Randomized, Controlled Trial of Regular Sildenafil Citrate in the Prevention of Altitude Illness

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
High Altitude Pulmonary Edema; Acute Mountain Sickness	Drug: Sildenafil citrate; Drug: Placebo	Phase 4

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	62 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Randomized, Controlled Trial of Regular Sildenafil Citrate in the Prevention of Altitude Illness
Study Start Date :	March 2003
Actual Study Completion Date :	February 2008

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1; Sildenafil citrate	Drug: Sildenafil citrate; 50mg tds
Placebo Comparator: 2; Placebo	Drug: Placebo; Placebo tds

Outcome Measures

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Primary Outcome Measures :

1. Pulmonary Artery Systolic Pressure (PASP)

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Participant in Apex 2 high altitude expedition

Exclusion Criteria:

• Previous history of high altitude pulmonary edema

Contacts and Locations

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Sponsors and Collaborators

Altitude Physiology Expeditions

University of Edinburgh

Investigators

Principal Investigator:	Matthew Bates	Altitude Physiology Expeditions

More Information

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Additional Information:

Research group website coordinating future studies 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

Responsible Party:	Director, Altitude Physiology Expeditions
ClinicalTrials.gov Identifier:	NCT00627965 History of Changes
Other Study ID Numbers:	Sildenafil1
First Posted:	March 4, 2008
Last Update Posted:	March 4, 2008
Last Verified:	February 2008

Keywords provided by Altitude Physiology Expeditions:

Sildenafil citrate; Prevention; High Altitude Pulmonary Edema	Acute Mountain Sickness; Healthy Lowland Subjects; Pulmonary Artery Systolic Pressure

Additional relevant MeSH terms:

Altitude Sickness; Pulmonary Edema; Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Citric Acid; Sildenafil Citrate; Anticoagulants	Calcium Chelating Agents; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Urological Agents