Application of Biomarkers Change to Predict Outcome of Patient With Severe Sepsis

• Conditions: Severe Sepsis; Septic Shock; Multiple Organ Failure; Systemic Inflammatory Response Syndrome (SIRS); Sepsis

• Registration Number: NCT02871895
• Lead Sponsor: Chang Gung Memorial Hospital

Brief Summary

In 2004, the Surviving Sepsis Campaign (SSC) introduced guidelines for the management of severe sepsis and septic shock, as well as strategies for bedside implementation. The treatment recommendations were organized in two bundles. In an international study, enrolling adult patients with severe sepsis admitted to these intensive care units, investigators found that while mortality from severe sepsis is high (44.5%), compliance with resuscitation and management bundles is generally poor in much of Asia. Investigators need to identify the patients at risk for high in-hospital mortality in order to take appropriate steps.

From their past studies, investigators found that sepsis involved inflammation and coagulation. The multiple organ involvement was associated with interaction of novel biomarkers such as cytokines. There is limited data regarding comparing and application of biomarkers of different characteristic on sepsis treatment. A simultaneous detection of multiple cytokines may provide significant prognostic information. For other biomarkers, promising observation data have been put forward, but their potential needs to be evaluated in large-scale, well-designed prospective intervention studies before clinical use can be recommended. Besides many clinical studies on biomarkers were confounded by its lack of standard bundle care for severe sepsis patient.

Here investigators performed a systematic study aimed at evaluating

1. the individual and combined diagnostic accuracy of biomarkers for predicting mortality;

2. whether trend change in biomarker level more useful for above prediction;

3. which biomarker or biomarker combination checked can predict patients at risk of evolving with severe organ dysfunctions.

Detailed Description

Variables will be tested for their association with the outcome using Pearson chi-square test for categorical data and Mann-Whitney U test for numerical data. Comparison the different groups will be conducted by using Mann-Whitney U test for numerical data and using Pearson chi-square test for categorical data. The time course of biomarker plasma levels will be assessed by analysis of variance. Multivariate analysis will be performed using a logistic regression model to estimate the odds ratio of organ failure and dying, along with the 95% confidence interval (CI). Forward and backward selection procedures will be used to iteratively select the variables potentially related to death.

Discrimination will be assessed using the area under the receiver operating characteristic curve to evaluate how well the model distinguished patients who lived from those who died and whether progression of organ dysfunction. A survival analysis will be performed using Kaplan-Meier curves and the log-rank test. Analyses will be completed and a two-tailed p\<0.05 will be considered significant.

Study Timeline

• Study Start: 2013-07
• Study First Submitted: 2015-09-01
• Study First Submitted QC: 2016-08-17
• Study First Posted: 2016-08-18
• Status Verified: 2018-06
• Last Update Submitted: 2018-07-16
• Last Update Posted: 2018-07-18
• Primary Completion: 2018-12
• Study Completion: 2018-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

• Severe sepsis
• Septic shock

Exclusion Criteria

• Patients are < 18 yrs
• Patients are immunocompromised (treatment with corticosteroids >1 mg/kg equivalent prednisone)
• Bone marrow or organ transplant recipients,
• Leucopenia [white blood cells count< 109/L] or neutropenia [polymorphonuclear granulocyte count <0.5 109/L]
• Hematologic malignancy
• Acquired immune deficiency syndrome

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Development of immune dysfunction score to predict 28-day mortality of sepsis patients	baseline and 4 weeks, up to 24 weeks	Several existing scoring systems developed for mortality prediction, such as APACHE II and Sequential Organ Failure Assessment score (SOFA score). However, none of these take immune dysfunction status into account. With a substantial degree of heterogeneity in the sepsis response ranging from cytokines storm to immunoparalysis, better patient stratification is needed. Investigators aimed to develop and validate a scoring system (minimum:0 to maximum:6 scores) that can determine patients' immune dysfunction status related to outcomes.

Secondary Outcome Measures

Name	Time	Method
Deteriorated dynamic acute kidney injury (AKI) stage associated with immune dysfunction and higher mortality in Septic Patients Admitted to Intensive Care Unit	baseline and 4 weeks, up to 24 weeks	A series of inflammatory cytokines participated into the mechanism and associated with the severity and worsening of AKI. We assumed the dynamic change of the AKI containing even better predictive value rather than evaluating the AKI in a single time point. We categorized septic patients into 4 groups based on the variation of AKI stage. In addition to mortality comparison, we also made an investigation to the relationships of immune cytokines in those sepsis patients.
To determine whether delta pulse pressure at day 3 compared with day 1 affect survival outcomes in patients who were diagnosed sepsis and septic shock.	baseline and 4 weeks	Pulse pressure is the difference between the systolic and diastolic blood pressures. It arises from the interaction of cardiac ejection and the properties of the arterial circulation. A wide pulse pressure is associated with increased cardiovascular mortality. However, a widened pulse pressure was suggested as a potential prognostic indicator of decreased mortality in patients with sepsis in a retrospective electronic medical record review. In clinical practice, pulse pressure variation can help predict fluid responsiveness in patients. Furthermore, we sought to determine whether stratification of septic patients according to the changes of pulse pressure (value of pulse pressure at day 3 minus value of pulse pressure at day 1) and status of whether still in need of vasopressor at day 3 could help predict survival. The host immune response to sepsis during progression may play an important role.

Trial Locations

Locations (1)

Chang Gung Memorial Hospital; 🇨🇳 Kaohsiung, Taiwan