Travel Medicine and Infectious Disease (2014) 12, 29e39

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.elsevierhealth.com/journals/tmid

REVIEW

Prevention of high altitude illness

Ken Zafren a,b,c,d,*

a
Department of Emergency Medicine, Alaska Native Medical Center, Anchorage, AK, USA
b
Division of Emergency Medicine, Stanford University Medical Center, Palo Alto, CA, USA
c
Himalayan Rescue Association, Kathmandu, Nepal
d
International Commission for Mountain Emergency Medicine (ICAR MEDCOM), USA

Received 11 October 2013; received in revised form 5 December 2013; accepted 10 December 2013
Available online 22 December 2013

KEYWORDS Summary High altitude illness e Acute Mountain Sickness (AMS), High Altitude Cerebral
High altitude; Edema (HACE) and High Altitude Pulmonary Edema (HAPE) e can be prevented or limited in
Acclimatization; severity by gradual ascent and by pharmacologic methods. The decision whether to use phar-
Acute mountain macologic prophylaxis depends on the ascent rate and an individual’s previous history of alti-
sickness; tude illness. This review discusses risk stratification to determine whether to use
High altitude cerebral pharmacologic prophylaxis and recommends specific drugs, especially acetazolamide, dexa-
edema; methasone and nifedipine. This review also evaluates non-recommended drugs. In addition,
High altitude this review suggests non-pharmacologic methods of decreasing the risk of severe altitude
pulmonary edema illness. There are also brief sections on how to decrease sleep disturbance at high altitude,
travel to high altitude for patients with pre-existing illness and advice for travelers ascending
to high altitude.
ª 2013 Elsevier Ltd. All rights reserved.

Introduction risk of high altitude illness, especially acute mountain sick-

Death from high altitude illness is a terrible waste and almost
always avoidable. Suffering from high altitude illness is al-
ways unpleasant and usually preventable. For residents of
altitudes below 2500 m, especially those who live at altitudes
less than 1200 m, travel to altitudes above 2500 m carries a
* 10181 Curvi St., Anchorage, AK 99507, USA.
E-mail address: zafren@alaska.com.
ness (AMS), high altitude cerebral edema (HACE) and high
attitude pulmonary edema (HAPE). Sleep disturbance at
altitude is normal, even in the absence of altitude illness.
Altitude illness is caused by decreased oxygen availability
due to low atmospheric pressure (hypobaric hypoxia).
Although the percentage of oxygen in ambient air is constant
at about 21%, atmospheric pressure decreases as altitude
increases. At higher altitudes less oxygen is available, lead-
ing to hypoxia. Acclimatization is the process by which peo-
ple who travel to high altitude adapt physiologically to
hypoxia over a period of days to weeks. A rate of ascent that is

1477-8939/$ - see front matter ª 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tmaid.2013.12.002
30
faster than the rate of acclimatization results in altitude
illness. Individuals differ greatly in the rate at which they can
ascend without developing altitude illness. Most healthy
people can acclimatize to a wide range of altitudes. The fact
that acclimatization is adaptive rather than maladaptive is
likely related to human adaptations that allow the fetus to
tolerate a hypoxic existence.
Acute high altitude illnesses
AMS is a complex of symptoms affecting individuals who travel
to high altitude. The diagnosis is based on the presence of
headache and at least one other cerebrally-mediated symp-
tom including anorexia, nausea, vomiting, dizziness, fatigue or
poor sleep [1]. Onset is typically 6e12 h after arrival at altitude
[2], but can be seen in as little as 2 h and as long as 4 days [3].
HACE is the severe form of AMS. HACE is differentiated from
AMS by encephalopathic signs of confusion and ataxia.
HAPE, a type of noncardiogenic pulmonary edema, is the
pulmonary form of acute altitude illness. It is the most
common serious altitude illness and the most common
cause of death from altitude illness [4]. Onset is most
frequently after the second night at altitude. Early symp-
toms are fatigue, weakness, dyspnea on exertion and dry
cough [5]. These progress to shortness of breath at rest with
tachycardia, tachypnea, low-grade fever and orthopnea. A
cough with frothy pink sputum is a late sign. HAPE may be
associated with AMS or HACE, but can occur without AMS.
The pathophysiology of HAPE is not completely understood,
but pulmonary hypertension is an important etiologic fac-
tor. Cold exposure and exertion are risk factors for the
development of HAPE [6e8].
