The Usefulness of Inflammatory Markers to Predict Poor Outcomes for Trauma Patients

Trauma Injury Clinical Trial

Official title:

Comparison of Inflammatory Markers (Serum Mitochondrial DNA, Delta Neutrophil Index, Inflammatory Cytokines) According to the Injury Severity, and Development of Risk Prediction Model Using Inflammatory Markers for Trauma Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05441787
• Other study ID #: PMT2022
• Secondary ID: 2022R1I1A1A01068
• Status: Recruiting
• Start date: July 25, 2022
• Est. completion date: May 31, 2025

Study information

• Verified date: August 2023
• Source: Wonju Severance Christian Hospital
• Contact: Kwangmin Kim
• Phone: +82-10-8810-1208
• Email: lukelike[@]yonsei.ac.kr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

1) Research Hypothesis 1. Trauma -> Inflammation -> Severe inflammation -> Poor prognosis 2. If the degree of inflammation in the serum is precisely measurable, the prognosis of patients with trauma can be predicted. In addition, if inflammatory processes linked to serum mitochondrial DNA copy number (smtDNAcn) and delta neutrophil index (DNI) are demonstrated, early intervention to improve outcomes in patients with trauma and a poor prognosis may be possible. 2) Basis of Research Hypothesis 1. The Sequential Organ Failure Assessment (SOFA) score is currently used as a measurement tool to evaluate the severity and prognosis of critically ill patients. Recently, some studies reported that the DNI, an inflammatory index, is useful as a prognostic index. Although DNI is a simple prognostic index, further studies are necessary to investigate its usefulness as a reliable prognostic index for severely injured patients. 2. Therefore, this study aimed to: i. prospectively analyze the effectiveness of DNI by measuring the degree of inflammation in severely injured patients; ii. Measure serum mitochondrial DNA, which is suggested as a mechanism preceding DNI elevation, and identify the sequence of inflammatory steps leading to circulating mitochondrial DNA as a damage-associated molecular pattern (DAMP), DNI, neutrophils, and inflammatory cytokines; and iii. Establish the effectiveness of each indicator as a prognostic factor, construct a prediction model for poor prognosis, and prove the effectiveness of the final risk model.

Description:

1) Research Objectives 1. Quantitative measurement of serum mtDNA copy number (smtDNAcn), delta neutrophil index (DNI), and inflammatory cytokines [interleukin (IL) -1β/2/6/12, Interferon (IFN-ℽ), Tumor necrosis factor (TNF-α), IL-4/10)] over time 2. Analysis of correlation between smtDNAcn, DNI, and inflammatory cytokines (IL-1β/2/6/12, IFN-ℽ, TNF-α, IL-4/10) at initial presentation, on trauma days #1 and #2, and poor outcomes [multiorgan distress syndrome (MODS), mortality] 3. Construction and validation of a prognostic index using biological markers associated with inflammation (smtDNAcn, DNI, and inflammatory cytokines) 2) Contents of the Research Project 1. Measurement of biological indicators over time - Measurement of smtDNAcn, DNI, and inflammatory cytokines over time using polymerase chain reaction (PCR) and multiplex assay in patients classified as severely injured based on the injury severity score (ISS) (ISS ≥16). 2. Analysis of correlation between biologic markers and poor outcomes (MODS, mortality) - Identification of independent risk factors to predict poor outcomes such as MODS and mortality among inflammatory markers (serum mtDNA copy number, DNI, neutrophil count, and inflammatory cytokines) in this study. 3. Predictive Model Construction and Validation - Construction of a scoring system using inflammatory markers (smtDNAcn, DNI, neutrophils, and cytokines) and comparison with the SOFA score 3) Strategies and methods for the research project 1. A. Subjects: all trauma patients who visited Wonju Severance Christian hospital, regional trauma center. 2. Study period and patients recruitment i. 1st and 2nd year (until construction of prognostic scoring system): 200 patients (MODS:50, mortality: 50) ii. 3rd year (for validation): 100 patients (MODS: 30, mortality: 30) 3. Measurement of serum mtDNA copy number, DNI, and inflammatory cytokines i. Blood sampling: At the initial presentation and again on trauma days #1 and #2. ii. smtDNAcn, cytokines (IL-1β/2/6/12, IFN-ℽ, TNF-α, IL-4/10) by PCR, multiplex, and DNI using an automatic cell analyzer. 4. Analysis of correlation between biologic markers and poor outcomes (MODS, mortality) i. Statistical analysis of inflammatory markers such as smtDNAcn, cytokines (IL-1β/2/6/12, IFN-ℽ, TNF-α, IL-4/10) measured at the initial presentation, on trauma day #1, and #2 between severely injured patients with no poor outcomes and those with poor outcomes such as MODS and mortality risk. 5. Risk model construction using inflammatory markers to predict MODS and mortality risk i. Recruitment of 100 severely injured patients for validation on 3rd year during study period ii. The recruited patients were divided into low-risk and high-risk groups according to the new risk model, cut-off value of each inflammatory marker, and SOFA score. iii. Comparison of sensitivity and specificity of the new risk model, inflammatory markers, and SOFA score.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: May 31, 2025
• Est. primary completion date: May 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

