High Altitude Pulmonary Edema Prevention

Abstract and Commentary

By Michele Barry MD, FACP

Dr. Barry is Professor of Medicine, Co-Director, Tropical Medicine and International Travelers' Clinic, Yale University School of Medicine

Dr. Barry is a consultant for the Ford Foundation, and receives funds from Johnson & Johnson.

Synopsis: What agents are available to prevent or abort high-altitude pulmonary edema, particularly for those who are already known to be susceptible?

Source: Maggiorini M, et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema. Ann Int Med. 2006;145:497-506.

This is a sentinel article involving a randomized, double-blind, placebo-controlled study which took 29 adult patients with a history of high altitude pulmonary edema (HAPE) from 490 m to an ascent of 4559 m within 24 hours, treating them for 2 days with either prophylactic tadalafil 10 mg orally, twice a day, dexamethasone 8 mg orally twice a day or a placebo twice daily, starting on the morning of ascent. In these HAPE-susceptible individuals who had a 60 to 70% likelihood of again developing HAPE under study conditions, Maggiorini and colleagues performed the following tests at the summit: chest radiography to survey for infiltrates, Doppler echocardiography to measure systemic pulmonary artery pressures and cardiac output, and nasal potentials as a surrogate marker of alveolar sodium transport in order to determine if alveolar fluid re-absorption was affected by any of the study drugs.

The incidence of HAPE was 78% in the placebo-treated group but was reduced to 13% and 0% in the tadalafil and dexamethasone groups, respectively. This reduction in risk was comparable to nifedipine's efficacy (a 10% incidence of HAPE) and potentially better than salmeterol's (a 33% incidence of HAPE), two established prophylactic drugs tested under the same conditions on the same mountain in earlier studies.1,2

Dexamethasone decreased the incidence of AMS, but tadalafil did not. However, patients taking dexamethasone had mild, clinically insignificant, hyperglycemia. Dexamethasone did not stimulate sodium transport via surrogate markers, nasal potentials or a decrease in expression of the alpha-1 subunit of Na+, K+, - ATPase in leukocytes. The authors conclude that although acetazolamide (Diamox®) is the standard of care for prevention of AMS, dexamethasone may be the ideal prophylaxis to reduce the risk of HAPE and AMS in HAPE-susceptible persons who must ascend rapidly, as it now has been shown to prevent both AMS and HAPE in this population.

Commentary

Rapid ascent to altitudes greater than 2500 m may cause acute mountain sickness (AMS) or high altitude pulmonary edema. In non-acclimatized mountaineers, the prevalence of AMS and HAPE at 4559 m is approximately 50% and 4%, respectively. AMS is not a prerequisite for HAPE. However, if a person has a history of HAPE, undergoing another high altitude rapid climb puts them at a 60% risk of contracting HAPE again. HAPE begins when a critical level of hypoxic pulmonary vasoconstriction causes mean pulmonary artery pressures to exceed 35 to 40 mm Hg. Reduction in hypoxic pulmonary vasoconstriction (HPV) by descent, oxygen supplementation, nitric oxide, portable hyperbaric bags or pulmonary vasodilators have all been shown to be effective therapy for HAPE.

Tadalafil, a phosphodiesterase-5 inhibitor like sildenafil (Viagra®), reduces hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension by blocking the breakdown of cyclic GMP, the intracellular mediator of the vasodilatory efforts of nitric oxide. Dexamethasone's preventative effects had been felt to be caused by anti-inflammatory effects on both cellular and cytokine responses. As HAPE pulmonary lavage fluid does not contain inflammatory cells, the unusual finding from Maggiorini's study is that dexamethasone was 100% effective in treating HAPE, surprisingly by reducing pulmonary artery pressures. Very recent studies have shown that glucocorticoids can increase pulmonary vascular endothelial nitric oxide (NO) synthase and increase NO levels—which fits nicely with the data that HAPE-susceptible people have a lower pulmonary generation of vascular nitric oxide when exposed to hypoxia.3

The "elephant on the mountain" in this study—why was acetazolamide Diamox® not used in one of the arms? Animal studies have shown Diamox® to be effective in preventing HAPE as well as AMS, but no human studies have been carried out.4 Moreover, adverse effects of high-dose dexamethasone that were not monitored beyond 48-hour treks represent unrealistic scenarios in real life. Taking dexamethasone on an extended trek could lead to hyperglycemia, hypercalciuria, protein catabolism, immunosuppression and steroid psychosis.

An accompanying editorial questions whether inhaled corticosteroids can substitute for oral dosing and whether genomic factors, sympathetic tone alterations, surfactant production or cell-to-cell tight junction strengthening may play a role in dexamethasone's preventing HAPE.5 For now we await studies by this extremely organized and thoughtful group on whether acetazolamide is as effective as dexamethasone in preventing AMS and HAPE, and which dexamethasone regimen has the best risk-benefit profile.

References

  1. Bärtsch P, et al. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med. 1991;325:1284-1289.
  2. Sartori C, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med. 2002;346:1631-1636.
  3. Busch T, et al. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema. Am J Respir Crit Care Med. 2001;163:368-373.
  4. Höhne C, et al. Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs. J Appl Physiol. 2004;97:515-521.
  5. Swenson ER. Hypoxic lung whiteout: Further clearing but more questions from on high. Ann Intern Med. 2006;145:550-552.