Children living at high altitude are at risk for re-ascent or re-
entry HAPE after spending 2 weeks or more at sea level [9,10].
The fact that re-entry HAPE requires spending at least 2 weeks
at sea level suggests that loss of acclimatization is an impor-
tant factor. Children living at high altitude likely develop
increased pulmonary hypertension in response to rapid ascent.
Poor sleep with disordered sleep stages and periodic
breathing is normal at high altitude and not necessarily
pathological [11]. Periodic breathing of altitude, which occurs
almost exclusively during sleep and is not associated with
heart failure, is not the same as CheyneeStokes breathing,
which is occurs in patients with congestive heart failure. Pe-
riodic breathing of altitude and CheyneeStokes breathing are
both characterized by cycles of crescendo-decrescendo
respiration with apneic pauses. The cycles of Cheynee-
Stokes breathing (40e90 s) are longer than the cycles of
altitude periodic breathing (12e34 s) [12]. Apneic pauses,
related to changes in respiratory control at altitude, can lead
to severe hypoxemia, which may cause morning headaches
and may worsen AMS. Periodic breathing decreases with
acclimatization, but does not completely resolve [13].
Prevention of acute mountain sickness
Gradual ascent
The most effective method to prevent AMS is gradual
ascent. Observational data are overwhelmingly clear,
although there are few prospective studies [14,15].
K. Zafren
Individuals who have previous experience can adjust their
rate of ascent based on whether they have acclimatized
rapidly or slowly in the past.
AMS takes several hours to develop. The critical altitude
determining whether AMS develops is the altitude at which
the traveler sleeps each night, referred to as “sleeping
altitude.” This is probably due to relative hypoxemia during
sleep compared to the awake state.
For unacclimatized individuals going from sea level or from
altitudes below 1200 m directly to altitudes above 2500 m,
spending one or more nights at an intermediate elevation,
typically 1500e2200 m decreases the risk of AMS [16].
Ideally, travelers ascending above 3000 m should spend 2
or 3 nights at 2800e3000 m before ascending further. There
is no standard guideline regarding the nightly gain in
sleeping altitude but there are some published recommen-
dations. (Please see Table 1: Recommendations For Gradual
Ascent.) The Himalayan Rescue Association (HRA) has
traditionally recommended ascending no more than 300 m/
day with a rest day (no ascent in sleeping altitude) for every
additional 600e900 m and no single day gain greater than
800 m [17]. The Wilderness Medical Society (WMS) guidelines
recommend limiting ascent to 500 m/day with a rest day
every 3e4 days [18]. Because there is so much individual
variation in the rate of acclimatization, neither of these
general recommendations offers complete protection
against AMS. Individuals are less likely to develop AMS by
following the more conservative HRA guidelines. The goal of
guidelines for gradual ascent is not complete prevention of
AMS. Some individuals will develop AMS in spite of adher-
ence to the guidelines, but it is more likely to be mild and
less likely to be life-threatening (HACE).
Following the “mountaineers rule: climb high, sleep
low,” is commonly thought to aid acclimatization. The only
evidence in favor of this practice is anecdotal. Travelers
who do not have symptoms can safely ascend as far as they
like during the day, especially on rest days. This takes
advantage of the fact that altitude illness takes hours to
develop. Moderate exercise, avoiding strenuous exercise,
maintaining adequate hydration, eating a high carbohy-
drate diet [19] and avoiding the use of sedative/hypnotic
drugs, including alcohol, are all thought to help prevent
AMS.
Aerobic exercise training confers no advantage for
acclimatization, although it is definitely helpful to prepare
for activities such as trekking and climbing at low or high
Table 1 Recommendations for gradual ascent. Intended
for individuals going from altitude <1200 m directly to al-
titudes >2500 m. Optional: Spend 1 or more nights at an
intermediate altitude (1500e2200 m). Optional: Spend 2e3
nights at 2800e3000 m before further ascent.
Recommendation HRA [17] WMS [18]
Daily ascent 300 m 500 m
(sleeping altitude)
Rest day Every Every 3e4 days
600e900 m
Maximum single 800 m No recommendation
day gain
Prevention of high altitude illness
altitudes. Some physically fit individuals allow their ability
to ascend rapidly to lure them into ascending too rapidly.
This increases their risk of developing altitude illness.
