Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Sufentanil
Phase: PHASE1
Conditions: Healthy
Sponsor: University of Texas Southwestern Medical Center

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The effects of low-dose analgesics on cardiovascular function (STU-2021-0579) 
NCT04959812 
8/18/2023 
 
 
 

Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
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V2Mar2018 
PROTOCOL FORM / RESEARCH DESCRIPTION 
 
If an item does not apply to your research project, indicate that the question is "not applicable” – do not leave 
sections blank 
 
Click once on the highlighted entry in each box to provide your response.  Click the item number/letter or 
word, if hyperlinked, for detailed instructions for that question.  If your response requires inserting a table, 
picture, etc, you may need to first delete the box that surrounds the answer and then insert your table or other 
special document. 
 
1.  Purpose and objectives.           List the purpose and objectives: 
 
The objective of this study is to identify whether sublingual sufentanil decreases tolerance to a simulated 
hemorrhagic insult in humans.  
 
2.  Background. 
• 
Describe past experimental and/or clinical findings leading to the formulation of your study.   
• 
For research involving investigational drugs, describe the previously conducted animal and human 
studies.   
• 
For research that involves FDA approved drugs or devices, describe the FDA approved uses of 
this drug/device in relation to your protocol.   
• 
Attach a copy of the approved labeling as a product package insert or from the Physician’s Desk 
Reference.   
You may reference sponsor’s full protocol or grant application (section number and/or title) or if none, 
ensure background includes references. 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
a. Background 
Hemorrhage is the leading cause of battlefield and civilian trauma deaths.  In the early stages of a 
hemorrhagic injury, autonomic compensatory mechanisms are engaged that are vital to maintain blood 
delivery to vital organs.  
 
Hemorrhagic injuries are virtually always accompanied with pain. Pain management of an injured 
soldier is a critical component of the medical care of that casualty. It is critical that the employed 
analgesic not compromise autonomic responses requisite to maintain arterial blood pressure, and thus 
blood flow, in a hemorrhaging individual.  Sublingual sufentanil was recently approved by the FDA and 
is being deployed on the battlefield as and analgetic. No studies have evaluated the effects of 
analgesic doses of sufentanil on tolerance to a simulated (or actual) hemorrhagic insult in humans.   
 
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. Thus, the 
objective of this work is to identify the effects of sublingual sufentanil on tolerance to a simulated 
hemorrhagic challenge in humans. 
 

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b. Current practice 
A 30 microgram dose of sufentanil (trade name: Dsuvia) is administered sublingually for the 
management of acute pain. 
 
3.  Study Design.  
Describe the study design (e.g., single/double blind, parallel, crossover, etc.)  Consider inserting a scheme 
to visually present the study design. 
 
We will conduct a double-blind, placebo-controlled, crossover study. Following informed consent and 
screening, eligible participants will be randomized to complete the sufentanil or the placebo trial first, with the 
other “agent” administered during the subsequent visit. During these experimental visits, we will administer 
two assessments of pain perception (described in greater detail below), then administer sufentanil 
sublingually or a placebo pill also sublingually, perform the simulate hemorrhagic tolerance assessment 
(lower-body negative pressure), and then re-assess the measures of pain perception. The graphics below 
depicts the study design and experimental protocol, respectively.  
 
 
 
 
 
 
 
4.  Research Plan / Description of the Research Methods:   
4.a.  Provide a comprehensive narrative describing the research methods.   
     1) Provide the order in which tests/procedures will be performed,  
     2) Provide the setting for these events and a description of the methods used to protect privacy 
during the study.   
     3) Provide the plan for data analysis (include as applicable the sample size calculation) 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
Consent, 
Screening, 
Questionnaires
Sufentanil 
Trial
Placebo 
Trial
Sufentanil 
Trial
Placebo 
Trial
randomized
Instrumentation and quiet rest 
(30-90 minutes)
Pre-drug baseline & 
pain assessments
Progressive LBNP 
tolerance test
Post-LBNP recovery, pain assessments, 
and de-instrumentation
Sufentanil or Placebo 
Administration
EXPERIMENTAL PROTOCOL
~30 min wait

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Inclusion: 
• 
18-45 years of age  
• 
Healthy 
• 
Body mass index less than 33 kg/m2 
• 
Body mass greater than or equal to 60 kg 
• 
Speak English 
 
Exclusion: 
• 
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 60 kg 
• 
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 can 
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. 
 
