- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03147352
Prognosis and Treatment of Necrotizing Soft Tissue Infections: A Prospective Cohort Study (ProTreat)
ProTreat - Prognosis and Treatment of Necrotizing Soft Tissue Infections: A Prospective Cohort Study
Study Overview
Status
Intervention / Treatment
Detailed Description
Introduction:
Necrotizing soft-tissue infections (NSTI) are among the most serious and deadly infections known. They are characterized by rapidly progressing soft-tissue inflammation with necrosis and can quickly cause multiple organ failure and death. Mortality has been shown to be 25-35 %, with survivors coping with amputations and prolonged rehabilitation.
Currently, there is a lack of proper tools to evaluate the severity and prognosis of NSTI in individual patients. This results in necessary, yet sometimes overzealous surgical debridement, culminating in prolonged patient rehabilitation and invalidity. Hyperbaric oxygen therapy (HBOT) may be added as adjunctive therapy of NSTI. However, there is no clear understanding of the effectiveness of HBOT on NSTI. The investigators seek to remedy these two issues by examining multiple biomarkers over the course of several studies.
Methodology:
Location: Copenhagen University Hospital, Rigshospitalet, Denmark.
Design: Observational cohort study.
Cohort: All NSTI patients in Denmark since 2013.
Controls: 50-100 Patients undergoing elective, orthopedic surgery at Rigshospitalet.
Biomarkers: soluble thrombomodulin, syndecan-1, sE-selectin, VE-cadherin, protein C, suPAR.
Sample size calculations:
1: The test kits the investigators will be using to measure the primary outcome sTM (Human sCD141 ELISA kit, Nordic Biosite) have an interassay standard variation of 0.58 ng/ml. In order to be certain that measured changes in sTM concentration are not a result of interassay standard deviation, the investigators have set the mimimum relevant difference in sTM to 3 x the interassay standard variation, thus 1.75 ng/ml.
The investigators prepared a power calculation using a Wilcoxon rank sum test. Assuming an estimated standard deviation of 4.6 ng/ml and a mean of 9.9 ng/ml, the investigators will need to include a maximum of 150 NSTI patients and 50 elective surgery patients to reach a statistical power of at the very least 60 % (a very conservative estimate) and presumably closer to 85 % (more realistic estimate) at a 5 % significance level. The estimates depend on data distribution.
2: The test kits the investigators will be using to measure the primary outcome sE-selectin (Human CD62E ELISA kit, Diaclone) have an interassay standard variation of 0.37 ng/ml. In order to be certain that measured changes in sE-selectin concentration are not a result of interassay standard variation, the investigators have set the mimimum relevant difference in sE-selectin to 3 x the interassay standard variation, thus 1.1 ng/ml.
Assuming an estimated standard deviation of 209 ng/ml (septic shock) vs. 23 ng/ml (severe sepsis and sepsis) and means of 295 vs. 181 ng/ml, respectively, the investigators will need to include at least 132 NSTI patients and 50 elective surgery patients to reach a statistical power of 90 % at a 5 % significance level.
3: suPAR levels during NSTI have never previously been examined. In order to estimate sample size and since NSTI patients are also septic, the investigators are basing the sample size calculation on a previous study concerning the correlation between suPAR and sepsis. This study found statistically significant correlation between suPAR levels and mortality in 141 patients. This is also the goal of this study. Further studies have also found significant correlations between suPAR, sepsis and mortality in 132 patients. The investigators will include at least 150 NSTI patients during this study.
Statistical considerations:
To check whether the HBOT treatment has an effect on the range of biomarkers, the investigators will analyze the means and variances of the biomarkers in the NSTI group and the two control groups, the orthopaedic patients and the sepsis patients. Non-parametric data will be log-transformed and will be presented as median values with IQR. Wilcoxon rank sum tests will be used for group comparisons. Fisher's exact test will be used for categorical data. Correlation analysis will be performed using Spearman rank correlation or Pearson correlation. To assess the quality of suPAR as a predictor of health outcomes, a model selection exercise will be conducted with various types of regression models. The type of regression will vary with the type of health-outcome, with suPAR as the predictor in all cases. Receiver operating characteristic (ROC) curve analysis will be applied to determine suPARs accuracy as a marker of severity and mortality in patients with NSTI. The investigators will construct Kaplan-Meier curves for survival data. Statistically significant results are when p<0.05.
