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BRIEF COMMUNICATION
Tadalafil and Acetazolamide Versus Acetazolamide for the Prevention
of Severe High-Altitude Illness
Eyal Leshem, MD,∗ Yehezkel Caine, MD,† Elliot Rosenberg, MD,‡ Yoram Maaravi, MD,§
Hagai Hermesh, MD,|| and Eli Schwartz, MD∗
∗
Center for Geographic Medicine and Internal Medicine C, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of
Medicine, Tel Aviv, Israel; † Chronic Ventilation Unit and Director’s Office, Herzog Hospital, Jerusalem, Israel; ‡ Department
of Occupational Medicine, Ministry of Health, Jerusalem, Israel; § Department of Rehabilitation and Geriatrics,
Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel; || Adult Outpatient Department, Geha Mental
Health Center, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv, Israel
DOI: 10.1111/j.1708-8305.2012.00636.x
See the Editorial by Buddha Basnyat, pp. 281–283 of this issue.
We report an open-label study comparing tadalafil and acetazolamide (n = 24) versus acetazolamide (n = 27) for prevention of
high-altitude illness (HAI) at Mt. Kilimanjaro. Tadalafil group had lower rates of severe HAI compared with controls (4% vs 26%,
p = 0.03), mostly because of decreased high-altitude pulmonary edema rates (4% vs 22%, p = 0.06).
H
igh-altitude illness (HAI) is the collective term
for acute mountain sickness (AMS), high-altitude
cerebral edema (HACE), and high-altitude pulmonary
edema (HAPE). HAI is prevalent among trekkers
and mountaineers at altitudes above 2,500 m. Mt.
Kilimanjaro (5,895 m) is the highest mountain in Africa.
Ascent to Kilimanjaro is commonly performed within 5
to 6 days allowing little time for acclimatization.1
HAPE is a pathologic process initiated by hypoxic
pulmonary vasoconstriction causing elevated pulmonary arterial pressure. Tadalafil, a PDE5 inhibitor,
is effective in reducing the incidence of HAPE in
susceptible adults (ie, those with a history of a previous
episode of HAPE) exposed to altitude.2 The use of
PDE5 inhibitors for prevention of severe HAI was never
systematically evaluated in healthy (non-susceptible)
climbers. Moreover, current high rates of severe HAI on
Kilimanjaro despite the use of acetazolamide prophylaxis prompted us to evaluate tadalafil as potential HAI
prophylaxis.3 – 6 The aim of the study was to clinically
The study was presented at the 12th Conference of the
International Society of Travel Medicine, Boston, USA, 8–12
May, 2011 (FC4).
Corresponding Author:
Professor Eli Schwartz, MD,
Center of Geographic Medicine, Sheba Medical Center, 52621
Tel Hashomer, Israel. E-mail: [email protected]
© 2012 International Society of Travel Medicine, 1195-1982
Journal of Travel Medicine 2012; Volume 19 (Issue 5): 308–310
evaluate the efficacy of adding tadalafil to standard
acetazolamide prophylaxis for the prevention of severe
HAI in participants of groups climbing Kilimanjaro.
Methods
We conducted an open-label study of tadalafil 20 mg
qd (Cialis, Eli Lilly, Geneva, Switzerland) and acetazolamide 125 mg bid (Uramox, Taro, Haifa, Israel)
versus acetazolamide 125 mg bid for the prevention
of severe HAI in healthy trekkers climbing Mt.
Kilimanjaro. All groups used an identical 6-day ascent
route sleeping at altitudes: 3,000, 3,800, 4,600, 4,100,
4,700 m and on the 6th day, summit attempt to altitude
5,895 m, and sleeping altitude 3,200 m. Both intervention and control groups began study medication
on day 3.
Recruitment took place during meetings held 4 weeks
prior to the ascent. Exclusion criteria were age <18,
previous episode of severe HAI (HAPE or HACE),
ischemic heart disease, or contraindications for tadalafil
or acetazolamide. Participants signed an informed
consent form and were allocated (tadalafil or control)
according to their preference. The study was approved
by the institutional review board at Sheba Medical
Center (ClinicalTrials.gov identifier: NCT01060969).
