Evaluation of the Heparin Binding Protein Levels in Sepsis

Sepsis Clinical Trial

— HBP  

Official title:

Heparin Binding Protein (HBP) in Sepsis for the Prediction of Disease Progression

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02533011
• Other study ID #: 602986
• Status: Completed
• Phase: N/A
• First received: July 16, 2015
• Last updated: September 22, 2017
• Start date: July 2015
• Est. completion date: July 2017

Study information

• Verified date: September 2017
• Source: Christiana Care Health Services
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1055
• Est. completion date: July 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Infection
• Sepsis
• Septic Shock
• Shock, Septic
• Toxemia

Intervention

Other:
• HBP lab test
Plasma level of Heparin Binding Protein will be evaluated on extra blood specimens already collected as part of standard of care.

Locations

Country	Name	City	State
United States	Christiana Care Health System	Newark	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Christiana Care Health Services

Country where clinical trial is conducted

United States, 

References & Publications (22)

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Herwald H, Cramer H, Mörgelin M, Russell W, Sollenberg U, Norrby-Teglund A, Flodgaard H, Lindbom L, Björck L. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell. 2004 Feb 6;116(3):367-79. — View Citation

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Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589-96. — View Citation

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr;31(4):1250-6. Review. — View Citation

Linder A, Akesson P, Brink M, Studahl M, Björck L, Christensson B. Heparin-binding protein: a diagnostic marker of acute bacterial meningitis. Crit Care Med. 2011 Apr;39(4):812-7. doi: 10.1097/CCM.0b013e318206c396. — View Citation

Linder A, Fjell C, Levin A, Walley KR, Russell JA, Boyd JH. Small acute increases in serum creatinine are associated with decreased long-term survival in the critically ill. Am J Respir Crit Care Med. 2014 May 1;189(9):1075-81. doi: 10.1164/rccm.201311-2097OC. — View Citation

Macheboeuf P, Buffalo C, Fu CY, Zinkernagel AS, Cole JN, Johnson JE, Nizet V, Ghosh P. Streptococcal M1 protein constructs a pathological host fibrinogen network. Nature. 2011 Apr 7;472(7341):64-8. doi: 10.1038/nature09967. — View Citation

McNamara C, Zinkernagel AS, Macheboeuf P, Cunningham MW, Nizet V, Ghosh P. Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence. Science. 2008 Mar 7;319(5868):1405-8. doi: 10.1126/science.1154470. — View Citation

Murugan R, Karajala-Subramanyam V, Lee M, Yende S, Kong L, Carter M, Angus DC, Kellum JA; Genetic and Inflammatory Markers of Sepsis (GenIMS) Investigators. Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival. Kidney Int. 2010 Mar;77(6):527-35. doi: 10.1038/ki.2009.502. Epub 2009 Dec 23. — View Citation

Reinhart K, Bauer M, Riedemann NC, Hartog CS. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev. 2012 Oct;25(4):609-34. doi: 10.1128/CMR.00016-12. — View Citation

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Shapiro N, Howell MD, Bates DW, Angus DC, Ngo L, Talmor D. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med. 2006 Nov;48(5):583-90, 590.e1. — View Citation

Shapiro NI, Trzeciak S, Hollander JE, Birkhahn R, Otero R, Osborn TM, Moretti E, Nguyen HB, Gunnerson KJ, Milzman D, Gaieski DF, Goyal M, Cairns CB, Ngo L, Rivers EP. A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Crit Care Med. 2009 Jan;37(1):96-104. doi: 10.1097/CCM.0b013e318192fd9d. — View Citation

Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013 Mar 2;381(9868):774-5. doi: 10.1016/S0140-6736(12)61815-7. — View Citation

Yende S, D'Angelo G, Kellum JA, Weissfeld L, Fine J, Welch RD, Kong L, Carter M, Angus DC; GenIMS Investigators. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med. 2008 Jun 1;177(11):1242-7. doi: 10.1164/rccm.200712-1777OC. Epub 2008 Mar 27. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Infection with organ dysfunction, defined as PIRO (Predisposition, Insult, Response, Organ Dysfunction) Score greater than 5	Patients with septic shock or severe sepsis	72 hours after meeting sepsis criteria