Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 41
Healthy volunteers: yes

Brief summary:
The purpose of this project is to test how fentanyl, an analgesic currently employed in the pre-hospital setting by the US Army, alters the capacity to tolerate a hemorrhagic insult in humans.

Detailed description:
Pain management on the battlefield is critical for the wellbeing of the soldier. Given that a hemorrhagic injury on the battlefield is virtually always associated with pain, it is paramount that the selected pain medication does not disrupt appropriate physiological mechanisms that are beneficial towards the maintenance of blood pressure and vital organ blood flow during that hemorrhagic insult. Current guidelines for the selection of pain medications of a hemorrhaging soldier are based upon limited scientific evidence, with the vast majority of supporting studies being conducted on anesthetized animals. Thus, the interaction between hemorrhagic shock and pain medications commonly employed on the battlefield is yet to be determined in the conscious humans.

With this background, we will test the hypothesis that fentanyl will impair the capacity for a conscious human to tolerate a hemorrhagic insult.

The obtained data will provide the necessary scientific evidence in humans to support the Committee on Tactical Combat Casualty Care (CoTCCC) guidelines on the analgesic of choice for moderate to severe injuries where the casualty is in hemorrhagic shock. Notably, such data will identify the analgesic that least compromises a human's ability to tolerate a hemorrhagic insult, ultimately providing critical information to the combat medic on which analgesic should be employed for such an injury.

Arms:
arm 1: Fentanyl will be administered intravenously during one visit. arm 2: Placebo (saline) will be administered intravenously during one visit.

Interventions: intervention 1: Fentanyl intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will receive 75 ug Fentanyl while the effects of this drug on tolerance to a hemorrhagic insult will be assessed. intervention 2: Subjects will receive saline while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.

Protocol document:
ICF_005.pdf: 
Official title: Analgesics in the pre-hospital setting: Implications on 
hemorrhage tolerance - Fentanyl 
 
NCT number: NCT04136548 
Document date: 09-04-2019 


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The University of Texas Southwestern Medical Center 
Parkland Health & Hospital System 
Children’s Medical Center 
Retina Foundation of the Southwest 
Texas Scottish Rite Hospital for Children 
Texas Health Presbyterian Hospital Dallas 
 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Title of Research: 
Analgesics in the pre-hospital setting: Implications on 
hemorrhage tolerance – Fentanyl  
 
Funding Agency/Sponsor: 
U.S. Army Medical Research and Material Command 
 
Study Doctors: 
Craig G. Crandall, Ph.D. 
 
You may call the study doctor or research personnel during regular office hours at 214-
345-4619. At other times, you may call them Dr. Crandall at 972-522-8859. You may 
also contact study personnel at 214-345-6771 during normal office hours. 
 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate. As the researchers discuss this consent form with you, please 
ask him/her to explain any words or information that you do not clearly understand. The 
purpose of the study, risks, inconveniences, discomforts, and other important 
information about the study are listed below. If you decide to participate, you will be 
given a copy of this form to keep. 
 
Why is this study being done? 
This study, which is funded by the U.S. Army, is being done to better understand the 
how the three recommended analgesics (pain medication) currently employed in the 
pre-hospital setting by the US Army—fentanyl, morphine, and ketamine—will alter the 
capacity to tolerate a serious injury leading to major blood loss in humans. 
 
Why is this considered research?  
This is a research study because it involves an organized, step-by-step investigation 
(including research development, testing and evaluation) designed to contribute 
information that can be used by many people. In this case, information will be collected 
in order to better identify the pain medication that least compromises a human’s ability 
to tolerate a serious injury resulting in blood loss.   
 
The following definitions may help you understand this study:  
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 Researchers means the study doctor and research personnel at the Institute for 
Exercise and Environmental Medicine (IEEM) at Texas Health Presbyterian 
Hospital Dallas. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you are a healthy male or female 
between the ages of 18 and 45.   
 
Do I have to take part in this research study?” 
No. You have the right to choose whether you want to take part in this research study.  
If you decide to participate and later change your mind, you are free to stop participation 
at any time. 
 
If you decide not to take part in this research study it will not change your legal rights or 
the quality of health care that you receive at UT Southwestern Medical Center, Texas 
Health Presbyterian Hospital Dallas, or any of their affiliates. 
 
How many people will take part in this study? 
Approximately thirty people will take part in this study at the Institute for Exercise and 
Environmental Medicine. 
 
What is involved in the study? 
If you volunteer to take part in this research study, you will be asked to sign this consent 
form and will have the following tests and procedures. All of the tests and procedures 
are done solely for the purpose of the study and are not intended to diagnose or treat 
medical problems. 
 
Screening Procedures 
To help decide if you qualify to be in this study, the researchers will ask you 
questions about your health, including medications you take and any surgical 
procedures you have had. 
 
You may also have to fill out certain forms or have the following exams, tests or 
procedures: 
 Physical exam and medical history; 
 Vital signs such as blood pressure and heart rhythm/rate; 
 Electrocardiogram (ECG), a tracing of the electrical activity of the heart;  
 Urine drug screen; 
 Urine pregnancy test for women who are able to bear children; and 
 Demographic information (age, sex, ethnic origin). 
 
Procedures and Evaluations during the Research 
This study will require 3 visits to the laboratory with a total time commitment of 
approximately 13 hours.  
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On the first visit, we will ask you questions about your health and obtain your vital 
signs (heart rate, blood pressure, ECG, etc). We will thoroughly discuss the protocol 
with you and will familiarize you with the procedures that will be used during the next 
two visits. 
 
On visits 2 and 3, the procedures performed will be identical, with the exception that 
during one visit you will receive fentanyl (pain medication) and during one visit you 
will receive saline (placebo) during the other visit. The order of these visits will be 
randomized. You will be instrumented and rest quietly by lying down. After a period 
of resting measurements, we will perform 3 pain tests (pressure algometer, thermal 
grill illusion test, and a cold pressor test). You will then receive the drug or placebo 
along with the lower-body negative pressure (LBNP). We will then wait for the effects 
of the drug to subside. After this waiting period, you will receive a second dose 
which will be followed by the same 3 pain tests. 
 
For this study, the following measures and procedures will be performed (see below 
for descriptions): 
 Fentanyl infusion (via venous catheter) 
 Saline infusion (via venous catheter) 
 Lower body negative pressure (LBNP) 
 Heart rate and rhythm 
 Blood pressure (arm and finger) 
 Internal temperature (via temperature sensing pill or rectal probe) 
 Skin temperature 
 Cardiac output  
 Microneurography 
 Forearm blood flow 
 Brain blood flow 
 Skin blood flow 
 End-tidal carbon dioxide 
 Compensatory reserve index  
 Tissue oxygen saturation 
 Oxygen saturation  
 Venous catheter (and venous blood samples) 
 Pain assessment: cold pressor test, thermal grill illusion test, and pressure 
algometry 
 Body weight 
 Urine sample 
 
Description of Procedures 
The measures and procedures in this study are designed for research, not for medical 
purposes. They are not useful for finding problems or diseases. However, you will be 
told if the researchers notice something unusual. You and your regular doctor can 
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decide together whether to follow up with more tests or treatment. Because the 
measures and procedures done in this study are not for medical purposes, the research 
results will not be sent to you or to your regular doctor.  
 
Fentanyl infusion (via venous catheter): 
Description of Procedure: Fentanyl is a pain medication used to treat moderate to 
severe pain. 
Potential Risks: Though rare, you may also experience diarrhea, constipation, dry 
mouth, dizziness, confusion, weakness, sweating, decreased urination, fainting, heavy 
breathing, and seizures. These experiences generally go away within an hour when we 
stop the drug infusion. In extremely rare conditions you may have difficulty breathing. In 
these extremely rare conditions, you will be given a drug, Naloxone, to counteract this 
condition. An anesthesiologist will be present at all times to monitor and ensure your 
safety. This drug exposes you to the risks of addiction, abuse, and misuse. 
Duration of Procedure: For the experimental day that this drug is used, you will be 
given this drug twice.  Each drug infusion will last less than 5 minutes. 
 
Saline infusion (via venous catheter): 
Description of Procedure: Saline will be infused through the venous catheter to 
maintain patency of the catheter. In addition, on one of the experimental days, saline 
will be infused as a placebo to the pain medication. 
Potential Risks: There are no known risks associated with the infusion of saline. Your 
kidneys will eliminate this excess fluid in your system. 
Duration of Procedure: The infusion will begin once the venous catheter in inserted 
and will remain for the duration visits 2 and 3. 
 
Lower body negative pressure:   
Description of Procedure: This procedure causes fluid in your body to shift from your 
chest and upper body to your lower body. While lying on your back, you will be sealed in 
a box-like chamber from the waist down. Suction will be applied inside the box to your 
lower body. The level of suction will increase until the researchers determine that the 
test is over or you request to stop. 
Potential Risks: Dizziness, light-headedness, and nausea are common side effects. If 
this should happen, we will stop the procedure and you should begin to feel better 
almost immediately. On rare occasion, a person may faint. 
Duration of Procedure: This procedure can last anywhere from 5-50 minutes for visits 
2 and 3 (10-100 minutes total). 
 
