Clinical trial NCT03686813
Conditions: Edema, Pulmonary Immersion Diving
Sponsor: Duke University
Start date: 2019-07-15; Completion date: 2021-10-29
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: Each participant will be studied with active drug and placebo. arm 2: Sildenafil 50 mg orally one hour (once) before immersed exercise
Interventions: intervention 1: Sildenafil Citrate intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Oral sildenafil, 50 mg intervention 2: Placebo

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
Sildenafil for Prevention of Swimming-Induced Pulmonary Edema (SIPE) 
 
NCT03686813 
 
Document Date: 12/14/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Purpose of the Study 
  
Problem to be Addressed. The problem addressed in this proposal is occurrence of immersion 
pulmonary edema (SIPE) during heavy exertion while swimming or diving in cold water. 
Hypothesis and Specific Aim. We hypothesize that a 50 mg dose of sildenafil will reduce or eliminate 
SIPE in susceptible individuals. The specific aim will be to perform a randomized placebo-controlled 
study of 20 SIPE-susceptible volunteers. The aim of this proposal is to test the effectiveness of a 
standard dose of sildenafil for prevention of SIPE in healthy SIPE-susceptible individuals. The objective is 
to perform a placebo controlled trial of a single 50 mg dose of sildenafil one hour before a 40-minute 
exercise during head-out immersion in 20°C water. 
Deliverable. The aim is verify a pharmacological method to prevent SIPE in susceptible individuals. 
 
Background & Significance 
 
Immersion pulmonary edema (IPE, also known as swimming-induced pulmonary edema, SIPE) is a 
condition in which cough, hemoptysis, dyspnea and hypoxemia develop after surface swimming or 
diving, often in young, healthy individuals (1-11). It has been reported predominantly in males, including 
naval trainees during strenuous swimming (6,7,10,12,13). The condition generally spontaneously 
resolves within 24 hours or with β2 adrenergic agonist or diuretic therapy, but it can be fatal (5,14). 
SIPE-susceptible individuals have higher pulmonary artery (PA) and PA wedge pressures during exercise 
in cold water (15). Thus it is believed that SIPE represents a form of hemodynamic pulmonary edema 
due to excessive pulmonary vascular pressures in response to cold water exercise. 
 
There are some risk factors for SIPE, which include swimming or diving in cold water (1,3,11), negative 
static lung load (16), heavy exertion (3,4,6-8,10-12), fluid loading (12) and low vital capacity (7). Other 
predisposing factors are hypertension, left ventricular hypertrophy (LVH) and other cardiac 
abnormalities (17). It also tends to recur in susceptible individuals (1,3,7,11,13,17). Pulmonary 
hemorrhage can also occur in certain breath-hold divers due to pressure-related engorgement of the 
pulmonary vasculature induced by descent when lung volume is at or below residual volume. In those 
susceptible to hemorrhage certain genotypes (related to eNOS and angiotensin converting enzyme) 
have been observed to be more frequent (18), providing plausible rationale that genotyping may also be 
predictive of SIPE-susceptibility. 
 
Approximately 30-40 cases per year are observed at the Naval Special Warfare Center (8,10,19). Cases of 
SIPE are also seen at the Naval Diving and Salvage Training Center. Its prevalence in 2.4-3.6 km open sea 
swimming trials has been reported to be from 1.8-60%, depending upon the severity (7,13). Prevalence 
during SEAL training is 1-3% of trainees during spring, summer and fall, and 5% in the winter (20). 
Pulmonary edema in a normal lung occurs when pulmonary artery (PA) wedge pressure acutely exceeds 
a critical value of 18-25 mmHg (21-23). Both PA and PA wedge pressures increase during immersion, 
primarily due to central redistribution of blood from the extremities (24,25), which engorges the central 
veins, heart and pulmonary vessels (24,26-28). This peripheral to central redistribution of blood is 
augmented by cold water immersion (28,29) and attenuated by a concurrent reduction in venous tone 
(26). Studies from our lab have demonstrated significant pulmonary arterial and venous hypertension 
(and systemic hypertension) during submersion, particularly in cold water (28). We have demonstrated 
that in SIPE-susceptible volunteers the peripheral-to-central blood redistribution leads to excessively 
high PA and PA wedge pressures at levels sufficient to precipitate pulmonary edema. 
 


