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Both Tadalafil and Dexamethasone May Reduce the Incidence of High-Altitude Pulmonary Edema: A Randomized Trial

Marco Maggiorini, MD; Hans-Peter Brunner-La Rocca, MD; Simon Peth, MD; Manuel Fischler, MD; Thomas Böhm, MD; Alain Bernheim, MD; Stefanie Kiencke, MD; Konrad E. Bloch, MD; Christoph Dehnert, MD; Robert Naeije, MD, PhD; Thomas Lehmann, MD; Peter Bärtsch, MD; and Heimo Mairbäurl, PhD
[+] Article and Author Information

From University Hospital Zürich, Zürich, University Hospital Basel, Basel, and Kantonsspital Chur, Chur, Switzerland; Université de Bruxelles, Brussels, Belgium; and Medical Clinic VII, University of Heidelberg, Heidelberg, Germany.


Acknowledgments: The authors thank the study participants; the hut keepers and the Sezione Varallo of the Club Alpino Italiano for providing an excellent research facility at the Capanna Regina Margherita; Sonja Engelhardt, Christiane Herth, and Hanna Bosshard for expert technical assistance; and Toshiba Switzerland AG for providing ultrasonic equipment.

Grant Support: By the Hartmann-Müller Foundation, the Pierluigi Crivelli Foundation, and the Anna Fedderson-Wagner Fonds (Switzerland).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Marco Maggiorini, MD, Intensive Care Unit, Department of Internal Medicine, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland; e-mail, klinmax@usz.unizh.ch.

Author Contributions: Conception and design: M. Maggiorini, H.-P. Brunner-La Rocca, P. Bärtsch, H. Mairbäurl.

Analysis and interpretation of the data: M. Maggiorini, H.-P. Brunner-La Rocca, S. Peth, A. Bernheim, S. Kiencke, K.E. Bloch, R. Naeije, P. Bärtsch, H. Mairbäurl.

Drafting of the article: M. Maggiorini, S. Peth, P. Bärtsch, H. Mairbäurl.

Critical revision of the article for important intellectual content: M. Maggiorini, H.-P. Brunner-La Rocca, K.E. Bloch, R. Naeije, P. Bärtsch, H. Mairbäurl.

Final approval of the article: M. Maggiorini, H.-P. Brunner-La Rocca, M. Fischler, T. Böhm, A. Bernheim, S. Kiencke, K.E. Bloch, T. Lehmann, R. Naeije, P. Bärtsch, H. Mairbäurl.

Provision of study materials or patients: M. Maggiorini, A. Bernheim.

Statistical expertise: M. Maggiorini.

Obtaining of funding: M. Maggiorini, P. Bärtsch, H. Mairbäurl.

Administrative, technical, or logistic support: M. Maggiorini, H.-P. Brunner-La Rocca, T. Böhm, C. Dehnert, P. Bärtsch, H. Mairbäurl.

Collection and assembly of data: M. Maggiorini, H.-P. Brunner-La Rocca, S. Peth, M. Fischler, T. Böhm, A. Bernheim, S. Kiencke, K.E. Bloch, C. Dehnert, R. Naeije, T. Lehmann.

Current Author Addresses: Dr. Maggiorini: Intensive Care Unit, Department of Internal Medicine, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.

Drs. Brunner-La Rocca, Bernheim, and Kiencke: Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.

Drs. Peth, Dehnert, Bärtsch, and Mairbäurl: Medical Clinic VII, Sports Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.

Dr. Fischler: Department of Internal Medicine, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.

Dr. Böhm: Department of Radiology, Kantonsspital, CH-7000 Chur, Switzerland.

Dr. Bloch: Division of Pneumology, Department of Internal Medicine, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.

Dr. Naeije: Department of Physiology, Erasme Campus CP 604, 808 Lennik Road, B-1070 Brussels, Belgium.

Dr. Lehmann: Department of Internal Medicine, Kantonsspital, CH-7000 Chur, Switzerland.


Ann Intern Med. 2006;145(7):497-506. doi:10.7326/0003-4819-145-7-200610030-00007
Text Size: A A A

When treatment was given 24 hours before rapid ascent to 4559 m, both tadalafil and dexamethasone reduced the incidence of HAPE after arrival at high altitude in persons with 1 or more previous episodes of HAPE. Moreover, dexamethasone prevented the excessive increase in systolic pulmonary artery pressure; its vasodilatory effect was comparable to that of the selective pulmonary vasodilator tadalafil (a phosphodiesterase-5 inhibitor). Dexamethasone, but not tadalafil, decreased the incidence of AMS in these HAPE-susceptible adults.