Heart rate and rhythm (electrocardiogram): 
Description of Procedure: Sticky patches will be applied to your skin to measure the 
heart’s electrical signals. It is possible that a small amount of chest hair may need to be 
shaved to get the patches to stick. 
Potential Risks: You may develop a rash or redness where the patches were attached. 
This mild rash often goes away without treatment. 
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Duration of Procedure: Heart rate and rhythm will be measured during the entire 
duration of visits 2 and 3 (approximately 5.5 hours per visit, 11 hours total). It will also 
be checked on visit 1. 
 
Arm blood pressure: 
Description of Procedure: Your blood pressure will be monitored using a cuff placed 
on your upper arm that is inflated and deflated periodically. 
Potential Risks: Other than some potential discomfort associated with cuff inflation, 
there is no risk to this procedure. 
Duration of Procedure: The cuff will be on your upper arm during the entire 
experiment. We will take blood pressure measurements at different time points during 
visits 2 and 3. It will also be checked on visit 1. Each measurement will last 
approximately 30 seconds. 
 
Finger blood pressure: 
Description of Procedure: In order to continuously monitor your blood pressure during 
the experiment, a small blood pressure cuff will be placed on one of your fingers. 
Potential Risks: Occasionally, some people experience some mild discomfort in the 
finger after a prolonged period of inflation. If this occurs, notify the researchers and the 
cuff will be deflated to give the finger a rest. Other than this potential discomfort, there 
are no known risks to this procedure. 
Duration of Procedure: Finger blood pressure will be measured during the entire 
duration of visits 2 and 3 (approximately 5.5 hours per visit, 11 hours total). 
 
Internal body temperature (via temperature sensing pill): 
Description of Procedure: In order to measure your internal body temperature, you 
will be asked to swallow a pill about the size of a large vitamin at the beginning of the 
experiment. The pill typically passes though the gastrointestinal tract in 1 to 7 days. 
Potential Risks: Although very rare, there are some risks associated with taking the 
temperature pill. It is possible that you could inhale it into your lungs. The pill could also 
cause a perforation (tear), blockage or infection of the intestinal tract. The pill could 
become stuck in your intestinal tract and require endoscopy or surgery to remove it. You 
should not take this pill if you weigh less than 80 pounds, nor should you take this pill if 
you have or have had any gastrointestinal disease or surgery or if you have any 
implanted medical devices. You may not have a magnetic resonance imaging (MRI) 
procedure performed with this pill in your body. Duration of Procedure: Internal 
temperature will be measured during the entire duration of visits 2 and 3. 
 
Internal body temperature (via rectal probe): 
Description of Procedure: If for medical reasons or other reasons, you are unable to 
use the temperature sensor pill, a rectal probe may be used. The researcher will ask 
you to insert a single-use rectal temperature probe to a pre-marked depth of 
approximately 8 to 12 cm (approximately 3 to 5 inches). You will insert and remove the 
probe in a private room. You may not have a rectal probe if you have or have had any 
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heart conditions, inflammatory bowel or colon disease, and/or rectal or anal surgery. 
You may not use the probe if you currently have hemorrhoids (internal or external), 
rectal bleeding, diarrhea or fecal impaction in the rectum. The probe will be removed 
after completion. 
Potential Risks: Although it is very rare, it is possible that you could puncture your 
anus or rectum or get an infection.   
Duration of Procedure: Internal temperature will be measured during the entire 
duration of visits 2 and 3 (approximately 5.5 hours per visit, 11 hours total). 
 
Skin temperature: 
Description of Procedure: Skin temperature will be measured by taping temperature 
probes to your skin. 
Potential Risks: There is no risk associated with this procedure. 
Duration of Procedure: Skin temperature will be measured during the entire duration 
of visits 2 and 3 (approximately 5.5 hours per visit, 11 hours total). 
 
Cardiac output: 
Description of Procedure: The amount of blood being pumped by the heart will be 
measured by analyzing the air you breathe out. For this procedure, you will breathe a 
small amount of harmless gases (a mixture of oxygen, nitrous oxide and sulfur 
hexafluoride) through a mouthpiece.  
Potential Risks: There is no risk associated with this procedure. 
Duration of Procedure: Each cardiac output measurement will last about 30 
seconds. This procedure will be measured periodically during the visits 2 and 3. 
 
Microneurography:   
Description of Procedure: Nerve signals from the nerves in the arm [i.e. median nerve 
(inside portion of the middle part of your arm), radial nerve (inside portion of your 
forearm), or posterior cutaneous nerve (outside portion of your forearm)] will be 
measured. To locate the nerves, we use a brief local exposure to electric current. 
Tingling from this current will only be felt in areas close to where the current is given. 
For example, if we are looking for nerve signals in the right arm, you will only feel the 
tingling at the location where the current is given. This causes twitching of the  
arm muscles and may cause a tingling sensation. These sensations may be annoying 
but are not painful and disappear when the stimulation is stopped. When a nerve track 
is located, we insert a small sterile needle (an electrode about the size of an 
acupuncture needle) through the skin. You may feel some slight discomfort during 
needle insertion. The recording needle is advanced into the nerve. When the tip of the 
needle enters the nerve, you may notice a dull aching or tingling sensation. A second 
needle serves as a reference electrode and is inserted just under the skin, a few inches 
away from the nerve. Once the needles are in place you will not feel any discomfort. 
This method of recording nerve signals in human subjects has been used in over 3000 
studies since 1979. We have performed over 200 recordings in our laboratory without 
any complications.   
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Potential Risks: There is a slight potential risk of a temporary pins and needles 
sensation or increased sensitivity to touch in the leg or arm following the test; however, 
this feeling goes away within 2 to 7 days. This sensation may be similar to what is felt 
after jogging. A few subjects have noted some tiredness, soreness, or tingling in their 
leg or arm muscles up to one week after the study. This sensation is thought to be 
related to the muscle twitches which are part of the procedure for localizing the nerve. 
Duration of Procedure: The microneurography needle will remain in position for the 
duration of visits 2 and 3 and will be removed at the end of the study (approximately 5.5 
hours per visit, 11 hours total).  
 
Forearm blood flow: 
Description of Procedure: Doppler ultrasound will be used to measure the amount of 
blood flowing into your arm using a gel covered ultrasound probe. This procedure is 
similar to standard ultrasound tests done to examine the health of babies prior to birth. 
Potential Risks: There is no risk or discomfort.  
Duration of Procedure: This procedure will be measured periodically during visits 2 
and 3. Each measurement takes approximately 2-3 min to perform. 
 
Brain blood flow:   
Description of Procedure: A gel covered probe will be placed on the side of your 
forehead as well as the front of your neck. Sound waves will be used to record blood 
flow inside your head.  We may also assess brain blood flow by measuring blood flow in 
vessels in your neck that deliver blood to your brain. This procedure is similar to 
standard ultrasound tests done to examine the health of babies prior to birth. 
Potential Risks: There is no risk associated with this procedure. 
Duration of Procedure: Brain blood flow will be measured during the entire duration of 
the experimental days (approximately 5.5 hours per visit, 11 hours total). 
 
Skin blood flow: 
Description of Procedure: Skin blood flow will be measured using laser-Doppler 
devices. These devices use very low power laser light to detect the amount of blood 
circulating at the skin surface.   
Potential Risks: There are no risks associated with using these devices to measure 
skin blood flow; they are painless and harmless in all respects. 
Duration of Procedure: Skin blood flow will be measured during the entire duration of 
visits 2 and 3 (approximately 5.5 hours per visit, 11 hours total). 
 
End tidal carbon dioxide (CO2) (capnography):   
Description of Procedure: The amount of carbon dioxide that you exhale will be 
monitored from a nasal cannula (a plastic tube that fits behind your ears and two small, 
short prongs that are placed in your nostrils). 
Potential Risks: There is no known risk involved with this procedure. 
Duration of Procedure: The amount of carbon dioxide you exhale will be measured 
during the entire duration of visits 2 and 3 (approximately 5.5 hours per visit, 11 hours 
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total). 
 
Compensatory Reserve Index: 
Description of Procedure: A small cuff will be placed on one of your fingers to take 
measurements pertaining to the blood flow in your finger. 
Potential Risks: there are no known risks to this procedure. 
Duration of Procedure: This procedure will be measured during the entire duration of 
visits 2 and 3 (approximately 5.5 hours per visit, 11 hours total). 
 