Risk stratification for preventing altitude illness
The incidence of AMS increases with a rapid rate of ascent
and with the absolute altitude attained, affecting two-
thirds of climbers who make rapid ascents of Mt. Rainier
(4392 m) [20] and one half to over three quarters of hikers
on Mt. Kilimanjaro (5895 m) [21,22]. The incidence of HACE
is typically far lower but has been reported to be as high as
31% in Himalayan pilgrims after a one-day ascent to 4300 m
[23]. The incidence of HAPE is less than 3% in most studies,
but has not been reliably reported for rapid ascents above
4000 m, except in individuals known to be susceptible to
HAPE. Although there are no published data, both HAPE and
HACE seem to be more common and more likely to be fatal
as altitude increases, with especially high risk at altitudes
above 5500 m even with gradual ascent.
In most situations, gradual ascent is the safest method
to prevent altitude illness. However, gradual ascent is not
always possible. Many itineraries such as direct flights from
sea level to high altitude destinations such as Lhasa, Tibet
(3650 m) or Cusco, Peru (3400 m) do not allow gradual
ascent. Some individuals are “slow acclimatizers” who may
not have the time to ascend gradually enough to avoid AMS.
The Wilderness Medical Society has published a scheme
that classifies the risk of AMS into low, moderate and high
categories based on the ascent profile and the past medical
history of the individual [18]. (Please see Table 2: Risk
Categories For Acute Mountain Sickness, modified from Luks
et al., 2010. [18]) For low risk ascents, prophylactic medi-
cation is not needed. For moderate and high-risk ascents,
the advisability of using prophylactic medication is based
partly on the ascent itself and partly on the individual’s
past history of altitude illness. All individuals with a history
of HAPE or HACE should strongly consider taking medication
to prevent altitude illness when ascending above 2500 m.
Prediction of individual susceptibility to altitude
illness
There have been many unsuccessful attempts to predict
individual susceptibility to AMS at sea level or during
ascent. In spite of anecdotal evidence, low hypoxic venti-
latory response (HVR) at low altitude does not predict
susceptibility to AMS [24]. Failure to increase HVR at 3611 m
en route to 4559 m is correlated with later development of
AMS, but has minimal individual predictive value. Studies of
subjects known to be susceptible to AMS [25] or to HAPE
[26] show that they have lower oxygen saturations
measured by pulse oximetry (SpO2) than controls during
exposure to simulated high altitude in a hypobaric cham-
ber. These observations on highly selected populations have
not proven useful in prospectively predicting individual
susceptibility [27,28].
Complex methods have been studied, including baseline
cerebral autoregulation index at sea level [29] and an index
consisting of SpO2, hematocrit and the maximum velocity of
clot formation at an intermediate altitude [30]. Neither
31
Table 2 Risk stratification for altitude illness (modified
from Luks 2010 [18]). Intended for unacclimatized in-
dividuals going from altitude <1200 m to altitudes >2500 m.
Risk Criteria
category
Low No previous history of altitude illness,
ascending to
2800 m
Taking 2 days to reach 2800 m with
subsequent increases in sleeping altitude
<500 m/d
Moderate Previous history of AMS, ascending to
2500e2800 m in 1 day
No history of AMS and ascending to
2800e3500 m in 1 day
Increase in sleeping altitude >500 m/d
starting between 3000 and 3500 m
High History of AMS, ascending to
2800 m in 1 day
Previous history of HAPE or HACE
Ascending to >3500 m in 1 day
Increase in sleeping altitude
>500 m/d starting above 3500 m
Member of a group with individual
moderate or high risk
Very rapid ascent (e.g. Mt. Kilimanjaro)
method demonstrates reasonable ability to predict indi-
vidual susceptibility. The authors of a large 17-year study of
hypoxic exercise testing concluded that a combined mea-
sure of low HVR and exercise-induced oxygen desaturation
correlates with subsequent development of altitude illness
[28]. Due to methodologic weaknesses, including the loss to
follow-up of two-thirds of the study population, heteroge-
neous ascent profiles, use of acetazolamide by some of the
subjects and the use of a self-reported questionnaire as the
measure of acute mountain sickness, this study was unable
to show that the testing predicted individual susceptibility.
It is tempting to use a simple method such as pulse ox-
imetry, but several studies have shown that SpO2 measured
during ascent is not useful to predict susceptibility to AMS
on further ascent [31]. Some of these studies clearly had
negative results [32,33]. Others claimed to show that pulse
oximetry was useful [34,35], but had very low positive
predictive values. Use of variations, such as changes in SpO2
rather than the absolute value [32,35] or use of post-
exercise SpO2 did not [35] improve prediction.