Data:
Data will be handled according to the National Data Protection Agency. All original records (including consent forms and questionnaires) will be archived at the trial site for 15 years. The National Data Protection Agency has approved the biobank (RH-2016- 199). Data checks have been programmed into the data registry to warn when input variables are outside of predefined possible clinical range. All registry data will be compared to external data sources, i.e. medical records, to ensure accuracy. Standard Operating Procedures have been implemented regarding data collection. Patients with missing data for calculating for example SAPS II scores etc. will be excluded from the study.
Ethics:
The trial will adhere to the Helsinki Declaration and Danish law. The National Ethics Committee and the Regional Ethics Committee (H-16021845) have approved this study.
Biomarker analyses, data extraction and interpretation will be performed once the recruitment of participants has ended.
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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Copenhagen, Denmark, 2100
- Copenhagen University Hospital, Rigshospitalet
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
NSTI cohort:
All NSTI patients treated at the University Hospital of Copenhagen, Rigshospitalet.
Orthopaedic control cohort:
Undergoing elective orthopedic surgery (non-pathological fractures, joint replacement surgery or spine surgery) at Copenhagen University Hospital
Description
Inclusion criteria for NSTI patients (both of which must be met):
- Diagnosed with NSTI based on surgical findings (necrosis of any soft tissue compartment; dermis, hypodermis, fascia or muscle)
- Admitted to the Intensive Care Unit (ICU) and/or operated for NSTI at Copenhagen University Hospital
Exclusion Criteria for NSTI patients:
- They are categorized as non NSTI in the operating theatre
Inclusion criteria for orthopaedic control patients:
- Undergoing elective orthopedic surgery (non-pathological fractures, joint replacement surgery or spine surgery) at Copenhagen University Hospital
Exclusion criteria for orthopaedic control patients:
- Ongoing infection or inflammatory condition
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
NSTI patients
NSTI is 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 that spreads along tissue structures.
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Hyperbaric oxygen therapy with 100 % oxygen at 1.8 ATA for 2 hours.
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Orthopaedic control patients
Elective orthopaedic control patients.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
sTM and sE-selectin as biomarkers of HBOT effect in NSTI patients
Time Frame: At admission, and during the next 3 days in the ICU
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Changes in plasma sTM and sE-selectin concentrations in NSTI patients, compared with the control group
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At admission, and during the next 3 days in the ICU
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suPAR as a biomarker of disease severity and prognosis in NSTI patients with and without septic shock
Time Frame: At admission
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Association between plasma suPAR levels and NSTI mortality, and SAPS II and SOFA scores
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At admission
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Amputation rate
Time Frame: During ICU admission (expected average of 8 days)
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At any anatomical site
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During ICU admission (expected average of 8 days)
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Microbial etiology
Time Frame: During ICU admission (expected average of 8 days)
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Tissue and blood samples
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During ICU admission (expected average of 8 days)
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Time from admission to primary hospital until first surgery/debridement
Time Frame: 2 days
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2 days
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Mortality
Time Frame: While in the ICU, and at 28, 90, 180 days
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Mortality
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While in the ICU, and at 28, 90, 180 days
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ICU scoring systems
Time Frame: During ICU admission (expected average of 8 days)
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SAPS II (day 1) APACHE II (day 1) SOFA, GCS excluded (day 1-7)
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During ICU admission (expected average of 8 days)
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Multiple organ failure
Time Frame: During ICU admission (expected average of 8 days)
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Multiple organ failure
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During ICU admission (expected average of 8 days)
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Debridements
Time Frame: During ICU admission (expected average of 8 days)
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Number of debridements
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During ICU admission (expected average of 8 days)
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Ventilator treatment
Time Frame: During ICU admission (expected average of 8 days)
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Ventilator treatment during stay at ICU
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During ICU admission (expected average of 8 days)
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Renal replacement therapy
Time Frame: During ICU admission (expected average of 8 days)
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Renal replacement therapy during stay at ICU
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During ICU admission (expected average of 8 days)
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Vasopressor treatment
Time Frame: During ICU admission (expected average of 8 days)
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Vasopressor treatment during stay at ICU
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During ICU admission (expected average of 8 days)
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Steroid treatment
Time Frame: Up to 7 days before surgical diagnose at primary hospital
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Steroid treatment (injection/oral intake) up to development of NSTI
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Up to 7 days before surgical diagnose at primary hospital
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HBOT and endothelial biomarkers
Time Frame: At admission, and the next 3 days in the ICU
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Any differences in sTM, syndecan-1, sE-selectin, VE-cadherin and protein C levels between NSTI patients who do not receive HBOT within the first 24 hours of ICU admission (because they are deemed too unstable for HBOT) vs. those who receive HBOT within the first 12 and 24 hours of ICU admission
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At admission, and the next 3 days in the ICU
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Biomarkers and disease severity
Time Frame: At admission, and the next 3 days in the ICU
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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 suPAR, sTM and sE-selectin will be investigated to see if there is a correlation between disease severity in these groups
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At admission, and the next 3 days in the ICU
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Ole Hyldegaard, MD, PhD, Rigshospitalet, Denmark
- Principal Investigator: Peter V Polzik, MD, Rigshospitalet, Denmark
Publications and helpful links
General Publications
- Kayal S, Jais JP, Aguini N, Chaudiere J, Labrousse J. Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infection. Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 1):776-84. doi: 10.1164/ajrccm.157.3.9705034.