Tissue oxygen saturation: 
Description of Procedure:  A small sensor will be placed on your skin in order to 
measure the amount of oxygen in your muscle or brain. 
Potential Risks: There is no known risk involved with this procedure. 
Duration of Procedure: The sensor will remain in place for the entire duration of visits 
2 and 3 (approximately 5.5 hours per visit, 11 hours total). 
 
Oxygen Saturation: 
Description of Procedure: The amount of oxygen in your blood will be measured by 
pulse oximetry by placing a sensor on either your finger, arm, leg or earlobe. 
Potential Risks: There are no known risks associated with this procedure. 
Duration of Procedure: Oxygen saturation will be measured during the entire duration 
of visits 2 and 3 (approximately 5.5 hours per visit, 11 hours total). 
 
Venous catheter and blood samples:  
Description of Procedure: To collect blood during the experiment, a sterile catheter 
will be inserted into a superficial vein of one of your arms. This procedure allows for 
blood to be taken multiple times with the insertion of only one needle.  Information about 
the blood clotting process will be examined by obtaining approximately 2 tablespoons of 
blood each draw from your peripheral intravenous catheter. The following tests will be 
performed: 
 Plasma catecholasmine and 
vasopressin concentrations 
 Standard Complete Blood 
Count (CBC) and chemistry 
profile including platelet 
count 
 Prothrombin Time (PT) 
 Activated Partial 
Thromboplastin Time (aPTT) 
 Thromboelastograph 
Hemostasis Analysis  
 D-dimer 
 Fibrinogen 
 Tissue Plasminogen 
Activator (tPA) 
 Antithrombin III 
 Protein C 
 Plasminogen activator 
inhibitor-1 (PAI-1) 
 Von Willebrand factor (vWF) 
antigen 
 Factors V and VIII 
 
Potential Risks: There is a small risk of infection and a still smaller risk of a blood clot 
or breakage of the catheter. The likelihood of these complications is remote (about 1 in 
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10,000) when the procedure is carried out by trained personnel and proper equipment is 
used, as during this study. There is also a small risk of the catheter perforating the vein 
or not being inserted into a blood vessel. You may have discomfort, bleeding, and/or 
bruising and on rare occasions, you may feel dizzy or faint. 
Duration of Procedure: The catheter will be inserted once at the beginning of both the 
experiment days and will remain in a vein for the duration of the experiment. Blood will 
be taken approximately 4 times during the visits 2 and 3 (8 times total). A total of 
approximately 80 to 100 mL of blood will be collected during your visit. The catheter will 
be removed at the end of the experiment days. 
 
Cold pressor test:  
Description of Procedure: For this test, you will place one hand up to the wrist in ice 
slurry water for a period of 2-3 min. You will report the pain that you are experiencing on 
a scale of 0 to 10, 0 being no pain and 10 being the worst imaginable pain. 
Potential Risks: For the cold pressor test, there is a risk that the procedure may 
become too painful and your blood pressure may rise. If this occurs, the procedure will 
be terminated by removing your hand from the ice water slurry.  
Duration of Procedure: The cold pressor test will be performed for a period of 2-3 min 
throughout visits 2 and 3 (approximately 6-9 min per visit, 12-18 min total).  
 
Thermal grill illusion test:  
Description of Procedure: For this test, you will place one hand or forearm on a 
device that consists of alternating tubes with cold and warm water. You will report the 
discomfort that you are experiencing on a scale of 0 to 10, 0 being no pain and 10 being 
the worst imaginable pain. 
Potential Risks: For this test, there is a risk that the procedure may become too 
painful. If this occurs, the procedure will be terminated by removing your hand/forearm 
from the device.  
Duration of Procedure: The thermal grill illusion test will be performed for a period of 
30 seconds throughout visits 2 and 3 (approximately 90 seconds per visit, 3 min total).  
 
Pressure algometry:  
Description of Procedure: For this test, a rubber tip from a digital algometer will be 
placed on your finger or thumb. Pressure to that area will increase until you first start to 
feel pain. 
Potential Risks: For this test, you will begin to experience pain.  As soon as you 
experience the pain, the procedure will be terminated by removing the tip of the device.  
Duration of Procedure: This test will be performed for a period of 2 minute throughout 
visits 2 and 3 (approximately 6 min per visit, 12 min total).  
 
Body weight: 
Description of Procedure: You will be asked to stand on a scale in a private room and 
record your nude body weight. 
Potential Risks: There are no risks associated with this procedure. 
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Duration of Procedure: Each weight measurement will take about 30 seconds. 
 
Urine sample: 
Description of Procedure: You will be asked to urinate into a cup from which we will 
assess the density of your urine, conduct a pregnancy test (if applicable), and conduct a 
drug screening test.  Drugs that your urine will be screened for include marijuana, 
cocaine, opiates (such as heroin, morphine, hydrocodone, oxycodone and methadone), 
barbiturates, benzodiazepines, and methamphetamines. If this drug test is positive for 
one of these agents, you will not be permitted to participate in the study. A positive drug 
test will not be indicated in your records and this information will remain confidential. 
Potential Risks: There is no risk associated with this procedure. 
Duration of Procedure: You will be asked to urinate into a cup at the beginning of each 
experimental visit. 
 
How long can I expect to be in this study? 
You will be required to spend no more than 3 partial days (a total of approximately 13 
hours) in the laboratory at the Institute for Exercise and Environmental Medicine at 
Texas Health Presbyterian Hospital Dallas. 
 
You can choose to stop participating for any reason at any time. However, if you decide 
to stop participating in the study, we encourage you to tell the researchers. You may be 
asked if you are willing to complete some study termination tests. 
 
What are the risks of the study? 
Study Procedure/Intervention 
See risks associated with each of the measures and procedures listed above. Because 
of your participation in this study, you are at risk for the above mentioned side effects. 
You should discuss these with the researchers and your regular health care provider.  
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this cannot be 
guaranteed.  
 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 
concerned about other, unknown side effects, please discuss this with the researchers. 
 
How will risks be minimized or prevented?   
You will be closely monitored at all times during your participation in the study to 
determine whether there are complications that need medical care. It is your 
responsibility to report any unusual signs, symptoms, or pain to the research team, keep 
appointments, and follow the recommendations of the researchers or the research 
nurse. Also, report any change in your legal name, address, or telephone number. 
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Throughout the tests, you will be closely monitored by a highly skilled research nurse 
under the direction of Dr. Benjamin Levine, Professor of Medicine and Cardiology at UT 
Southwestern Medical Center and founding Director of the Institute for Exercise and 
Environmental Medicine. Moreover, Joseph Hendrix, MD (a board certified 
anesthesiologist) will administer the analgesics and will continuously monitor the 
subjects throughout the protocol. Dr Hendrix has specialized training in Pain Medicine, 
which includes the administration of the assessed drugs in his clinical practice; thus, he 
is well versed in the administration of these drugs and any potential adverse effects. 
 
Due to the side effects from taking fentanyl, you are not permitted to drive home after 
the experimental days.  You will need to have a responsible adult bring you home. The 
responsible adult can either drive you home or accompany you home using ground 
transportation (bus, train, or taxi service). It is also recommended that you have 
someone watch over you for the rest of the day and overnight. 
 
What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
 Tell the researchers before you take any new medication, even if it is prescribed 
by another doctor for a different medical problem or something purchased over 
the counter. 
 Tell your regular doctor about your participation in this study. 
 Report to the researchers any injury or illnesses while you are on study even if 
you do not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes. You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is important 
to your health or safety. 
 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the study, 
you should report them to the researchers right away. Telephone numbers where they 
can be reached are listed on the first page of this consent form. 
 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the 
nearest hospital emergency room, or call 911 (or the correct emergency telephone 
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number in your area). Tell emergency personnel about any medications you are taking, 
including any medications you are taking for this study.   
 
What are the possible benefits of this study? 
If you agree to take part in this study, there will not be any direct benefit to you. 
 
We hope the information learned from this study will benefit the U.S. military by aiding in 
the treatment of soldiers injured on the battlefield. Information gained from this research 
could lead to better treatment and management of individuals involved with traumatic 
injuries in the pre-hospital setting, e.g. traffic collisions.   
 
What options are available if I decide not to take part in this research study? 
This is not a treatment study. You do not have to participate. 
 
Will I be paid if I take part in this research study? 
Yes, you will be paid $35.00 per hour. You will receive a check in the mail from Texas 
Healthy Presbyterian Hospital Dallas approximately 6 weeks after your visit. There is no 
maximum amount you can be paid. You will simply be compensated for your time on an 
hourly basis.   
 
There are no funds available to pay for lost time away from work and other activities, 
lost wages, or child care expenses. 
 
If required, you will be reimbursed for your transportation to and from the research 
center (for example cab or bus fare). In order to receive reimbursement, you will need to 
turn in all your receipts to the research coordinator. 
 
Your Social Security Number (SSN) will be given to Texas Health Presbyterian Hospital 
Dallas in order to process your payment as required by law. This information will remain 
confidential unless you give your permission to share it with others, or if we are required 
by law to release it. 
 
