Diving, Edema, Pulmonary, Immersion
Conditions
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.
Interventions
DRUGSildenafil Citrate
Oral sildenafil, 50 mg
DRUGPlacebo Oral Tablet
Placebo
Sponsors
United States Department of Defense
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo controlled
Intervention model description
Double blind, randomized
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy volunteers between 18 and 45 years * History of swimming-induced pulmonary edema
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Oral Tablet, Then Sildenafil Citrate Each participant first received placebo oral tablet one hour (once) before immersed exercise. After a washout period of at least 7 days, they then received Sildenafil citrate 50 mg orally one hour (once) before immersed exercise. | 10 |
| Sildenafil Citrate, Then Placebo Oral Tablet Each participant first received Sildenafil citrate 50 mg orally one hour (once) before immersed exercise. After a washout period of at least 7 days, they then received placebo oral tablet one hour (once) before immersed exercise. | 8 |
| Total | 18 |
Baseline characteristics
| Characteristic | Placebo Oral Tablet, Then Sildenafil Citrate | Total | Sildenafil Citrate, Then Placebo Oral Tablet |
|---|---|---|---|
| Age, Continuous | 38.6 years STANDARD_DEVIATION 6 | 38.1 years STANDARD_DEVIATION 6 | 37.5 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 18 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 18 Participants | 8 Participants |
| Region of Enrollment United States | 10 Participants | 18 Participants | 8 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 0 / 10 | 0 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 |
Outcome results
Primary
Number of Participants With Pulmonary Edema
One or more of: hypoxemia, productive cough, pulmonary edema on chest radiograph, wheezing on chest auscultation.
Time frame: During or immediately after exercise in cold water, approximately one hour and 40 minutes
Population: Each participant was studied with active drug and placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Oral Tablet | Number of Participants With Pulmonary Edema | 7 Participants |
| Sildenafil Citrate | Number of Participants With Pulmonary Edema | 9 Participants |
p-value: 0.317McNemar
Secondary
Number of Participants Who Found the Exercise Easiest When Given Sildenafil Citrate Versus When Given Placebo
Time frame: Immediately after exercise in cold water, approximately one hour and 40 minutes
Population: Each participant was studied with active drug and placebo.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo Oral Tablet | Number of Participants Who Found the Exercise Easiest When Given Sildenafil Citrate Versus When Given Placebo | Placebo Oral Tablet | 5 Participants |
| Placebo Oral Tablet | Number of Participants Who Found the Exercise Easiest When Given Sildenafil Citrate Versus When Given Placebo | Sildenafil Citrate | 9 Participants |
| Placebo Oral Tablet | Number of Participants Who Found the Exercise Easiest When Given Sildenafil Citrate Versus When Given Placebo | No Difference | 4 Participants |
p-value: 0.29McNemar
Secondary
Number of Participants With Comet Tails Seen on Ultrasound of the Lungs
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.
Time frame: Immediately after exercise in cold water, approximately one hour and 40 minutes
Population: Each participant was studied with active drug and placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Oral Tablet | Number of Participants With Comet Tails Seen on Ultrasound of the Lungs | 17 Participants |
| Sildenafil Citrate | Number of Participants With Comet Tails Seen on Ultrasound of the Lungs | 14 Participants |
p-value: 0.18McNemar
Secondary
Number of Participants With Dyspnea Leading to Voluntary Premature Cessation of Exercise
Voluntary premature cessation of exercise due to shortness of breath.
Time frame: During or immediately after exercise in cold water, approximately one hour and 40 minutes
Population: Each participant was studied with active drug and placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Oral Tablet | Number of Participants With Dyspnea Leading to Voluntary Premature Cessation of Exercise | 10 Participants |
| Sildenafil Citrate | Number of Participants With Dyspnea Leading to Voluntary Premature Cessation of Exercise | 8 Participants |
p-value: 0.317McNemar
Secondary
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
Post-exercise 10% decrease in forced vital capacity (FVC) or forced expiratory volume in one second (FEV1).
Time frame: Immediately after exercise in cold water, approximately one hour and 40 minutes
Population: Each participant was studied with active drug and placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo Oral Tablet | 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 | 3 Participants |
| Sildenafil Citrate | 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 | 3 Participants |
p-value: >0.999McNemar