Healthy adults will be recruited via online and paper flyers, emails to the Texas Health System (reaches over 
18,000 people), local universities (inclusive of UTSW), and our institutional participant database. Participants 
must be free from underlying serious medical conditions (detailed via medical history, physical exam), non-
smokers, have a body mass index less than 33 kg/m2, and will be excluded if they have any current 
cardiometabolic diseases (e.g., diabetes, heart disease). Individuals who are pregnant, planning to become 
pregnant, or breastfeeding will be excluded. We will also exclude those with a history of drug abuse. 
 
As described above, all participants will complete an informed consent and screening for eligibility. 
Participants will be randomized to complete either the sufentanil or placebo trial first. During these 
experimental visits, we will administer two assessments of pain perception (described in greater detail below), 
then administer sufentanil sublingually or a placebo pill also sublingually, perform the simulate hemorrhagic 
tolerance assessment (lower-body negative pressure), and then re-assess the measures of pain perception. 
 
The setting for all visits will be the Institute for Exercise and Environmental Medicine. Trials will be conducted 
in controlled laboratory settings. During the experimental visits (sufentanil and placebo), we will record 
baseline cardiovascular measures. UT-Southwestern anesthesiologist Joseph Hendrix, MD, or a research 
nurse (with direct oversight from Dr. Hendrix) will administer sufentanil (30 microgram tablet) or placebo tablet 
during each experimental visit (i.e., participants will receive only one 30 microgram tablet of sufentanil).  We 
will assess brachial blood pressure, nervous system activity via ultrasound-guided microneurography from 
the upper arm, beat-to-beat arterial blood pressure via photoplethysmography, cerebral perfusion via 
transcranial Doppler, limb blood flow via Doppler ultrasound, heart rate via electrocardiogram, respiration rate 
and end-tidal CO2 via capnography from a nasal cannula, peripheral oxygen saturation via pulse oximetry, 
compensatory reserve via photoplethysmography, and plasma catecholamine concentrations from serial 
blood samples collected throughout the visit (~4 tablespoons per experimental visit). In addition, both before 
and after sufentanil/placebo administration, pain perception will be accessed via a cold pressor test (2-3 

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minutes of a hand placed in a water/ice slurry) and via a pressure algometer assessment (pressure applied 
to the hand to the point if discomfort). 
 
Data analysis will be performed as done previously in Dr. Craig Crandall’s laboratory in companion studies 
addressing the same questions but with ketamine (STU 092017-068), fentanyl (STU 092017-069), and 
morphine (STU 092017-070). Specifically, we will compare cardiovascular data (inclusive of nervous system 
activity data) between time points (baseline and post-drug/placebo administration) and conditions.  We will 
also assess tolerance to the simulated hemorrhage challenge between sufentanil and placebo trials. All data 
will be analyzed while blind to condition and with proper co-variate analysis 
 
Personal health information (PHI) that is collected will be kept in a key-lock filing cabinet in a key-lock room 
only accessible to study team members within a numeric-padlocked laboratory. As described in the eIRB 
portal, a coded number system will be used in place of the participants name to de-identify their research 
information collected. A participant ID key, only accessible to study team members, will link the participants 
‘information with the coded number. Additionally, we follow all applicable University of Texas Southwestern 
IRB and Institute of Exercise and Environmental Medicine (i.e., where the research will take place) guidelines 
for protecting research participant privacy. 
 
Up to 60 participants are anticipated to enroll in this study. No study has evaluated the effects of sufentanil 
on lower-body negative pressure (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% (P<0.001).  Though we expect 
sufentanil to likewise reduce LBNP tolerance, we do not anticipate as large of a reduction as that observed 
with heat stress. The power analysis was calculated using G*Power [Ttests – Means:  Difference between 
two dependent means (matched pairs)] using an estimated reduction in the cumulative stress index to 
sufentanil of 25% relative to LBNP tolerance of a normothermic subjects taking a placebo (i.e., placebo: 
988±402 units; sufentanil: 741±300 units).  These predictions resulted in an effect size of 0.68.  Having a 
correlation of 0.5, with a study power=0.80 at an adjusted alpha=0.05, yielded an estimated subject size of 
15 individuals.  That value was inflated to 30 subjects (15 male and 15 female) to permit a comparison in the 
primary responses within sexes. Given the potential for subject dropouts, we propose to recruit up to  60 
individuals to obtain complete datasets from 30 subjects. Since the effects of sufentanil on LBNP tolerance 
has never been assessed, the indicated values are estimates and thus interim power analyses will be 
performed, with the number of required subjects adjusted based upon the variance of the obtained data. 

