Download Chapter 144 - High-Altitude Medicine

CHAPTER 144 High-Altitude Medicine
Michael Yaron, Ryan D. Paterson, and Christopher B. Davis
EPIDEMIOLOGY
High-altitude illness represents a spectrum of clinical entities that
have hampered the activities of mountaineers, merchants, military
forces, aviators, and explorers throughout time. This illness is seen
clinically in one of several forms that overlap and share a common
pathophysiologic mechanism. Acute mountain sickness (AMS) is
the relatively benign and self-limited presentation, whereas highaltitude pulmonary edema (HAPE) and high-altitude cerebral
edema (HACE) represent the potentially life-threatening manifestations of high-altitude illness.
Worldwide, it is estimated that approximately 40 million individuals live above 8000 feet, and 25 million live above 10,000 feet.1
Rather than these high-altitude residents, the groups at risk for
acute altitude illnesses are those who ascend into mountainous
regions. Mountain sports activities and tourism are attracting
increasing numbers of participants each year. This, combined with
the rapid ascent, made possible by air transportation results in
more unacclimatized individuals at risk for high-altitude illness.
More than 1 million visitors travel annually to the remote high
mountain ranges of Asia, Africa, and South America.1 Approximately 35 million visitors travel annually to high-altitude recreation areas in the western United States.1
The incidence of high-altitude illness depends on many variables, including the rate of ascent, previous altitude exposure, and
individual genetic susceptibility.2,3 Sleeping altitude, final altitude
reached, and duration of stay at altitude are also risk factors for
AMS development.4 AMS is common (67% incidence) among
mountain climbers on Mt. Rainier who ascend quickly (1 or 2
days) to 14,410 feet.5 Trekkers who fly into the Khumbu region to
explore the Mt. Everest area have a higher incidence of AMS (47%)
compared with those who walk (23%).6 Skiers who visit resorts in
the western United States from sea level generally fly or drive to
the region but sleep at relatively lower altitudes than the other
groups mentioned. Among this population, AMS occurs in
approximately 25%.7 Given the large number of visitors (approximately 25 million) in Colorado each year, this is not a trivial
matter. The incidence of HAPE varies from 0.01 to 2% in most
studies but has reached 15.5% among soldiers flown directly to
14,500 feet without a chance to acclimatize at a lower altitude.6,8
The incidence of HACE is lower, and although it frequently occurs
with HAPE, it can be seen as an isolated entity. Both HAPE and
HACE are more common with a longer duration of visit and
higher sleeping altitude.
1928
Age may be a relative risk factor. Most studies of children
suggest that they have the same incidence of AMS as adults do.9-12
One small study of tourists in Chile evaluated children 4 to 48
months old and found higher AMS scores and lower oxygen saturations compared with those of their parents.13 Younger individuals (<20 years old) are more likely to have HAPE, although HAPE
is extremely rare in children younger than 2 years. Gender does
not affect the incidence of AMS2; however, women may have less
risk for development of HAPE.6,7,14,15 No relationship appears to
exist between AMS development and the menstrual cycle.16
The number of older travelers visiting mountain resorts is
increasing. Many of these individuals have underlying health
problems, including lung disease (10%), heart disease (25%), and
hypertension (30%). Despite these conditions, the risk for AMS
development in adults older than 50 years may be less than in
younger age groups.2,17 One study found no difference in the incidence or severity of AMS in climbers older than 50 years compared with a matched cohort of younger climbers.18 Nevertheless,
there are indications that elders may not react well to acute highaltitude exposure. Pulmonary vital capacity decreases almost one
third in elders ascending from sea level to 14,000 feet for 1 week,
producing a large decrease in both oxygen saturation and maximal
oxygen uptake during exercise.
DEFINITIONS
Moderate altitude is between 8000 and 10,000 feet of elevation.
Although most people do not experience significant arterial
oxygen desaturation until they reach higher altitudes, high-altitude
illness is common with rapid ascent above 8000 feet, and individuals with underlying medical problems may be predisposed to
development of altitude illness at lower levels.
High altitude is between 10,000 and 18,000 feet. Most serious
altitude illness occurs at these levels. The pathophysiologic effects
of high altitude begin when the oxygen saturation of the arterial
blood begins to fall below the 90% level. The sigmoidal shape of
the oxyhemoglobin dissociation curve prevents a significant fall of
arterial oxygen saturation (Sao2) in most individuals until an altitude of approximately 12,000 feet. At this altitude, the steep
portion of the curve is encountered, and marked oxygen desaturation may occur with relatively small increases in altitude (Fig.
144-1). Some predisposed individuals may desaturate to less than
90% at altitudes as low as 8000 feet.
Chapter 144 / High-Altitude Medicine 1929
100
70
5,000 ft
8,000 ft
15,000 ft
20,000 ft
25,000 ft
60
29,029 ft
Oxygen saturation (%)
90
80
50
Box 144-1 Alveolar Gas Equation
PAO2 = PIO2 (PACO2 /R )
PAO2
PIO2
PACO2
R
Partial pressure of oxygen in alveolus
Partial pressure of oxygen in inspired air
Partial pressure of carbon dioxide in alveolus
Respiratory quotient
40
30
20
10
0
0
25
50
75
100
PO2 (mm Hg)
Figure 144-1. Oxygen-hemoglobin dissociation curve. Approximate
oxygen saturations are marked for several altitudes. PO2, partial pressure
of oxygen. (Data for 15,000-29,029 feet from Sutton JR, et al:
Operation Everest II: Oxygen transport during exercise at extreme
simulated altitude. J Appl Physiol 64:1309, 1988.)
Extreme altitude is above 18,000 feet. At this height, complete
acclimatization generally is not possible, and long visits above this
level result in progressive deterioration.
ENVIRONMENTAL
CONSIDERATIONS
Barometric pressure decreases logarithmically as the altitude rises.
The partial pressure of oxygen (Po2) in the atmosphere also
decreases as altitude rises, but it remains a constant 20.93% of the
barometric pressure. The shape of the earth is slightly flat at the
poles and bulging at the equator. The atmospheric envelope that
surrounds the earth has a similar shape; therefore, the barometric
pressure is lower at higher latitudes than it is at the equator. For
example, it has been calculated that it would be impossible for a
climber to reach the summit of Mt. Everest without supplemental
oxygen if the mountain happened to be in a more northern
latitude.19
The atmospheric envelope also undergoes a seasonal tide that
causes a variation in its local thickness. This results in barometric
pressures that are lower and “relative altitudes” that are higher
during the winter season. Local weather can also have a significant
effect on barometric pressure from day to day. A low-pressure
front can reduce the barometric pressure 12 to 40 mm Hg (5002500 feet) and result in a significant temporary increase in relative
altitude.
ACCLIMATIZATION
The term acclimatization refers to the series of integrated adaptations that take place at high altitude, which tend to restore the
oxygen pressures within the tissues toward normal sea-level values
despite the lowered Po2 of the atmosphere. These processes occur
gradually and involve multiple systems from protein synthesis to
respiratory, cardiovascular, and hematologic adjustments. Gradual
ascents made by mountaineers during several weeks have allowed
the successful summiting of many of the world’s highest peaks,
including Mt. Everest (29,029 feet), without supplemental oxygen.
Without this gradual approach to allow acclimatization, however,
rapid exposure to extreme altitude results in loss of consciousness,
and death may occur in a matter of minutes.
Acclimatization begins at the altitude that causes the oxygen
saturation of arterial blood to fall below sea-level values. The
altitude at which this occurs depends on the rate of ascent, the
duration of exposure, and the individual’s physiology. People with
preexisting conditions that reduce oxygen saturation or content
may have a decreased altitude tolerance. Of particular importance
are both acute and chronic cardiac and respiratory illnesses. Most
healthy, unacclimatized visitors to high altitude will not desaturate
significantly (to less than 90%) until they reach elevations higher
than 8000 feet.1
The risk of high-altitude illness also depends on an individual’s
inherent ability to acclimatize. Some people acclimatize easily
without having any clinical symptoms. Others may transiently
have AMS during acclimatization, and a few have marked reactions to altitude exposure, developing severe altitude illness. This
variability involves many genetic and epigenetic factors that moderate the process of acclimatization.3,20 Previous successful acclimatization may be predictive of future responses for adults in
similar conditions, but this may not be the case for children.21
One of the most important physiologic changes that occurs
during acclimatization is an increase in minute ventilation, causing
a decrease in the partial pressure of carbon dioxide (Paco2). The
alveolar gas equation states that as the Paco2 decreases, a corresponding increase in Pao2 occurs, thereby increasing arterial oxygenation (Box 144-1). Thus the level of ventilation determines
alveolar oxygen for a given inspired oxygen tension.
