Clinical trial NCT02533011: Evaluation of the Heparin Binding Protein Levels in Sepsis
Official title: Heparin Binding Protein (HBP) in Sepsis for the Prediction of Disease Progression
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Sepsis
Infection
Septic Shock
Keywords: Sepsis
Heparin Binding Protein
Lead sponsor: Christiana Care Health Services
Sponsor class: OTHER
First posted: 2015-08-26
Enrollment: 1055
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients admitted through the emergency department with infection.

Brief summary: Present criteria used to define sepsis are non-specific, making it difficult to both distinguish sepsis from other diseases and to predict which patients are likely to become more severely ill. In standard care, patients at risk of becoming more severely ill are neither identified nor indicated for resuscitative efforts until they develop hemodynamic insufficiency or organ failure; after progression to severe disease, mortality increases significantly. The identification of risk patients can lead to earlier initiation of resuscitation therapies and potentially lead to reduced morbidity and mortality. This study aims to determine whether Heparin-binding protein (HBP), which is secreted from neutrophils during infection and a mediator of vascular leakage, can act as a biomarker for the progression to severe sepsis with circulatory failure.

The objective of this study is to validate the utility of HBP to predict the development of delayed onset organ dysfunction in sepsis in patients and to compare the performance of HBP relative to currently used prognostic biomarkers in sepsis.

Detailed description: Sepsis is a heterogeneous disorder caused by an invasive infection that results in host inflammatory response. The underlying pathogenesis is complex and dependent on the etiologic microorganism, site of infection, and host factors. Present criteria defining sepsis (including change of body temperature, increased heart and respiration rates, and leukocytosis/leukopenia) are non-specific making it difficult to distinguish sepsis from other diseases and in particular to predict which patients are likely to become more severely ill. The consensus definition of sepsis has been debated over the past years and one suggested approach is to focus more on the presence of organ dysfunction. In standard care, patients at risk of becoming more seriously ill are not identified nor indicated for resuscitative efforts until they develop hemodynamic insufficiency or organ failure. However, after progression to severe disease mortality increases significantly. A recent study showed that almost a quarter of patients presenting with uncomplicated sepsis in an Emergency Department (ED) developed severe sepsis or septic shock within 72 hours. Delayed in-hospital progression to increased organ dysfunction was associated with increased transfer to the intensive care unit (ICU) and increased hospital length of stay. The identification of risk patients can lead to earlier initiation of resuscitation therapies and potentially lead to reduced morbidity and mortality. There are also increasing evidence that a single episode of severe sepsis has negative impact on quality of life and mortality several years after the actual incident. Also, recent studies indicate that less severe organ dysfunction, such as small increases in serum creatinine, are associated with increased long-term mortality among sepsis survivors.

Mechanisms that trigger the release of heparin-binding protein (HBP) from neutrophils in the presence of bacteria have previously been reported. HBP has several functions such as a chemo-attractant and as an activator of monocytes and macrophages. Also, it induces vascular leakage by interacting with the capillary endothelium and breaking cell barriers. In vivo studies have demonstrated that HBP released by the complex formed by the group A streptococcal M1 protein and fibrinogen induces a massive tissue edema contributing to severe organ damage. In clinical investigations, the release of HBP has been demonstrated in various infectious diseases caused by a wide array of bacteria. A recent single-center study of patients admitted for suspected infection and fever showed that plasma levels of HBP were significantly higher among patients who presented with or developed severe sepsis with circulatory failure.

A prospective observational study in a tertiary care Emergency Department. Patients must be identified and enrolled within 72 hours of qualifying inclusion criteria. At this time, unused blood samples collected for routine testing will be examined and the plasma level of HBP will be recorded; only blood samples processed by the lab within 3 hours of collection will be used. In addition, physiologic variables detailed in the data elements section, including mental status, metabolic, renal, heme, hepatic, respiratory, cardiovascular, resuscitation, and vasopressor use will be recorded. Patients who meet the inclusion criteria will be identified. Researchers will collect and record a resuscitation summary for a span of 4 hours; this data, outlined in the data elements section, will be linked to the quality improvement (QI) database of Sepsis Research. Additionally, the patient's HBP plasma levels will be measured from unused blood samples collected for routine lab testing time (T) 24, 48, and 72-hours (T24, T48, T72) after meeting the inclusion criteria (T0); resuscitation summaries will also be collected at T24, T48, T72. For patients meeting sepsis alert criteria, T0 will be defined as the time that the patient qualified; those enrolled based on Predisposition, Injury, Response, Organ dysfunction (PIRO) score will have T0 defined as the time hospital admission was ordered. Patients will be followed throughout their time in the hospital and their outcomes will be recorded.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of a bacterial or viral infection
* 18 years or older
* Meet the sepsis alert criterion (Hypotension (BP \< 90 after 2 L of fluids or lactate ≥ 4) OR
* PIRO (Predispose, Infection, Response, Organ dysfunction ) score ≥ 15 .

Exclusion Criteria:

* Minors (less than 18 years of age)
* Patients who do not meet sepsis criteria as described above

Primary outcomes:
measure: Infection with organ dysfunction, defined as PIRO (Predisposition, Insult, Response, Organ Dysfunction) Score greater than 5
timeFrame: 72 hours after meeting sepsis criteria
Secondary outcomes:
Other outcomes:
Locations:
city: Newark
country: United States
facility: Christiana Care Health System
state: Delaware
Study officials:
affiliation: Christiana Care Health Services
name: Ryan C. Arnold, MD
role: PRINCIPAL_INVESTIGATOR
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