With a technique developed in our lab we have the ability to examine susceptibility to SIPE and test 
medications that might prevent it. Identification of a medication to prevent SIPE would be applicable not 
only to Navy divers and swimmers, but civilians known to be at risk for SIPE (e.g. triathletes) and 
individuals with heart failure, for whom swimming exercise may be beneficial for aerobic fitness but 
dangerous because of a risk of inducing pulmonary edema (30). 
 
RELEVANCE 
 
SIPE remains a problem during training for SEALs and Special Warfare Combatant-Craft Crewmen. 
Nevertheless, SEAL candidates who experience SIPE have graduation rates similar to those who have not 
experienced it (31). Therefore, there must be a significant number of SIPE-susceptible operational SEALs 
and Special Warfare Combatant-Craft Crewmen who are at risk for SIPE during an operation. A 
medication with few side effects such as sildenafil that could prevent SIPE in susceptible individuals 
would be a valuable tool for use in mission-critical tasks where the individual best-suited for the task is 
SIPE-susceptible. An effective prophylactic drug would also be useful for civilians, particularly the 
increasing number of recreational triathletes in whom SIPE-susceptibility is around 1.5% (32). Deaths 
among amateur divers and triathletes due to SIPE have been reported (14,33,34). 
 
PRELIMINARY WORK 
 
Previous studies in our laboratory supported by NAVSEA have demonstrated that pulmonary artery and 
pulmonary artery wedge pressures are higher in thermoneutral water compared to the dry, and even 
higher in cold water (28). When compared with individuals with no SIPE history, SIPE-susceptible 
individuals have higher PA and PA wedge pressures during exercise submerged in cold water. This study 
demonstrated the following (15): 
 
SIPE-susceptible individuals have higher pulmonary artery and wedge pressures during exercise in cold 
water, thus demonstrating the mechanism for hemodynamic pulmonary edema in SIPE. 
 
Sildenafil, a drug known to reduce pulmonary artery pressure in other settings, also does so in SIPE-
susceptible individuals, suggesting that sildenafil may be an effective preventive medication. 
 
Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor that is used clinically for treatment of erectile 
dysfunction and primary pulmonary hypertension. It has a peak plasma level approximately one hour 
after oral ingestion and a 4-hour half-life (35). In normal individuals the drug induces a slight decrease in 
blood pressure at rest and during exercise in the dry (36), but no significant change during submersed 
exercise (15). While it is plausible that PDE-5 inhibitors could improve exercise performance (37), the 
evidence is mixed. Some studies have shown that sildenafil tends to improve exercise performance at 
altitude but not at sea level (38). More importantly, exercise performance is not impaired by either 
sildenafil or the similar drug tadalafil. In a group of trained cyclists and triathletes aged 18-35 years, oral 
sildenafil 50 or 100 mg had no adverse effect on a 10 km time trial or hemodynamic parameters during 
cycle exercise at 55% peak work for 60 minutes (39). In another study of fit volunteers aged 24-56 years, 
oral sildenafil 50 mg did not decrease O2max (40). In a test of anaerobic performance on a cycle 
ergometer in 20 healthy male athletes, oral tadalafil 20 mg had no adverse effect on mean power, peak 
power or fatigue during an incremental test to exhaustion (41). The same dose also had no adverse 
effect on aerobic performance in a study of 14 healthy male athletes (42). 
 
Sildenafil is the logical drug to test as a prophylactic against SIPE for the Navy because: 


Its hemodynamic properties in humans have been measured during cold water immersion under a Duke 
IRB (Pro00003158), providing a plausible rationale for its use as prophylaxis against SIPE (15). 
 
There is anecdotal evidence of its effectiveness in preventing SIPE (43). 
 
Sildenafil does not impair exercise performance (39,42). 
 
Overhydration was previously identified as contributing factor to SIPE: in one report each of 8 navy 
trainees who subsequently developed SIPE had consumed about 5 liters of water during two hours 
before exercise (12). This is confirmed by our most recent study (Pro00019996), in which oral pre-
loading with a standard rehydration solution (Pedialyte®) followed by 40 minutes of head-out immersed 
exercise in 20°C water produced SIPE manifestations in 7 of 9 individuals with previous SIPE and 1 of 14 
with no such history, thus providing a model for testing of an intervention to prevent SIPE. 
 