When a person arrives at high altitude, the peripheral chemoreceptors in the carotid bodies respond to a decrease in Pao2 and
signal the respiratory control center in the medulla to increase
ventilation. This increase in ventilation is known as the hypoxic
ventilatory response (HVR), which may be inhibited or stimulated
by numerous factors, including ethanol, sleep medications, caffeine, cocoa, prochlorperazine, and progesterone. The magnitude
of the HVR varies among individuals and may be genetically
predetermined.22
As ventilation increases, a respiratory alkalosis occurs that acts
as a negative feedback system on the central respiratory center,
limiting any further increase in ventilation. Within 24 to 48 hours
of ascent, the kidneys excrete bicarbonate in an effort to compensate for the alkalosis. As the pH normalizes, ventilation rises slowly,
reaching a maximum after 6 to 8 days. This process is enhanced
by acetazolamide. The ability to achieve an adequate HVR varies
and is related to the ability to acclimatize. A low HVR and relative
hypoventilation are implicated in the pathogenesis of both AMS
and HAPE.23 For the majority of people with intermediate HVRs,
however, ventilatory drive probably has no predictive value for
AMS development.24
The release of catecholamines on ascent stimulates the circulatory system to increase cardiac output. This is manifested by an
elevation in heart rate, blood pressure, cardiac output, and venous
tone.25 Except at extreme altitudes, acclimatization results in the
gradual return of the resting heart rate to near sea-level values.
Resting relative tachycardia is evidence of poor acclimatization. As
the altitude increases, a decrease in maximal heart rate capacity
occurs, and at the limits of acclimatization, maximal and resting
heart rates converge.
1930 PART IV ◆ Environment and Toxicology / Section One • Environment
The hematopoietic response to high-altitude acclimatization
consists of an increase in both hemoglobin and the number of red
blood cells. An early increase of up to 15% occurs in mean corpuscular hemoglobin concentration after rapid ascent to high
altitude. This is primarily a result of a fluid shift into the extravascular space. Long-term acclimatization leads to an increase in
plasma volume and total blood volume. Erythropoietin is secreted
in response to hypoxemia within hours of ascent, which in turn
stimulates the production of red blood cells, leading to new circulatory red blood cells in 4 or 5 days.26 During the next 2 months,
red blood cell mass increases in proportion to the degree of
hypoxemia.27
Hypoxemia also results in an increase in 2,3-diphosphoglycerate,
causing a rightward shift of the oxyhemoglobin dissociation
curve, which favors a release of oxygen from the blood to the
tissues. This is counteracted by the leftward shift of the oxyhemoglobin dissociation curve caused by the respiratory alkalosis from
hyperventilation. The result is a net null change in the oxyhemoglobin curve and an increase in oxygen-hemoglobin binding in
the lung, which raises Sao2.28,29 Some individuals with mutant
hemoglobin and high oxygen-hemoglobin affinity are found to
acclimatize more efficiently than their normal counterparts at
moderate altitudes.30
PATHOPHYSIOLOGY
The clinical syndromes of high-altitude illness are not discrete
entities but represent a spectrum of intertwined pathophysiologic
mechanisms. AMS and HACE appear to represent differing manifestations of altitude illness on the same continuum, whereas
HAPE appears to have a somewhat independent pathophysiologic
mechanism.
The symptoms of AMS develop several hours after arrival at
high altitude, whereas the development of HAPE and HACE generally requires several days of altitude exposure. Because hypobaric hypoxemia occurs within minutes of arrival, it cannot be
the direct cause of high-altitude illness. Instead, it appears to
be the initiating factor for a complex pathologic process that leads
to the development of the various clinical syndromes. The proposed mechanisms for the development of AMS, HAPE, and
HACE are represented schematically in Figure 144-2.
A poor HVR resulting in relative hypoventilation may be
due to either the individual’s genetic predisposition or extrinsic
factors, such as medications, that decrease the ventilatory drive.
Whenever the HVR is decreased, the protective effects of hyperventilation are lost and the hypoxemia of high-altitude exposure
is exacerbated.
High-altitude exposure (hypobaric hypoxia)
Periodic breathing during
sleep exacerbates hypoxemia
Poor hypoxic ventilatory
response (hypoventilation)
Hypoxemia
Cold and
exercise
Fluid retention
Cerebral
hypoxia
Sympathetic
discharge
Peripheral
vasoconstriction
Increased
pulm/cerebral
blood volume
Pulmonary artery
hypertension
Uneven vasoconstriction
Altered
cerebral
hemodynamics
Mediatorinduced
permeability
Increased cerebral
blood flow and volume
Capillary pressure
increase
Endothelial injury
Increased permeability
Altered
Na-dependent
alveolar clearance
Vasogenic edema
↑ ICP
Brain swelling
Overperfusion
HACE
HAPE
CNS volume buffering
Adequate
Inadequate
No AMS
AMS
↑ ICP
Figure 144-2. Proposed mechanisms for the development of acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and
high-altitude cerebral edema (HACE). CNS, central nervous system; ICP, intracranial pressure.
Chapter 144 / High-Altitude Medicine 1931
The centrally mediated periodic breathing associated with highaltitude exposure may result in periods of apnea during sleep,
causing severe arterial oxygen desaturation, which further exacerbates hypoxemia.31 Significant hypoxemia initiates multiple systemic responses that involve the circulatory, pulmonary, endocrine,
and central nervous systems.
Hypoxemia alters fluid homeostasis, resulting in a generalized
fluid retention followed by the shift of fluid into the intracellular
spaces. This is manifested by peripheral edema, decreased urinary
output, and increased body weight in patients with AMS. Several
different mechanisms may account for these fluid shifts, including
arginine vasopressin levels and sympathetic stimulation that may
be centrally mediated.32,33 Arginine vasopressin levels are elevated
in some cases of AMS and HAPE and decreased in others.34,35
Aldosterone, plasma renin, and atrial natriuretic levels are higher
in people with AMS.35-37
The hypoxemia that results from high-altitude exposure also
causes an increase in pulmonary artery resistance, leading to pulmonary hypertension and elevated capillary pressures that play
the cardinal role in the development of HAPE. Exercise and cold
stress at altitude may increase hypoxemia and exacerbate pulmonary hypertension.38,39 Pulmonary blood volumes and pulmonary
hypertension are increased by sympathetic nervous system stimulation and catecholamine release.40,41 In HAPE-susceptible individuals, pulmonary hypertension becomes severe, and an uneven
distribution of pulmonary vasoconstriction results in overperfusion, increased capillary pressures, distention, and leakage in the
remaining vessels.42-45 This explains the patchy nature of the infiltrate seen on a chest radiograph with HAPE (Fig. 144-3). The
mechanism for the uneven vasoconstriction in HAPE may be due
to decreased nitric oxide bioavailability at the pulmonary tissue
level, also leading to increased endothelial leakage and extracellular edema.46-48 Overperfusion of a restricted vascular bed as the
pathogenesis of HAPE is supported by the observation that people
born with congenital unilateral absence of a pulmonary artery are
susceptible to HAPE.49 These individuals deliver their entire
cardiac output to one lung, predisposing them to overperfusion
injury.
The importance of the excessive rise in pulmonary artery pressure in HAPE is emphasized because lowering of the pressure
during ascent prevents HAPE.50 This implicates increased vascular
pressure rather than inflammation as the primary cause of the
vascular leak. The resultant mechanical shear forces lead to endothelial damage and changes in membrane permeability.48 Inflammatory mediators appear to be a secondary response to the
mechanical injury caused by overperfusion.44,51 Once the vascular
leak occurs and alveolar fluid accumulates, a defect in transepithelial sodium transport impairs the clearance of alveolar fluid and
contributes to HAPE development.52-54 Alveolar fluid clearance is
upregulated by beta-adrenergic agonists, and inhaled beta-agonists
may successfully prevent and treat HAPE.54,55
Preexisting inflammation may also be a risk factor for HAPE. A
preexisting respiratory infection during ascent to high altitude
increases susceptibility to HAPE, particularly in children.56 Inflammation may “sensitize” the pulmonary endothelium to mechanical
injury and increase susceptibility to alveolar fluid accumulation
and HAPE during ascent.