The primary endpoint was severe HAI, defined as
HAPE or HACE. HAPE was diagnosed according to
309
Tadalafil for HAI Prevention
Discussion
the 1991 International Hypoxia Symposium criteria,
and HACE was diagnosed according to the Lake Louise
criteria.7 All groups were accompanied by physicians
trained in assessment and treatment of HAI. Group
physicians served as clinical evaluators for assessment of
the study endpoints.
The secondary endpoint was diagnosis of AMS
according to the Lake Louise criteria.7 Symptoms were
evaluated twice daily (self-assessment questionnaire) and
at the summit. We used a one-sided Fisher’s exact
test for the efficacy comparison, assuming that adding
tadalafil to acetazolamide was superior to acetazolamide
alone.
We studied trekkers with no previous history of
HAPE or HACE and found that adding tadalafil
to acetazolamide reduced the rate of severe HAI
compared with acetazolamide-treated controls. Most
of the difference between the groups was attributed to
the reduction of HAPE rate in the tadalafil group. This
finding is in concordance with the work of Maggiorini
and colleagues who showed a reduction in HAPE
incidence in susceptible individuals by using tadalafil or
dexamethasone.2 In contrast with Maggiorini’s study,
we included trekkers without a previous history of
HAPE.
PDE5 inhibitors act by blocking the breakdown of
cyclic GMP, an intracellular mediator of nitric oxide
vasodilatory effects, thereby inhibiting hypoxic pulmonary vasoconstriction and pulmonary hypertension.
This mechanism explains the possible efficacy in preventing HAPE in both susceptible and non-susceptible
individuals.
Severe HAI poses a major risk to trekkers, especially
at extreme altitudes.8 A moderate ascent rate of
300 m daily is the mainstay of prevention of severe
HAI. However, in major trekking areas such as Mt.
Kilimanjaro and the Himalayas, trekkers participate in
rapid ascents to extreme altitudes and acclimatization is
rarely done in accordance with recommendations.3 – 6,8
Results
Between the years 2006 and 2009, we assessed 68
participants in five groups for study eligibility. Fifty-five
climbers met the inclusion criteria and 51 had completed
the study protocol: 24 in the tadalafil group and 27 in the
control group (Table 1). Four climbers did not complete
the study protocol and were not included in the final
analysis (tadalafil, n = 3: 1 ankle sprain, 1 epistaxis, and
1 fever; control, n = 1: fever). All participants live at
altitude <800 m, and none of them had any activity
>2,000 m during the preceding 6 months. Tadalafil
and the control group participants had similar baseline
characteristics (Table 1).
Overall, 8 of the 51 (15.7%) participants developed
severe HAI (Table 1). Severe HAI rates were significantly lower in the tadalafil group when compared
with the control group [4.2% vs 25.9%; odds ratio
(OR) = 8.05 (0.91–71.1), p = 0.03]. A reduction in the
incidence of HAPE in the tadalafil group accounted
for most of the difference (4.2% vs 22.2%, p = 0.06).
All patients diagnosed with severe HAI developed the
condition during the summit day. During ascent days 4
and 5, higher AMS symptom scores were noted in the
tadalafil group compared with controls (day 4: 1.7 ± 1.4
vs 0.9 ± 1.3, p = 0.02; day 5: 2.1 ± 1.6 vs 1.0 ± 1.4,
p = 0.01).
Table 1
In such rapid ascents, high rates of severe HAI may
occur despite the use of acetazolamide. Indeed, two
previous studies described AMS rates in trekkers taking
acetazolamide prophylaxis on Mt. Kilimanjaro: Davies
and colleagues found 74% to 78% during the summit
day and Karinen and colleagues found AMS in 80%
of acetazolamide-treated climbers.3,5 Moreover, studies
have reported rates of up to 90% AMS, 18% HACE, and
13% HAPE in trekkers climbing Mt. Kilimanjaro.3,5,6
One study reported 14 tourist deaths attributed to
AMS on Kilimanjaro between 1996 and 2003.4 These
reports have prompted us to test an additional safe
intervention to prevent severe HAI on Mt. Kilimanjaro.