Design & Procedures 
 
The specific aim of this study will be addressed using a randomized, placebo controlled study of 
sildenafil in a group of individuals with proven susceptibility to SIPE. Volunteers between the ages of 18 
and 45 years will be recruited who have experienced documented SIPE. The medical record of each 
individual will be screened carefully for underlying predisposing conditions including heart valve disease, 
cardiomyopathy, untreated hypertension and coronary artery disease and obstructive lung disease. 
Every effort will be made to ensure that these exclusions are met before they come to Duke. Volunteers 
who have not undergone resting and stress echocardiography will undergo these studies in our facility. 
Each subject will undergo VO2max testing on the day before the study.  COVID testing will be performed 
prior to arrival at Duke. 
 
On the day of the study each volunteer will be allowed to eat a light breakfast. Pre-exercise blood 
pressure, heart rate and SpO2 will be recorded. Spirometry will be measured according to 
recommendations of the American Thoracic Society (1) using best of three efforts. One hour before the 
study the subject will be administered oral sildenafil (50 mg) or placebo in a re-encapsulated 
unidentifiable pill. During the 30 minutes before the study the subject will drink 2 L Pedialyte® then, 
while immersed to the neck in 20°C water, perform exercise on a cycle ergometer (60 rpm, approximate 
VO2=70% VO2max). Subjects will be instrumented with EKG, pulse oximetry and noninvasive blood 
pressure measurement. VO2 will be measured 10 minutes after the start of exercise using a metabolic 
cart (ParvoMedics, East Sandy, UT). Subjects will be periodically asked about symptoms of shortness of 
breath, cough, chest tightness and whether they can continue. If symptoms occur the chest will be 
auscultated. The exercise will be stopped when any of the following occur: 
Dyspnea 
Cough 
Audible wheezing 
Hypoxemia 
Unwillingness of the subject to continue 
 
Immediately following exercise subjects will be removed from the water. Post-exercise assessment will 
include chest auscultation and measurement of vital signs and spirometry. Chest radiography (PA and 
lateral) will be performed if pulmonary edema is suspected. Symptomatic subjects will be treated as 
appropriate with oxygen and albuterol until they are asymptomatic. 


Randomization will be performed by the Duke Pharmacy Investigational Drug Service such that half of 
the subjects will receive each drug first. Both subjects and investigators will remain blinded until the end 
of the study. 
 
The primary outcome will be pulmonary edema after exercise defined as one or more of the following: 
Hypoxemia (SpO2< 95% room air) 
Productive cough 
Pulmonary edema on chest radiograph 
Wheezing on chest auscultation 
Secondary outcomes will be: 
Voluntary premature cessation of exercise due to shortness of breath 
Post-exercise 10% decrease in forced vital capacity (FVC) or forced expiratory volume in one second 
(FEV1) 
‘Comet tails’ seen on ultrasound of the lungs (2) 
One blood sample will be obtained for extraction of DNA and storage in the Duke Biofluids Shared 
Resource for future analysis. 
 
Selection of Subjects 
  
Inclusion Criteria: 
Healthy volunteers between 18 and 45 years 
History of SIPE 
 
Exclusion Criteria: 
Pregnant women 
Significant heart valve disease 
Cardiomyopathy 
Untreated hypertension 
Coronary artery disease 
Obstructive lung disease 
VO2max < 25 mL/kg as estimated by the University of Houston Non-Exercise Test (1) 
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) 
Concomitant use of erythromycin or other potent cytochrome P450 3A4 inhibitors 
History of non-arteritic anterior ischemic optic neuropathy (NAION) 
COVID positive test 
Subjects who are already taking sildenafil for another indication 
 
The medical record of each individual will be screened carefully for underlying predisposing conditions. 
Every effort will be made to ensure that none of these exclusions are present before volunteers come to 
Duke. Volunteers who have not undergone resting and stress echocardiography as a result of previous 
workups will undergo these studies here. 
 
Risk/Benefit Assessment 
 
The main hazard in the proposed studies is the development of SIPE, although the risk is low. A physician 
will be monitoring the studies and will interrupt any exercise study in which signs of early SIPE develop. 


