The Role of Dysfunctional HDL in Sepsis

Completed

• Conditions: Septic Shock; Sepsis
• Interventions: Other: Observational study

• Registration Number: NCT02934997
• Lead Sponsor: University of Florida

Brief Summary

To determine the role of dysfunctional high density lipoprotein (Dys-HDL) in predicting or mediating progression to chronic critical illness or morbid long-term outcomes in patients being treated for community-acquired or hospital-acquired sepsis.

Detailed Description

The long-term goal of this research program is to characterize the antecedents and mediators of morbid long-term outcomes in patients with sepsis. Despite successful early management, sepsis is a disease with a high incidence of chronic critical illness (CCI - intensive care unit stay ≥ 14 days with organ dysfunction) and morbid long-term outcomes (functional dependence or death at 1 year), which occur frequently in early survivors. Both the rapid identification of patients at risk for morbid outcomes and the development of novel therapies are crucial for improving outcomes after sepsis. High density lipoprotein (HDL) defends against sepsis-associated organ injury by: 1) neutralizing bacterial endotoxin, 2) modulating innate cellular immunity and preventing release of inflammatory cytokines, and 3) preventing endothelial cell activation and dysfunction. However, HDL can become dysfunctional (Dys-HDL) in the setting of inflammation, losing protective functions and becoming pro-inflammatory. Our preliminary results demonstrate that Dys-HDL is present in early sepsis and that persistent Dys-HDL elevation (first 48 hours) is associated with adverse outcomes (death, hospice or nursing home care). The overall goal of this proposal is to investigate and fully characterize the role of Dys-HDL in a diverse population of patients with both CA and HA-sepsis. The central hypothesis of this study is that structural and functional changes in HDL during sepsis are associated with the persistent presence of Dys-HDL as well as the inflammation and endothelial dysfunction that lead to acute organ dysfunction, CCI, and morbid long-term outcomes. To test this, we will enroll 160 patients in a two-site, prospective, longitudinal, cohort study.

Study Timeline

• Study First Submitted: 2016-10-12
• Study First Submitted QC: 2016-10-12
• Study First Posted: 2016-10-17
• Study Start: 2016-11-01
• Primary Completion: 2019-05-03
• Study Completion: 2019-05-03
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-21
• Last Update Posted: 2020-02-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 88

Inclusion Criteria

• patients meeting the recently updated definition of sepsis (suspected or confirmed infection plus ≥ 2 SOFA points) OR septic shock (hypotension not responsive to 30 mL/kg IV fluids, vasopressor requirement, and lactate ≥ 2)23 and being treated with an institutional, evidence-based guideline (EBG) management bundle for sepsis within 24 hours which has been adopted at both sites.

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Exclusion Criteria

• significant traumatic brain injury (evidence of neurologic injury on CT scan and a GCS <8)
• refractory shock (likely death within 12 hours)
• alternative/confounding diagnosis causing shock (e.g., myocardial infarction or pulmonary embolus)
• uncontrollable source of sepsis (e.g., irreversible disease state such as unresectable dead bowel)
• patients deemed futile care or have advanced directives limiting resuscitative efforts
• severe CHF (NY Heart Association Class IV)
• Child-Pugh Class B or C liver disease
• HIV/AIDS causing severe immunocompromise
• organ transplant recipient on immunosuppressive agents
• known pregnancy
• inability to obtain informed consent
• diagnosed disorders of lipid metabolism.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Hospital-Acquired Sepsis	Observational study	UFH (Gainesville) is a Level 1 Trauma Center and surgical tertiary care center with 24 trauma intensive care unit (ICU) and 24 surgery ICU beds and are the primary ICUs for almost every surgical patient in the hospital and the location for recruitment for Project #1 of the Sepsis P50. Patients meeting the recently updated definition of sepsis (suspected or confirmed infection plus ≥ 2 SOFA points) OR septic shock (hypotension not responsive to 30 mL/kg IV fluids, vasopressor requirement, and lactate ≥ 2) and being treated with an institutional, evidence-based guideline (EBG) management bundle for sepsis within 24 hours in the UFH Surgical ICU will be approached for enrollment.
Community-Acquired Sepsis	Observational study	The Adult ED at UF JAX is a high volume, high acuity ED which treats approximately 90,000 patients per year. All CA-sepsis patients will be recruited from the UF JAX ED. Patients meeting the recently updated definition of sepsis (suspected or confirmed infection plus ≥ 2 SOFA points) OR septic shock (hypotension not responsive to 30 mL/kg IV fluids, vasopressor requirement, and lactate ≥ 2) and being treated with an institutional, evidence-based guideline (EBG) management bundle for sepsis within 24 hours presenting to the UF Health Jacksonville Emergency Department (ED) will be approached for enrollment.

Primary Outcome Measures

Name	Time	Method
Early sepsis-associated organ dysfunction, incidence of chronic critical illness and morbid long-term outcomes after sepsis.	1 year

Secondary Outcome Measures

Name	Time	Method
The temporal relationship between Dys-HDL and sepsis and endothelial biomarkers in patients with sepsis.	4 days
Explore changes in HDL function from patients with sepsis with rapid recovery versus patients with sepsis who develop CCI versus healthy controls.	90 days