Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Fentanyl

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT04136548
• Collaborator: United States Department of Defense (U.S. Fed)
• Enrollment: 41
• Location: 1
• Arms: 2
• Actual Duration (Months): 17.6
• Patients Per Site Per Month: 2.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Fentanyl; Other: Placebo	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Fentanyl
• Actual Study Start Date: Jun 1, 2019
• Actual Primary Completion Date: Nov 18, 2020
• Actual Study Completion Date: Nov 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fentanyl Fentanyl will be administered intravenously during one visit.	Drug: Fentanyl; Subjects will receive 75 ug Fentanyl while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.
Placebo Comparator: Placebo Placebo (saline) will be administered intravenously during one visit.	Other: Placebo; Subjects will receive saline while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.

Outcome Measures

Primary Outcome Measures

1. Cumulative Stress Index [12 months]

   Tolerance to a simulated hemorrhagic challenge will be assessed, for both the placebo and fentanyl limbs, by causing progressive central hypovolemia via lower-body negative pressure (LBNP). This progressive lower-body negative pressure challenge will be performed 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). The primary variable will be the quantification of lower-body negative pressure that is required to cause these symptoms. This quantification will be objectively measured via a cumulative stress index which is calculated as the sum of the product of the LBNP level and the duration of each level, until test termination (i.e., 40 mmHg x 3 min + 50 mmHg x 3 min, etc).

Secondary Outcome Measures

1. Pressure Pain Tolerance [12 months]

   Pain assessments will be conducted using a digital algometer to obtain maximum pain thresholds caused by pressure. This pain assessment technique is conducted by applying the tip of a hand-held digital algometer on the subject's digit. Force is 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. This assessment will be performed after the subject has received placebo and fentanyl.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy

• Non-obese (body mass index less than 30 kg/m2)

• Body mass greater than or equal to 65 kg

Exclusion Criteria:

• Subjects who have cardiac, respiratory, neurological and/or metabolic illnesses

• Any known history of renal or hepatic insufficiency/disease

• Pregnancy or breast feeding

• Current smokers, as well as individuals who regularly smoked within the past 3 years

• Positive urine drug screen

• Currently taking pain modifying medication(s)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• United States Department of Defense

Investigators

• Principal Investigator: Craig G Crandall, PhD, Institute for Exercise and Environmental Medicine

Study Documents (Full-Text)

• Study Protocol - Sep 4, 2019
• Statistical Analysis Plan - Oct 26, 2020
• Informed Consent Form - Sep 4, 2019

More Information

Publications

None provided.

• Responsible Party: Craig Crandall, Professor of Internal Medicine, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT04136548
• Other Study ID Numbers: STU 092017-069
• First Posted: Oct 23, 2019
• Last Update Posted: Jan 24, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Hemorrhage; Fentanyl

Study Results

Participant Flow

Pre-assignment Detail	Forty-one adults enrolled by providing written and oral consent. Of these 38, three adults were deemed not to be eligible based upon screening criteria prior to randomization. Therefore, only 38 adults were 'enrolled and randomized' (see 'Participant Flow' below).

Arm/Group Title	Placebo, Then Fentanyl	Fentanyl, Then Placebo
Arm/Group Description	Participants first received Placebo (75 ug) each (<5mins). After a washout period of lying down for resting for sometime , then Fentanyl (75 ug) is administered to each participant (<5 mins)	Participants first received Fentanyl (75 ug) visit. each (<5mins). After a washout period of lying down for resting for sometime , then Placebo (75 ug) is administered to each participant (<5 mins)
Period Title: Enrolled & Randomized
STARTED	19	19
COMPLETED	13	15
NOT COMPLETED	6	4
Period Title: Enrolled & Randomized
STARTED	13	15
COMPLETED	13	15
NOT COMPLETED	0	0
Period Title: Enrolled & Randomized
STARTED	13	15
COMPLETED	13	15
NOT COMPLETED	0	0
Period Title: Enrolled & Randomized
STARTED	13	15
COMPLETED	13	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants
Overall Participants	41
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	41 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	22 53.7%
Male	19 46.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4.9%
Not Hispanic or Latino	39 95.1%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 12.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 9.8%
White	32 78%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	41 100%

Outcome Measures

1. Primary Outcome

Title	Cumulative Stress Index
Description	Tolerance to a simulated hemorrhagic challenge will be assessed, for both the placebo and fentanyl limbs, by causing progressive central hypovolemia via lower-body negative pressure (LBNP). This progressive lower-body negative pressure challenge will be performed 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). The primary variable will be the quantification of lower-body negative pressure that is required to cause these symptoms. This quantification will be objectively measured via a cumulative stress index which is calculated as the sum of the product of the LBNP level and the duration of each level, until test termination (i.e., 40 mmHg x 3 min + 50 mmHg x 3 min, etc).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fentanyl	Placebo
Arm/Group Description	Fentanyl will be administered intravenously during one visit. Fentanyl: Subjects will receive 75 ug Fentanyl while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.	Placebo (saline) will be administered intravenously during one visit. Placebo: Subjects will receive saline while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.
Measure Participants	28	28
Mean (Standard Deviation) [mmHg x minutes]	647 (386)	676 (295)

2. Secondary Outcome

Title	Pressure Pain Tolerance
Description	Pain assessments will be conducted using a digital algometer to obtain maximum pain thresholds caused by pressure. This pain assessment technique is conducted by applying the tip of a hand-held digital algometer on the subject's digit. Force is 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. This assessment will be performed after the subject has received placebo and fentanyl.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Pressure pain tolerance was evaluated in a subset of individuals

Arm/Group Title	Fentanyl	Placebo
Arm/Group Description	Fentanyl will be administered intravenously during one visit. Fentanyl: Subjects will receive 75 ug Fentanyl while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.	Placebo (saline) will be administered intravenously during one visit. Placebo: Subjects will receive saline while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.
Measure Participants	17	17
Median (Inter-Quartile Range) [Kilograms]	1.6	1.1

Adverse Events

Time Frame	Adverse event data were collected from until discharge from the final data collection visit, which typically occurred 6 to 12 months after consent/screening.
Arm/Group Title	Placebo		Fentanyl
Arm/Group Description	Experimental visit with Placebo administration		Experimental visit with Fentanyl administration
All Cause Mortality
	Placebo		Fentanyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)
Serious Adverse Events
	Placebo		Fentanyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Fentanyl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.