The study will be conducted at the Center for Hyperbaric Medicine and Environmental Physiology within 
Duke Hospital, where diagnostic and therapeutic modalities including radiology, oxygen, 
bronchodilators, advanced monitoring and critical care facilities are immediately available. The 
investigative team has experience detecting and treating SIPE. Immersed exercise will be stopped 
immediately upon development of symptoms or signs suggestive of SIPE. Unlike development of SIPE in 
open water swimming, in the lab rapid removal from the water immediately reverses the 
hemodynamics that predispose to SIPE and allows appropriate support for resolution. 
 
With sildenafil administration, the common adverse reactions include headache, flushing, dyspepsia, 
nasal congestion, urinary tract infection, diarrhea, dizziness, nosebleeds, insomnia, and rash. These 
effects are generally mild to moderate, transient, and more common at the maximum recommended 
dose (100 mg) and above (1). There is risk of visual disturbances, with alteration in color vision and 
excessive brightness, but these are also dose-dependent and reversible (1). Non-arteritic anterior 
ischemic optic neuropathy (NAION) has been reported rarely in temporal association with the use of 
sildenafil and other phosphodiesterase-V (PDE5) inhibitors. This effect is much less likely with only a 
single administration of sildenafil, and the annual incidence of NAION in sildenafil users is 2.8 cases per 
100,000 men per year, similar to the estimated general incidence in the US (2.5-11.8/100,000/year) 
(2,3). It is difficult to determine if these events are related to PDE5 inhibitors or to other factors as those 
who experienced it already had autonomic or vascular risk factors for NAION (4). Single dose 
administrations of sildenafil in studies of high altitude pulmonary edema found no different secondary 
effects between sildenafil and placebo, and no erectile responses were reported in this setting as this 
effect would require sexual stimulus (5). No hemodynamic or other side effects were observed in an 
earlier study (6). 
 
The main benefit to these SIPE-susceptible subjects will be to know whether their risk of SIPE can be 
reduced by oral sildenafil 50 mg. 
 
Data Analysis & Statistical Considerations 
 
Power analysis has been performed using previously obtained data from Pro00019996. Conservatively 
assuming that the study will result in SIPE in 70% of individuals with placebo and 5% with sildenafil, 
using a two-sided McNemar’s test at alpha level 0.05 will achieve 96.7% power to detect a difference 
between sildenafil and placebo with N=20. There may be some washout of subjects due to screen 
failures or other reasons, however the same analysis reveals that a study of only 13 subjects will achieve 
81% power to detect a difference between sildenafil and placebo. For the final analysis, comparison of 
the numbers of SIPE cases after sildenafil and placebo will be performed using McNemar’s test (SAS 
software, SAS Institute, Cary, NC). N=40 subjects are planned for enrollment with the goal of 20 subjects 
participating and matched testing. 
 
Data & Safety Monitoring 
 
During the exercise portions of the study, subjects will be continuously monitored with EKG, SpO2, VO2 
and intermittent noninvasive blood pressure, as wll as with a physician adjacent to the immersion pool. 
Data will be uiploaded to REDCap, where all observations will be stored. Dr. Claude Piantadosi, who is 
not part of the study, will act as the safety monitor. He will review the data on a regular basis and will be 
consulted for any adverse event. 
  


All subjects will be monitored for safety while participating in the study and immediately (24 hours) 
post-participation, and the study investigators will be monitoring for adverse events throughout the 
course of the study. Dr. Claude Piantadosi will serve as the Independent Medical Monitor (also termed 
Research Monitor) for this study. He shall have authority to stop a research protocol in progress, remove 
individual human subjects from a research protocol, and take whatever steps are necessary to protect 
the safety and well-being of human subjects until the IRB can assess the monitor's report. The Research 
Monitor shall have the responsibility to promptly report his observations and findings to the IRB or other 
designated official. The Navy Human Research Protection Program will be notified of any adverse 
events. 
 