Will my insurance provider or I be charged for the costs of any part of this 
research study? 
No. Neither you, nor your insurance provider, will be charged for anything done only for 
this research study (i.e., the Screening Procedures, Experimental Procedures, or 
Monitoring/Follow-up Procedures described above).   
 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the top 
of this form immediately. 
 
Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center at Dallas or Texas 
Study ID: STU 092017-069   Date Approved: 9/4/2019


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DO NOT DISCLOSE 
 
 
Health Presbyterian Hospital of Dallas – Institute for Exercise and Environmental 
Medicine. 
 
You retain your legal rights during your participation in this research 
 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop taking 
part in the research study at any time. 
 
If you decide to stop taking part in this research study, it will not affect your relationship 
with the UT Southwestern staff or Texas Health Presbyterian Hospital Dallas doctors. 
Whether you participate or not will have no effect on your legal rights or the quality of 
your health care. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status 
will not be affected in any way. 
 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 The researchers believe that participation in the research is no longer safe for 
you. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 You are unable to keep appointments or to follow the researcher’s instructions. 
 
Will my information be kept confidential? 
Information about you that is collected for this research study will remain confidential, 
unless you give your permission to share it with others or if we are required by law to 
release it. You should know that certain organizations that may look at and/or copy your 
medical records for research, quality assurance, and data analysis include: 
 The U.S Army Medical Research and Material Command and/or the Department 
of Defense; 
 Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people;  
 The UT Southwestern Institutional Review Board; and 
 Texas Health Resources Institutional Review Board. 
 
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information". This authorization will give more details 
about how your information will be used for this research study, and who may see 
and/or get copies of your information. 
 
Are there procedures I should follow after stopping participation in this research? 
Study ID: STU 092017-069   Date Approved: 9/4/2019


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DO NOT DISCLOSE 
 
 
Yes. If you, the researchers, or the sponsor stops your participation in the research, you 
may be asked to do the following: 
 Let the researchers know immediately that you wish to withdraw from the 
research. 
 Discuss your future medical care, if any, with the researchers and/or your 
personal doctor. 
 
Whom do I call if I have questions or problems? 
For questions about the study, contact Craig Crandall, Ph.D. at 214-345-4623 or the 
research laboratory (IEEM) at 214-345-6771 during regular business hours. You may 
also contact Dr. Crandall at 972-522-8859 after hours and on weekends and holidays. 
 
For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060. 
Study ID: STU 092017-069   Date Approved: 9/4/2019


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DO NOT DISCLOSE 
 
 
SIGNATURES: 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
 
Your signature below certifies the following: 
 
 You have read (or been read) the information provided above. 
 You have received answers to all of your questions and have been told who to 
call if you have any more questions. 
 You have freely decided to participate in this research. 
 You understand that you are not giving up any of your legal rights. 
 
 
____________________________________________ 
 
 
Name of Participant (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Participant 
Date 
Time 
 
____________________________________________ 
 
 
Name of Person Obtaining Consent (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Person Obtaining Consent 
Date 
Time 
 
 
Study ID: STU 092017-069   Date Approved: 9/4/2019

SAP_004.pdf: 
Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Fentanyl 
NCT04136548 
Document Date: October 26, 2020 
Statistical Analysis Plan 


Statistical analysis 
The primary outcome variables are tolerance to the LBNP challenge with and without analgesic administration, 
as well as the hemodynamic and autonomic responses to the simulated hemorrhage insult.  The effects of any 
specific drug on LBNP tolerance will be evaluated via a paired T-test (i.e., placebo versus drug).  The enrolled 
subject will not be required to participate in the trials for all three drugs, but they will be required to complete 
both the placebo and drug trial for each specific drug.  To determine which study drug is the least detrimental 
on tolerance to the simulated hemorrhagic insult, and thus would be recommended to be employed for a soldier 
experiencing a hemorrhagic injury, we will use one way ANOVA to compare the magnitude of reduction in 
LBNP tolerance between each drug and the respective placebo condition. 
 
The effects of the administered drugs on hemodynamic and autonomic responses to each LBNP stage will be 
compared via two way mixed model ANOVA design, with main factors of drug and LBNP level (analyzed both 
by stage and by % completion of the entire LBNP protocol to pre-syncope). A significant interaction from those 
ANOVAs will be further explored via pairwise multiple comparison analyses.   
 
Analysis assumptions will be carefully evaluated, data transformations considered, and Bonferroni-Hochberg 
will be used to adjust for multiple testing as appropriate.   
 
Justification of sample size   
No study has evaluated the effects of analgesics on LBNP tolerance in humans. The power and sample size 
estimates are based on findings from Dr. Crandall’s laboratory showing reduced LBNP tolerance in the heat-
stressed individuals.  In that study heat stressed reduced LBNP tolerance by ~70% (997 cumulative stress index 
units to 303 cumulative stress index units; P<0.001). Though we expect the analgesics to likewise reduce LBNP 
tolerance, we do not anticipate as large of a reduction as that observed with heat stress. Thus, the sample size 
calculation was based upon an anticipated reduction in LBNP tolerance of half that seen with heat stress, i.e., 
~35% reduction in the cumulative stress index.  Given this anticipate outcome, coupled with the associated 
variances observed in that study (101), we anticipate 15 subjects per drug trial will be sufficient to address the 
primary hypothesis that the administered analgesic reduces tolerance to a simulated hemorrhagic insult, with a 
study power=0.80 at an adjusted alpha=0.015 to account for comparisons between drugs. That value was 
inflated to 30 subjects in total (15 male and 15 female) to permit a comparison in the primary responses 
between sexes for each of the administered drugs. That said, interim power analyses will be performed, with the 
number of required subjects adjusted based upon the variance of the obtained data.      
  

Prot_003.pdf: 
Official title: Analgesics in the pre-hospital setting: Implications on 
hemorrhage tolerance - Fentanyl 
 
NCT number: NCT04136548 
Document date: 09-04-2019 


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The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
Study Title: Analgesics in the pre-hospital setting: Implications on hemorrhage tolerance - Fentanyl 
Principal Investigator: Craig Crandall, Ph.D. 
Sponsor/Funding Source: Department of Defense—US Army 
Date:  
 
1. Introduction and Purpose: 
The purpose of this project is to test how the three recommended analgesics currently employed in 
the pre-hospital setting by the US Army—fentanyl, morphine, and ketamine—alter the capacity to 
tolerate a hemorrhagic insult in humans. 
 
Pain management on the battlefield is critical for the wellbeing of the soldier.  Given that a 
hemorrhagic injury on the battlefield is virtually always associated with pain, it is paramount that the 
selected pain medication does not disrupt appropriate physiological mechanisms that are beneficial 
towards the maintenance of blood pressure and vital organ blood flow during that hemorrhagic insult.  
Current guidelines for the selection of pain medications of a hemorrhaging soldier are based upon 
limited scientific evidence, with the vast majority of supporting studies being conducted on 
anesthetized animals.  Thus, the interaction between hemorrhagic shock and pain medications 
commonly employed on the battlefield is yet to be determined in the conscious humans.   
 
With this background, we will address the following Specific Aims: 
• 
Specific Aim 1: To test the hypothesis that each of the three analgesics currently employed in 
the pre-hospital setting by the US Army—fentanyl, morphine, and ketamine—will impair the 
capacity for a conscious human to tolerate a hemorrhagic insult.  
• 
Specific Aim 2: To test the hypothesis that ketamine will be the least detrimental in 
compromising tolerance to a simulated hemorrhagic insult. 
 
The data obtained from addressing these specific aims will provide the necessary scientific evidence 
in humans to support the Committee on Tactical Combat Casualty Care (CoTCCC) guidelines on the 
analgesic of choice for moderate to severe injuries where the casualty is in hemorrhagic shock.  
Notably, such data will identify the analgesic that least compromises a human’s ability to tolerate a 
hemorrhagic insult, ultimately providing critical information to the combat medic on which analgesic 
should be employed for such an injury.   
 
2. Background: 
Hemorrhage is the leading cause of battlefield and civilian trauma deaths (1–3).  During the recent 
Iraq and Afghanistan conflicts, 91% of potentially survivable casualties in US soldiers were 
hemorrhage related (4).  Hypovolemic shock associated with hemorrhage occurs in concert with a 
reduction in circulating blood volume, culminating in low tissue perfusion pressure and accompanying 
insufficient organ perfusion to meet metabolic demands.  In the early stages of a hemorrhagic injury, 
compensatory mechanisms that are vital to maintain perfusion pressure.  Depending on the severity 
of the hemorrhagic insult, these compensatory mechanisms are sufficient to maintain perfusion to vital 
organs, such as the heart and brain.  As hemorrhage continues, however, these physiological 
responses are no longer able to compensate for the loss of blood volume. The individual then 
transitions into a state of non-compensable hemorrhage, manifested by profound parasympathetic 
stimulation coupled with withdrawal of sympathetic stimulation resulting in decreases in systemic 
vascular resistance and cardiac output (5–8).  Arterial pressure then falls to the point where it is 
insufficient to perfuse these vital organs, culminating in death.   
 