• Injury severity score = 16

Exclusion Criteria:

• Age =18 years
• Pregnancy in women
• Death at initial presentation of the case
• Patients who refused to participate in the study

Related Conditions & MeSH terms

• Multiple Trauma
• Trauma Injury
• Trauma, Multiple
• Wounds and Injuries

Locations

Country	Name	City	State
Korea, Republic of	Wonju Severance Christian Hospital	Wonju	Gangwon

Sponsors (2)

Lead Sponsor	Collaborator
Wonju Severance Christian Hospital	National Research Foundation of Korea

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (10)

Bang HJ, Kim K, Shim H, Kim S, Jung PY, Choi YU, Bae KS, Kim IY, Jang JY. Delta neutrophil index for predicting mortality in trauma patients who underwent emergent abdominal surgery: A case controlled study. PLoS One. 2020 Mar 23;15(3):e0230149. doi: 10.1371/journal.pone.0230149. eCollection 2020. — View Citation

Faust HE, Reilly JP, Anderson BJ, Ittner CAG, Forker CM, Zhang P, Weaver BA, Holena DN, Lanken PN, Christie JD, Meyer NJ, Mangalmurti NS, Shashaty MGS. Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients. Chest. 2020 Jan;157(1):67-76. doi: 10.1016/j.chest.2019.09.028. Epub 2019 Oct 14. — View Citation

Hu Q, Ren J, Wu J, Li G, Wu X, Liu S, Wang G, Gu G, Li J. Elevated Levels of Plasma Mitochondrial DNA Are Associated with Clinical Outcome in Intra-Abdominal Infections Caused by Severe Trauma. Surg Infect (Larchmt). 2017 Jul;18(5):610-618. doi: 10.1089/sur.2016.276. Epub 2017 Apr 17. — View Citation

Kong T, Park YS, Lee HS, Kim S, Lee JW, You JS, Chung HS, Park I, Chung SP. The delta neutrophil index predicts development of multiple organ dysfunction syndrome and 30-day mortality in trauma patients admitted to an intensive care unit: a retrospective analysis. Sci Rep. 2018 Nov 30;8(1):17515. doi: 10.1038/s41598-018-35796-4. — View Citation

Krychtiuk KA, Ruhittel S, Hohensinner PJ, Koller L, Kaun C, Lenz M, Bauer B, Wutzlhofer L, Draxler DF, Maurer G, Huber K, Wojta J, Heinz G, Niessner A, Speidl WS. Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients. Crit Care Med. 2015 Dec;43(12):2633-41. doi: 10.1097/CCM.0000000000001311. — View Citation

Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF, Quintana C, Osorio JC, Wang Z, Zhao Y, Lawler LA, Christie JD, Meyer NJ, Mc Causland FR, Waikar SS, Waxman AB, Chung RT, Bueno R, Rosas IO, Fredenburgh LE, Baron RM, Christiani DC, Hunninghake GM, Choi AM. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med. 2013 Dec;10(12):e1001577; discussion e1001577. doi: 10.1371/journal.pmed.1001577. Epub 2013 Dec 31. — View Citation

Simmons JD, Lee YL, Mulekar S, Kuck JL, Brevard SB, Gonzalez RP, Gillespie MN, Richards WO. Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects. Ann Surg. 2013 Oct;258(4):591-6; discussion 596-8. doi: 10.1097/SLA.0b013e3182a4ea46. — View Citation

Thurairajah K, Briggs GD, Balogh ZJ. The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies. Eur J Trauma Emerg Surg. 2018 Jun;44(3):325-334. doi: 10.1007/s00068-018-0954-3. Epub 2018 Apr 9. — View Citation

Yamanouchi S, Kudo D, Yamada M, Miyagawa N, Furukawa H, Kushimoto S. Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: time course and the association with clinical status. J Crit Care. 2013 Dec;28(6):1027-31. doi: 10.1016/j.jcrc.2013.05.006. Epub 2013 Jun 18. — View Citation

Zhang Q, Itagaki K, Hauser CJ. Mitochondrial DNA is released by shock and activates neutrophils via p38 map kinase. Shock. 2010 Jul;34(1):55-9. doi: 10.1097/SHK.0b013e3181cd8c08. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality (dichotomous)	The number of deaths	Within 30 days after trauma
Primary	Multiorgan distress syndrome (dichotomous)	The number of patients with SOFA = 6	Within 30 days after trauma
Secondary	Hospital length of stay (continuous)	Measured in days from admission to discharge	From date of the admission until the date of first discharge from the hospital, assessed up to 60 days
Secondary	Intensive care unit (ICU) stay (continuous)	Measured in days from ICU admission to ICU out	From date of ICU admission (in cases of ICU admission at the initial presentation) until the date of first discharge from ICU, assessed up to 60 days