- Huttunen R, Syrjanen J, Vuento R, Hurme M, Huhtala H, Laine J, Pessi T, Aittoniemi J. Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: a prospective cohort study. J Intern Med. 2011 Jul;270(1):32-40. doi: 10.1111/j.1365-2796.2011.02363.x. Epub 2011 Mar 21.
- Backes Y, van der Sluijs KF, Mackie DP, Tacke F, Koch A, Tenhunen JJ, Schultz MJ. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. Intensive Care Med. 2012 Sep;38(9):1418-28. doi: 10.1007/s00134-012-2613-1. Epub 2012 Jun 16.
- Blann A, Seigneur M. Soluble markers of endothelial cell function. Clin Hemorheol Microcirc. 1997 Jan-Feb;17(1):3-11.
- Buras JA, Stahl GL, Svoboda KK, Reenstra WR. Hyperbaric oxygen downregulates ICAM-1 expression induced by hypoxia and hypoglycemia: the role of NOS. Am J Physiol Cell Physiol. 2000 Feb;278(2):C292-302. doi: 10.1152/ajpcell.2000.278.2.C292.
- Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007 Jun;454(3):345-59. doi: 10.1007/s00424-007-0212-8. Epub 2007 Jan 26.
- Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, Chappell D, Stoeckelhuber M, Welsch U, Reichart B, Peter K, Becker BF. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007 Oct 23;116(17):1896-906. doi: 10.1161/CIRCULATIONAHA.106.684852. Epub 2007 Oct 8.
- Polzik P, Johansson PI, Hyldegaard O. How biomarkers reflect the prognosis and treatment of necrotising soft tissue infections and the effects of hyperbaric oxygen therapy: the protocol of the prospective cohort PROTREAT study conducted at a tertiary hospital in Copenhagen, Denmark. BMJ Open. 2017 Oct 5;7(10):e017805. doi: 10.1136/bmjopen-2017-017805.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
- Infection
- Prognosis
- Bacterial Infections
- Risk Factors
- Staphylococcus aureus
- Biological markers
- Observational study
- Wounds and Injuries
- Endothelium
- syndecan-1
- Fasciitis
- Gangrene
- Fasciitis, Necrotizing
- Soft Tissue Infections
- Fournier's Gangrene
- Streptococcal septic shock syndrome
- Flesh eating bacteria
- Meleneys ulcer
- Streptococcus pyogenes
- Soft Tissue Infections/blood
- Necrosis/blood
- Necrosis/diagnosis
- Necrosis/mortality
- Necrosis/surgery
- Skin Diseases, Bacterial
- Hyperbaric oxygen therapy
- suPAR
- sTM
- sE-selectin
- VE-cadherin
- protein C
- HBOT
Additional Relevant MeSH Terms
- Pathologic Processes
- Necrosis
- Disease Attributes
- Musculoskeletal Diseases
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Clostridium Infections
- Infections
- Communicable Diseases
- Soft Tissue Infections
- Gangrene
- Fasciitis
- Fournier Gangrene
- Gas Gangrene
- Fasciitis, Necrotizing
Other Study ID Numbers
- PROTREAT1-PP-2017
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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