Inflammatory Markers in Trauma Patient Outcomes

Inflammatory Response to Trauma - Does Early Cytokine Modulation Improve Patient Outcome

It is unknown whether early modulation of inflammatory cytokines is associated with improved patient outcomes, reduced narcotic requirements in orthopaedic patient population, and improved patient subjective pain after hospital discharge. Preliminary animal and clinical studies have shown correlation between elevated blood cytokine concentrations during the acute phase of trauma and the development of post-traumatic complications. Early administration of nonsteroidal anti-inflammatory drug (NSAID) in animals significantly reduced inflammatory profiles, improved pulmonary edema, and enhanced arteriole vasoconstriction in response to hemorrhage. The ability to modify post-traumatic physiologic response via short-term administration of a non-steroidal anti-inflammatory drug (NSAID) may lead to improved patient outcome. In addition, given the current landscape for opioid epidemic in the United States, alternative non-opioid pain management during acute trauma has the potential to reduce opioid consumption and represents a pivotal component of multimodal analgesia strategy.

By doing this study, the investigators hope to learn how to provide the best care for all patients in the state of Kentucky. Patient participation in this research will last about 1 year.

Study Overview

• Status: Completed
• Conditions: Polytrauma
• Intervention / Treatment: Drug: Saline Solution; Drug: Ketorolac

Detailed Description

Accidental trauma is the 4th leading cause of death in the United States, and it is associated with a complex inflammatory response. This response is associated with post-traumatic complications such as; multi-organ dysfunction syndrome (MODS), bacterial pneumonia, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and post traumatic pain (PTP). It is unknown whether early modulation of inflammatory cytokines is associated with improved patient outcomes, reduced narcotic requirements, and improved patient subjective pain after hospital discharge.

Preliminary data has shown: (1) elevated blood cytokine concentrations during the acute phase of trauma are correlated with the development of fatal post-traumatic complications, (2) that early administration of a non-steroidal anti-inflammatory drug (NSAID) resulted in decreased blood serum levels of IL-6, Prostaglandin E2 (PGE2), improved pulmonary edema, and enhanced arterioles ability to vasoconstrict in response to hemorrhage in animal models, and (3) that the addition of the internal physiologic parameters (inflammatory cytokines) to New Injury Severity Score (NISS - a marker of the external anatomical insult) significantly improves the ability to predict hospital length of stay of trauma patients when compared to NISS alone. The investigator's group is the first to use an integrative approach that combines the external anatomic injury data with the internal physiologic response for accurate prediction of patient's clinical outcome. Therefore, if the investigators apply this same mindset to treatment, the investigators can improve the trauma patients' care by addressing both parameters as opposed to solely focusing on the external injury as done in the past. The ability to modify post-traumatic physiologic response via short-term administration of a NSAID may lead to improved patient outcome.

Over the last decade, clinicians remain puzzled over the safety of NSAID administration after fracture in terms of bone union. In addition, given the current landscape for opioid epidemic in the United States, alternative non-opioid pain management during acute trauma has the potential to reduce opioid consumption and represents a pivotal component of multimodal analgesia strategy.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

-

Exclusion Criteria:

