 breathing but this is difficult for ill patients to maintain for durations long enough to yield

492 benefit.

493 Pharmacologic Measures for Treatment of Altitude Illness

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 Luks AM Advising the High Altitude Traveler

494 Most of the medications used for prevention of altitude illness can also be used for

495 treatment of active disease (Table 3). The physiologic rationale underlying their use is the

496 same as described above, although the evidence base supporting their use for this purpose

497 is not as extensive as the evidence for use in prevention. Because dexamethasone has not

498 been studied in HAPE treatment, it cannot be recommended for this purpose. Case series

499 describe the use of -agonists in treatment of HAPE (17, 27), but they have not been

500 studied for this purpose and are not part of standard treatment protocols.

501 General Approach to Altitude Illness Treatment

502 Descent is the definitive treatment for all altitude illness, but is not required in all

503 situations. In fact, the majority of patients with AMS, the most common form of acute

504 altitude illness, can be treated with rest, symptomatic relief (e.g., acetaminophen or non-

505 steroidal anti-inflammatory medications for headache) and possibly acetazolamide or

506 dexamethasone while remaining at the same elevation. Failure to improve or worsening

507 symptoms with this conservative approach are indications for descent.

508 Descent should be initiated up front, however, in patients with incapacitating

509 symptoms of AMS or symptoms and signs of HACE or HAPE. If descent is not feasible,

510 patients should be treated with either supplemental oxygen or a portable hyperbaric

511 chamber when available. Dexamethasone should be started for patients with HACE while

512 nifedipine or a phosophodiesterase inhibitor should be initiated in patients with HAPE.

513 Dual pulmonary vasodilatory therapy should be avoided, however, due to a risk of

514 hypotension. Patients with HAPE who access a health care facility may not require

515 descent or pulmonary vasodilator therapy and, in many cases, can be treated with

516 supplemental oxygen, bed rest and close observation alone (33).

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 Luks AM Advising the High Altitude Traveler

517

Key Points

Descent is the best treatment for acute altitude illness

When descent is not feasible, supplemental oxygen and portable hyperbaric

chambers can be used for management of HACE, HAPE and very severe AMS

With limited exceptions, the same medications used for altitude illness prevention
can be used in altitude illness treatment
518

519

520

521 Summary

522 Upon ascent to high altitude, individuals are exposed to acute hypoxia and experience

523 a decrease in oxygen tensions at all points along the oxygen transport cascade. This

524 triggers a series of physiologic responses that help the body adapt to the lower oxygen

525 tensions and lead individuals to feel different than they would at sea level. While most

526 high altitude travelers tolerate the hypoxic conditions without difficulty, some individuals

527 manifest maladaptive responses that can lead to one of several forms of acute altitude

528 illness, including AMS, HACE and HAPE. Drawing on an understanding of the major

529 physiologic responses to acute hypoxia, providers can counsel patients about changes to

530 expect following ascent, the reasons individuals develop acute altitude illness and the

531 appropriate pharmacologic and non-pharmacologic measures for preventing and treating

532 these disorders should they develop.

533

534

535

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 Luks AM Advising the High Altitude Traveler

536 References
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745

746

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 Luks AM Advising the High Altitude Traveler

747 Table 1: Ways In Which Travelers Feel Different at High Altitude Due to Normal
748 Physiologic Responses to Hypoxia
749
Increased heart rate at rest and with any level of exertion compared to sea level
Increased respiratory rate and tidal volume
Increased frequency of urination
Dyspnea on exertion that resolves quickly with rest
Poor sleep (frequent arousals, insomnia, vivid dreams)
Transient lightheadedness upon assuming upright position
750

751

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 Luks AM Advising the High Altitude Traveler

752 Table 2. Summary of Clinical Features and Management of Acute High Altitude
753 Illnesses in the General Population
754
Acute Altitude
Epidemiology Clinical Features Prevention Treatment
Illness
Affects 22 77% Headache plus Slow ascent Stop ascending
of travelers to one or more of (above 2500 m,
1850 to 5895 m the following: limit increases in Acetaminophen
nausea, vomiting, sleeping elevation or NSAIDs for
Increased lethargy, to 500 m/day headache;
incidence at sustained light- Antiemetics;
higher elevations headedness Avoid
and with faster overexertion Mild to moderate
ascent profiles Normal illness:
neurologic exam Acetazolamide or Acetazolamide
Onset of and normal dexamethasone
symptoms within mental status with moderate- Severe cases:
Acute Mountain 6-10 hr of ascent high risk ascent dexamethasone
Sickness (AMS) profiles
Descend if
symptoms do not
improve in 1-2
days or worsen
on appropriate
treatment.

Further ascent
possible if
symptoms
resolve.