Special considerations for organized groups
Individuals traveling in organized groups are at increased
risk for developing high altitude illness, primarily due to the
need to follow an itinerary that may be too rapid for slow
acclimatizers. Unless the itinerary is clearly low risk, group
participants who do not have previous experience at alti-
tude or who have not ascended as rapidly as the planned
itinerary in the past should probably use prophylactic
medication.
Standard ascent profiles on some mountains are much
more rapid than the recommended rates of ascent. This
32 K. Zafren

exposes participants to a high risk of severe altitude illness.
Mt. Kilimanjaro (5895 m) deserves special mention [21,22].
Various routes take from 4 to 8 days to reach the summit,
with another 1.5 days to descend. The Marango (“Coca
Cola”) route, which takes 4 or 5 days to ascend, has the
highest incidence of altitude illness, which may be fatal. A
recent study claimed that acetazolamide is ineffective in
preventing AMS on this extremely rapid ascent [22]. The
Marango route is the most popular, partly because trekkers
are required to hire guides and to pay a daily National Park
fee, with a combined daily cost of more than US$100 [21].
This makes the longer routes more expensive. Reputable
trekking companies that use longer routes or require clients
to pre-acclimatize by climbing nearby mountains are at a
competitive disadvantage. They attempt to overcome this
disadvantage by publicizing the lower likelihood of being ill
and greater likelihood of reaching the summit on longer
itineraries, such as the Lemosho route, which takes 7 days
to ascend.
Groups following a moderate or high-risk itinerary should
be prepared to treat altitude illness if prevention fails. The
main means of treatment is by descent, supplemented by
medications. If feasible, groups should also carry a portable
hyperbaric chamber for treatment, unless descent could
always be easily accomplished with a vehicle.
When descent is not an option, a portable hyperbaric
chamber can treat and prevent progression of altitude
illness, allowing additional time to acclimatize, by simu-
lating descent [36]. A portable hyperbaric chamber can be
used in conjunction with medications for treatment. There
are three brands currently on the market: the Gamow
Bag, the Portable Altitude Chamber and the CERTEC Hy-
perbaric Chamber, all of which are functionally equivalent.
The patient is zipped inside a more-or-less cylindrical fabric
chamber that is pressurized by use of a foot or hand pump
to approximately 100 torr (about 700 kPa) above ambient
pressure. A pressure-relief valve limits the maximum
pressure. All current chambers require continued pumping
at a slow rate, usually once every 5 s, to prevent carbon
dioxide build-up by refreshing the air within the chamber
[37].The higher the altitude, the greater the simulated
descent. At 3000 m, the effective altitude inside the
pressurized chamber is 1555 m, a drop of 1445 m; at
4500 m, the simulated altitude is 2789 m, 1711 m lower
[17,38].
There are no standard treatment protocols for the
portable hyperbaric chamber. Treatment is guided by reso-
lution of symptoms and improvement in oxygen saturation
during treatment. Treatment sessions typically last about an
hour and can be repeated after a few minutes break if the
patient is not sufficiently improved. A single session may
lead to prolonged improvement [39]. However, delayed
repeat treatment sessions may sometimes be needed up to
several hours later if symptoms worsen after initial
improvement [38]. A small observational study at about
4300 m found an average treatment time of two hours for
AMS, four hours for HAPE and six hours for HACE [38].
Pharmacologic prevention of AMS
Individuals at moderate-high risk of AMS, based on ascent
profile and individual risk factors (Table 2) should use pro-
phylactic medication to prevent AMS. (Please see Table 3:
Recommended Medications For Prevention Of Altitude
Illness.) It is still helpful to ascend as gradually as is
reasonable. Unexpected situations requiring a change in
ascent profile may change a low or moderate risk itinerary
to one with a higher level of risk. As with gradual ascent,
use of prophylactic medication is no guarantee against
developing AMS, but will tend to limit the severity of the
symptoms.

Table 3 Recommended medications for prevention of altitude illness.

Medication Dose
AMS/HACE
Acetazolamide 125 mg by mouth twice daily
Pediatric: 2.5 mg/kg by mouth
twice daily
Dexamethasone 4 mg by mouth every 12 h for
passive ascent (sedentary travelers)
4 mg by mouth every 6 h for
active travelers
Pediatric: not recommended
Acetazolamide þ Dexamethasone Same as individual medications.
Use in emergency situations only.