The clinical manifestations of AMS and HACE are the result of
central nervous system dysfunction. The mechanistic theories
involve altered cerebral hemodynamics and inflammatory mediators.57,58 It is known that the vasodilatory response to hypoxemia
causes an increase of cerebral blood flow and volume.59,60 The
resulting hypoxemia leads to impaired vascular autoregulation,
causing increased pressure transmission to the brain’s capillary
beds.33,61,62 In addition, systemic hypertension from strenuous
exercise at high altitude may overwhelm the brain vasculature,
resulting in transcapillary leakage and vasogenic edema. In
A
B
Figure 144-3. Chest radiograph of a patient with high-altitude
pulmonary edema. A, Before treatment. B, After treatment. (Courtesy
Richard Nicholas, MD.)
susceptible individuals, these hemodynamic changes are likely to
contribute to clinical manifestations of AMS and HACE.63-65
Additional circumstances, however, may be necessary for the
development of vasogenic edema and clinical symptoms. Inflammatory mediators may contribute to edema formation. Vascular
endothelial growth factor, the inducible form of nitric oxide synthase, reactive cytokines, and free radical formation may mediate
brain endothelial permeability. The roles that these play in the
pathophysiologic process of altitude illness remain unclear.57,66-69
Whereas vasogenic edema has been implicated in the origin of
AMS, magnetic resonance imaging (MRI) reveals signal changes
present in subjects with and without clinical AMS. Thus the significance of vasogenic edema in AMS is questioned.70 In patients
with HACE, MRI studies reveal white matter changes consistent
with vasogenic edema that correlate with symptoms.71 Despite the
unclear role of vasogenic edema, a breakdown of the blood-brain
barrier remains the leading theory in AMS and HACE pathophysiology and is most likely due to a combination of mechanical
factors and biochemical mediation of permeability.59,72
MRI data do reveal that cytotoxic edema is also present in severe
AMS.73,74 Cytotoxic edema results from hypoxic cell damage most
often associated with ischemic hypoxic insults. Failure of the adenosine triphosphate–dependent sodium pump allows sodium to
1932 PART IV ◆ Environment and Toxicology / Section One • Environment
accumulate within the cells, increasing intracellular water to maintain the osmotic equilibrium. Cytotoxic intracellular water accumulation may not be the primary mechanism for the development
of HACE but rather the result of the increased cell ischemia initially caused by hemodynamic changes, vasogenic edema, biochemical mediators, and increased ratios of brain volume to
intracranial space.71,75
Hypobaria also appears to play a role in the development of
AMS. Sea-level experiments that expose subjects to hypoxia alone
do not result in AMS; however, when hypoxia is combined with
hypobaria, AMS does occur.76,77 Although microbubble formation
and fluid retention may be a mechanism, the exact pathophysiologic role of hypobaria in altitude illness is unclear.77
These responses to hypoxia and altitude exposure occur in both
susceptible individuals and those who remain free of AMS. Thus
there must be an overall factor in a subject at risk for AMS that
fails to compensate for the changes associated with altitude exposure. The “tight fit” hypothesis is proposed to explain AMS development and its inherent individual susceptibility.59,78 This theory
suggests that the development of AMS and HACE is due to a lack
of intracranial space to accommodate increasing volume from
brain swelling and edema that develop at altitude.58 The adequacy
of the space to buffer changes in brain and cerebrospinal fluid
(CSF) volume plays a key role in determining which individuals
have symptoms of altitude illness. As brain volume increases from
increased cerebral blood volume, the volume-buffering capacity
of the central nervous system may prevent an immediate rise of
intracranial pressure. As brain volume increases, the intracranial
CSF is displaced through the foramen magnum into the space
available in the spinal canal. Increased absorption of CSF by the
arachnoid villi and decreased CSF production also occur. Individuals with less intracranial and intraspinal CSF buffering capacity have less compliance and become more symptomatic (i.e.,
develop AMS) from mild brain swelling. This tight fit hypothesis
is supported by lumbar puncture, MRI, and computed tomography studies.59,78-80
ACUTE MOUNTAIN SICKNESS
Clinical Presentation
The symptoms of mild AMS are similar to those of a viral syndrome, an ethanol “hangover,” or simple physical exhaustion. The
vague nature of this presentation results in many misdiagnoses. In
the setting of recent high-altitude exposure, these symptoms
warrant a presumptive diagnosis of AMS until it is proven
otherwise.
For the diagnosis of AMS, a patient must be in the setting of a
recent gain in altitude, be at the new altitude for at least several
hours, and report a headache plus at least one of the following
symptoms: gastrointestinal upset (anorexia, nausea, or vomiting),
general weakness or fatigue, dizziness or lightheadedness, or difficulty in sleeping (Box 144-2).81 The headache may vary from
mild to severe, is generally bitemporal and throbbing in nature,
and is worse during the night and on awakening or on suddenly
becoming upright. Anorexia and nausea, with or without vomiting, are common, and the other symptoms described can range in
severity from mild to incapacitating. The disturbance of sleep
caused by periodic breathing is common in all visitors to high
altitudes but is exacerbated in the setting of AMS. The symptoms
of AMS develop within a few hours after arrival at high altitude
and generally reach maximum severity between 24 and 48 hours,
followed by a gradual resolution. Most individuals become
symptom free by the third or fourth day. Those who do not resolve
their symptoms should descend because they may develop more
serious manifestations of altitude illness, especially if they continue to ascend.
BOX 144-2 Acute Mountain Sickness
Incidence: 12 to 67%, varies with rate of ascent and individual
susceptibility; rare below 8000 feet, most common with rapid
ascent to altitudes above 10,000 feet
Symptoms and signs: Headache, anorexia, nausea, fatigue,
dizziness, difficulty sleeping
Treatment: Mild cases are usually self-limited and do not require
treatment; discontinue ascent, rest; for moderate case,
administer acetazolamide; ibuprofen, aspirin, or
acetaminophen for headache; prochlorperazine for nausea;
supplemental oxygen if available; descend if persistent or
severe; add dexamethasone in severe cases
Prevention: Gradual ascent to allow acclimatization; highcarbohydrate diet, avoidance of ethanol or smoking;
acetazolamide if ascent is rapid or known history of recurrent
acute mountain sickness
Among infants and very young children, AMS is manifested by
increased fussiness, decreased playfulness, decreased appetite, and
sleep disturbance.10 In most cases of AMS in very young children,
all of these symptoms are present. In children, many of the symptoms manifested by AMS can also result from the disruption of
normal routine. A change in environment, sleeping accommodation, or eating habits can result in a fussy, unhappy child. In addition, the occurrence of an acute illness can also mimic AMS in
young children. If occult bacteremia or another serious illness is
suspected in a young child, descent to lower altitude is recommended to eliminate the confounding variable of altitude illness.
There are no diagnostic physical findings in cases of mild AMS.
Although dyspnea on exertion is universal at high altitudes,
dyspnea at rest is an early indication of HAPE, and a careful
examination for pulmonary edema is indicated. Similarly, any evidence of cerebellar dysfunction, such as mild ataxia or alteration
in mentation, mandates descent because of early evidence of
HACE.
Ultrasonography is emerging as an early, noninvasive diagnostic
tool to assess intracranial pressure.82 Studies have demonstrated
that elevated intracranial pressure is associated with AMS and
HACE. Increasing intracranial pressure correlates directly with
optic nerve sheath diameter.83 It is possible to demonstrate that
subjects with symptoms and signs of AMS or HACE have enlarged
optic nerve sheath diameters, which may be a useful adjunct in
the diagnosis of AMS and HACE.84,85
Management
The management of AMS should include strict adherence to the
principle that after the symptoms of altitude illness occur, further
ascent to a higher sleeping altitude is contraindicated. Halting of
ascent or activity to allow further acclimatization may reverse the
symptoms; however, continuation of the ascent exacerbates the
underlying pathologic processes and may lead to disastrous results.
The presence of neurologic abnormalities (e.g., ataxia or altered
mentation) or evidence of severe pulmonary edema mandates
immediate descent because these signs indicate a progression of
AMS to the more dangerous forms of altitude illness.
Most mild AMS is treated by stopping of further ascent and
waiting for acclimatization. This may take 1 to 4 days. AMS that
becomes worse or does not respond to maintenance of altitude,
rest, and pharmacologic intervention necessitates descent. A
descent of 1500 to 3000 feet effectively reverses high-altitude
illness in most cases. Descent should be continued until improvement is seen, and efforts to minimize exertion should be instituted
during the descent.
Chapter 144 / High-Altitude Medicine 1933
Supplemental oxygen administration relieves AMS symptoms,
including small amounts (1-2 L/min) during sleep. In the wilderness, oxygen tanks are heavy and are usually unavailable in adequate amounts; therefore, oxygen therapy is usually reserved for
the more serious manifestations of high-altitude illness. In resort
settings, oxygen may be readily available for use in the hotel or
condominium. Hyperbaric therapy that simulates descent is also
effective.
