Clinical trial NCT03147352: Prognosis and Treatment of Necrotizing Soft Tissue Infections: A Prospective Cohort Study
Official title: ProTreat - Prognosis and Treatment of Necrotizing Soft Tissue Infections: A Prospective Cohort Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Necrotizing Soft Tissue Infection
Necrotizing Fascitis
Gas Gangrene
Fournier Gangrene
Keywords: Fasciitis
Gangrene
Fasciitis, Necrotizing
Soft Tissue Infections
Fournier's Gangrene
Streptococcal septic shock syndrome
Flesh eating bacteria
Meleneys ulcer
Wounds and Injuries
Streptococcus pyogenes
Staphylococcus aureus
Soft Tissue Infections/blood
Necrosis/blood
Necrosis/diagnosis
Necrosis/mortality
Necrosis/surgery
Prognosis
Risk Factors
Bacterial Infections
Infection
Skin Diseases, Bacterial
Observational study
Biological markers
Endothelium
suPAR
sTM
syndecan-1
sE-selectin
VE-cadherin
protein C
Hyperbaric oxygen therapy
HBOT
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Seventh Framework Programme
First posted: 2017-05-10
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
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

Brief summary: The investigators will analyze biomarkers related to the prognosis and treatment of necrotizing soft tissue infections (NSTI). The focus will be on whether certain endothelial and immune system biomarkers can function as markers of disease severity, mortality as well as the effects of hyperbaric oxygen therapy (HBOT). Biomarkers will be measured upon admission to an intensive care unit at Copenhagen University Hospital and during the following 3 days.

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.

Eligibility criteria: 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

Primary outcomes:
measure: sTM and sE-selectin as biomarkers of HBOT effect in NSTI patients
timeFrame: At admission, and during the next 3 days in the ICU
measure: suPAR as a biomarker of disease severity and prognosis in NSTI patients with and without septic shock
timeFrame: At admission
Secondary outcomes:
measure: Mortality
timeFrame: While in the ICU, and at 28, 90, 180 days
measure: Amputation rate
timeFrame: During ICU admission (expected average of 8 days)
measure: ICU scoring systems
timeFrame: During ICU admission (expected average of 8 days)
measure: Multiple organ failure
timeFrame: During ICU admission (expected average of 8 days)
measure: Debridements
timeFrame: During ICU admission (expected average of 8 days)
measure: Microbial etiology
timeFrame: During ICU admission (expected average of 8 days)
measure: Time from admission to primary hospital until first surgery/debridement
timeFrame: 2 days
measure: Ventilator treatment
timeFrame: During ICU admission (expected average of 8 days)
measure: Renal replacement therapy
timeFrame: During ICU admission (expected average of 8 days)
measure: Vasopressor treatment
timeFrame: During ICU admission (expected average of 8 days)
measure: Steroid treatment
timeFrame: Up to 7 days before surgical diagnose at primary hospital
measure: HBOT and endothelial biomarkers
timeFrame: At admission, and the next 3 days in the ICU
measure: Biomarkers and disease severity
timeFrame: At admission, and the next 3 days in the ICU
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital, Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Peter V Polzik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: Ole Hyldegaard, MD, PhD
role: STUDY_DIRECTOR
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