HAPE
Nifedipine 60 mg (slow release) by mouth
daily in 2e3 divided doses
Salmeterol 125 mg inhaled twice daily
Use only with nifedipine
in very high risk individuals.
Start/Stop
Start: day before ascent
Stop: after 2 days at highest
sleeping altitude or when starting
descent
Start: day of ascent
Stop: after 2e3 days at highest
sleeping altitude or when
starting descent
Do not use for >10 days.
Same as individual medications
Start: day before ascent
Stop: after 5 days at highest
sleeping altitude or when
starting descent.
Start and stop at the same
time as nifedipine
Prevention of high altitude illness
In most cases, the preferred medication for prevention
of AMS is acetazolamide. For rare individuals who cannot
take acetazolamide, dexamethasone is generally safe and
effective if used according to standard recommendations.
Please refer to the sections on acetazolamide and dexa-
methasone below for details on the use of these drugs.
Occasionally individuals who are not acclimatized may
need to ascend rapidly to altitudes above 3500 m and
immediately perform strenuous physical work. Examples of
this situation are rescue and military operations. This is the
only circumstance in which acetazolamide and dexameth-
asone should be used simultaneously to prevent altitude
illness [18].
Acetazolamide
For individuals who are susceptible to acute mountain
sickness or for whom a rapid ascent is necessary, acet-
azolamide, a carbonic anhydrase inhibitor, is the drug of
choice for pharmacologic prevention of AMS [18]. Acet-
azolamide, unlike other drugs, accelerates the rate of
acclimatization rather than masking symptoms. Acetazol-
amide is a respiratory stimulant that causes metabolic
acidosis by increasing renal excretion of bicarbonate. This
promotes hyperventilation by increasing hypoxic ventila-
tory drive and allowing increased respiratory alkalosis [40].
These changes mimic the natural process of
acclimatization.
An effective prophylactic dose of acetazolamide is
125 mg twice daily [41e43]. The pediatric dose is 2.5 mg/kg
twice daily up to 125 mg/dose [18]. A meta-analysis in 2000
concluded that the number needed to treat with acet-
azolamide 750 mg daily to prevent AMS was less than three.
The authors also asserted, “Acetazolamide 500 mg does not
work.” [44] They would have found that acetazolamide
500 mg daily was effective had they not classified one study
[45] as negative that appeared to meet their criteria as a
positive study [46]. Three subsequent meta-analyses, have
concluded that acetazolamide 125 mg twice daily is
effective for prevention of AMS [47e49]. These studies
showed little or no difference in effectiveness among doses
of 250 mg, 500 mg and 750 mg daily.
Acetazolamide should be started the day before ascent
and continued for two days after ascent. If ascent continues,
as in trekking or mountaineering, acetazolamide can be
stopped after two days at the highest sleeping altitude or at
the beginning of descent. Because acetazolamide is a diuretic
it causes increased urination; the second dose should usually
be taken at dinnertime rather than at bedtime.
Doses higher than 125 mg twice daily have increased side
effects, especially paresthesias, that are often most un-
comfortable in the fingers. Acetazolamide can ruin the
taste of carbonated beverages, including beer, by pre-
venting hydration of carbon dioxide on the tongue.
Acetazolamide is a non-antibiotic sulfonamide, which
means that it has low cross-reactivity with sulfa antibiotics.
Rare individuals may be allergic to both sulfa antibiotics
and acetazolamide. Individuals who are allergic to sulfa
drugs and who have multiple other drug allergies are
advised to take a test dose of acetazolamide at least
several days prior to travel [50]. The most common allergic
reaction is a rash. Anaphylactic reactions are rare, but have
been reported.
33
Dexamethasone
Dexamethasone has been shown to be effective in pre-
vention of AMS in two randomized controlled trials [51,52].
Unlike acetazolamide, dexamethasone does not speed
acclimatization. The mechanism of action is unknown, but
may be related to euphoric and antiemetic effects [53].
Dexamethasone effectively masks symptoms. Discontinua-
tion unmasks symptoms causing a “rebound effect.” Its use
in prevention of AMS should be limited to those who do not
have time for gradual ascent and who cannot take acet-
azolamide. The effective dose is 4 mg every 12 h (or 2 mg
every 6 h) [54] for sedentary subjects in a chamber study,
but this was not effective in active subjects at altitudes
above 4000 m [55]. The recommended dose for active
subjects above 4000 m is 4 mg every 6 h [56]. The combi-
nation of acetazolamide and dexamethasone has been
shown to be superior to acetazolamide alone in preventing
AMS in a single study of active subjects [45]. Because alti-
tude illness takes several hours to develop, dexamethasone
should be started on the day of ascent and discontinued
after 2e3 days at the highest sleeping altitude or when
starting descent. However, dexamethasone should not be
used for more than 10 days in order to prevent steroid
toxicity and adrenal suppression. Dexamethasone should
not be used in children due to safety concerns.