Treatment of headache, nausea, and insomnia can be beneficial
during the course of mild AMS. Aspirin, ibuprofen, and acetaminophen are useful for the treatment of high-altitude headache.
Narcotic analgesics should be avoided because of depression of the
HVR and respiratory drive during sleep. For nausea and vomiting,
prochlorperazine, unlike other antiemetics, stimulates the HVR.86
Periodic breathing causes insomnia, which is best treated with the
respiratory stimulant acetazolamide.87 Doses of acetazolamide as
low as 62.5 to 125 mg at bedtime may prevent periodic breathing
and eradicate insomnia. Benzodiazepines and other sedativehypnotics should be avoided because of their tendency to decrease
ventilation during sleep. Some climbers experience unusual reactions to diazepam at high altitudes, including agitation, hallucinations, and disorientation. These reactions can occur in individuals
who have previously used diazepam at lower altitudes without any
difficulties.88 Some studies suggest that low doses of benzodiazepines alone or in combination with acetazolamide are safe at high
altitude.89-92 Nonbenzodiazepine sleep agents (zolpidem and
zaleplon) do not depress ventilation and may prove useful in
AMS-related insomnia.93
Acetazolamide accelerates acclimatization and, if it is given early
in the development of AMS, rapidly resolves symptoms. A dose of
250 mg of acetazolamide at the onset of symptoms and repeated
twice daily is effective therapy for AMS.94,95 The treatment of AMS
in children is not formally studied, but anecdotal experience supports the use of acetazolamide in children.96 The dose for children
is 2.5 mg/kg/dose given twice daily to a maximum of 250 mg.
Acetazolamide is a carbonic anhydrase inhibitor that induces a
renal bicarbonate diuresis, causing a metabolic acidosis that
increases ventilation and arterial oxygenation. This respiratory
stimulation improves sleep when the hypoxemia caused by periodic breathing is eradicated by acetazolamide. The diuretic effects
attenuate fluid retention common in patients with AMS. This
agent also lowers CSF volume and pressure, which may play an
additional role in its therapeutic and prophylactic use. Non–
carbonic anhydrase inhibitory effects of acetazolamide include
chemoreceptor effects on ventilatory drive, alterations of cerebral
blood flow, relaxation of smooth muscles, and upregulation of
fluid resorption in the lungs.97,98
The most common adverse reactions to acetazolamide are paresthesias and polyuria. Less common reactions include nausea,
drowsiness, tinnitus, and transient myopia. Carbonic anhydrase
inhibition at the tongue causes dysgeusia, altering the flavor of
carbonated beverages, including beer. Acetazolamide is a nonantibiotic sulfa compound that carries a low risk of cross-reactivity
for individuals with an allergy to sulfa antibiotics.99 Those with
known sulfonamide allergy may consider administration of a trial
dose of acetazolamide in a controlled environment before ascent.
A history of anaphylaxis or severe skin reactions to any sulfacontaining medication makes the use of acetazolamide contraindicated. Acetazolamide should be avoided in breast-feeding
mothers and pregnant women.
Dexamethasone is an effective alternative treatment of AMS. An
initial dose of 8 mg is followed by 4 mg every 6 hours.100 No significant adverse reactions are reported; however, symptoms can
recur when the treatment is withdrawn. Although dexamethasone
can resolve the symptoms of AMS, it does not play a role in acclimatization. Concurrent use with acetazolamide is advocated by
some to promote acclimatization.101,102 It is known to have
anti-inflammatory properties, possibly to reduce cerebral blood
flow,103 and to block the action of vascular endothelial growth
factor.66 Reduction of AMS symptoms with the use of dexamethasone may be the result of these or its euphoric effects. We believe
that dexamethasone should generally be reserved for use in the
setting of acetazolamide intolerance or in more advanced cases of
AMS, especially to help facilitate descent.
Individuals with AMS may resume their ascent after their symptoms resolve. Reascent with acetazolamide in these individuals is
recommended. Caution in these susceptible individuals requires
their understanding that should their symptoms recur, further
ascent should be halted.
Prevention
Most of the symptoms of mild AMS are benign and well tolerated.
These symptoms, however, can be unpleasant and debilitating to
the point that travel, business, or vacation plans should be interrupted. Up to 50% of individuals with AMS report a decrease in
activity.7
Slow ascent, allowing adequate time for acclimatization, is the
best method of prevention; however, the time constraints of many
vacationers often make slow ascent unrealistic. The major concern
lies in the sleeping altitude during any individual ascent. Ideally,
the first night should not be spent at an altitude higher than 9200
feet, with a subsequent increase (to a new sleeping altitude) of not
more than 1600 feet each night. One extra night of acclimatization
(at the same sleeping altitude) should be added for every 3000 to
5000 feet of altitude gain above 10,000 feet. Excursions during the
day to higher altitudes with a return to a lower sleeping altitude
aid in acclimatization.
Altitude preexposure regimens in artificially hypoxic environments have been evaluated to facilitate acclimatization. It appears
that little protection from subsequent altitude exposure occurs
with preexposure regimens lasting less than 8 to 12 hours.104,105
Mild to moderate exercise is thought to aid in acclimatization;
however, overexertion can contribute to the development of
AMS.38 Maintenance of adequate hydration is also recommended.
Guidelines for adequate hydration should target relatively clear
(unconcentrated) urine and normal volume of urine output. Recommendations for hyperhydration are frequently given in the lay
literature, yet no evidence supports this advice.106,107 Drinking of
excessive amounts of free water may lead to hyponatremia and
possibly complicate altitude illness.
The rate of ascent and prior history of altitude illness should be
considered in the assessment of the risk for development of altitude illness and the choice of prevention strategies (Table 144-1).
Individuals in low-risk situations should not need medications for
prophylaxis, and ascent should be gradual to prevent illness. In
some cases, such as arrival at a high-altitude airport or the immediate dispatch of rescue personnel to high altitude, a slow ascent
is impossible. Mountain climbers commonly ascend at rates that
are higher than recommended, and some individuals continue to
suffer AMS symptoms despite gradual ascent. Individuals who
have a known susceptibility to the development of AMS and those
for whom slow ascent is impractical fall into the moderate- and
high-risk categories and should consider prophylactic medication
in addition to gradual ascent.4
Numerous studies demonstrate the effectiveness of acetazolamide in prevention of AMS in adults.5,6,108 Lower dosages provide
prophylaxis similar to that of higher dosages with fewer adverse
reactions. Many studies demonstrate that 250 mg twice daily starting 24 hours before ascent and continuing for the first 2 days at
high altitude is effective. For avoidance of side effects, a dose of
125 mg given twice daily is effective.4 Although it is unstudied, the
recommended dosage of acetazolamide for AMS prophylaxis for
children is 2.5 mg/kg/dose up to 125 mg total given twice daily,
1934 PART IV ◆ Environment and Toxicology / Section One • Environment
Table 144-1 Risk Categories for Acute Mountain Sickness
RISK CATEGORY
DESCRIPTION
Low
Individuals with no prior history of altitude illness
and ascending to ≤9200 ft
Individuals taking ≥2 days to arrive at 82009800 ft with subsequent increases in sleeping
elevation <1600 ft/day
Moderate
Individuals with prior history of AMS and
ascending to 8200-9200 ft in 1 day
No history of AMS and ascending to >9200 ft in
1 day
All individuals ascending >1600 ft/day (increase in
sleeping elevation) at altitudes above 9800 ft
High
History of AMS and ascending to ≥9200 ft in 1 day
All individuals with a prior history of HAPE or
HACE
All individuals ascending to >11,500 ft in 1 day
All individuals ascending >1600 ft/day (increase in
sleeping elevation) above >11,500 ft
Very rapid ascents (e.g., Mt. Kilimanjaro)
Modified from Luks AM, et al: Wilderness Medical Society consensus guidelines for the
prevention and treatment of acute altitude illness. Wilderness Environ Med 21:146155, 2010.
AMS, acute mountain sickness; HACE, high-altitude cerebral edema; HAPE,
high-altitude pulmonary edema.
