Clinical trial NCT00627965: Randomized, Controlled Trial of Regular Sildenafil Citrate in the Prevention of Altitude Illness
Official title: Randomized, Controlled Trial of Regular Sildenafil Citrate in the Prevention of Altitude Illness
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: High Altitude Pulmonary Edema
Acute Mountain Sickness
Keywords: Sildenafil citrate
Prevention
High Altitude Pulmonary Edema
Acute Mountain Sickness
Healthy Lowland Subjects
Pulmonary Artery Systolic Pressure
Lead sponsor: Altitude Physiology Expeditions
Sponsor class: OTHER
Collaborators: name: University of Edinburgh
First posted: 2008-03-04
Enrollment: 62
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine whether regular oral use of sildenafil citrate can prevent or attenuate high altitude illnesses.

Detailed description: High altitude pulmonary oedema (HAPE) is a life-threatening non-cardiogenic lung injury precipitated by exaggerated pulmonary hypertension. The incidence of this rapidly progressive illness, among the estimated 40 million visitors to high altitude each year, may be as high as 0.5-2.0%. The pathogenesis of HAPE is multifactorial and may include impaired clearance of alveolar fluid, increased pulmonary vascular permeability and genetic susceptibility. Elevated pulmonary artery pressure (PAP) caused by hypoxic pulmonary vasoconstriction (HPV) is a key prerequisite for the development of HAPE and thus the reduction of PAP is paramount in the prophylaxis and treatment of this devastating illness.

Nitric oxide (NO) is thought to play an important role in the exaggerated HPV that characterises HAPE. NO, constitutively produced in the lung by the enzyme endothelial nitric oxide synthase (eNOS), increases intracellular cGMP in pulmonary vascular smooth muscle and activates cGMP-dependent protein kinase, ultimately leading to a reduction in intracellular calcium and smooth muscle relaxation. HAPE-susceptible individuals exhale less NO during both normobaric and hypobaric hypoxia suggesting that a deficiency of NO synthesis may predispose to HAPE. At high altitude, inhaled NO causes a significantly greater reduction in the systolic PAP of HAPE-susceptible individuals compared to its effect on the PAP of HAPE-resistant subjects, but the administration of NO would be impractical in the field. Most recently, work has concentrated on another target in the NO pathway.

Sildenafil citrate is an orally active, potent and selective phosphodiesterase type-5 (PDE-5) inhibitor. PDE-5 is the predominant enzyme responsible for degradation of cGMP in the lung. In a small sea level study, Zhao et al. demonstrated that pre-treatment with sildenafil nearly completely abolished the pulmonary vasopressor response to breathing hypoxic gas in healthy humans. More recently, studies at altitude have also shown reductions in pulmonary artery systolic pressure (PASP) in subjects taking sildenafil at high altitude.

One potential problem with the use of sildenafil at altitude is that PDE-5 inhibitors may worsen symptoms of acute mountain sickness (AMS). Headache is a defining symptom in AMS and is a prominent side effect of sildenafil.

We conducted a double-blind placebo-controlled randomised trial to assess the effect of regular sildenafil administration on PASP and Lake Louise AMS score at an altitude of 5200 m.

Eligibility criteria: Inclusion Criteria:

* Participant in Apex 2 high altitude expedition

Exclusion Criteria:

* Previous history of high altitude pulmonary edema

Primary outcomes:
measure: Pulmonary Artery Systolic Pressure (PASP)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Altitude Physiology Expeditions
name: Matthew Bates
role: PRINCIPAL_INVESTIGATOR
References:
citation: MacCormick IJ, Somner J, Morris DS, MacGillivray TJ, Bourne RR, Huang SS, MacCormick A, Aspinall PA, Baillie JK, Thompson AA, Dhillon B. Retinal vessel tortuosity in response to hypobaric hypoxia. High Alt Med Biol. 2012 Dec;13(4):263-8. doi: 10.1089/ham.2011.1097.
citation: Bates MG, Thompson AA, Baillie JK, Sutherland AI, Irving JB, Hirani N, Webb DJ. Sildenafil citrate for the prevention of high altitude hypoxic pulmonary hypertension: double blind, randomized, placebo-controlled trial. High Alt Med Biol. 2011 Fall;12(3):207-14. doi: 10.1089/ham.2011.0007.