Demographic characteristics and main study outcomes
Male gender (%)
Age, y (mean ± standard deviation)
Age range, y
Severe HAI
HAPE
HACE
AMS (Lake Louise score > 3)
Summiting Mt. Kilimanjaro
All participants
(n = 51)
Tadalafil and acetazolamide
group (n = 24)
Acetazolamide
group (n = 27)
Odds ratio (95%
confidence interval), p∗
36 (70%)
49 ± 10.6
19–68
8 (16%)
7 (14%)
2 (4%)
28 (55%)
47 (92%)
19 (79%)
51 ± 6.9
19–68
1 (4%)
1 (4%)
0
12 (50%)
23 (95%)
17 (63%)
47 ± 12.9
23–62
7 (26%)
6 (22%)
2 (7%)
16 (59%)
24 (88%)
NS
NS
8.05 (0.91–71.1), 0.03
6.57 (0.72–59.1), 0.06
NA (NA), 0.27
1.45 (0.47–4.4), 0.35
2.87 (0.27–29.6), 0.35
Tadalafil 20 mg qd and acetazolamide 125 mg bid (n = 24) versus acetazolamide 125 mg bid (n = 27) for the prevention of severe HAI. AMS, HAPE, and HACE rates
during the summit day are shown.
Severe HAI = severe high-altitude illness (defined as HAPE or HACE); HAPE = high-altitude pulmonary edema; HACE = high-altitude cerebral edema; AMS = acute
mountain sickness on summit day only; NA = non-applicable; NS = not significant.
∗
One-sided Fisher’s exact test.
J Travel Med 2012; 19: 308–310
310
Our trekkers participated in group efforts to summit
Mt. Kilimanjaro characterized by rapid ascent profile
and exposure to very high altitude with high risk of
severe HAI. Thus, our findings may only be applicable
to non-susceptible adult trekkers planning a rapid ascent
to extreme altitude.
We observed a mild negative effect of tadalafil on
AMS symptoms at the lower altitudes (4,100–4,700 m)
but not on the summit day. However, a recent study
performed at similar altitude reported a tendency
toward lower cerebral symptoms scores (AMS-C
Environmental Symptoms Questionnaire) in tadalafiltreated climbers compared with placebo controls.9 The
main difference between the groups in our study was
due to increased headache score in the tadalafil group
(on days 4 and 5). Tadalafil-induced headache, a known
side effect of the drug, probably contributed to this
finding. Thus, further studies of the effects of PDE5
inhibitors on AMS symptoms are warranted.
The major limitation of this study is its openlabel non-randomized design. This kind of design
may bias self-reported endpoints, such as symptom
reporting questionnaires, toward the intervention
group. However, these limitations probably exert a
much lower impact on objective endpoints such as
development of HAPE or HACE. A second limitation is
the limited sample size of the study. Although the rate of
severe HAI was eight times higher in the control group,
the OR confidence interval was only nearly significant
(probably a result of the small sample size). We used
clinical criteria for the diagnosis of HAI, which may
have resulted in the overdiagnosis of study endpoints.
However, there is no evidence that using other methods
of diagnosis (radiography and pulse oxymetry) would
have resulted in higher specificity.10
In conclusion, our results suggest that tadalafil may
be effective in preventing severe HAI, mostly HAPE,
during rapid ascents at high altitude. At lower altitude,
tadalafil side effects such as headache may counterbalance its benefits. Because of the study limitations, our
findings should prompt further evaluation by a larger
blinded randomized study.
Acknowledgments
The authors thank the study participants.
J Travel Med 2012; 19: 308–310
Leshem et al.
Declaration of Interests
The authors state that they have no conflicts of interest
to declare.
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