Altitudes listed in the table refer to the altitude at which the person sleeps. Ascent is
assumed to start from elevations <4000 ft. The risk categories described pertain to
unacclimatized individuals.
and this weight-based approach may reduce side effects in smaller
adults. Ibuprofen compared with acetazolamide is equally efficacious in preventing headache.109
Dexamethasone also prevents AMS.103 The lowest effective
dosage is 2 mg every 6 hours or 4 mg every 12 hours.4,110 Some
patients experience the rapid onset of AMS after dexamethasone
is discontinued. Dexamethasone does not facilitate acclimatization but rather reduces nausea and enhances mood. In most cases,
dexamethasone use should be reserved for treatment of AMS
rather than for prophylaxis. Military or rescue personnel rapidly
ascending to high altitude and individuals with acetazolamide
intolerance are candidates for prophylaxis with dexamethasone.
The combination of acetazolamide and dexamethasone may be
more effective than either drug alone.101
Because of its antioxidant properties, Ginkgo biloba was proposed for preventive therapy of AMS. The results of several studies
are mixed, with some supporting the use of ginkgo and others
showing no evidence to support a role in AMS management.111,112
These contradicting findings may be due to the variability of composition among commercially available ginkgo products, and thus
determination of its clinical usefulness in the prevention or treatment of AMS is difficult.113 Acetazolamide remains the compound
of choice for AMS prophylaxis.
Oxygen is an effective prophylactic modality for rescue personnel. Adequate supplies should be available to ensure the safety of
all team members for the entire duration of the rescue. Air drops
of oxygen can be lifesaving when weather or terrain prevents the
immediate arrival of rescue personnel.
HIGH-ALTITUDE
PULMONARY EDEMA
HAPE is the most common fatal manifestation of severe highaltitude illness (Box 144-3). Although HAPE is uncommon below
10,000 feet, it can occur and even be fatal at altitudes as low as
8000 feet. Episodes occurring between 8000 and 10,000 feet are
usually related to heavy exercise; but at higher altitudes, pulmonary edema can also occur at rest or with light activity.42
Box 144-3 High-Altitude Pulmonary Edema
Incidence: 0.01 to 15%, varies with rate of ascent; rare below
8000 feet and more common above 14,500 feet; usually
occurs 2-4 days after arrival at high altitude
Symptoms and signs: Dyspnea at rest, cough, fatigue,
headache, anorexia, cyanosis, rales, tachypnea, tachycardia
Treatment: Patients with mild cases may recover with bed rest;
moderate cases can be treated with bed rest and
supplemental oxygen if clinical monitoring is available; severe
cases require oxygen and descent; use hyperbaric therapy if
available; if oxygen or descent is unavailable, then nifedipine
30 mg slow-release every 12 hours; consider tadalafil 10 mg
every 12 hours (unstudied)
Prevention: Gradual ascent and recognition of early AMS
symptoms so that ascent is stopped before HAPE develops;
with previous HAPE history, use nifedipine 30 mg slow-release
every 12 hours during ascent, then continue for 3 days
(monitor for hypotension)
AMS, acute mountain sickness; HAPE, high-altitude pulmonary edema.
Some individuals are susceptible and experience HAPE with
each ascent to altitude. Rarely, the congenital absence of a pulmonary artery exaggerates the pulmonary vascular response to
hypoxia, resulting in recurrent HAPE at elevations lower than
expected.49 Many patients, however, have a single episode of HAPE
and subsequently are able to return to high altitude without a
recurrence. Conversely, those with previously uneventful highaltitude exposures may have HAPE develop in a future ascent.
Individuals who have been residents at high-altitude locations
for extended periods may have pulmonary edema develop on
reascent from a trip to low altitude. This phenomenon has been
termed reentry HAPE. The incidence of reentry HAPE is not
established; however, there seems to be an increased risk for children and young adults and possibly a greater incidence compared
with HAPE experienced by low-altitude residents during their
initial ascent.114,115 This apparent increased susceptibility among
children for development of HAPE is probably the result of developmental changes in pulmonary vascular reactivity and tone.
Clinical Presentation
The initial symptoms of HAPE usually begin insidiously 2 to 4
days after arrival at high altitude. Most cases occur during the
second night, but HAPE may develop rapidly, with early symptoms apparent after just a few hours at high altitude. Marked
dyspnea on exertion, fatigue with minimal-to-moderate effort,
prolonged recovery time, and dry cough are early manifestations
of the disease. The symptoms of AMS usually occur concurrently
with the development of HAPE.
As the HAPE patient deteriorates, usually through the night,
the dyspnea intensifies with effort and is unrelieved by rest.
Dyspnea at rest should be recognized as a red flag that warns of
the development of a serious pulmonary problem. The cough
becomes productive of copious amounts of clear, watery sputum,
and hemoptysis may be seen in severe cases. As the condition
intensifies, cerebral edema or simply severe hypoxemia causes
central nervous system dysfunction, such as ataxia and altered
mentation. Coma may follow and precede death in a few hours if
oxygen therapy or descent is not instituted.
The physical examination reveals a few rales in patients with
mild HAPE, usually found in the region of the right middle lobe,
progressing to unilateral or bilateral rales and then to diffuse
bilateral rales and also rhonchi and gurgles audible without the
stethoscope. Cyanosis of the nail beds alone may progress to
severe central cyanosis. Tachypnea and tachycardia become more
Chapter 144 / High-Altitude Medicine 1935
pronounced as severity increases. Elevated temperatures are
common, and a concurrent respiratory tract infection is occasionally seen, especially in children.56
Ancillary Tests
Chest radiographs can help elucidate the nature of the illness. The
infiltrates seen in HAPE victims are alveolar and patchy in distribution, with areas of clearing between the patches. Unilateral infiltrates may be present in mild cases; however, bilateral infiltrates
are seen in more advanced cases, with involvement of the right
midlung field being most common (see Fig. 144-3). Pleural effusion is rare but may be present in severe cases. The extent of the
edema on the chest radiograph roughly parallels the clinical severity. Of note, the radiographic findings of cardiomegaly, bat-wing
distribution of infiltrates, and Kerley B lines, which are typical of
cardiogenic pulmonary edema, are absent in cases of HAPE.
Radiographic evidence of HAPE clears rapidly after initiation
of treatment; some mild cases may clear in 4 to 6 hours, and most
clear by 24 hours. Radiographs of patients with severe HAPE may
reveal infiltrates that persist for as long as 2 weeks, even though
the clinical symptoms have resolved.
An electrocardiogram reveals tachycardia and evidence of rightsided heart strain, including right axis deviation, P wave abnormalities, tall R waves in the precordial leads, and S waves in the
lateral leads.42 Hemodynamic studies reveal increased pulmonary
vascular resistance, elevated pulmonary artery pressures, and
normal pulmonary wedge pressures. Echocardiographic studies
demonstrate high estimated pulmonary artery pressures, pulmonary vascular resistance, and normal left ventricular function.41
Ultrasonography to estimate pulmonary artery pressure is an
emerging modality in the early detection and diagnosis of HAPE.
Demonstration of high pulmonary artery pressures with normal
left ventricular function is associated with HAPE and HAPE susceptibility.41,116 Ultrasound lung comet tails, indicating extravascular water, may also be seen to support a HAPE diagnosis.117,118
Differential Diagnosis
Pneumonia can be misdiagnosed in the setting of HAPE because
the symptoms and signs of pneumonia are similar to those of
HAPE. The incidence of pneumonia and the common organisms
responsible for pneumonia at high altitude are unknown, but visitors to high altitudes may be predisposed to acquire bacterial
infections because of impaired T-lymphocyte function.119 Patients
who present with symptoms compatible with pneumonia at high
altitude should be treated for HAPE. If any doubt exists about the
diagnosis of HAPE versus pneumonia, empirical antibiotic therapy
should be initiated. Because of the mild immunosuppression coincident with high-altitude exposure, the treatment of any serious
pulmonary infection at high altitude requires oxygen, descent, and
antibiotics.
High-altitude bronchitis and pharyngitis are common problems among climbers. They may result from the increased ventilation of cold, dry air across the upper airway mucosa, causing
mucosal inflammation. Copious sputum production is sometimes
seen, and antibiotic therapy usually is not helpful. Coughing
spasms may be severe and require treatment with antitussives.
Other therapeutic measures include hydration, lozenges, and
steam inhalation.
Death from pulmonary embolism at high altitude is described.120
Hypercoagulability may result from altitude effects and hyperviscosity caused by elevation in hematocrit and dehydration. Venous
stasis, caused by immobility when the individual is confined to a
sleeping bag inside a tent, is also a predisposing factor for deep
venous thrombosis. The symptoms and signs of pulmonary
embolism can mimic those of HAPE; however, embolic disease
tends to have a more rapid onset, and pleuritic chest pain is a more
prominent feature.