ICF_000.pdf: 
Sildenafil for Prevention of Swimming-Induced Pulmonary Edema (SIPE) 
Duke IRB #: Pro00100971 
NCT #: 
NCT03686813 


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 1 of 8
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You are being asked to take part in this research study because you have experienced immersion pulmonary 
edema (swimming-induced pulmonary edema, SIPE). Research studies are voluntary and include only people 
who choose to take part. Please read this consent form carefully and take your time making your decision. As 
your study doctor or study staff discusses this consent form with you, please ask him or her to explain any words 
or information that you do not clearly understand. We encourage you to talk with your family and friends before 
you decide to take part in this research study. The nature of the study, risks, inconveniences, discomforts, and 
other important information about the study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. Richard Moon will conduct the study and it is funded by the US Navy. The sponsor of this study, the Navy, 
will pay Duke University to perform this research, and these funds may reimburse part of Dr. Moon’s salary.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. Moon will be your doctor for the study and will be in contact with your regular 
health care provider throughout the time that you are in the study and afterwards, if needed.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to determine the effectiveness of the drug sildenafil in preventing SIPE in individuals 
who have experienced SIPE previously.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 40 people will take part in this study at Duke University Medical Center, with the goal of 20 
subjects participating and completing testing.
Concise Summary
The purpose of this study is to determine whether the drug sildenafil prevents or reduces the likelihood of 
developing pulmonary edema (fluid in the lungs) during swimming or diving (immersion pulmonary edema 
or swimming-induced pulmonary edema, SIPE). The information we learn by doing this study may help us to 
recommend preventive measures for individuals who experience this condition. 
If you participate in this study you will undergo a COVID test, exercise testing, a breathing test, ultrasound 
of your lungs and possibly your heart, and have a small sample of blood taken. You will then drink 
Pedialyte™ (an oral electrolyte solution) then perform exercise head-out in cold (20°C) water for 40 
minutes. During the exercise you will be monitored for symptoms of SIPE. If you develop SIPE you will be 
removed from the water and if needed receive treatment. This exercise will be performed twice, with the 
exercise periods at least one week apart. In addition to the Pedialyte, you will receive either sildenafil or an 
inactive tablet. Neither you nor the investigators will know which one you received until the study is over. If 
you develop symptoms a chest x-ray may be needed.
If you are interested in learning more about this study, please continue to read below.
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 2 of 8
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHAT IS INVOLVED IN THE STUDY?
If you agree to be in this study, you will be asked to sign and date this consent form. You will have the following 
tests and procedures to make sure that you are eligible: 

Physical exam and medical history

Vital signs

Blood tests

Electrocardiogram (EKG), a tracing of the electrical activity of the heart

Breathing test (pulmonary function test, PFT)

If you have not already had one, an echocardiogram and stress echo study

Ultrasound scan of your lungs

COVID testing
If you are eligible, following a 2 liter drink of Pedialyte (a flavored oral resuscitation fluid), you will exercise for 
40 minutes on a bicycle in an immersion tank while breathing through a mask. An immersion tank is like a pool 
where your body is underwater and your head is out. The water is cold 19-21°C (66-70°F). The mask will 
measure how much oxygen your body consumes while you exercise. You will perform this exercise twice: once 
after taking a 50 mg tablet of sildenafil, and once after a dummy pill (placebo, an inactive substance in a form 
that looks like the active drug, sildenafil). Following the exercise study you will have another breathing test and 
ultrasound scans of your lungs. 
The two exercise studies will be on different days at least a week apart. The order in which you take the drug 
and placebo (active drug then placebo or placebo then active drug) will be randomized (like drawing numbers 
from a hat) and the identity of the active drug and the placebo will be masked so that neither you nor the 
investigators will know which pill is taken for either day until the end of the study. During the exercise your 
heart and blood oxygen will be continuously monitored, and blood pressure will be measured every few 
minutes. You will also be monitored for manifestations suggesting SIPE development such as shortness of 
breath, cough or reduced blood oxygen level. If it is suspected that you may have SIPE you will be removed from 
the water, taken to a warm room and if needed, treated with oxygen and an inhaled medication (albuterol) that 
facilitates removal of water from your lungs. You may also undergo x-ray of your chest.
THERE ARE SEVERAL IMPORTANT CONSIDERATIONS:

Participation in this study is voluntary.

You may terminate your participation at any time.