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Figures

Grahic Jump Location
Figure 1.
Flow diagram of the study.

Twenty-nine participants were recruited and underwent prealtitude tests, after which they were randomly assigned to treatment groups. *Two participants in the tadalafil group were withdrawn from the study early because they required treatment for severe acute mountain sickness (AMS) with oxygen and dexamethasone before the first night at 4559 m, but high-altitude pulmonary edema (HAPE) was not diagnosed at the time of withdrawal. However, the duration of exposure to 4559 m may not have been long enough to develop HAPE.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Proportion of participants without high-altitude pulmonary edema (HAPE) during their stay at high altitude.

Development of HAPE during time spent at 4559 m necessitated withdrawal from the study. The 2 participants in the tadalafil group who were withdrawn from the study because of severe acute mountain sickness a few hours after arrival at 4559 m were treated as censored observations at the time of withdrawal. P = 0.001 for placebo versus tadalafil, P < 0.001 for placebo versus dexamethasone, and P > 0.2 for dexamethasone versus tadalafil (log-rank test). The data below the figure indicate the number of participants who remained in the study.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Increase in systolic pulmonary artery pressure upon ascent to 4559 m.

Only 8 participants were evaluated in the tadalafil group; 2 were withdrawn from the study early because of severe acute mountain sickness. Values are presented as the mean (95% CI) systolic pulmonary artery pressure at 490 m and 4559 m. P values are shown in Table 3. HAPE= high-altitude pulmonary edema.

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References

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Comments

Submit a Comment
Mental Effects of Dexamethasone
Posted on October 9, 2006
Buddha Basnyat
Nepal International Clinic
Conflict of Interest: None Declared

Dear Sir,

Neither this article nor the accompanying editorial(1) comments on the important mental side effects of dexamethasone which may include euphoria and mental disorientation. These are potentially dangerous adverse side effects that deserve mention especially if you are climbing a jagged edge or trekking in remote high altitude mountain regions.

Sincerely, Buddha Basnyat

1 Swenson ER. Hypoxic lung whiteout: Further clearing but more questions from on high. Annals. 2006; 145: 550-552.

Conflict of Interest:

None declared

High Altitude Limerick
Posted on October 11, 2006
Peter T. Smyth
GLencoe Regional Health Services
Conflict of Interest: None Declared

Reaching the summit was quite-a-thrill, My lungs doing great on todalafil. And to also protect, It's the other effect, When I fell I didn't role down-the-hill.

Conflict of Interest:

None declared

Dose Adjustment of Drugs
Posted on October 24, 2006
Matiram Pun
Member of Mountain Medicine Society of Nepal (MMSN), Maharajgunj Campus, Institute of Medicine
Conflict of Interest: None Declared
The authors (M Maggiorini et al) have come up with the impressive outcome from their trial (Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema. A randomized trial.) (1). They have used Tadalafil 10mg or Dexamethasone 8mg twice daily from the morning of the day before ascent till the end of the study. The concern is about dose adjustments of both of these drugs for the trial. Previously another Phosphodiesterase-5 inhibitor Sildenafil has been used 3 x 40mg/day 6-8hrs after arrival to high altitude and maintained for six days to inhibit altitude-induced hypoxemia and pulmonary hypertension (2). Similarly, the other study uses sildenafil 25 or 100mg 8 hourly for 12 weeks to treat high altitude pulmonary arterial hypertension (3). In both of the studies, it has been found effective. In case of dexamethasone, it has been used 8 mg initially and followed by 4 mg every 6 hourly to treat high-altitude cerebral edema (4). Therefore, could authors explain how they chose their drug regimen for their trial of prophylaxis?

REFERENCES:

1. Maggiorini M, Brunner-La Rocca H, Peth S, Fischler M, Böhm T, Bernheim A, et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema. A randomized trial. Ann Intern Med. 2006; 145:497-506

2. Richalet J, Gratadour P, Robach P, Pham I, De´chaux M, Joncquiert-Latarjet A, et. al.Sildenafil Inhibits Altitude-induced Hypoxemia and Pulmonary Hypertension. Am J Respir Crit Care Med Vol 171. pp 275"“281, 2005

3. Aldashev AA, Kojonazarov BK, Amatov TA, Sooronbaev TM, Mirrakhimov MM, Morrell NW, et al.Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax 2005; 60:683"“687.