Management
In remote settings, where oxygen and medical expertise may be
unavailable, immediate descent is a lifesaving measure after diagnosis of HAPE. Delay of descent while HAPE progresses or waiting
for rescue personnel to initiate evacuation can prove fatal. Descents
of 3000 feet are generally adequate for a rapid recovery; however,
descent should continue until symptoms resolve.
Warmth and rest are also important in HAPE therapy for avoidance of cold- or exercise-induced pulmonary hypertension. Mild
cases of HAPE can be treated without descent or oxygen with 1 or
2 days of bed rest. Oxygen administration increases the rate of
improvement. Moderate cases can be treated without descent if
bed rest and adequate supplies of supplemental oxygen are available. Any treatment plan that does not include descent necessitates
serial examinations by clinicians with experience in management
of high-altitude illness.
On difficult terrain or in weather conditions that hamper efforts
to descend, oxygen administration (or hyperbaric therapy) can be
a lifesaving measure. Rescue personnel should air drop oxygen
supplies if immediate evacuation to lower altitudes will be delayed.
High-flow rates of oxygen (6-8 L/min) by mask should be delivered initially to victims with severe HAPE until improvement is
seen. Flow rates can then be lowered until recovery or descent is
completed. Delivery of oxygen with a continuous positive airway
pressure mask is more efficacious than normal oxygen delivery
and may improve alveolar fluid clearance.121
Hyperbaric therapy simulates descent without the administration of supplemental oxygen.122 Several portable, lightweight
(approximately 15 pounds), fabric hyperbaric chambers are available and pressurized manually (Fig. 144-4). These chambers generate 103 mm Hg (2 psi) above the ambient pressure. This
simulates a descent of 4000 to 5000 feet at moderate altitudes, and
at the summit of Mt. Everest it would simulate a descent of
approximately 9000 feet. These devices can be lifesaving in patients
with HAPE and HACE. Some nonambulatory patients are able to
descend under their own power after a few hours in hyperbaric
chambers.123
In treatment of HAPE, medications that lower pulmonary
artery pressure, pulmonary blood volume, and pulmonary vascular resistance or enhance alveolar fluid clearance are useful but not
as effective as oxygen and descent. Diuretic therapy is no longer
recommended in the treatment of HAPE as it may result in a
profound volume loss in patients who are already intravascularly
Figure 144-4. Gamow bag (left) and Certec bag (right): lightweight,
portable hyperbaric chambers. Note the attached foot-operated
pressure pump. (Courtesy Thomas Dietz, MD.)
1936 PART IV ◆ Environment and Toxicology / Section One • Environment
depleted.4,124 Some investigators argue that during the state of
antidiuresis found with severe AMS, however, no documented
deleterious effects from diuretic therapy exist.125
The advent of pulmonary vasodilators has displaced the use of
diuretics for HAPE. Nifedipine, a pulmonary vasodilator, is especially useful when oxygen is unavailable or descent is impossible.41,126 Nifedipine does not improve pulmonary hemodynamics
as much as oxygen or descent does, and it does not have an additive effect when it is administered with oxygen.41 Treatment with
30 mg of a slow-release nifedipine preparation administered twice
daily is effective.127 Patients should be monitored for the development of hypotension during nifedipine administration.
Phosphodiesterase type 5 inhibitors are less likely to produce
hypotension. Although they are known to be useful for HAPE
prevention, only anecdotal reports of treatment exist, and they
remain unstudied for HAPE therapy.55 Alveolar fluid clearance is
upregulated by beta-adrenergic agonists in animal models, and
inhaled beta-agonists have been used anecdotally for therapy of
HAPE (salmeterol 125 µg inhaled twice daily). 53,54
No evidence exists that the concurrent use of these medications
with oxygen has any benefit beyond the use of oxygen alone. The
mainstay of treatment remains immediate oxygen if it is available
and descent. Should these treatments not be available, nifedipine
should be initiated.
at altitude for 3 days.4,131 Less evidence exists to support the routine
use of other pulmonary vasodilators for HAPE prevention.
Phosphodiesterase type 5 inhibitors are selective pulmonary
vasodilators that increase cyclic guanosine monophosphate availability. Sildenafil (40 mg every 8 hours) and tadalafil (10 mg every
12 hours) are effective in preventing HAPE.50,132-134 The phosphodiesterase type 5 inhibitors have the added benefit that they are
less likely than calcium channel blockers to induce systemic hypotension. A few additional medication options may be considered
for prevention. Minimal data demonstrate that dexamethasone
(8 mg every 12 hours) started 2 days before ascent also prevents
HAPE. Unpublished data from animal models revealed that dexamethasone decreases pulmonary capillary leakage through downregulation of the inflammatory cascade, decreasing alveolar fluid
accumulation.102 To enhance alveolar clearance, salmeterol 125 µg
inhaled twice daily may be used as an adjunct to nifedipine in
patients with a clear history of HAPE recurrence, although side
effects are common at this high inhaled dose.4 Finally, clinical
experience suggests that acetazolamide aids in acclimatization and
prevents HAPE, and it has utility in reduction of hypoxic pulmonary vasoconstriction.128-130
Disposition
HACE is the least common but most severe form of high-altitude
illness. Death from HACE at as low as 8200 feet is reported,
although most cases occur above 12,000 feet. Mild AMS can progress to severe HACE with coma in as few as 12 hours. Although
the usual time course is 1 to 3 days for the development of severe
symptoms, it may occur in 5 to 9 days (Box 144-4).135,136
Mild to moderate cases of HAPE can be treated with oxygen, rest,
and careful monitoring. Resort physicians at moderate altitudes
observe HAPE patients receiving oxygen therapy to ensure adequate oxygenation. These patients are then discharged to their
hotel with supplemental oxygen and monitored for improvement
or deterioration. In severe HAPE or milder cases that do not
improve with therapy, descent is warranted. Rapid recovery is
usually seen after descent to lower altitudes, and observation of
the patient in the emergency department to ensure adequate room
air oxygenation is generally adequate. On occasion, admission to
the hospital is indicated to maintain the Sao2 greater than 90%. In
the hospital, continuous positive airway pressure improves gas
exchange in HAPE patients. Hypocapnia, alkalosis, and radiographic evidence of HAPE may persist for several days. After
oxygen saturation remains greater than 90% on room air and
clinical improvement is apparent, the patient can be discharged.
If the patient requires air travel to return home (cabin pressures
equal approximately 8000 feet), additional recovery time before
travel or arrangement for supplemental oxygen administration is
advised. Detection of a heart murmur in a patient with HAPE
should lead to an evaluation searching for cardiac structural
anomalies that may increase pulmonary vascular resistance. An
evaluation for underlying congenital heart disease is warranted
after an episode of HAPE in a young child.
The recovered victim may be able to reascend (generally in 2-3
days) when symptoms resolve and oxygen levels remain acceptable
off supplemental oxygen at rest and with mild exercise. Reascent
with pulmonary vasodilator medication should be considered.
Prevention
As with all forms of serious altitude illness, a gradual ascent that
allows time to acclimatize and immediate cessation of further
ascent at the onset of symptoms are the most effective means of
prevention. Individuals with a prior history of HAPE should also
avoid extreme exertion during the first 2 days at altitude. With
a prior history of HAPE, prophylactic therapy should be
considered.128-130 The preferred medication for HAPE prevention
is the nonspecific pulmonary vasodilator nifedipine, 30 mg
(controlled-release) two times daily before ascent and continued
HIGH-ALTITUDE
CEREBRAL EDEMA
Clinical Presentation
HACE is characterized by evidence of global cerebral dysfunction.
The symptoms of severe AMS (headache, fatigue, and vomiting)
as well as those of HAPE (cough and dyspnea) are often present.
HACE-specific signs include ataxia, generalized seizures, slurred
speech, rarely focal neurologic deficits, and altered mentation,
which can range from mild emotional lability or confusion to
hallucinations and decreased levels of consciousness that may
proceed to coma and death.135 MRI of patients with HACE
reveals white matter changes consistent with vasogenic edema
(Fig. 144-5).71
Altered consciousness and cerebellar ataxia are the most sensitive signs for early recognition of HACE.137 The early appearance
of ataxia reflects the particular sensitivity of the cerebellum to
hypoxia. Ataxia alone is an indication for immediate descent.