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4.b.  List of the study intervention(s) being tested or evaluated under this protocol 
 N/A -  this study does not test or evaluate an intervention.    Skip to item 4.d. 
# 
Study intervention(s) being tested or evaluated under the 
protocol 
 
 
 
Add or delete rows as needed 
 
Affiliate 
 
Place a check 
next to 
institution(s) 
where the  
intervention will 
be performed 
Local 
Standard 
Practice?  
Indicate 
whether the 
intervention is 
considered 
acceptable 
practice locally 
for applicable 
institutions 
1 
Sufentanil/Placebo administration  
☐ UTSW 
☐ Yes 
☐ PHHS 
☐ Yes 
☐CMC 
☐ Yes 
☒THR 
☐ Yes 
☐TSRH 
☐ Yes 
☐ Other: _____ 
☐ Yes 
 
 
4.c.  Risk:Benefit Analysis of study interventions being tested or evaluated under this protocol 
For each study intervention identified in section 6b above, complete a risk:benefit analysis table. 
 
(Two tables are provided, copy & paste additional tables as needed or delete both tables if this study does 
not test an intervention) 
 

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4.c. 
Study Intervention #1 
Sufentanil/Placebo Trials 
List each group exposed to this 
intervention on a separate line. 
(e.g., experimental, control, Arm A, 
Arm B, etc) 
Or state All Groups/Subjects 
For each group, list the benefits of this intervention.  (Benefits can 
be directly from the intervention or from a monitoring procedure 
likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
All subjects 
Learning of screening information (e.g., resting blood pressure) may 
positively contribute to the participant’s well being 
If you are requesting a Waiver of Informed Consent, complete the table below. 
 
If you have a consent form, list the reasonably foreseeable risks in the consent form (and do not 
complete this section).   
 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, 
legal harms) 
Do not delete frequency.  Frequency must be estimated because it will assist you with determining which 
adverse events will require prompt reporting.   
 
Not serious 
Serious  
Likely 
These risks are expected to 
occur in more than 20 out of 
100 subjects. 
• 
N/A 
• 
N/A   
 
Not serious 
Serious 
Less likely  
These risks are expected to 
occur in 5-20 subjects or less 
out of 100 subjects. 
• 
N/A   
• 
N/A   
 
 
Serious 
Rare  
These risks are expected to 
occur in less than 5 subjects 
out of 100  
 
• 
N/A   
 

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4.d. List ALL other research procedures or components not listed in table 4.b. 
        The combination of Tables 4b and 4d should account for all of the 
research procedures that will take place during this study. 
 
Consider grouping similar procedures under a single component (e.g., blood 
work, CT = safety assessments) 
 
 
 
# Research 
component 
• 
individual 
procedures 
 
example: 
Eligibility 
Assessments 
• 
History and 
physical 
• 
Questionnaire 
• 
Laboratory 
tests 
Add or delete rows 
as needed 
Column A 
Local Standard 
Practice Indicate 
the number of 
times each 
procedure will be 
performed as 
stipulated in the 
research plan 
that would be 
performed if the 
participant were 
not 
participating in 
the study. 
Column B 
Research Only  
Indicate the number of 
times each procedure will 
be performed solely for 
research purposes 
(meaning that the 
participant would not 
undergo the same number 
of procedures or would not 
undergo the procedure(s) 
at the same frequency if 
they were not participating 
in the study) 
Column D 
Risks 
If you are requesting a 
Waiver of Informed Consent, 
complete the table below. 
 
List the reasonably expected 
risks for each procedure or 
group of procedures under the 
following categories as 
appropriate: 
• Serious and likely; 
• Serious and less likely; 
• Serious and rare; 
• Not serious and likely; 
• Not serious and less likely 
1 Eligibility 
assessments 
 
 
 
 
Body height and 
mass, waist and hip 
circumference 
0 
Body height = 1, body 
mass recorded at each 
visit, waist and hip 
circumference = 1 
 
 
Heart rate and 
rhythm via 12-lead 
ECG 
0 
1 
 
 
Brachial blood 
pressure 
0 
Usually 3 to 5 measures 
 
2 Other assessments 
 
 
 
 
Health history 
assessment 
0 
1 
 
 
Lower-body negative 
pressure tolerance 
assessment 
0 
2 
 
3 Blood sampling 
 
 
 
 
Blood sampling 
0 
Up to 10 draws (up to 5 
draws per visit; baseline, 
and up to 4 time points 
post-drug/placebo 
administration). Total blood 
withdrawn: ~8 tablespoons. 
 