Affects < 1% of Preexisting AMS Slow ascent Descend until

travelers to or HAPE symptoms resolve
elevations above symptoms (not Avoid
3000 m universally overexertion If descent not
present) possible,
Many affected Acetazolamide or supplemental
High Altitude individuals have Ataxia, altered dexamethasone oxygen or a
Cerebral Edema preceding AMS mental status with moderate- portable
(HACE) symptoms Severe lassitude, high risk ascent hyperbaric
somnolence, profiles chamber
coma
Dexamethasone
Focal neurologic
deficits No further ascent
uncommon and until individual is

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 Luks AM Advising the High Altitude Traveler

should prompt asymptomatic

consideration of while off
other diagnoses treatment
medications
Potentially fatal if
not recognized
and treated
promptly

Affects 0.2 to 8% Mild disease: Slow ascent Descend until

of travelers dyspnea and symptoms
between 2500 and arterial O2 Avoid resolve; avoid
5500 m with desaturation out overexertion over-exertion on
greater incidence of proportion to descent
at higher that expected Nifedipine for
elevations and among normals individuals with If descent not
with faster ascentwith similar prior history of possible,
ascent rates at a HAPE (alternative: supplemental
Onset within 2-5 given elevation; phosphodiesterase oxygen or a
days of ascent decreased inhibitors) portable
Can occur without exercise hyperbaric
preceding AMS performance, dry chamber
symptoms cough
Nifedipine or
Severe disease: phosphodiesteras
High Altitude
dyspnea with e inhibitor (may
Pulmonary
mild exertion or not be necessary
Edema (HAPE)
at rest; cough if supplemental
with pink, frothy oxygen
sputum; cyanosis available).

May see Avoid concurrent

concurrent signs use of nifedipine
or symptoms of and
AMS or HACE phosphodiesteras
e inhibitor
Potentially fatal
of not recognized No further ascent
promptly until individual is
asymptomatic
while off
treatment
medications
755
756

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 Luks AM Advising the High Altitude Traveler

757 Table 3. Medications Used for Prevention and Treatment of Acute Altitude Illness
758
Primary
Medication Use Dosage
Mechanism
Increase in 125 or 250 mg every
AMS Prevention
ventilation by 12 hours
Acetazolamide
generation of a
metabolic acidosis AMS Treatment * 250 mg every 12 hours
2 mg every 6 hours or
AMS Prevention
4 mg every 12 hours
Unclear
Dexamethasone mechanism of AMS Treatment 4 mg every 6 hours
action
8 mg once then 4 mg
HACE Treatment
every 6 hours (22)
30 mg sustained
Pulmonary HAPE Prevention and
Nifedipine release version every
vasodilation Treatment
12 hours
Alterations in
alveolar epithelial
Salmeterol HAPE Prevention 125 g every 12 hours
sodium and water
transport
Pulmonary HAPE Prevention and
Sildenafil 50 mg every 8 hours
vasodilation Treatment **
Pulmonary HAPE Prevention and 10 mg every 12
Tadalafil
vasodilation Treatment *** hours
759 * The role of acetazolamide in AMS treatment is not well-documented compared to its
760 role in prevention.
761 ** Clinical studies have not documented a benefit for prevention or treatment of HAPE
762 *** Clinical studies have only shown benefit in prevention of HAPE
763
764

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 Luks AM Advising the High Altitude Traveler

765 Figure Legends

766 Figure 1. Physiologic Responses to Acute Hypoxia. The decrease in barometric pressure

767 (PB) following ascent leads to a series of physiologic responses across multiple organ

768 systems with further downstream consequences. Some of these responses are mediated by

769 Hypoxia-Inducible Factors (HIF) while others occur in a HIF-independent manner.

770

771 Figure 2. Time Course of Selected Physiologic Responses to Hypoxia. For each of the

772 responses displayed, distance along the horizontal axis represents the length of time over

773 which the response is seen while changes in vertical height represent changes in the

774 magnitude of the response over time.

775

776 Figure 3. Hypoxia Inducible Factor- Activity In Normoxia and Hypoxia. In normoxia

777 (Panel A), HIF-1 is degraded in a prolyl hydroxylase-dependent pathway. In hypoxia

778 (Panel B) prolyl hydroxylase activity is decreased, HIF-1 escapes degradation and

779 combines with HIF-1 to form a complex that enters cell nuclei and induces gene

780 transduction with multiple downstream effects (58, 69).

781

Page 35
 Hypoxic pulmonary
vasoconstriction Pulmonary
artery pressure
Cardiac
output
sympathetic
activity Heart rate

Blood
pressure

Peripheral Hypoxic Acute

chemoreceptor ventilatory respiratory
activity response alkalosis
PB PIO2 PAO2 Pa O2

Diuresis and Plasma

natriuresis volume
Hemoglobin
EPO concentration
secretion
Angiogenesis
VEGF
activity Vascular
permability
 Hemoglobin
Concentration

Erythropoietin
Concentration

Pulmonary Artery
Pressure

Ventilation

Heart Rate

Minutes Days Weeks

Time of Exposure to Hypoxia

A Normoxia

HIF-1
degradation
Prolyl
hydroxylase O2
Gene
HIF-1 HIF-1, transcription

HIF-1

B Hypoxia

Mitochondrial genes Energy usage

HIF-1
degradation
Glycolytic enzyme genes Anaerobic metabolism
Prolyl
hydroxylase
Gene Angiogenesis
HIF-1 HIF-1, VEGF genes
induction

HIF-1 EPO genes Erythropoiesis

Nitric oxide (NO) Increased NO

synthetase genes availability; vasodilation