Other non-pharmacologic methods of preventing
AMS
Spending several days to several weeks at a moderate
altitude, most often 2200e3000 m, prior to traveling to
higher altitude is a variant of graded ascent that is clearly
effective [15]. It is not a practical strategy for most people,
due to time constraints. Pre-acclimatization, by spending
time in hypobaric environments, especially during sleep,
can be effective [57], or ineffective [58,59], depending on
the exposure protocol and the subsequent ascent [60].
Adequate exposure protocols are impractical for most
people due to the large amount of time required. Hypobaric
conditions can be achieved by low pressure or, more easily,
by nitrogen enrichment.
Forced or “over” hydration is not effective in preventing
altitude illness. This practice has the potential to cause
hyponatremia. Adequate fluid intake may be helpful in
preventing altitude illness [61,62], although this effect may
be due to preventing dehydration, which can mimic AMS.
Although there is no published study on the risk of
ascending with an upper respiratory infection, anecdotal
evidence strongly suggests that this increases the risk of
AMS. Individuals with a cold or bronchitis should consider
halting ascent or ascending very gradually in order to pre-
vent AMS.
Other pharmacologic methods of preventing AMS
Ibuprofen
The common drug, ibuprofen, a nonsteroidal anti-
inflammatory drug (NSAID) has shown promise in the pre-
vention of AMS. The proposed mechanism is the anti-
inflammatory effect. Ibuprofen reduced the incidence of
AMS in one randomized placebo-controlled trial [63]. In a
34
larger trial with a high attrition rate, ibuprofen was
effective in preventing AMS in the intent-to-treat group,
but not in those who completed the study [64]. The authors
suggested that subjects in the placebo group were more
likely to develop AMS and therefore to drop out of the trial.
Both studies used a dose of 600 mg three times daily. If
these promising results are confirmed in further studies,
ibuprofen may be a reasonable alternative or addition to
acetazolamide in some situations.
Ginkgo biloba
“Ginkgo biloba does e and does not e prevent acute
mountain sickness,” was the equivocal title of a two-part
placebo-controlled study in which one part showed
reduced incidence and severity of AMS compared to pla-
cebo and the other part showed no advantage [65]. This
title also describes the results of other studies with some
claiming to show efficacy of Ginkgo in preventing AMS
[66e68] and some showing no effect [69,70]. These varying
results may be due to the fact that studies have used
different preparations, but the evidence for efficacy is
hardly convincing. Ginkgo is an herbal medicine with no
standard preparation. The composition varies between
sources and even from a single source over time.
Other drugs for the prevention of AMS
Based on intention to treat analysis, sumitriptan reduced
the incidence of AMS from 45% to 23% in a small randomized
placebo-controlled trial [71]. Gabapentin reduced the inci-
dence of AMS from 47% to 34% and also reduced the severity
in a randomized placebo-controlled trial in which the pri-
mary outcome measure was high altitude headache [72].
In contrast to ibuprofen, the NSAID naproxen showed no
benefit in preventing AMS in a randomized placebo-
controlled altitude chamber study [73]. Spironolactone
has shown no benefit in preventing AMS [74e76]. Other
drugs that have been tested and have not been shown to be
effective in preventing AMS include antacids [77], magne-
sium [78], calcium channel blockers [79], medrox-
yprogesterone [80] and antioxidants [81].
Coca
Travelers to high altitude locations in the Andes are often
offered coca tea or coca leaves for prevention of AMS.
There are some reports of coca use to prevent AMS in other
parts of the world as well. There have been no studies of
the efficacy of coca, a weak form of cocaine, in preventing
altitude illness. Although legal in parts of South America,
these products are illegal in most other parts of the world.
Sorojchi pills
Soroche (also spelled sorojchi) is a South American word
that refers to altitude illness. Sorojchi pills, containing
aspirin, salophen and caffeine, are for sale over the
counter in Bolivia and Peru. They are marketed for pre-
vention and treatment of altitude illness. Salophen is an
ester of acetylsalicylic acid and paracetamol (acetamino-
phen in some countries) that decomposes into aspirin and
paracetamol in the gut. Sorojchi pills have not been tested
K. Zafren
and have no known benefit in preventing AMS. They might
be effective in reducing headaches.