Retinal hemorrhages are common but often occur as an isolated
finding. Papilledema and occasionally cranial nerve palsy also
occur in the setting of increased intracranial pressure. Differentiation between HACE and stroke may be difficult. Although it is
rare, the occurrence of cerebral thrombosis and transient ischemic
attacks, in the absence of high-altitude illness, is documented at
Box 144-4 High-Altitude Cerebral Edema
Incidence: Lower than 1 or 2%, uncommon as a pure entity;
usually associated with the presence of severe AMS and HAPE
Symptoms and signs: Ataxia, severe headache, nausea and
vomiting, altered mentation, seizures, coma
Treatment: Immediate evacuation to a lower altitude; oxygen,
bed rest, dexamethasone, and hyperbaric therapy while
awaiting descent
AMS, acute mountain sickness; HAPE, high-altitude pulmonary edema.
Chapter 144 / High-Altitude Medicine 1937
138,139
high altitude.
The absence of any other evidence for highaltitude illness or the persistence of signs despite adequate treatment of high-altitude illness suggests the presence of a vascular
lesion.
Management
Early recognition and initiation of descent are the keys to successful therapy for HACE. High-flow oxygen should be administered
if it is available because oxygen alone reduces intracranial blood
flow at high altitude.58 Steroid therapy is recommended and may
result in recovery from HACE without neurologic deficits. The
initial dose of dexamethasone is 8 mg parenterally or orally in
mild cases, followed by 4 mg every 6 hours.
Patients with severely altered levels of consciousness require
tracheal intubation. Hyperventilation, diuretics (e.g., furosemide),
and hypertonic solutions (e.g., mannitol) may be used to manage
severely elevated intracranial pressure. Caution is warranted
because many patients with HACE are already volume depleted
from poor fluid intake; diuretic use could compromise adequate
intravascular volume and reduce cerebral perfusion pressure.
Hyperbaric treatment of HACE is also effective and may result
in temporary improvement and allow self-rescue. Conversely,
coma may persist for several days after descent to lower altitudes,
so placement of HACE patients in a hyperbaric device may only
delay the more comprehensive care available in the hospital
setting.
Long-term neurologic deficits, such as ataxia and cognitive
impairment, are reported after recovery from acute episodes
of HACE. Both transient and long-lasting neurobehavioral
impairments can occur in mountaineers after climbing to
extreme altitude without experiencing clinical HACE.140 Some
of these sequelae can persist for 1 year. Because of the potential
for long-lasting neurologic injury, the clinician who treats highaltitude illness should be extremely sensitive to the early manifestations of HACE. Early treatment of HACE generally results in
good outcomes, but after coma is present, the mortality rate
exceeds 60%.141
HIGH-ALTITUDE
RETINAL HEMORRHAGE
Figure 144-5. Axial proton-weighted magnetic resonance image
of a mountain climber with high-altitude cerebral edema. The arrow
demonstrates the markedly increased signal (edema) in the splenium of the corpus callosum. (Courtesy Peter Hackett, MD.)
A
High-altitude retinal hemorrhage (HARH) is the most common
type of retinopathy in visitors to high altitude.142 These hemorrhages are common at altitudes above 17,500 feet, although they
can occur at lower levels.143
The exact incidence of HARH is unknown because most
patients are asymptomatic, with HARH noted only on retinoscopy. HARH is not generally related to the presence of mild AMS
but does seem to be related to strenuous exercise at high altitude.
At any altitude, in the setting of severe HAPE or HACE, retinal
hemorrhages are commonly noted, but the mechanism remains
unclear.143,144
Hemorrhages usually spare the macula (Fig. 144-6). Retinal
hemorrhages usually resolve without treatment in 2 or 3 weeks.
With macular involvement, central scotomas may be noticed for
several years, gradually resolving. In some cases, however, these
visual defects are permanent. HARH is more likely to occur among
individuals with a previous history of these hemorrhages, but the
underlying risk remains unclear. This usually does not pose a
contraindication to return to high altitude unless the macular
region is involved.
B
Figure 144-6. High-altitude retinal hemorrhages. A, Acute. B, After 1 week of resolution. (Courtesy Charles Houston, MD.)
1938 PART IV ◆ Environment and Toxicology / Section One • Environment
CARBON MONOXIDE TOXICITY
Respiratory Illnesses
Carbon monoxide (CO) poisoning can occur at altitude from the
use of fires and combustion stoves to keep warm and to prepare
food in the high-altitude environment. If CO poisoning occurs at
altitude, it can be more devastating because of the lower oxygen
pressures and the body’s baseline hypoxic state. CO binds to
hemoglobin and prevents oxygen release to the body’s tissues that
are already, relative to sea level, hypoxic. It is easy to confuse the
symptoms and signs of CO poisoning and AMS as both include
headache, nausea, dizziness, dyspnea, and lassitude.145,146 If there
is doubt, a person should leave the enclosed space and descend or
use supplemental oxygen if it is available.147-149
Travelers with COPD to moderate altitudes have underlying anatomic and physiologic changes that predispose them to development of hypoxemia, sleep apnea, pulmonary hypertension, and
ventilation disorders. COPD is a risk factor for the development
of AMS.7 Although oxygen saturation remains more than 90% in
a healthy, awake individual until an altitude of 8000 feet, patients
with COPD may desaturate below 90% at lower altitudes. Travel
to 5000 feet did not result in significant desaturation below 90%
in one group of COPD patients and did not produce significant
adverse effects on the systemic circulation in another group at
8000 feet.150 High altitude increases hypoxic pulmonary vasoconstriction and may potentiate the development of cor pulmonale,
which is known to adversely affect survival at sea level.151 Colorado, for example, has a relatively low incidence of COPD but
a higher mortality rate than expected from emphysema.152 Individuals with chronic COPD should be advised of the potential
need for oxygen supplementation when traveling to moderate
altitude, especially if they are already using oxygen at sea level or
if dyspnea or fatigue becomes worse. Use of a pulse oximeter can
guide the need for increased oxygen supplementation.
Patients with asthma, on the other hand, may have fewer problems at altitude because of decreased allergens and pollutants and
decreased airflow turbulence. There are no descriptions of asthma
exacerbations due to altitude, although oxygen saturations might
be lower at elevation. Even those with exercise-induced bronchospasm do not have worsening symptoms while exercising at 5000
feet.153 In addition, AMS incidence is not increased in asthmatics.153 People with asthma traveling to higher elevations should
continue their usual medications and carry a rescue supply of
bronchodilators and steroids.
Patients who ascend to high altitude with preexisting primary
or secondary pulmonary hypertension should be considered
HAPE susceptible, and those with primary pulmonary hypertension should be considered at increased risk for HAPE.154 Patients
with known pulmonary hypertension should be advised against
travel to higher elevations. If travel cannot be avoided, supplemental oxygen should be used. Prophylactic nifedipine SR, 30 mg twice
daily for the duration of the stay at altitude, can prevent HAPE.126
Phosphodiesterase type 5 inhibitors and steroids may also be
used.50
ALTITUDE AND UNDERLYING
MEDICAL CONDITIONS
Individuals with diseases such as moderate to severe chronic
obstructive pulmonary disease (COPD) and coronary artery
disease may have a more difficult time acclimatizing because these
disease states are often aggravated by the hypoxic atmosphere at
higher elevations. They may predispose these individuals to the
development of high-altitude illness. Table 144-2 describes the risk
associated with travel to altitude in individuals with a variety of
underlying comorbidities.
Risk Associated with Travel to Altitude
in Individuals with a Variety of
Table 144-2 Underlying Comorbidities
ADVISABILITY OF EXPOSURE TO HIGH ALTITUDE FOR COMMON
CONDITIONS (WITHOUT SUPPLEMENTAL OXYGEN)
Probably No Extra Risk
Young and old
Fit and unfit
Mild obesity
Diabetes
Previous coronary artery bypass grafting (without angina)
Mild chronic obstructive pulmonary disease (COPD)
Asthma
Low-risk pregnancy
Controlled hypertension
Controlled seizure disorder
Psychiatric disorders
Neoplastic diseases
Inflammatory conditions
Caution
Moderate COPD
Asymptomatic pulmonary hypertension
Compensated congestive heart failure
Morbid obesity
Sleep apnea syndromes
Troublesome arrhythmias
Stable angina or coronary artery disease
High-risk pregnancy
Sickle cell trait
Cerebrovascular diseases
Any cause of restricted pulmonary circulation
Seizure disorder (not taking medication)
Radial keratotomy
Contraindicated
Sickle cell anemia (with history of crises)
Severe COPD
Symptomatic pulmonary hypertension
Uncompensated congestive heart failure
Modified from Hackett PH, Roach RC: High altitude medicine. In Auerbach P ed:
Wilderness Medicine. Philadelphia, Elsevier, 2007, p 2-36.