A blood sample will be obtained, from which DNA will be extracted and stored for possible future 
studies to determine whether there is a genetic predisposition to SIPE. You may decline this portion 
even if you participate in the exercise study. Your genes are made up of DNA. DNA is short for 
deoxyribonucleic acid. DNA contains information that determines in part the traits, such as eye color, 
height, or disease risk, that are passed on from parent to child.
HOW LONG WILL I BE IN THIS STUDY?
The study will last at least 7 days, however you may return home after the first study and come back to Duke for 
the second exercise study at a mutually convenient time. You can choose to stop participating at any time.
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 3 of 8
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Clinically relevant results of this research will be communicated with you as soon as they are known. When the 
study has been completed and the data fully analyzed the results will be communicated to you in writing.
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. You should discuss 
these with the study doctor and your regular health care provider if you choose. Sildenafil may cause some, all 
or none of the side-effects listed below.
Risks associated with sildenafil: With sildenafil administration, the common adverse reactions include headache, 
flushing, dyspepsia (upset stomach), nasal congestion, urinary tract infection, diarrhea, dizziness, nosebleeds, 
insomnia, and rash. These effects are generally mild to moderate, transient, and more common at the maximum 
recommended dose (100mg) and exposures above that. There is risk of visual disturbances, with alteration in 
color vision and excessive brightness, but these are also dose-dependent and reversible. Sudden vision loss in 
one eye has been reported rarely after with the use of sildenafil and other similar drugs. This effect is much less 
likely with only a single administration of sildenafil, and it is not possible to determine if these events are related 
to these drugs or to other factors.
More likely

Headache

Flushing

Upset stomach

Nasal congestion

Nausea
Less likely

Visual symptoms such as redness, pain or sensitivity

A rapid heart rate or changes in your blood pressure.

Abnormal vision

Back pain, muscle pain

Ringing in the ears or dizziness.