4. West, JB. The Physiologic Basis of High-Altitude Diseases. Ann Intern Med. 2004;141 : 789-800

Conflict of Interest:

None declared

Dexamethasone, tadalafil and high altitude pulmonary edema
Posted on February 2, 2007
Marco Maggiorini
Intensive Care Unit University Hospital Zurich, Switzerland
Conflict of Interest: None Declared

Authors replay: I thank Mr Pun and Dr. Ghimire, and Dr Basnyat for their interest and comments on our recent publication. When we designed and performed our study Richalet et al. (1) and Aldashev et al. (2) had not yet published their work on sildenafil to show that it decreases hypoxic pulmonary hypertension. Sildenafil needs to be taken in rather short time-intervals due to its short half life of 4 to 5 hours. Since in our study the effectiveness of two drugs was tested, we needed to match the time of drug intake and chose the phosphodiestrase 5 inhibitor tadalafil with a long half-life (17 hours) . The recommended dosage of tadalafil to treat erectile dysfunction is 10 to 20 mg. Thus, tadalafil 10mg every 12 hours appeared reasonable. Rock and coworkers (3) reported that 4mg dexamethasone every 12 hours significantly reduced symptoms and signs of AMS whereas 1 or 0.25mg were ineffective.. We decided to increase the dose to its maximum used to treat AMS, which was 16mg/day (2 x 8mg) based on previous trials where 4 x 4mg had been used. Based on our subjects clinical background this doseage applied on only 4 consecutive days appeared safe, an assumption that was confirmed in our study. Dr. Basnyat notched that we did not comment on possible dangerous mental side effect of dexamethasone. During our study we daily assessed the mental status of all participants and did not observe any symptoms of inappropriate euphoria or mental disorientation. Moreover, to our knowledge there are no studies indicating that dexamethasone impairs cognitive functions at high altitude. Conversely, two studies on mountaineers above 4000m, who received 8 to 16mg dexamethasone per day, showed an improvement of reaction times and mood status but no effects on personality in cognitive and psychomotor tests (4, 5). Thus, these results suggest that the use of dexamethasone at high altitude might even improve a mountaineer's awareness while climbing exposed ridges or trekking paths. However, at the present time we cannot generally recommend the routine use of dexamthasone for high altitude pulmonary edema prophylaxis for a time period longer than a few days because of its well-known long term side effects and the lack of safety data in the context of a trekking or climbing expedition in remote areas.

1. Richalet JP, Gratadour P, Robach P, Pham I, Dechaux M, Joncquiert- Latarjet A, et al. Sildenafil Inhibits the Altitude-induced Hypoxemia and Pulmonary Hypertension. Am J Respir Crit Care Med. 2004;29:29.

2. Aldashev AA, Kojonazarov BK, Amatov TA, Sooronbaev TM, Mirrakhimov MM, Morrell NW, et al. Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax. 2005 Aug;60(8):683-7.

3. Rock PB, Johnson TS, Larsen RF, Fulco CS, Trad LA, Cymerman A. Dexamethasone as prophylaxis for acute mountain sickness. Effect of dose level. Chest. 1989;95:568-73.

4. Lafleur J, Giron M, Demarco M, Kennedy R, BeLue R, Shields C. Cognitive effects of dexamethasone at high altitude. Wilderness Environ Med. 2003 Spring;14(1):20-3.

5. Jobe JB, Shukitthale B, Banderet LE, Rock PB. Effects of Dexamethasone and High Terrestrial Altitude on Cognitive Performance and Affect. Aviat Space Environ Med. 1991;62(8):727-32.

Conflict of Interest:

None declared

Submit a Comment

Summary for Patients

A Comparison of Medications Used to Prevent High-Altitude Pulmonary Edema

The summary below is from the full report titled “Both Tadalafil and Dexamethasone May Reduce the Incidence of High-Altitude Pulmonary Edema. A Randomized Trial.” It is in the 3 October 2006 issue of Annals of Internal Medicine (volume 145, pages 497-506). The authors are M. Maggiorini, H.-P. Brunner-La Rocca, S. Peth, M. Fischler, T. Böhm, A. Bernheim, S. Kiencke, K.E. Bloch, C. Dehnert, R. Naeije, T. Lehmann, P. Bärtsch, and H. Mairbäurl.

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