Cardiovascular
Individuals with a history of congestive heart failure, coronary
artery disease, dysrhythmias, or coronary bypass surgery are rarely
studied in the high-altitude setting. In theory, people with diseased
myocardium should be advised to avoid high altitude because of
decreased environmental oxygen availability. No studies report
increased mortality in visitors to these locations. To the contrary,
long-term residents at high altitude may be protected from coronary artery disease by increased collateral vessel formation or a
decrease in the development of atherosclerosis.155-157
Many elderly people with known or suspected coronary artery
disease have been safely exposed to acute hypoxia at altitude while
breathing low oxygen mixtures or when being placed in a hypobaric chamber.158 In contrast, another investigation of elderly
people with known coronary disease does demonstrate some
risk.159
Patients with heart disease have increased sympathetic activity
during the first 3 days at altitude, as do all travelers. The resultant
increase in heart rate and blood pressure increases cardiac work
and myocardial oxygen consumption, and this could increase dysrhythmias. Although both cardiac rhythm abnormalities and ST
segment and T wave electrocardiographic changes are reported,
none of these changes are associated with any clinical evidence of
Chapter 144 / High-Altitude Medicine 1939
158,160
Limited data suggest no increased risk
myocardial ischemia.
for sudden cardiac death or myocardial infarction at altitudes up
to 8000 feet.
The small increase in heart rate and blood pressure that occurs
on first visiting altitude might exacerbate angina in patients with
known disease. Even when individuals with stable angina are exercised, there is conflicting evidence for the probability of inducing
malignant dysrhythmias.159,161 In a study of 22 patients with recent
percutaneous coronary intervention or coronary artery bypass
graft with a submaximal exercise routine at 11,400 feet, there is no
evidence of myocardial ischemia or significant arrhythmias despite
an elevated oxygen demand, heart rate, and lactate level.162 Travelers with heart disease who ascend to moderate altitudes do not
appear to have an increased incidence of AMS.7,17
Travelers with mild stable coronary artery disease should be
advised to ascend gradually, to limit activity especially in the first
few days at elevation, and to continue antianginal and antihypertensive medications. Individuals who have more severe, symptomatic coronary disease or those in a high-risk group (low ejection
fraction, abnormal stress test results, and high-grade ventricular
ectopy) should avoid travel to high altitudes. Ascent to moderate
elevations can be suggested on an individual basis with the previously mentioned precautions. Individuals with heart failure who
travel to altitude may require increased use of diuretics to promote
diuresis and acclimatization. Acetazolamide prophylaxis may be
useful to speed acclimatization and to prevent AMS and its accompanying fluid retention.130 If the anticipated workload at altitude
is greater than the individual is accustomed to at sea level, exercise
stress testing at this increased workload before ascent should be
considered.163
Hypertension
High-altitude travel produces a mild increase in blood pressure
and heart rate in healthy individuals because of increased catecholamine activity and resultant sympathetic tone. This increase
begins in the first few days after ascent, is maximal at 2 or 3 weeks,
and returns to baseline values over time because of a downregulation of adrenergic receptors if one stays at high altitude or on
descent to sea level.164,165 No studies demonstrate an increased
predisposition for altitude illness in patients with underlying
hypertension.166
The incidence of hypertension in sea-level dwellers traveling to
high altitude is 10 to 25%.167 Although there is no difference in
blood pressure readings in either normotensive or hypertensive
individuals when blood pressure is measured at low altitudes
(3000 feet), significant increases occur in both blood pressure and
heart rate at altitudes above 9800 feet.168 This suggests that people
with severe hypertension should travel only to moderate altitudes.
For individuals who have mild hypertension while traveling at
altitude, treatment is not routinely necessary because the hypertension will rarely become dangerously high and will improve on
descent. Although individual variability exists, patients with
hypertension should be monitored frequently in the first few
days at altitude and antihypertensive medications continued.
For hypertensive patients with a rapid rise in blood pressure
and who will be staying for several weeks, an alpha-blocker, nifedipine, or angiotensin-converting enzyme inhibitor should be
considered.169
Seizures
Travel to altitude is implicated as a precipitant for seizure activity.
There are numerous reports of altitude-provoked seizures, but
epidemiologic data are lacking. Seizures attributable to high altitude are typically generalized tonic-clonic in nature.170 A focal
seizure at altitude should prompt a thorough workup for a
space-occupying lesion. Several pathophysiologic mechanisms are
implicated. These include sleep deprivation from periodic breathing, hyperventilation, and the direct effect of hypobaric hypoxia.170
These mechanisms are postulated to induce a metabolic state that
lowers the seizure threshold. Seizures not responding to supportive care can be treated with benzodiazepines. Should an epileptic
who is already taking seizure medicine experience a breakthrough
seizure at altitude, standard seizure evaluation is warranted, and
acetazolamide at 250 mg twice daily may be added. Acetazolamide
itself has antiepileptic properties and may ameliorate the altituderelated metabolic derangements.171
Sickle Cell Disease
Patients with sickle cell disease are affected by the hypoxemia
occurring at low to moderate altitudes (5000-6500 feet). Up to
20% of patients with hemoglobin sickle cell and sickle cell–
thalassemia disease may experience a vaso-occlusive crisis, even
under pressurized aircraft conditions.172 Oxygen is therefore
advised for air travelers who have sickle cell disease.
Although most people with sickle cell trait remain asymptomatic, this subgroup can experience the development of left upper
quadrant pain as a result of splenic ischemia or infarction. Nonblacks, usually of Mediterranean origin, who have sickle cell trait
may be more prone to the development of splenic infarctions than
are blacks.173,174
Pregnancy
Studies of permanent high-altitude residents in Colorado and
Peru show an increased incidence of complications in maternal,
fetal, and neonatal life.1,175,176 Infants born at high altitude have a
lower birth weight compared with infants born at sea level because
of a combination of factors, including altitude-related effects on
fetal growth, changes in uterine blood flow, and increased premature births.
Pregnancy-induced hypertension, proteinuria, and peripheral
edema (manifestations of toxemia and preeclampsia) are more
common at high altitudes and may also be related to maternal and
uterine hypoxemia.177,178 Although hypertension in pregnancy is
more common at high altitudes, no evidence exists for an increase
in spontaneous abortions, abruptio placentae, or placenta previa.
Travel by pregnant women to moderate altitudes appears to be
safe, but caution is advised for lowland women with normal pregnancies who wish to travel above 13,000 feet, for pregnant women
who wish to remain at high altitude for a prolonged period, and
for women with complicated pregnancies.
Radial Keratotomy
Although it is currently less popular, radial keratotomy may cause
individuals to experience hyperoptic (farsighted) visual changes
with ascent above 9000 feet.179 This results from corneal swelling
from ambient hypoxia because the cornea is markedly sensitive to
both systemic and ambient oxygen tension.180 In normal corneas,
this swelling is uniform. After radial keratotomy, the swelling is
exacerbated and inconsistent secondary to the pattern of the incisions.181 Photorefractive keratotomy and LASIK, which use laser
techniques that do not produce incisions but instead shave the
cornea and corneal stroma, respectively, do not result in similar
problems.179,182
ACKNOWLEDGMENT
The authors would like to acknowledge Dr. Benjamin Honigman
for his contributions to previous editions of this chapter.
1940 PART IV ◆ Environment and Toxicology / Section One • Environment
KEY CONCEPTS
■ The symptoms of AMS can resemble a viral syndrome and
include headache, nausea, anorexia, fatigue, and insomnia.
■ The management of altitude illness must include adherence
to the principle that after the symptoms occur and until
symptoms resolve, further ascent is contraindicated.
■ Dyspnea at rest is an early symptom of HAPE. As the HAPE
patient’s condition deteriorates, the dyspnea intensifies with
effort and is unrelieved by rest.
■ Altered consciousness and cerebellar ataxia must be
recognized as early signs of HACE, and descent is mandatory.
■ Effective prophylaxis options for altitude illness include
acetazolamide for AMS and nifedipine for HAPE.
Phosphodiesterase type 5 inhibitors are selective pulmonary
vasodilators that increase cyclic guanosine monophosphate
availability. Sildenafil (40 mg every 8 hours) and tadalafil
(10 mg every 12 hours) are effective in preventing
HAPE.50,132-134
■ Narcotic analgesics should be avoided because of depression
of the HVR and respiratory drive during sleep. For nausea
and vomiting, prochlorperazine, unlike other antiemetics,
stimulates the HVR.
The references for this chapter can be found online by
accessing the accompanying Expert Consult website.
Chapter 144 / High-Altitude Medicine 1940.e1
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