Reducing the Incidence of High-Altitude Pulmonary Edema

Dear Friends!
Here are the critics of one the finest RCTs!

First

Matiram Pun and Laxmi V. Ghimire, MBBS

17 April 2007 | Volume 146 Issue 8 | Page 613


TO THE EDITOR:

In their randomized trial, Maggiorini and colleagues (1) report their impressive outcome that both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema. They used a dosage of 10 mg twice daily for tadalafil or 8 mg twice daily for dexamethasone from the morning of the day before ascent until the end of the study. We are concerned about the dose adjustments of both drugs for the trial. A previous study used the phosphodiesterase-5 inhibitor sildenafil at a dosage of 40 mg 3 times daily at 6 to 8 hours after arrival at high altitude that was maintained for 6 days to inhibit altitude-induced hypoxemia and pulmonary hypertension (2). Similarly, another study used a sildenafil dosage of 25 mg or 100 mg every 8 hours for 12 weeks to treat high-altitude pulmonary arterial hypertension (3). Both studies found the treatments to be effective. In the case of dexamethasone, an initial dose of 8 mg, followed by 4 mg every 6 hours, has been used to treat high-altitude cerebral edema (4).

Could the authors explain how they chose the drug regimen for their prophylaxis trial?


Author and Article Information

From Institute of Medicine and Tribhuvan, University Teaching Hospital, and Nick Simons Institute, Kathmandu, Nepal.

Potential Financial Conflicts of Interest: None disclosed.


References


1. Maggiorini M, Brunner-La Rocca HP, 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. [PMID: 17015867].[Abstract/Free Full Text]

2. Richalet JP, Gratadour P, Robach P, Pham I, Déchaux M, Joncquiert-Latarjet A, et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med. 2005;171:275-81. [PMID: 15516532].[Abstract/Free Full Text]

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;60:683-7. [PMID: 16061711].[Abstract/Free Full Text]

4. West JB. The physiologic basis of high-altitude diseases. Ann Intern Med. 2004;141:789-800. [PMID: 15545679].[Free Full Text]

The link:
Reducing the Incidence of High-Altitude Pulmonary Edema -- Pun and Ghimire 146 (8): 613 -- Annals of Internal Medicine


Next Critic:

Buddha Basnyat, MS, MSc

17 April 2007 | Volume 146 Issue 8 | Page 613

TO THE EDITOR:

The article by Maggiorini and colleagues (1) and its editorial (2) do not comment on the important mental side effects of dexamethasone, which may include euphoria and mental disorientation. These are potentially dangerous adverse side effects, especially if you are climbing a jagged edge or trekking in remote high-altitude mountain regions, and they deserve mention.


Author and Article Information

From Nepal International Clinic, Lal Durbar, Kathmandu, Nepal.

Potential Financial Conflicts of Interest: None disclosed.


References


1. Maggiorini M, Brunner-La Rocca HP, 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. [PMID: 17015867].[Abstract/Free Full Text]

2. Swenson ER. Hypoxic lung whiteout: further clearing but more questions from on high [Editorial]. Ann Intern Med. 2006;145:550-2. [PMID: 17015875].[Free Full Text]

The link:
Reducing the Incidence of High-Altitude Pulmonary Edema -- Basnyat 146 (8): 613 -- Annals of Internal Medicine


The RESPONSE of the above Letter:

Marco Maggiorini, MD, and Heimo Mairbäurl, PhD

17 April 2007 | Volume 146 Issue 8 | Pages 613-614

IN RESPONSE:

We 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 and colleagues (1) and Aldashev and colleagues (2) had not yet published their work on sildenafil, which both showed that sildenafil decreases hypoxic pulmonary hypertension. Sildenafil must be taken in rather brief intervals because of its short half-life of 4 to 5 hours. Because we tested the effectiveness of 2 drugs in our study, we needed to match the time of drug intake and chose the phosphodiesterase-5 inhibitor tadalafil with a long half-life (17 hours). The recommended dose of tadalafil to treat erectile dysfunction is 10 to 20 mg; thus 10 mg of tadalafil every 12 hours seemed reasonable.

Rock and colleagues (3) reported that 4 mg of dexamethasone every 12 hours statistically significantly reduced symptoms and signs of acute mountain sickness, whereas 1 mg or 0.25 mg of dexamethasone was ineffective. We decided to increase the dose to the maximum used to treat acute mountain sickness, which was 16 mg/d (8 mg twice daily) on the basis of previous trials that used 4 mg four times daily. On the basis of our participants' clinical background, applying this dosage on only 4 consecutive days seemed safe, an assumption that was confirmed in our study.

Dr. Basnyat noticed that we did not comment on possible dangerous mental side effect of dexamethasone. During our study, we assessed the mental status of all participants daily and did not observe any symptoms of inappropriate euphoria or mental disorientation. Moreover, to our knowledge, no studies indicate that dexamethasone impairs cognitive functions at high altitude. Conversely, 2 studies on mountaineers at altitudes higher than 4000 meters, who received 8 to 16 mg of dexamethasone daily, 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, we cannot generally recommend the routine use of dexamethasone for high-altitude pulmonary edema prophylaxis for 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.


Author and Article Information

From University Hospital Zürich, Zürich, Switzerland, and the University of Heidelberg, Heidelberg, Germany.

Potential Financial Conflicts of Interest: None disclosed.


References

1. Richalet JP, Gratadour P, Robach P, Pham I, Déchaux M, Joncquiert-Latarjet A, et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med. 2005;171:275-81. [PMID: 15516532].[Abstract/Free Full Text]

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;60:683-7. [PMID: 16061711].[Abstract/Free Full Text]

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. [PMID: 2920585].[Abstract/Free Full Text]

4. Lafleur J, Giron M, Demarco M, Kennedy R, BeLue R, Shields C. Cognitive effects of dexamethasone at high altitude. Wilderness Environ Med. 2003;14:20-3. [PMID: 12659245].[Medline]

5. Jobe JB, Shukitt-Hale B, Banderet LE, Rock PB. Effects of dexamethasone and high terrestrial altitude on cognitive performance and affect. Aviat Space Environ Med. 1991;62:727-32. [PMID: 1930053].[Medline]

The Link:
Reducing the Incidence of High-Altitude Pulmonary Edema -- Maggiorini and Mairbäurl 146 (8): 613 -- Annals of Internal Medicine



And the original article is :

Both Tadalafil and Dexamethasone May Reduce the Incidence of High-Altitude Pulmonary Edema: A Randomized Trial -- Maggiorini et al. 145 (7): 497 -- Annals of Internal Medicine


Best wishes,
mati