The Role of Dysfunctional HDL in Sepsis

The Role of Dysfunctional HDL in Community and Hospital Acquired Sepsis

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock
• Intervention / Treatment: Other: Observational study

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 Type: Observational
• Enrollment (Actual): 88

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with sepsis or septic shock presenting to both sites.

Description

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.

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Community-Acquired Sepsis; 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.	Other: Observational study
Hospital-Acquired Sepsis; 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.	Other: Observational study

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: National Institute of General Medical Sciences (NIGMS)

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): May 3, 2019
• Study Completion (Actual): May 3, 2019

Study Registration Dates

• First Submitted: October 12, 2016
• First Submitted That Met QC Criteria: October 12, 2016
• First Posted (Estimate): October 17, 2016

Study Record Updates

• Last Update Posted (Actual): February 24, 2020
• Last Update Submitted That Met QC Criteria: February 21, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: septic shock; sepsis; cholesterol; high density lipoprotein
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Toxemia; Shock, Septic
• Other Study ID Numbers: IRB201701349-N; UFlorida (Other Identifier: University of Florida); 1K23GM115690-01 (U.S. NIH Grant/Contract); UFJ2016-032 (Other Identifier: University of Florida, Jacksonville)