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

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT03621085
• Collaborator: United States Department of Defense (U.S. Fed)
• Enrollment: 43
• Location: 1
• Arms: 2
• Actual Duration (Months): 37
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this project is to test how ketamine, an analgesics 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
Hemorrhage; Healthy	Drug: Ketamine Hydrochloride; Other: Placebo	Phase 4

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 ketamine 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: 43 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 - Ketamine
• Actual Study Start Date: Jun 1, 2018
• Actual Primary Completion Date: Jun 30, 2021
• Actual Study Completion Date: Jun 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine Subjects will receive up to 20 mg Ketamine Hydrochloride while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.	Drug: Ketamine Hydrochloride; A total of 20 mg of Ketamine Hydrochloride will be administered intravenously
Placebo Comparator: Placebo Subjects will receive placebo while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.	Other: Placebo; Subjects will receive placebo

Outcome Measures

Primary Outcome Measures

1. Cumulative Stress Index [12 month]

   Tolerance to a simulated hemorrhagic challenge will be assessed, for both the placebo and ketamine 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 ketamine.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

• 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	Texas Health Presbyterian Hospital Dallas	Dallas	Texas	United States	75231

Sponsors and Collaborators

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

Investigators

• Principal Investigator: craig G Crandall, Ph.D., University of Texas Southwestern Medical Center

Study Documents (Full-Text)

• Study Protocol - Sep 23, 2019
• Statistical Analysis Plan - Aug 30, 2021
• Informed Consent Form - Sep 23, 2019

More Information

Publications

• Watso JC, Huang M, Moralez G, Cramer MN, Hendrix JM, Cimino FA 3rd, Belval LN, Hinojosa-Laborde C, Crandall CG. Low dose ketamine reduces pain perception and blood pressure, but not muscle sympathetic nerve activity, responses during a cold pressor test. J Physiol. 2021 Jan;599(1):67-81. doi: 10.1113/JP280706. Epub 2020 Oct 20.

• Responsible Party: Craig Crandall, Professor of Internal Medicine, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03621085
• Other Study ID Numbers: STU 092017-068
• First Posted: Aug 8, 2018
• Last Update Posted: Nov 26, 2021
• Last Verified: Oct 1, 2021

• 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; Ketamine

Study Results

Participant Flow

Arm/Group Title	Ketamine First, Then Placebo	Placebo First, Then Ketamine
Arm/Group Description	Ketamine visit (20 mg) first, then Placebo visit (saline)	Placebo visit (saline) first, then Ketamine visit (20 mg)
Period Title: Enrollment
STARTED	22	21
COMPLETED	16	14
NOT COMPLETED	6	7
Period Title: Enrollment
STARTED	16	14
COMPLETED	16	14
NOT COMPLETED	0	0
Period Title: Enrollment
STARTED	16	14
COMPLETED	16	14
NOT COMPLETED	0	0
Period Title: Enrollment
STARTED	16	14
COMPLETED	16	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants
Overall Participants	43
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	43 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	23 53.5%
Male	20 46.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 16.3%
Not Hispanic or Latino	36 83.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.3%
Asian	5 11.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 4.7%
White	33 76.7%
More than one race	1 2.3%
Unknown or Not Reported	1 2.3%
Region of Enrollment (participants) [Number]
United States	43 100%

Outcome Measures

1. Primary Outcome

Title	Cumulative Stress Index
Description	Tolerance to a simulated hemorrhagic challenge will be assessed, for both the placebo and ketamine 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 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	Subjects will receive up to 20 mg Ketamine Hydrochloride while the effects of this drug on tolerance to a hemorrhagic insult will be assessed. Ketamine Hydrochloride: A total of 20 mg of Ketamine Hydrochloride will be administered intravenously	Subjects will receive placebo while the effects of this drug on tolerance to a hemorrhagic insult will be assessed. Placebo: Subjects will receive placebo
Measure Participants	30	30
Mean (Standard Deviation) [mmHg x minutes]	635 (391)	649 (362)

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 ketamine.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Pressure pain tolerance was evaluated in a subset of individuals

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	Subjects will receive up to 20 mg Ketamine Hydrochloride while the effects of this drug on tolerance to a hemorrhagic insult will be assessed. Ketamine Hydrochloride: A total of 20 mg of Ketamine Hydrochloride will be administered intravenously	Subjects will receive placebo while the effects of this drug on tolerance to a hemorrhagic insult will be assessed. Placebo: Subjects will receive placebo
Measure Participants	20	20
Mean (Standard Deviation) [Kilograms]	3.3 (1.0)	1.6 (0.6)

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.
Adverse Event Reporting Description	Each participant completed both drug and placebo conditions, therefore, groups are combined for adverse event reporting.
Arm/Group Title	Ketamine		Placebo
Arm/Group Description	Ketamine trials		Placebo trials
All Cause Mortality
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Serious Adverse Events
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (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.