Hemorrhagic injuries are always accompanied with pain, as long as the individual remains conscious.  
Pain management of an injured soldier is a critical component of the medical care of that casualty (9–


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11).  Current recommendations for analgesics in the pre-hospital setting, i.e., on the battlefield, 
include opioids (morphine, fentanyl) and N-methyl-D-aspartate (NMDA) antagonists (ketamine) 
(10,11).  Combat medics receive guidelines that originate from the Committee on Tactical Combat 
Casualty Care (CoTCCC) in choosing the ideal analgesic, based upon the type and severity of the 
injury (10,11).  Specifically, if the causality is experiencing moderate to severe pain AND the casualty 
is not in circulatory shock or respiratory distress and is not expected to develop either condition, then 
fentanyl is recommended, with morphine as an alternative if intravenous access has been obtained 
(10).  Conversely, if the casualty is in hemorrhagic shock or respiratory distress, or s/he is expected to 
develop either of these conditions, then ketamine is recommended (10).  However, the scientific basis 
for such recommendations are primarily limited to research in fully anesthetized (i.e., unconscious) 
animals.  For example, anesthetic doses (i.e., high doses that are unlikely to be employed in the pre-
hospital setting) of drugs such as ketamine reduce or remove the otherwise beneficial 
sympathoexcitatory responses and corresponding peripheral vasoconstriction during a hemorrhagic 
insult in mammals (7,12,13).  Moreover, morphine reduces hemorrhagic tolerance in fully 
anesthetized rats (14), greatly increasing mortality. To our knowledge, no studies have evaluated the 
effects of analgesic doses of medications commonly employed in the pre-hospital setting on tolerance 
to a simulated (or actual) hemorrhagic insult in humans.  Consistent with this concern, it is particularly 
noteworthy that “No studies have been published from the current conflict that review outcomes in 
combat causalities as a function of the type and route of analgesia used in combat casualties as well 
as the type and severity of wounds sustained, and physiological parameter indicative of circulatory or 
respiratory status.” Quote from 2014 by Butler et al. (10).  
 
We propose that if sufficient doses of commonly employed analgesics are administered to humans, 
otherwise appropriate cardiovascular responses to the hemorrhagic insult will be suppressed, thereby 
reducing the ability of the individual to tolerate that insult.  That said, the effects of analgesic doses of 
such agents (i.e., doses that are recommended for the pre-hospital setting) on physiological 
responses necessary to preserve tolerance to a hemorrhagic insult in humans is entirely unknown.  
Moreover, the aforementioned guidelines by the CoTCCC for condition-specific analgesics are not 
based upon hypothesis driven scientific evidence in humans, but rather primarily from fully 
anesthetized animals.  Thus, the applicability of that research to a soldier experiencing a hemorrhagic 
injury is questionable and remains a significant gap in the knowledgebase.     
 
 
3. Concise Summary of Project: 
Three separate protocols, one for each analgesic—fentanyl, morphine, and ketamine will be 
employed.   
 
Three laboratory visits will be required for this protocol.  
 
The first visit will begin with the consenting process. Should the interested subject qualify and agree to 
participate in the study, he/she will undergo two separate experimental visits (placebo and fentanyl) 
each conducted on a different day.  The protocol for each experimental visit is identical. After 
instrumentation, subjects will rest quietly followed by baseline data collection and then assessments 
of pain (via algometer, thermal grill, and the cold pressor test; order randomized).  Subjects will then 
receive the drug along with the progressive lower-body negative pressure (LBNP).  If necessary, after 
waiting for the effects of the first administration of this drug to subside, the drug will again be 
administered, followed by a recording of post-drug data and re-performance of the pain assessments.  
For the placebo trial, saline (sodium chloride 0.9% or if unavailable, 5% dextrose in water) will be 
administered where “Drug Administration” is indicated above. The enrolled subject will be required to 
complete both placebo and drug challenges for each drug.   
 
4. Study Procedures: 


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All procedures in this protocol are experimental.  Therefore, none of the procedures are "standard of 
care." 
 
Experimental Protocol:  
Each subject will undergo two separate experimental visits (placebo and drug), each conducted on a 
different day, with the order randomized.  The selected dose (see below) is not expected to cause 
unconsciousness or significant sedation.  For females, testing will be conducted during the same 
phase of the menstrual cycle or contraceptive use.  
 
The protocol, and approximate times, for each experimental visit is illustrated in Figure 1.   
 
Following instrumentation and a quiet resting period, baseline data will be obtained.  This will be 
followed by three validated methods of pain assessment via a digital algometer, thermal grill, and a 
cold pressor test.  Following the pain assessment, the doses of the analgesic (or placebo) will be 
administered, with these doses being consistent with the US Army’s CoTCCC guidelines (10):   
Fentanyl: (placebo and 75 µg intravenous) 
 
 
Next, a progressive LBNP challenge will be completed until the onset of syncopal symptoms (defined 
as: profound bradycardia, a precipitous drop in arterial blood pressure and accompanying narrowing 
of pulse pressure, a sustained systolic blood pressure less than 80 mmHg, and/or subjective 
symptoms such as light-headedness, sweating, nausea, or dizziness).  After waiting for the effects of 
the first administration of this drug to subside, the drug will again be administered, followed by a re-
performance of the pain assessments.   The purpose of repeated (i.e., two) drug administrations per 
trial is to ensure that the subject receives the peak concentration of the drug at the time of the LBNP 
testing as well as during the pain assessments.  Blood for the assessment of hemostatic responses 
will be drawn at the following time points to evaluate hemostatic function: baseline, after drug 
administration but before progressive LBNP, immediately after LBNP, and 60 min after LBNP. 
 
The following data/specimens will be measured/collected and recorded.  
• 
Heart rate and rhythm: electrocardiogram (ECG) 
• 
Arterial blood pressure:  
o R-wave gated automated auscultation of the brachial artery (Tango+) 
o B Beat-by-beat arterial blood pressure will be obtained via photoplethysmography 
(Finometer/Nexfin) 
• 
Internal body temperature: from an ingestible temperature sensing pill (HQ Inc) (or rectal 
probe) 
   
 
 
      Figure 1: Timeline of each experimental day.   
105 min:
Instrumentation and 
Quiet Rest
30 min:
Baseline 
Data 
Collection & 
Pain 
Assessments
Drug/Placebo 
Administration
45 min: 
Progressive 
LBNP to the 
onset of 
syncopal 
signs/symptoms 
60 min:
Recovery to allow for 
drug effects to 
subside & Pain 
Assessments
60 min:
Recovery to allow for 
drug effects to 
subside & Pain 
Assessments
30 min: 
Data Collection 
& Pain 
Assessments
Drug/Placebo 
Administration


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• 
Skin temperature: thermocouples attached at various locations on the subject 
• 
Cardiac output: measured by gas rebreathing (Innocor) 
• 
Muscle sympathetic nerve activity: microneurography 
• 
Forearm blood flow: doppler ultrasound of brachial artery 
• 
Cerebral blood flow: transcranial Doppler and vessel diameters via Doppler ultrasound 
• 
Skin (cutaneous) blood flow: laser Doppler flowmetry 
• 
End tidal carbon dioxide: capnography 
• 
Oxygen saturation: pulse oximetry 
• 
Muscle and brain oxygen saturation: near infrared spectroscopy 
• 
Compensatory reserve index: photoplethysmography of finger blood flow 
• 
Body mass 
• 
Venous catheter and blood samples: see list below 
• 
Saline infusion (via venous catheter) 
• 
Subjective pain reporting to pain assessments (cold pressor test and thermal grill illusion test) 
• 
Maximum pain threshold: digital algometer 
• 
Urine specific gravity 
• 
Drug screening 
• 
Pregnancy test 
 
 
The following assays will be performed for each of the blood draws on the experimental visits:   
 
• 
Plasma catecholamine and vasopressin concentrations 
• 
Standard Complete Blood Count (CBC), venous blood gas and chemistry profile including 
platelet count 
• 
Prothrombin Time (PT): Evaluates the integrity of the extrinsic coagulation pathway. 
• 
Activated Partial Thromboplastin Time (aPTT): Evaluates the integrity of the intrinsic 
coagulation pathway. 
• 
Thromboelastograph Haemostasis Analyzer (TEG 5000): Provides multiple markers of clot 
formation and degradation from a cell-based whole-blood assay using a computer based 
analysis.   
• 
D-dimer: A marker of fibrinolysis. 
• 
Fibrinogen: Protein that thrombin coverts to fibrin during the clotting process. 
• 
Tissue Plasminogen Activator (tPA): A protein that contributes to the breakdown of clots 
through catalyzing the conversion of plasminogen to plasmin. 
• 
Antithrombin III: Inactivates enzymes facilitating coagulation (factors Xa and IIa). 
• 
Protein C: An anticoagulant that contributes to the regulation of clotting by inactivating factors 
V and VIII, as well as by disinhibiting fibrinolysis through inactivation of PAI-1 (see below). 
• 
Plasminogen activator inhibitor-1 (PAI-1): It inhibits tissue plasminogen activator (tPA, see 
above), thereby inhibiting fibrinolysis. 
• 
Von Willerand factor (vWF) antigen: A measure of the quantity or mass of Von Willerand 
protein in plasma, which contributes to the early stages of clotting. 
• 
Factors V and VIII: Factors essential in blood coagulation. Factor V is a critical cofactor for 
factor X which in turn activates factor II to IIa (Thrombin). Factor VIII is a critical cofactor for 
the factor IX-medicated activation of factor X. 
 
