Biomarkers in Patients With Flesh-eating Bacterial Infections (BIONEC)

February 14, 2016 updated by: Ole Hyldegaard

Biomarkers in Necrotizing Soft Tissue Infections - Aspects of the Innate Immune Response

The purpose of this study is to investigate the immune response in patients with necrotizing soft tissue infections (NSTI). The investigation will focus on inflammatory and vasoactive biomarkers as prognostic markers of severity and mortality at admission to Rigshospitalet and the following 3 days

Study Overview

Status

Completed

Conditions

Detailed Description

Necrotizing soft tissue infection (NSTI) is a complex, multi-factorial disease with diverse microbiological etiology and varying co-morbidities. The rapidly spreading infection may cause extensive soft tissue damage, limb loss, and multiple organ failure. The incidence of NSTIs has increased over the past years and the fatality rates are still high despite increased focus on these patients (20-30%). The extensive inflammatory response is thought to be a main course of death. However, it is unknown which biomarkers that are responsible for the deleterious effects and how these molecular mediators are modulated during the infection and treatment regimes. Thus, there is a need for novel insight into the immune system disturbances in order to improve outcome of NSTIs.

Location: Copenhagen University Hospital, Rigshospitalet, Denmark.

Design: Observational cohort study.

Cohort: NSTI patients in Denmark.

Controls: 50-100 Patients undergoing elective, orthopedic surgery at Rigshospitalet.

Biomarkers: The investigators will focus on three major groups of biomarkers: Acute-phase proteins, cytokines and vasoactive biomarkers.

Sample size calculations:

  1. Acute-phase proteins: The investigators expect a mean PTX3-concentration at admission at 120 nmol/L in patients without septic shock and a mean PTX3-concentration at 210 nmol/L in patients with septic shock. With an estimated standard deviation at 100 nmol/L, the inclusion of 52 patients will be able to detect a significant difference with a statistical power of 90% at a 5% significance level. Since the groups are unequal the investigators will need to include 82 patients (N'=52(1+4)^2/4*4).
  2. Cytokines: In a pilot study with seven NSTI patients, the investigators found a minimal clinically relevant difference in IL-6 concentration in NSTI patients with LRINEC < 6 and ≥ 6 to be 1050 pg/ml. With an estimated standard deviation at 2000 pg/ml, the inclusion of 114 patients will be able to detect a significant difference with a statistical power of 80% at a 5% significance level.
  3. Vasoactive proteins: The investigators expect a mean NOx-concentration at admission at 90 μmol/L in patients without septic shock and a mean NOx-concentration at 145 μmol/Lin patients with septic shock. With an estimated standard deviation at 70 μmol/L, the inclusion of 70 patients will be able to detect a significant difference with a statistical power of 90% at a 5% significance level. Since the groups are unequal the investigators will need to include 110 patients (N'=70(1+4)^2/4*4).

Data: Data will be handled according to the National Data Protection Agency. All original records (incl. consent forms and questionnaires) will be archived at trial site for 15 years. The National Data Protection Agency has approved the biobank (2007-58-0015, J. nr. 30-1282).

Ethics: The trial will adhere to the Helsinki Declaration and Danish law. The National Ethics Committee and the Regional Ethics Committee have approved the inclusion of the NSTI patients (CVK-1211709) and the control patients, including biomarker analyses (H-2-2014-071).

Biomarker analyses, data extraction and interpretation will be performed once the recruiting of participants has ended.

Study Type

Observational

Enrollment (Actual)

169

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
        • Copenhagen University Hospital, Rigshospitalet

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

All NSTI patients treated at the University Hospital of Copenhagen, Rigshospitalet

Description

Inclusion Criteria for patients with NSTI:

  • Necrotizing soft tissue infection based on surgical findings
  • Age >18 years
  • Admitted to/planned to be admitted to the ICU at Rigshospitalet and/or operated for NSTI at Rigshospitalet

Exclusion Criteria for patients with NSTI:

  • Patients who at the operating theatre were categorized as non-NSTI patients

Inclusion Criteria for control patients:

  • Patients undergoing elective orthopedic surgery (non-pathologic fractures, joint replacement surgery, back surgery) at Rigshospitalet
  • Age >18 years

