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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

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).

High-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 evaluate the efficacy of adding tadalafil to standard acetazolamide prophylaxis for the prevention of severe HAI in participants of groups climbing Kilimanjaro.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

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 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.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

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).

Table 1. Demographic characteristics and main study outcomes
 All participants (n = 51)Tadalafil and acetazolamide group (n = 24)Acetazolamide group (n = 27)Odds ratio (95% confidence interval), p*
  • 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.

Male gender (%)36 (70%)19 (79%)17 (63%)NS
Age, y (mean ± standard deviation)49 ± 10.651 ± 6.947 ± 12.9NS
Age range, y19–6819–6823–62 
Severe HAI8 (16%)1 (4%)7 (26%)8.05 (0.91–71.1), 0.03
HAPE7 (14%)1 (4%)6 (22%)6.57 (0.72–59.1), 0.06
HACE2 (4%)02 (7%)NA (NA), 0.27
AMS (Lake Louise score > 3)28 (55%)12 (50%)16 (59%)1.45 (0.47–4.4), 0.35
Summiting Mt. Kilimanjaro47 (92%)23 (95%)24 (88%)2.87 (0.27–29.6), 0.35

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).

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

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] 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. 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 tadalafil-treated 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 open-label 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.

Declaration of Interests

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

The authors state that they have no conflicts of interest to declare.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References