Prevention of high altitude pulmonary edema
As with AMS, gradual ascent is the preferred method of
preventing HAPE, but the recommended rates of ascent will
not prevent the development of HAPE in all individuals.
Most of the pharmacologic methods of preventing HAPE act
to reduce pulmonary hypertension. All of the randomized
controlled trials of pharmacologic prevention of HAPE have
been done with subjects who are known to have a high
susceptibility to HAPE (HAPE-S) who followed a very rapid
ascent profile. It is not known to what extent the results of
these pharmacologic trials for HAPE prevention apply to the
general population and with more gradual ascent rates.
Individuals who have never had HAPE should not use
medications for prophylaxis. For individuals who have pre-
viously had HAPE, nifedipine is the preferred medication to
prevent recurrence. Salmeterol, which is thought to work
by a different mechanism, can be added in very high-risk
individuals [18].
There have been no studies of drugs to prevent re-ascent
HAPE. Acetazolamide seems to be helpful in practice [18].
Since bed rest with or without oxygen is helpful in treat-
ment of re-ascent HAPE [9], bed rest on return to high
altitude would likely be helpful for prevention.
Gradual ascent
Gradual ascent at the same rate used to prevent AMS, is
effective in preventing HAPE, although there are no formal
studies [82,83]. The optimal rate of ascent, as with AMS, is
not known. Some HAPE-susceptible individuals may still
develop HAPE, even with a conservative ascent profile, but
for most travelers, the likelihood of developing AMS is much
greater than that of developing HAPE.
Nifedipine
Nifedipine, a calcium channel blocker, is the preferred
medication for the prevention of HAPE. In a randomized
placebo-controlled study, 7 of 11 HAPE-susceptible subjects
who received placebo developed HAPE compared to 1 of 10
subjects who received nifedipine [84]. In addition to this
single study, there is extensive clinical experience with the
use of nifedipine to prevent HAPE in HAPE-susceptible in-
dividuals. The recommended dosage is 60 mg/day (slow
release) in 2 or 3 divided doses. In North America the avail-
able dose of nifedipine (slow release) is 30 mg, while in
Europe the dose is 20 mg. Nifedipine should be started the
day before ascent and continued for 5 days at the highest
sleeping altitude unless the individual descends sooner [84].
Salmeterol
Salmeterol is a long-acting inhaled beta-agonist that is
thought to promote sodium-dependent clearance of alve-
olar fluid. In a randomized placebo-controlled study with 37
subjects, the incidence of HAPE was 74% with placebo and
Prevention of high altitude illness
33% with salmeterol [85]. The dose used was 125 mg twice
daily, a very high dose that is likely to cause significant side
effects in many patients. There is little or no clinical
experience to support the use of salmeterol in the pre-
vention of HAPE. The Wilderness Medical Society guidelines
suggest, “Salmeterol should only be considered as a sup-
plement to nifedipine in high-risk individuals with a clear
history of recurrent HAPE.” [18]
Tadalafil
Tadalafil is a Phosphodiesterase 5 inhibitor that decreases
pulmonary hypertension by blunting hypoxic pulmonary
vasoconstriction. In a single randomized placebo-controlled
study 10 HAPE-susceptible subjects received tadalafil 10 mg
twice daily during a rapid ascent to 4559 m [86]. Two of the
subjects receiving tadalafil withdrew from the study due to
severe AMS on arrival at 4559 m, although they did not have
HAPE prior to descent. Only 1 of the remaining 8 subjects
who received tadalafil developed HAPE. In the placebo
group, 7 of 9 subjects developed HAPE. The occurrence of
AMS with tadalifil may have discouraged further trials as
well as the accumulation of any clinical experience using
tadalafil in the prevention of HAPE. Tadalafil cannot be
recommended to prevent HAPE in the absence of further
study.
Dexamethasone
The study of tadalafil described above also included a
dexamethasone arm. Although dexamethasone decreased
pulmonary hypertension in the study, the mechanism of
action for prevention of HAPE was unknown. None of the
HAPE-susceptible subjects who ascended rapidly to 4559 m
while taking dexamethasone 16 mg daily developed HAPE
[86]. Only 3 of 10 subjects taking dexamethasone devel-
oped AMS, compared to 7 of 10 taking tadalafil and 8 of 9
taking placebo. There is little or no clinical experience
involving the use of dexamethasone to prevent HAPE. Until
further data become available, dexamethasone should not
be used to prevent HAPE.