Rashes. 
If you develop SIPE it may be recommended that you receive albuterol by inhalation to facilitate clearance of the 
excess water from your lungs. Albuterol is a very safe drug with uncommon side effects, which can include the 
following: tremors, dizziness, nervousness, headache, insomnia, nausea, dyspepsia, nasal congestion, throat 
pain, increased heart rate, high blood pressure, bronchospasm, cough, bronchitis, wheezing.
Drug interactions: For your safety, you must tell the study doctor or nurse about all the prescription drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, and natural remedies that you are taking before you 
start the study and before taking any of these products while you are on the study.
In addition, during the exercise study you may become cold, or may develop SIPE, with accompanying shortness 
of breath, cough and low levels of blood oxygen. 
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 4 of 8
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
FOR THOSE OF REPRODUCTIVE POTENTIAL
Female
Being a part of this study while pregnant may expose the unborn child to significant risks, some of which may be 
currently unforeseeable. Therefore, pregnant women will be excluded from the study. If you are a woman of 
childbearing potential, a blood pregnancy test will be done (using 1 teaspoon of blood drawn from a vein by 
needle-stick), and it must be negative before you can continue in this study. If sexually active, you must agree to 
use appropriate contraceptive measures for the duration of the study. Medically acceptable contraceptives 
include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal 
contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a 
condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive measures such 
as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use. If you 
do become pregnant during this study or if you have unprotected sex, you must inform your study physician 
immediately.
Male
Your participation in this research may damage your sperm, which could cause harm to a child that you may 
father while on this study. Such harm may be currently unforeseeable. If you are sexually active, you must agree 
to use a medically acceptable form of birth control in order to be in this study. Medically acceptable 
contraceptives include: (1) surgical sterilization (such as a vasectomy), or (2) a condom used with a spermicide. 
Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable 
methods for routine use. You should inform your partner of the potential for harm to an unborn child. She 
should know that if pregnancy occurs, you will need to report it to the study doctor, and she should promptly 
notify her doctor.
RISKS OF RADIATION: 
If you take part in this research, you will have one or more medical imaging studies or treatments. The tests or 
treatments you will have include a chest x-ray. These tests or treatments involve a small amount of radiation. 
The radiation exposure from this research is about 200 microsievert. To give you an idea about how much 
radiation you will get, we will compare it to the amounts that people encounter in daily life. There is radiation 
that naturally occurs from space and from rocks in the soil. This natural radiation is greater at higher altitudes. 
This research gives you about the same amount of radiation as you would get from living in a high altitude city 
such as Denver for 12 days, or taking 4 airplane flights from New York to Los Angeles. The radiation dose we 
have discussed is what you will receive from this study only, and does not include any exposure you may have 
received or will receive from other tests.
A possible health problem seen with radiation exposure is the development of cancer later in life. This extra 
cancer risk is higher at younger ages and for girls and women. The extra lifetime risk of dying of a fatal cancer 
due to the radiation exposure from this research is minimal. At such low radiation exposures, scientists disagree 
about the amount of risk. These estimates are very uncertain, and there may be no extra risk at all.
Risks of Drawing Blood:
Risks associated with drawing blood from your arm include momentary discomfort and/or bruising. Infection, 
excess bleeding, clotting, or fainting are also possible, although unlikely.
Drug and Food Interactions:
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 5 of 8
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, herbal 
products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are taking before you 
start the study and before starting to take any of these products while you are on the study.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may be direct medical benefit to you. You will learn whether 
sildenafil may reduce the possibility of future SIPE episodes. This information will be provided to you. We hope 
that in the future the information learned from this study will benefit other people who are susceptible to SIPE. 
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that information about 
you is kept confidential, but we cannot guarantee total confidentiality. Your personal information may be 
viewed by individuals involved in this research and may be seen by people including those collaborating, 
funding, and regulating the study. We will share only the minimum necessary information in order to conduct 
the research. Your personal information may also be given out if required by law. 
As part of the study, results of your study-related laboratory tests, x-rays, and procedures may be reported to 
the Navy. In addition, your records may be reviewed in order to meet federal or state regulations. Reviewers 
may include representatives and affiliates of the US Navy, the Duke University Health System Institutional 
Review Board, and others as appropriate. If any of these groups review your research record, they may also 
need to review your entire medical record.
All of the blood, urine and x-ray studies are being done only because you are in this study. The study results will 
be provided to you and/or sent to your physician at your request.
Expiration date or event for the retention of records
The study results will be retained in your research record for at least six years after the study is completed. At 
that time either the research information not already in your medical record may be destroyed or information 
identifying you may be removed from such study results at DUHS. Any research information in your medical 
record will be kept indefinitely. Some information collected in research studies is maintained in your medical 
record. However, for this study that information will be inaccessible until the end of the study, unless your 
physicians decide that it is necessary for your care. 
This information may be further disclosed by the sponsor of this study. If disclosed by the sponsor, the 
information is no longer covered by federal privacy regulations. If this information is disclosed to outside 
reviewers for audit purposes, it may be further disclosed by them and may not be covered by federal privacy 
regulations.
While the information and data resulting from this study may be presented at scientific meetings or published in 
a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy rules. 
Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. If you decide 
to share private information with anyone not involved in the study, the federal law designed to protect your 