Exclusion Criteria for control patients:

  • Patients with ongoing infections

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Patients with NSTI
Definition: An infection that requires acute hospitalization with intensive care treatment and/or surgery as a consequence of severe soft tissue infection in subcutis, muscle and/or fascia and are spreading along tissue structures.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PTX3, NOx and IL-6 as early markers of disease severity in NSTI patients with and without septic shock
Time Frame: Admission, first 24 hours
Primary analysis: Association between PTX3-, NOx-, and IL6-concentration and septic shock (PTX3, NOx) or LRINEC ≥ 6 (IL-6) in NSTI patients at time of admission to Rigshospitalet
Admission, first 24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: 28, 90, 180 days
28, 90, 180 days
Amputation rate
Time Frame: During ICU admission (expected average of 8 days)
At any anatomical site
During ICU admission (expected average of 8 days)
ICU-scoring systems
Time Frame: During ICU admission (expected average of 8 days)
SAPS II (day 1) APACHE II (day 1) SOFA, GCS excluded (day 1-7), Anaya-score
During ICU admission (expected average of 8 days)
Multiple organ failure
Time Frame: During ICU admission (expected average of 8 days)
During ICU admission (expected average of 8 days)
Number of debridements
Time Frame: During ICU admission (expected average of 8 days)
During ICU admission (expected average of 8 days)
Microbial etiology
Time Frame: During ICU admission (expected average of 8 days)
Tissue and blood samples
During ICU admission (expected average of 8 days)
Time from admission to primary hospital until first surgery/debridement
Time Frame: 2 days
2 days
Ventilator treatment, renal replacement therapy, vasopressor treatment during stay at ICU
Time Frame: During ICU admission (expected average of 8 days)
During ICU admission (expected average of 8 days)
Steroid treatment (injection/oral intake) up to development of NSTI
Time Frame: Up to 7 days before surgical diagnose at primary hospital
Up to 7 days before surgical diagnose at primary hospital
Inflammatory biomarkers
Time Frame: Admission and the following 3 days
Secondary analysis: The association between inflammatory biomarkers such as CRP, procalcitonin, mannose-binding-lectin and ficolin-1,2,3, cytokines and septic shock, LRINEC ≥ 6 and SAPS II at admission and the following 3 days
Admission and the following 3 days
Vasoactive biomarkers
Time Frame: Admission and the following 3 days
Secondary analysis: The association between vasoactive biomarkers such as NOx (nitrite, NO2-, and nitrate, NO3-,), L-arginine, asymmetric dimethylarginine, hydrogen sulfide, reactive oxygen species, ICAM-1, E-selectin and septic shock, LRINEC ≥ 6 and SAPS II at admission and the following 3 days
Admission and the following 3 days
The effects of immunoglobulin on inflammatory biomarkers
Time Frame: Admission and the following 3 days
A subgroup analysis will be performed on patients randomized to immunoglobulin or saline as immunoglobulin might affect the biomarker response (PTX3, NO, IL-6). The randomized double-blinded study was initiated April 2014 and registered at ClinicalTrials.gov (NCT02111161).
Admission and the following 3 days
Biomarkers and Severity of disease
Time Frame: Admission and the following 3 days
Subgroup analysis: Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock will be diagnosed according to standardized criteria (American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee) and the biomarkers will be investigated to see if there is a correlation between disease severity and mortality in these groups.
Admission and the following 3 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ole Hyldegaard

Collaborators

Seventh Framework Programme

Investigators

  • Principal Investigator: Marco Bo Hansen, MD, Rigshospitalet, Denmark
  • Study Director: Ole Hyldegaard, MD, PhD, Rigshospitalet, Denmark

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2013

Primary Completion (Actual)

February 1, 2016

Study Completion (Actual)

February 1, 2016

Study Registration Dates

First Submitted

June 29, 2014

First Submitted That Met QC Criteria

July 1, 2014

First Posted (Estimate)

July 3, 2014

Study Record Updates

Last Update Posted (Estimate)

February 17, 2016

Last Update Submitted That Met QC Criteria

February 14, 2016

Last Verified

February 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BIONEC1-MBH-2014

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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