Acetazolamide
Due to the efficacy of acetazolamide in speeding acclima-
tization it is likely to be effective in preventing HAPE as
well as AMS and HACE. This seems consistent with clinical
observations, but has never been studied. Acetazolamide is
known to decrease hypoxic pulmonary vasoconstriction
(HPVC) in animal models [87,88]. Human studies have had
mixed results, with one study showing blunted HPVC [89]
and another that failed to show the effect [90]. Acetazol-
amide has been used to prevent re-ascent HAPE [18].
Prevention of sleep disturbance due to
periodic breathing
Although periodic breathing and poor sleep are normal in
travelers at high altitude and do not represent altitude
illness, they are annoying, can cause fatigue and may
35
contribute to AMS. Acetazolamide 62.5e125 mg by mouth
at dinnertime decreases or eliminates periodic breathing
and improves the quality of sleep at altitude [11,91,92].
Acetazolamide is the preferred drug for sleep disturbances
at altitude. If acetazolamide is ineffective, zolpidem or
zaleplon and related drugs would be a good choice [93,94].
Benzodiazepines can cause respiratory depression, but
seem to be safe if used at the usual doses for insomnia at
high altitude [95]. A recent small study suggested that sleep
quality was better with temazepam than with acetazol-
amide [96].
High altitude travel for special populations
Although they are generally at no greater risk for altitude
illness than the general population, there are special con-
siderations for preventing altitude illness in the very young
[97,98], pregnant women [99e101] and the elderly [102].
Patients with pre-existing medical conditions should be
carefully evaluated prior to traveling to high altitude
[103,104]. Travel to high altitude is generally contra-
indicated in patients with conditions that are predictably
worsened by hypoxia, including uncompensated congestive
heart failure, severe pulmonary hypertension [105] and
sickle cell anemia. Patients with lung disease may need to
limit ascent and may require supplemental oxygen at
moderate altitudes [106]. Less is known about the risks of
travel to altitude with other pre-existing conditions. Au-
thors of review articles have made recommendations
regarding high altitude travel for patients with congenital
heart disease [107], neurologic disease [108] and chronic
kidney disease [109], among other conditions.
A very useful reference is the review by Luks and
Swenson, “Medication and Dosage Considerations in the
Prophylaxis and Treatment of High-Altitude Illness,” [50]
which discusses the indications and dosing of common
drugs used for prevention of high altitude illness for pa-
tients with underlying medical conditions. The authors also
discuss renal and hepatic dosage adjustments.
Advising travelers
Medical professionals who advise travelers should be aware
of the risks of high altitude illness. They should be able to
evaluate proposed ascent profiles and prescribe medica-
tions appropriately when gradual ascent is not feasible. The
consequences of poor advice can be severe [110].
Practically speaking, prevention of altitude illness
should include recognition and treatment of developing
altitude illness in order to prevent progression to increased
severity or death. A simple scheme, the “Golden Rules” of
altitude illness, that can easily be taught to travelers was
developed by The Himalayan Rescue Association [17].
Rule 1: “If you are ill at altitude, your symptoms are due
to altitude illness until proven otherwise.”
Rule 2: “If you have altitude symptoms don’t go any
higher.”
Rule 3: “If you are feeling very ill or getting worse, or if
you cannot walk heel-to-toe in a straight line, descend
immediately.
36
Rule 4: Never send anyone with altitude illness down
alone.”
Conclusion
Altitude illness can usually be prevented, or at least limited
in severity, by ascending gradually. If gradual ascent is not
feasible and for individuals who are susceptible to altitude
illness, medications should be used to prevent serious
altitude illness. The medication of choice to prevent AMS is
acetazolamide. Acetazolamide can also be used to improve
sleep at high altitude. Dexamethasone can be used to
prevent AMS by individuals who cannot take acetazolamide.
Nifedipine is the preferred medication for HAPE-susceptible
individuals going to high altitude when gradual ascent is not
feasible.
Funding
This work was unsupported.
Conflict of interest
The author has written research articles, practice guide-
lines, review articles and other teaching materials on the
prevention and treatment of acute mountain sickness.
Dr. Zafren is an unpaid consultant to the Himalayan
Rescue Association.
The author declares that there are no conflicts of
interest.
Acknowledgments
The author would like to thank Stuart Harris, MD, for his
helpful review of the manuscript.
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