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4 Cardiovascular and 
other physiological 
measures 
 
 
 
 
Heart rate and 
rhythm via ECG 
0 
continuous throughout 
visits 
 
 
Brachial blood 
pressure 
0 
several throughout visits, 
several in the 24-hour 
period after experimental 
visits 
 
 
Finger blood 
pressure 
0 
continuous throughout 
visits 
 
 
Microneurography for 
nervous system 
activity assessment 
0 
continuous throughout 
visits (needles placed at 
beginning of visits and 
removed before discharge) 
 
 
Brain blood flow 
0 
continuous throughout 
visits 
 
 
Limb blood flow 
0 
several throughout the 
experimental visits 
 
 
End-tidal carbon 
dioxide 
0 
continuous throughout 
visits 
 
 
Pulse oximetry 
0 
continuous throughout 
visits 
 
 
Tissue oxygen 
saturation 
0 
continuous throughout 
visits 
 
 
Urine sample 
0 
once each visit 
 
5 Sufentanil 
Administration 
0 
Once 
 
 
 
 
5.  Safety Precautions.  (Describe safeguards to address the serious risks listed above.) 
a.  Describe the procedures for protecting against or minimizing any potential risks for each of the more 
than minimal risk research procedures listed above. 
Sufentanil administration: 30 micrograms of sufentanil will be administered once during one of the two 
experimental visits. The product that will be used will be a DsuviaTM sublingual tablet, or similarly packaged 
placebo. 
Risks and their mitigation: After sufentanil administration, it is possible participants will temporarily (e.g., 
to several minutes) experience low blood pressure, high heart rate, disorientation, become tired or dizzy, 
and/or develop a headache. While some individuals may feel discomfort from one or more of these 
sensations, it is expected that they will subside within a few minutes. In rare cases subjects may become 
nauseous or vomit. In extremely rare conditions individuals may have difficulty breathing. In such extreme 
cases, when medical treatment is needed, we will immediately stop testing and monitor the participant 
until all vital signs are within safe limits. Naloxone will completely reverse all opioid effects within 2 
minutes of IV administration and 5 minutes of intramuscular administration. However, at the dose in the 
study proposed, we do not expect that significant respiratory depression will occur.  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 whenever sufentanil is administered to observe 
and intervene should the patient exhibit the slightest evidence of respiratory depression well before any 

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patient danger should arise.  Standard airway intervention equipment will always be readily available. We 
have safely performed similar trials, using identical experimental procedures, with ketamine (STU 
092017-068), fentanyl (STU 092017-069), and morphine (STU 092017-070) administrations without major 
complications in 40+ young adults in the previous two years. 
 
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,  
• 
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   
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, uber, or taxi service).  The subject will also receive 
the recommendation to have someone observe them for the rest of the day and overnight. 
 
Lower-body negative pressure (LBNP): LBNP to pre-syncope will be used to simulate a hemorrhagic 
injury. LBNP is performed by the subject lying on a table with their lower body (from iliac crest) inside an 
airtight container.  A vacuum source is connected to that container.  40 mmHg negative pressure will 
initially be applied to the chamber for 3 min, with this pressure decreasing by 10 mmHg every 3 min until 
signs and/or symptoms of pre-syncope are observed (e.g., bradycardia, sustained systolic blood pressure 
<80 mmHg, nausea, lightheadedness, and/or diaphoresis). This approach is a validated method to 
simulate a hemorrhagic challenge (see PMID: 15016789). Dr. Crandall’s laboratory has performed this 
procedure on hundreds of individuals (inclusive of 40+ individuals who received ketamine, morphine, or 
fentanyl) without any adverse incidents.  
Risks and their mitigation: The possible risks of this procedure are light-headedness, feeling faint, nausea 
and rarely a subject may faint. If this occurs, the procedure will be stopped and the subject will begin to 
feel better almost immediately. 
 
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.   
Risks and their mitigation: These typical responses are immediately reduced 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.   
Risks and their mitigation: Removal of the applied pressure immediately relieves the painful sensation, 
and the subject can voluntarily stop the test at any time. A pre-set maximum of 3 kg of pressure will 
ensure there is no damage to the tissue.    
 