 
How Data/Specimens will be Collected 
• 
Cardiac and vascular variables: Heart rate and rhythm will be obtained from the ECG. Blood 
pressure will be obtained on the upper arm by automated auscultation of the brachial artery, 
while beat-by-beat blood pressure will be obtained from the finger via photoplethysmography. 


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Cardiac output will be measured by inert gas rebreathing using the Innocor system. Stroke 
volume will be calculated from the measurements of heart rate and cardiac output. Oxygen 
saturation will be measured using a pulse oximeter.  Cerebral perfusion will be measured by 
transcranial Doppler.  Cerebral and forearm blood flow will be measured by Doppler 
ultrasound.  
• 
Thermal variables: Internal body temperature will be measured using an ingestible telemetric 
pill (or a rectal thermocouple probe). A weighted average of skin temperature will be obtained 
from thermocouples attached to the following six sites: upper chest, upper back, lower 
abdomen, lower back, thigh, and calf. Skin (cutaneous) blood flow will be measured by laser 
Doppler flowmetry.  
• 
Pain variables: Pain assessments will be conducted using a digital algometer to obtain 
maximum pain thresholds caused by pressure.  Pain assessment will also be measured by the 
subject rating his/her pain level (range 0 to 10, with 0 being no pain and 10 being the worst 
pain imaginable) during hand placement into an ice water bath (cold pressor test) as well as 
on a device consisting of 15 tubes alternating with perfused warm or cold water (thermal grill).   
• 
Other data/specimens: Muscle/brain oxygenation will be measured using a near infrared 
spectroscopy sensor that will be secured to the skin. End-tidal carbon dioxide will be 
measured via capnograph. Muscle sympathetic nerve activity will be measured using 
microneurography. Compensatory reserve index will be estimated by recording 
photoplethysmography signals from the finger. Body mass will be measured using a scale in a 
private area. Venous blood samples will be collected from a peripheral arm vein. Urine specific 
gravity, drug screening and a pregnancy test will be determined from a urine sample collected 
at the beginning of the visit. 
 
Volume Collected 
• 
Urine: 1 – 2 ounces collected at the beginning of each visit 
• 
Blood: A maximum of 100 mL of blood will be collected during visits 2 and 3. 
 
De-identified data will be sent to the U.S. Army Institute of Surgical Research (USAISR) at Ft. Sam 
Houston, Texas for their assistance in analyzing and interpreting the observations.  No subject 
information will be sent with these data and no subject information will be exchanged with USAISR.  
Furthermore, the USAISR will not be given access to the coding links back to subject identifiable 
information. 
 
Chronological Detail 
The times listed below are approximate and listed in order, from subject arrival.  
 
All Specific Aims – 3 visits/subject (preliminary session: ~1 hour; 2 experimental visits: ~5.5 hours 
each; total time ~12 hours): 
 
Visit 1 (preliminary visit) (~1 h) 
• 
60 min: consent form, HIPAA authorization, W-9 tax form, and self-reported medical history; 
resting blood pressure, 12 lead ECG, pregnancy test, if applicable, procedure familiarization, 
and drug screen; instruction sheet for experimental visits will be provided 
 
Visits 2 and 3 (experimental visits) – 2 visits (~5.5 hours each visit) 
• 
15 min: urine sample (pregnancy test, if applicable), nude body weight measurement, 
instrumentation with ECG, blood pressure cuff, skin temperature thermocouples 
• 
90 min: supine position assumed, insertion of an IV catheter in a vein of the arm, and muscle 
sympathetic nerve activity signal obtained 
• 
30 min: baseline data collection followed by pain assessments (cold pressor test, thermal grill 
illusion, and pressure algometry) 


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• 
45 min: drug administration (placebo or fentanyl) followed by progressive LBNP to the onset of 
syncopal signs/symptoms (blood pressure, cardiac output, forearm blood flow, cerebral blood 
flow, pulse oximeter, blood samples collected; heart rate, muscle sympathetic nerve activity 
measured continuously) 
• 
60 min: recovery  
• 
30 min: drug administration (placebo or fentanyl) data collection followed by pain assessments 
(cold pressor test, thermal grill illusion, and pressure algometry) 
• 
60 min: recovery followed by pain assessments (cold pressor test, thermal grill illusion, and 
pressure algometry)  
 
 
Primary Outcome Variables 
The primary outcome variable will be the ability to tolerate the LBNP challenge prior to the onset of 
signs and symptoms associated with ensuing syncope.   
 
Study Endpoints 
Data collection will end when 30 subjects (15 men and 15 women) have completed the experimental 
protocol. 
 
Sample Size Justification 
No study has evaluated the effects of analgesics on LBNP tolerance in humans.  The power and 
sample size estimates are based on findings from Dr. Crandall’s laboratory showing reduced LBNP 
tolerance in the heat-stressed individuals (15).  In that study heat stressed reduced LBNP tolerance 
by ~70% (997 cumulative stress index units to 303 cumulative stress index units; P<0.001).  Though 
we expect the analgesics to likewise reduce LBNP tolerance, we do not anticipate as large of a 
reduction as that observed with heat stress.  Thus, the sample size calculation was based upon an 
anticipated reduction in LBNP tolerance of half that seen with heat stress, i.e., ~35% reduction in the 
cumulative stress index.  Given this anticipate outcome, coupled with the associated variances 
observed in that study (15), we anticipate 15 subjects per drug trial will be sufficient to address the 
primary hypothesis that the administered analgesic reduces tolerance to a simulated hemorrhagic 
insult, with a study power=0.80 at an adjusted alpha=0.015 to account for comparisons between 
drugs.  That value was inflated to 30 subjects in total (15 male and 15 female) to permit a comparison 
in the primary responses between sexes for each of the administered drugs.  That said, interim power 
analyses will be performed, with the number of required subjects adjusted based upon the variance of 
the obtained data.      
 
5. Sub-Study Procedures: 
Not applicable 
 
6. Criteria for Inclusion of Subjects: 
• 
18-45 years of age  
• 
Healthy 
• 
Non-obese (body mass index less than 30 kg/m2) 
• 
Body mass greater than or equal to 65 kg 
• 
Speak English 
 
7. Criteria for Exclusion of Subjects: 
• 
Subjects not in the defined age range 
• 
Subjects who have cardiac, respiratory, neurological and/or metabolic illnesses 
• 
Any known history of renal or hepatic insufficiency/disease 
• 
Pregnancy or breast feeding 
• 
Body mass less than 65 kg 


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• 
Current smokers, as well as individuals who regularly smoked within the past 3 years 
• 
Subjects who cannot speak or read English 
• 
Positive urine drug screen 
• 
Currently taking pain modifying medication(s) 
 
Although this study requires relatively uncomplicated procedures, inclusion of non-English speaking 
subjects would compromise subject safety. Consequently, it is imperative that the research and 
medical staff are able to communicate instantly and effectively with subjects, without the need of a 
translator. Therefore, the investigators feel that inclusion of non-English speakers would markedly and 
unnecessarily increase the risk to those participants. 
 
8. Sources of Research Material: 
“Research Material” (i.e., data) will be obtained from healthy human subjects. See section 4: Study 
Procedures for a list of data that will be obtained.     
 
Healthy individuals: Complete datasets will be obtained from a total of 30 individuals (15 men and 15 
women).  Subjects will be 18-45 years. 
 
Due to screening failures (e.g., not determined to be healthy, use of medication, etc.), we anticipate 
50 subjects will be consented to achieve the desired 30 subjects. 
 
