Sildenafil for Swimming-Induced Pulmonary Edema (SIPE) Prevention

Phase 2

Completed

• Conditions: Edema, Pulmonary; Immersion; Diving
• Interventions: Drug: Placebo Oral Tablet; Drug: Sildenafil Citrate

• Registration Number: NCT03686813
• Lead Sponsor: Duke University

Brief Summary

This trial is testing the effectiveness of a single oral dose of sildenafil (50 mg) taken 1 hour before a provocative event on the subsequent development of swimming-induced pulmonary edema.

Detailed Description

Immersion pulmonary edema (also known as swimming-induced pulmonary edema, SIPE) is a condition in which the lungs fill with fluid (pulmonary edema) during a dive or vigorous swim, causing cough with bloody sputum, shortness of breath and reduced blood oxygen levels. In the Navy this usually occurs in young, healthy individuals such as SEAL and Special Warfare Combatant-Craft trainees. SIPE generally resolves spontaneously within 24 hours but it can be fatal. It is believed that SIPE is responsible for some deaths in civilians during triathlons. This proposal aims to test a drug to prevent SIPE.

Depending upon severity, the prevalence of SIPE is reported in up to 60% during 2.4-3.6 km open sea swimming trials in the Israel Defense Force. In SEAL training in the US approximately 40 cases per year (around 3%) have been reported, more commonly during winter, when it is observed in up to 5% of trainees. Return to duty time can be up to 7 days. SIPE also affects other groups of highly fit individuals such as triathletes. In susceptible individuals it tends to recur, thus a preventive medicine would be useful for both Navy SEALs and civilians.

The aim of this study will be to provide the Navy an FDA-approved drug that can be used to prevent SIPE. The investigators hypothesize that sildenafil administration to SIPE-susceptible individuals one hour before a swim in cold water will reduce or eliminate the risk of SIPE. The method to be used to test this hypothesis will be a 40-minute period of exercise immersed to the neck in 20°C water, a test that results in SIPE symptoms in the majority of susceptible individuals. The investigators plan to study 20 individuals who have previously experienced SIPE. Each volunteer will be tested twice. Either sildenafil or an inactive drug (placebo) administered in random order will be given prior to each exercise. For each participant exercise periods will be performed at least 7 days apart. The identity of the drug and placebo will be concealed from the investigators and the volunteers until the end of the study. The number of instances in which SIPE manifestations after sildenafil and placebo will then be compared.

Availability of a drug that can prevent SIPE would provide the Navy with a useful tool that could be administered to SEALs who have experienced SIPE prior to critical missions. It would also be useful for civilians who have experienced SIPE but wish to continue with the precipitating exercise such as swimming or competing in triathlons, and also for patients with heart failure for whom swimming induces shortness of breath or pulmonary edema.

Study Timeline

• Study First Submitted: 2018-09-24
• Study First Submitted QC: 2018-09-25
• Study First Posted: 2018-09-27
• Study Start: 2019-07-15
• Primary Completion: 2021-10-29
• Study Completion: 2021-10-29
• Status Verified: 2022-10
• Results First Submitted: 2022-10-28
• Results First Submitted QC: 2022-10-28
• Last Update Submitted: 2022-10-28
• Results First Posted: 2022-11-22
• Last Update Posted: 2022-11-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

• Healthy volunteers between 18 and 45 years
• History of swimming-induced pulmonary edema

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Exclusion Criteria

• Pregnant women
• Significant heart valve disease
• Cardiomyopathy
• Uncontrolled hypertension
• Coronary artery disease
• Obstructive lung disease
• VO2max <25 mL/kg as estimated by the University of Houston Non-Exercise Test
• Previous adverse reaction to sildenafil
• Use of antihypertensives or other drugs that are known to interact adversely with sildenafil (e.g. nitrates, alpha adrenergic blockers)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo Oral Tablet	Each participant will be studied with active drug and placebo.
Sildenafil	Sildenafil Citrate	Sildenafil 50 mg orally one hour (once) before immersed exercise

Primary Outcome Measures

Name	Time	Method
Number of Participants With Pulmonary Edema	During or immediately after exercise in cold water, approximately one hour and 40 minutes	One or more of: hypoxemia, productive cough, pulmonary edema on chest radiograph, wheezing on chest auscultation.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Found the Exercise Easiest When Given Sildenafil Citrate Versus When Given Placebo	Immediately after exercise in cold water, approximately one hour and 40 minutes
Number of Participants With Dyspnea Leading to Voluntary Premature Cessation of Exercise	During or immediately after exercise in cold water, approximately one hour and 40 minutes	Voluntary premature cessation of exercise due to shortness of breath.
Number of Participants With Post-exercise 10% Decrease in Forced Vital Capacity (FVC) or Forced Expiratory Volume in One Second (FEV1) as Measured by Spirometry	Immediately after exercise in cold water, approximately one hour and 40 minutes	Post-exercise 10% decrease in forced vital capacity (FVC) or forced expiratory volume in one second (FEV1).
Number of Participants With "Comet Tails" Seen on Ultrasound of the Lungs	Immediately after exercise in cold water, approximately one hour and 40 minutes	A "comet tail" artefact is a short path reverberation artefact that weakens with each reverberation, resulting in a vertical echogenic artefact that rapidly fades as it continues in to the ultrasound image.

Trial Locations

Locations (1)

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States