health information privacy may no longer apply to the information you have shared. Other laws may or may not 
protect sharing of private health information.
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 6 of 8
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
A representative from the sponsor may be present as an observer at certain study visits/procedures. 
WHAT ARE THE COSTS TO YOU?
There will be no cost to you for the tests performed for the procedure or the experiment itself. You will also 
receive any treatment of the mild SIPE expected in this study at no cost. You or your insurance provider will be 
responsible and billed for any other costs of medical care, including copayments and deductibles. Routine 
medical care services are those that you would have received for your condition if you were not participating in 
this research study. Not all services are covered by insurance. Some procedures or scans may require pre-
authorization by your insurance plan. We will notify you if we learn that a service is not covered by your 
insurance plan as part of the pre-authorization process. If it is not covered, you will be responsible for paying for 
it. The amount of your out-of-pocket expense will depend on your insurance plan. For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study. You may have 
more or higher co-pays than with a Medicare Advantage plan. Please discuss the costs of the study with Dr. 
Moon. At your request, a Financial Counselor in the clinic may provide you with an estimate of costs for routine 
services.
The study sponsor, US Navy, has agreed to pay for services and procedures that are done solely for research 
purposes. Please talk with the study team about the specific services and procedures that the sponsor will pay 
for, and the ones for which you or your insurance will be responsible.
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately. If you have 
any questions or concerns about appropriate billing, contact your study team coordinator so that he/she can 
help find a resolution.
WHAT ABOUT COMPENSATION?
You will be reimbursed up to $2000 for your expenses related to your participation (travel, lodging, food) for 
each single part of the experiment ($4000 for two exercise periods). In addition, $1000 will be paid to you for 
your participation in a complete study (two sessions at least a week apart). If you are withdrawn from the study 
or withdraw voluntarily, you will receive $100 for traveling to Duke for screening, and $450 for each exercise 
period. Payment received as compensation for participation in research is considered taxable income to the 
research subject. If payment to an individual exceeds $600 in any one calendar year, Duke University is required 
to report this information to the Internal Revenue Service (IRS). Research subject payments to a non-employee 
of Duke University exceeding $600 during any calendar year will result in a 1099 (Miscellaneous Income) form 
being issued to the individual and a copy sent to the IRS.
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you are 
injured as a result of your participation in this research study. However, there is no commitment by Duke 
University, Duke University Health System, Inc., or your Duke physicians to provide monetary compensation or 
free medical care to you in the event of a study-related injury.
For questions about the study or research-related injury, contact Dr. Moon at 919-684-8762 during regular 
business hours and at 919-684-8111, pager ID #970-5290 after hours and on weekends and holidays.
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 7 of 8
Subject*Initials_________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the study at 
any time. If you withdraw from the study, no new data about you will be collected for study purposes unless the 
data concern an adverse event (a bad effect) related to the study. If such an adverse event occurs, we may need 
to review your entire medical record. All data that have already been collected for study purposes, and any new 
information about an adverse event related to the study, will be sent to the study sponsor.
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of benefits to 
which you are entitled, and will not affect your access to health care at Duke. Nonparticipation or withdrawal 
from this study will not affect your job status if you are a Duke employee and will not affect your grades if you 
are a Duke student. If you do decide to withdraw, we ask that you contact Dr. Moon in writing and let him know 
that you are withdrawing from the study. His mailing address is: Dept. of Anesthesiology, Box 3094, Duke 
University Medical Center, Durham, NC 27710, USA. 
We will tell you about new information that may affect your health, welfare, or willingness to stay in this study.
The sponsor or regulatory agencies may stop this study at any time without your consent. Reasons why this 
might occur include large numbers of side effects of the study. If this occurs, you will be notified.
Photographs are taken to demonstrate protocols used in research studies. You will be asked if you agree to be 
photographed before any are taken. If taken, such photographs might be presented at meetings describing the 
research, in which case a bar will be placed in the photograph over the area of your eyes to make the 
photograph less identifiable. You will not be identified nor will your individual results discussed in such cases.
Please read the sentence below and put your subject initial next to your choice. No matter what you decide to 
do, your decision will not affect your care.
1. “I agree to be photographed.”
_____________
Subject’s Initials 
2. “I do not agree to be photographed.”
_____________
Subject’s Initials
A description of this clinical trial will be available on https://clinicaltrials.gov/ as required by US Law. This Web 
site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions or 
suggestions about the research, contact Dr. Moon at 919-919-684-8762 during regular business hours and at 
919-684-8111, pager ID #970-5290 after hours and on weekends and holidays.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke University 
Health System Institutional Review Board (IRB) Office at (919) 668-5111.
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021


Consent to Participate in a Research Study
Title: Sildenafil for Prevention of Swimming-Induced 
Pulmonary Edema (SIPE)
IRB #: Pro00100971
Page 8 of 8
*
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
STATEMENT OF CONSENT
“The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I have 
been allowed to ask questions, and my questions have been answered to my satisfaction. I have been told 
whom to contact if I have questions, to discuss problems, concerns, or suggestions related to the research, or to 
obtain information or offer input about the research. I have read this consent form and agree to be in this study, 
with the understanding that I may withdraw at any time. I have been told that I will be given a signed and dated 
copy of this consent form.”
__________________________________________
___________ ____________
Signature of Subject
Date
 Time
__________________________________________
___________ ____________
Signature of Person Obtaining Consent
Date
 Time
DUHS IRB
IRB NUMBER: Pro00100971
IRB REFERENCE DATE: 10/28/2021
IRB EXPIRATION DATE: 12/19/2021