9. Recruitment Methods and Consenting Process: 
Subjects will be recruited from the Dallas/Fort Worth area using an IRB approved existing database of 
over 2500 subjects held at the Institute for Exercise and Environmental Medicine, IRB# STU 122010-
188. Subjects will also be recruited using approved recruitment texts and flyers informing them of the 
study and requesting potential subjects to contact our recruiting staff. The text will be used to recruit 
via ResearchMatch, CenterWatch, the Community Research Registry at UT Southwestern Medical 
Centre, Facebook, twitter, home owner associations, local churches, health and fitness centers/clubs, 
university and community alumni associations, country clubs, local university campuses, as well as e-
mail notices sent within UT Southwestern Campus Updates and throughout the Texas Health 
Resources network. Qualified staff within the Thermal and Vascular Physiology Laboratory at the 
Institute for Exercise and Environmental Medicine, will assist with subject recruiting, obtaining 
informed consent, and scheduling logistics. 
 
A qualified member of the research team will perform an initial contact with interested individuals via 
the telephone. During this initial contact, the member of the research team will explain the study 
(purpose, procedures, risks, benefits, alternatives to participation, etc.) in lay language. Furthermore, 
the research team member will perform an initial screening to ensure that the inclusion criteria are met 
and that the subject does not meet any of the exclusion criteria to participate in the study. If all 
inclusion criteria are met, the individual will be familiarized with the procedures used during data 
collection. The interested individual will subsequently be invited to visit the laboratory, during which 
he/she will be provided adequate time to read the consent, ask additional questions and consider 
his/her options. Care will be taken that the subject is not pressured but that staff is available to 
address any questions. If the potential subject indicates that they would like to participate, open-
ended questions will be asked to assess comprehension. If however, the potential subject needs 
additional time he/she can take the consent home to consider further. Staff phone numbers will be 
provided for questions. For subjects that agree to participate in the study, the potential subject will be 
asked to sign the consent form, fill out a self-reported medical history and we will measure their 
resting blood pressure, perform a resting 12 lead ECG, and collect a urine specimen to complete a 
urine drug screen to ensure they qualify for the study.  
 
A partial waiver of HIPAA Authorization will be sought for the purpose of recruiting. Screening 
information is required to determine the eligibility of potential subjects, which is necessary in order to 


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meet the study aim. This research cannot practicably be carried out without this waiver to determine 
eligibility, as it will not be practical to contact/consent before determining eligibility. Excessive amounts 
of time and other resources could potentially be wasted inviting subjects to participate without proper 
preliminary screening that would help determine eligibility. With regard to information collected, all 
preliminary screening information will be shredded if it is determined that the individual does not 
qualify or if the subject is not consented. If the individual qualifies and is consented, the preliminary 
screening information will be included in the subject’s laboratory chart. 
 
Persons from vulnerable populations will not be invited to participate. Potential subjects will not be 
coerced to participate, nor will coercive language be used in any recruitment materials. When 
presenting the study to subjects, all risks will be outlined, and it will be explained as completely 
voluntary. 
 
Subjects will be paid $35.00 per hour. If a subject stops taking part in the study or is withdrawn by the 
research team, they will receive payment for the hours they have competed. If needed, ground 
transportation to and from the research center (IEEM) will be provided or reimbursed.  Subjects will 
receive a check in the mail from Texas Health Presbyterian Hospital Dallas approximately 6 weeks 
after each visit.  There is no maximum amount that subjects can be paid. There will be no funds 
available to pay for lost time away from work and other activities, or lost wages.   
 
10. Potential Risks: 
The techniques utilized in the research project that pose potential risks are outlined below: 
 
Peripheral intravenous (IV) catheter and saline infusion:  A sterile catheter will be inserted into an arm 
vein for the purposes of analgesic administration (i.e. fentanyl, morphine, and ketamine) and blood 
collection. In order to maintain patency of the catheter, saline will be infused through the venous 
catheter.   There is a small risk of infection and a still smaller risk of a blood clot or breakage of the 
catheter. The likelihood of these complications is remote (about 1 in 10,000) when the procedure is 
carried out by trained personnel and proper equipment is used, as during this study. There is also a 
small risk of the catheter perforating the vein or not being inserted into a blood vessel. The subject 
may have discomfort, bleeding, and/or bruising and on rare occasions, a person may feel dizzy or 
faint. 
 
Analgesic (Fentanyl) administration: 
Fentanyl is a potent, synthetic opioid pain medication with a rapid onset and short duration of action.  
It is a pure agonist of the mu-opioid receptors in the brain.  Fentanyl has common side effects (>10% 
of patients) such as diarrhea, nausea, constipation, dry mouth, somnolence, confusion, weakness, 
sweating, and less frequently (3-10% of patients) hallucinations, dyspnea, apnea, hypoventilation, and 
urinary retention.  The higher the dose, the greater frequency and severity of adverse effects.  
Fentanyl has a therapeutic index of 300 (therapeutic index = median lethal dose (LD50)/ lowest 
median effective dose (ED50).  Respiratory depression is the most serious risk when dealing with 
fentanyl.  There is a specific, rapid and complete antagonist readily available.  Naloxone will 
completely reverse all opioid effects within 2 minutes IV, 5 minutes IM, and 8 minutes intranasal 
administrations.  This provides several routes of administration as a safety backup should IV access 
be lost.  However, at the doses and times in the study proposed, it is not our intent or expectation that 
significant respiratory depression will occur.  Moreover, we will monitor the patient's vital signs 
continuously.  We will monitor pulse oximetry and end tidal carbon dioxide continuously. These two 
monitors will provide sufficient accuracy and robustness to administer this medication safely.  An 
anesthesiologist will be present at all times to observe and intervene should the patient should the 
slightest evidence of respiratory depression well before any patient danger should arise.  All standard 
airway intervention equipment will be readily available at all times. 
 


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Microneurography: There is a slight risk of a temporary pins and needles sensation or increased 
sensitivity to touch in the leg or arm during and following the test; however this feeling goes away 
within 2 to 7 days. This sensation may be similar to what is felt after jogging. A few subjects have 
noted some tiredness, soreness, or tingling in their leg or arm muscles up to one week after the study. 
This sensation is thought to be related to muscle twitches which are part of the procedure for 
localizing the nerve.  
 
Thermal grill illusion test: This technique for pain assessment does not cause any damage to human 
tissue and therefore presents no risks.  The thermal grill apparatus consists of alternating tubes 
perfused with cold and warm water at innocuous temperatures.  Contact with the apparatus elicits an 
“illusion” consistent with a painful burning sensation upon.  Withdrawal from contacting the interlaced 
tubes immediately alleviates these painful sensations.  Subjects are in contact with the thermal grill for 
thirty seconds for each test and can voluntarily remove the hand at any time.   
 
Cold pressor test:  This widely used technique for pain assessment presents minimal risk.  For this 
test, immersion of the hand in ice cold water will elicit painful sensations as well as an increase in 
blood pressure.  These typical responses are immediately lessened to pretest levels with the removal 
of the subject’s hand from the ice water.  The maximum duration for this test is three minutes and the 
subject can voluntarily remove the hand from the ice water at any time.   
 
Pressure algometry: This pain assessment technique is conducted by applying the rubber tip of a 
hand-held digital algometer on the subject’s digit.  Force will be gradually increased and the peak 
force is recorded when the subject first reports a painful sensation.  Removal of the pressure from the 
algometer immediately relieves the painful sensation and the subject can voluntarily stop the test at 
any time.   
 
Measurement of internal temperature: Intestinal temperature will be measured with a temperature-
sensing pill (HQ Inc) that is swallowed by the subject and which transmits temperature to a receiver 
as it traverses the digestive tract. The pill is eventually passed out of the body without pain or 
discomfort. Although exceptionally rare, there are some risks associated with taking this pill. It is 
possible that the pill could be inhaled into the subject’s lungs. The pill could also cause a perforation, 
blockage or infection of the intestinal tract, requiring endoscopy or surgery to remove it. This pill 
should not be taken if the subject weighs less than 80 pounds, nor should the subject take this pill if 
they have or have had any gastrointestinal disease or surgery. The research nurse will also check 
each subject’s medical history prior to the pill being swallowed. Should a subject have any 
contraindications in taking the pill, this procedure will not be obtained, rather rectal temperature will be 
obtained.  
 
If rectal temperature is used the subject will self-insert a small, single-use rectal temperature probe 
approximately 3 mm in diameter (Mon-a-therm General Purpose Temperature Probe). This probe will 
be inserted to a pre-marked depth of 15 cm. The subjects will self-insert and remove the rectal prove 
in a private room. The rectal thermocouple will not be inserted if they have or have had any heart 
conditions, inflammatory bowel or colon disease, and/or rectal or anal surgery. They also may not use 
the probe if they currently have hemorrhoids (internal or external), rectal bleeding, diarrhea or fecal 
impaction in the rectum. Each subject’s medical history will be verified prior to self-insertion of the 
rectal probe by the research nurse. 
 
Electrocardiogram:  In some cases, individuals have developed a rash or redness where the patches 
were attached. This rash is mild and typically resolves without treatment. 
 
Lower body negative pressure: The possible risks of this procedure are light-headedness, feeling 
faint, nausea and rarely a subject may faint. If this occurs, the procedure will stopped and the subject 
will begin to feel better almost immediately. 