Microneurography: Nerve signals from the nerves in the arm [i.e. median nerve (inside portion of the 
middle part of the arm), radial nerve (inside portion of the forearm), or posterior cutaneous nerve (outside 
portion of the forearm)] will be measured. To locate the nerves, we use ultrasound imaging. When the nerve 
is located, we insert a small sterile needle (an electrode about the size of an acupuncture needle) through 
the skin. The participant 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, the participant may notice a tingling, 

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pins and needles, cramping, or dull achy sensation. A second needle serves as a reference electrode and 
is inserted just under the skin, a couple of inches away from the nerve. Once the needles are in place it is 
extremely unlikely the participant will feel any discomfort. This method of recording nerve signals in human 
participants has been used in over 3000 studies since 1979. We have performed over 300 recordings in 
our laboratory without any major complications. In rare cases, individuals may have tenderness, soreness, 
or numbness in the nerve recording area for a few days that subsides without treatment. 
Risks and their mitigation: Consistent with published guidelines for microneurography, we will limit the nerve 
search time (from needle insertion until an adequate signal is acquired) to 60 minutes. Also, we will not 
record from the same nerve within one 28-day period. While not anticipated, we will stop this technique if 
they feel too much discomfort from microneurography. Participants will be instructed not to perform heavy 
lifting and to avoid rubbing/massaging the upper arm for ~24 hours to reduce the potential for inflammation-
related acute neuropathy (occurs in fewer than 1% of cases). 
 
Blood draws: A sterile catheter will be inserted into an arm vein for blood collection of plasma 
catecholamine concentrations. A total of ~8 tablespoons of blood will be withdrawn across all visits.  
Risks and their mitigation: 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 (less than 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 participant may have 
discomfort, bleeding, and/or bruising and on rare occasions, a person may feel dizzy or faint. 
 
Health history assessment: Participants will fill out a survey related to their physical well-being. 
Risks and their mitigation: It is possible individuals may feel uncomfortable while completing this survey. 
We will ensure all participants are aware of this procedure during the informed consent visit. If a participant 
is uncomfortable completing all of the survey, they will be reminded that 1) their participation is entirely 
voluntary, 2) that only study investigators will have access to the surveys and their results, and 3) only de-
identified results will be shared in scientific meetings and/or in future scientific manuscripts. 
 
 
b.  Where appropriate, discuss provisions for ensuring necessary medical or professional intervention in 
the event of adverse events, or unanticipated problems involving subjects. 
When the participant is undergoing any testing, they will be supervised by an ACLS trained nurse and/or 
physician. Of note, a board-certified anesthesiologist will always be present when sufentanil is 
administered. There is a fully stocked “crash cart” with a defibrillator and medications (including naloxone) 
within 50 feet of the laboratory. IV anti-arrhythmic medications are rapidly available if a sustained but not 
life-threatening arrhythmia were to occur. Airway management equipment is also stocked in that cart. 
Furthermore, the Texas Health Resource Emergency Room is minutes away if an escalation of care is 
required. 
 
Upon screening, participants will be given contact information for a nurse to contact in case any adverse 
event occurs following discharge from experimental days. However, this is unlikely to occur given the 
short-acting effects of sufentanil and the fact that participants are not discharged until vital signs are 
similar to that of baseline values. 
 
c.  Will the safeguards be different between/among groups?   
 
Yes 
 
No 
 
 
 

Statistical Analysis 
Data was assessed for normality and are presented as means ± SD or medians [interquartile 
ranges], when appropriate. Based on our prior data investigating pharmacologic agents’ effects 
on tolerance to LBNP (12, 24, 25), a sample size of n = 15 was estimated, but to maintain 
consistency with the previous studies, we recruited 29 individuals. Paired t-tests or Wilcoxon 
Signed-Rank tests were used for all paired comparisons (e.g., Urine-specific gravity, CSI, pain 
ratings, differences in CSI between the sexes etc.). Plasma catecholamine concentrations were 
compared between trials (placebo vs. sufentanil) using mixed-effects model analyses. 
Cardiovascular and cerebrovascular responses were evaluated every 30 seconds for the cold 
pressor test [time x trial], and the last minute of each LBNP stage [LBNP stage x trial], with the 
variables with each challenge compared using repeated-measures two-way ANOVAs or mixed-
effects model. If a significant interaction was identified, a post hoc Šidák multiple comparison 
test was employed. Α < 0.05 was considered statistically significant. Data were analyzed using 
GraphPad Prism 9 (GraphPad Software Inc., La Jolla, CA, USA).