• Patient age < 18 or > 65
• Patients with injury more than 24 hours prior to evaluation
• Hemorrhagic shock or risk of significant hemorrhage.
• Patients with preexisting inflammatory medical condition such as inflammatory arthropathy or inflammatory bowel disease
• Patients with acquired immunodeficiency syndrome (AIDS)
• Patients who are pregnant
• Patients with active GI bleed or ulceration
• Patients with chronic use of steroids or immune modulating drugs or history of organ transplantation
• Patients with preexisting chronic renal, liver, or lung disease
• Patients with history of myocardial infarctions
• Patients with chronic heart failure
• Patients with allergy to NSAID
• Patients with coagulation defects (Clotting factor deficiencies, thrombophilia, or any bleeding disorder)
• Patients receiving chronic opioid therapy or treatment for opioid use disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard of Care without NSAID; Polytrauma participants will receive standard of care in addition to saline solution according to standard ATLS and standard ICU routine medical care.	Drug: Saline Solution; Participants will receive 10 ml of saline solution IV every 6 hours for their first 5 days of hospitalization; Other Names: Normal Saline
Experimental: Standard of Care with NSAID; Participants in the group will receive Ketorolac in addition to standard of care for the standard ATLS or ICU routine medical care.	Drug: Ketorolac; Participants will receive Ketorolac at 30 mg IV every 6 hours for their first 5 days of hospitalization; Other Names: Toradol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Hospital Stay	Duration of the hospital stay will be calculated from electronic health record	Up to 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Interleukin 1	Daily blood collections during the first 5 days of hospitalization. Interleukin 1 will be measured by the sandwich ELISA, and data will be presented as change in the baseline level of Interleukin 1 from presentation to the emergency room to day 5 of hospitalization.	baseline and day 1, 2, 3 ,4 and 5
Change in Interleukin 6	Daily blood collections during the first 5 days of hospitalization. Interleukin 6 will be measured by the sandwich ELISA, and data will be presented as change in the baseline level of Interleukin 6 from presentation to the emergency room to day 5 of hospitalization.	baseline and day 1, 2, 3 ,4 and 5
Change in Interleukin 10	Daily blood collections during the first 5 days of hospitalization. Interleukin 10 will be measured by the sandwich ELISA, and data will be presented as change in the baseline level of Interleukin 10 from presentation to the emergency room to day 5 of hospitalization.	baseline and day 1, 2, 3 ,4 and 5
Change in Prostaglandin E-2	Blood will be collected over the course of 5 days of hospitalization. Prostaglandin E-2 will be measured by the sandwich ELISA, and data will be presented as change in the baseline level of Prostaglandin E-2 from presentation to the emergency room to day 5 of hospitalization	baseline and day 1, 2, 3 ,4 and 5
Post Traumatic Complications	The Incidence of post traumatic complications in the patients which includes, but is not limited to the occurrence of SIRS, MODS, bacterial pneumonia, and ARDS will be recorded throughout the duration of the hospital stay, usually up to 30 days. Data will be presented as the percent of participants with a diagnosed post traumatic complication of any kind.	Up to 30 days
Mortality	The Incidence of death related to the initial trauma/traumatic complications will be recorded for the first 30 days.	Up to 30 days
Change in Patient Pain Scores	The patient reported pain scores (visual analog pain scores) will be recorded throughout the course of the hospital stay. The scores are reported by the patients and range from 0 indicating no pain to 10 meaning the worst pain imaginable. These will be reported as daily averages.	Up to 30 days
Morphine Milligram Equivalents in House	The the morphine milligram equivalents (MME) will be recorded throughout the course of the hospital stay. These will be reported as daily totals.	Up to 30 days
Change in Inpatient Subjective Pain Reports	This will be in the form of patient response. If patient reports severe levels of pain this will be documented accordingly. Data will be collected periodically during hospitalization which typically lasts less than 30 days.	up to 30 days
Change in Outpatient Subjective Pain Reports	Patients reports of level of pain and how much it inhibits their daily activities will be recorded in the outpatient setting. This will be reported for each patient follow-up visit. Several visits are possible and data will only be collected for the first year of follow-up . Data will be presented as the change in subject pain over time (up to 356 days)	up to 365 days

Collaborators and Investigators

• Sponsor: Arun Aneja
• Investigators: Principal Investigator: Arun Aneja, MD, University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2019
• Primary Completion (Actual): June 20, 2023
• Study Completion (Actual): June 20, 2023

Study Registration Dates

• First Submitted: September 12, 2018
• First Submitted That Met QC Criteria: September 13, 2018
• First Posted (Actual): September 14, 2018

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: trauma; opioid; inflammation; Inflammatory cytokine
• Additional Relevant MeSH Terms: Wounds and Injuries; Multiple Trauma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ketorolac
• Other Study ID Numbers: 43611

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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