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Loss of confidentiality:  Anytime information is collected there is a potential risk for loss of 
confidentiality. Every effort will be made to keep information confidential, however, this cannot be 
guaranteed. 
 
All other procedures (blood pressure, cardiac output, stroke volume, skin temperature, forearm blood 
flow, cerebral blood flow, skin blood flow, compensatory reserve index, end tidal carbon dioxide, 
oxygen saturation, muscle and brain oxygen saturation, body mass, urine specific gravity, drug 
screening, and pregnancy test) have little or no risk involved. 
 
Overall, it is our opinion that the benefits derived from the proposed studies far outweigh the risks. 
The researchers are experienced with all procedures outlined in this study.  A critical care trained RN 
will monitor the well-being of each subject and will be available as needed. Moreover, Joseph 
Hendrix, MD (a board certified anesthesiologist) will oversee the administration of the analgesics and 
will continuously monitor the subjects throughout the protocol.  Dr Hendrix has specialized training in 
Pain Medicine, which includes the administration of the assessed drugs in his clinical practice; thus, 
he is well versed in the administration of these drugs and any potential adverse effects.  In addition, 
Benjamin D. Levine, MD, Medical Director of the Institute for Exercise and Environmental Medicine, or 
cardiology fellows currently working at the Institute for Exercise and Environmental Medicine, will be 
available to assist as needed. 
 
11. Subject Safety and Data Monitoring: 
The researchers are experienced with all procedures outlined in this study. All subjects must be 
healthy to participate. The risks and benefits will be explained to the subjects before each signs an 
institutionally-approved consent form. 
 
Craig Crandall, Ph.D will oversee subject safety and data integrity throughout the study. Dr. Crandall 
has conducted studies such as these for ~20 years and is qualified to perform these responsibilities. 
Data monitoring will include study accrual rate, participant experience, study 
attrition/withdrawals/dropouts, patterns of adverse and/or unanticipated events, patterns of protocol 
violations and/or deviations and changes in risk/benefit. The data will be reviewed at least on a 
quarterly basis. A progress report summarizing the data will be submitted to the IRB at the time of 
continuing review and more frequently as indicated.  
 
As with all studies involving human subjects, there are risks associated with experimentation.  To 
reduce these risks, all subjects must be healthy to enroll.  Since the CoTCCC guidelines for dosing of 
the indicated drugs are not weight specific, each subject must have a body mass of at least 65 kg to 
enroll in the study to further reduce the risk to any subject.  As stated above, Joseph Hendrix, MD (a 
board certified anesthesiologist) will oversee the administration of the analgesics and will continuously 
monitor the subjects throughout the protocol.  Dr. Hendrix has specialized training in Pain Medicine, 
which includes the administration of the assessed drugs in his clinical practice; thus, he is well versed 
in the administration of these drugs and any potential adverse effects.  The protocol dictates that 
subjects remain awake/conscious throughout the procedures. The absence of significant sedation or 
altered of mental status will be ensured by prompt reply to verbal commands given to the subject.  
The subjects will have their vital signs monitored continuously with standard patient monitors.  
Resuscitative equipment will be readily available, including but not limited to supplemental oxygen, 
suction capacity, cardiac arrest cart with intravenous fluid and drugs (including naloxone), airway and 
intubation devices.  Dr. Hendrix will intervene to ensure patient safety with any or all of these 
resources should the subject have any derangements outside of acceptable normal parameters for 
their vital signs.  Upon the conclusion of the protocol, subjects will not be permitted to leave the 
laboratory until all of the following discharge variables are met:  
• 
The subject presents with an Aldrete score (post-anesthesia discharge scoring system) 
matching baseline,  


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• 
The subject demonstrates a awareness of time, person, and place and is able to answer 
questions appropriately 
• 
The subject is able to stand up and walk for 5 minutes without assistance (supervised) 
• 
The subject is able to drink water and eat crackers without reports of nausea 
• 
The subject able to void   
Moreover—to be consistent with THR/UTSW hospital guidelines—the subject will be required to have 
a responsible adult bring them home.  The responsible adult can either drive the subject home or 
accompany the subject home using ground transportation (bus, train, or taxi service).  The subject will 
also receive the recommendation to have someone observe them for the rest of the day and 
overnight. 
 
The doses of the drugs are expected to cause analgesia, but with the subject remaining conscious 
and responsive to verbal commands.  These drugs are routinely administered for pain control in the 
absence of significant sedation.  Nevertheless, if after the first or second administration of the 
selected analgesic the subject is not responding appropriately to verbal commands (e.g., is 
excessively sleepy/sedated) or experiences any related adverse responses to the administered drug, 
the trial will be cancelled for that subject.   
 
Subjects who, during the study, manifest a new onset, previously hidden or unknown cardiovascular, 
neurological or metabolic disease/illness will be removed from the study. 
 
 
The study will be stopped immediately for safety if a serious, unexpected problem or adverse event 
occurs. The entire project will be terminated if this event is determined to place future participants at 
undue risk. 
 
12. Procedures to Maintain Confidentiality: 
1) Information will be given to the principal investigator and his staff only.  
2) Information concerning subject’s medical histories will be furnished by the subjects to the staff.  
3) This information will be used to determine qualification for participation in the investigation.  
4) Personal information will remain in the subject’s study chart and will not be released in any form to 
others unless permitted by the subject.  
5) The consenting process for each subject will be conducted in a private room. 
6) No subject will be identified by name or initials outside the laboratory records. All computer 
records will be coded and will not include the subject’s name. All coded computer records will be 
saved on password protected computer systems and data files are maintained on a secure server. 
7) The signed consent form will be kept on file in the subject’s laboratory chart. Paper records of 
experiments and copies of executed consent forms will be locked in cabinets located in the 
research nurse’s office which is locked whenever the nurse is not present. 
8) The urine specimens collected for the drug screening will not be labeled and will be directly 
handed to a member of the study team by the participant (making it anonymous). There is no 
processing required as the results appear on the side of the specimen collection cup.  
 
Screening is conducted by staff via the phone or face-to-face interview in a private area. Study visits 
(including consenting) take place in the lab and are restricted to authorized personnel only. 
 
As part of Texas Health Presbyterian Hospital Dallas, we utilize two identifiers (name and date of 
birth) to process subject samples through the IEEM biochemistry lab.  
 
All data collected will be de-identified and only research personnel will have access. All digital 
recordings will be locked and password protected. Paper records will be handled as stated above.  
After three years, if the information is no longer needed, it will be shredded or otherwise appropriately 
destroyed so as to be unreadable. However, any time information is collected; there is a potential risk 


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for loss of confidentiality. Every effort will be made to keep information confidential; however, this 
cannot be guaranteed. 
 
13. Potential Benefits: 
We do not anticipate that individuals participating in the research will receive any direct benefit.   
 
As a result of the proposed studies, upon the completion of this objective, the Department of Defense 
will be provided with critical information regarding improved care of the hemorrhaging victim in a pre-
hospital setting. Combat injuries associated with hemorrhage are almost always accompanied with 
severe acute pain. This project focuses on evaluating analgesics employed by combat medics in the 
pre-hospital setting, with an objective of identifying the/those analgesic(s) that do not, or only 
minimally, impair tolerance to a simulated hemorrhagic challenge in humans. Since hemorrhage is 
often encountered on the battlefield, it is imperative that the administered analgesic does not impede 
physiological responses that protect against ensuing hypovolemic shock. That is, the optimal 
analgesic used for battlefield trauma should provide pain control without impeding appropriate 
physiological responses to hemorrhage. The proposed experiments will serve to identify the effects of 
three currently recommended analgesics in the pre-hospital setting (morphine, fentanyl, and 
ketamine) on tolerance to a simulated hemorrhage in conscious humans.  The proposed work will also 
explore possible sex differences that may affect one’s ability to compensate for a hemorrhagic 
challenge while receiving each of these three analgesics. 
 
With regard to those outside the military, the experiments outlined in this application will determine the 
effect of currently employed pain medications on tolerance to a simulated hemorrhage in humans. 
These data will identify the pain medication that least compromises a human’s ability to tolerate such 
an insult, thereby providing critical information to the pre-hospital medics on which pain medication 
should be employed for such an injury.  Obtaining these data will be the first step in the continuum of 
research that will culminate in an increased understanding of the link between analgesia and 
hemorrhage. Moreover, the proposed work is particularly unique in that it will be the first investigation 
conducted in conscious humans to identify the optimal pain medication that will only minimally impair 
compensatory responses to a hemorrhagic injury, and thus the ability to “survive” that insult.  This 
information will be valuable to both the military and civilian populations as it will improve pre-hospital 
care of the hemorrhaging victim. 
 
 
14. Biostatistics: 
Not applicable – This project was peer reviewed by the Department of Defense (US Army) 
 
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