Dan Hao
student
University of KY
Lexington, Kentucky, United States
Disclosure information not submitted.
chieko Mineo
professor
University of Texas Southwestern Medical Center, United States
Disclosure information not submitted.
Philip Shaul
professor
University of Texas Southwestern Medical Center, United States
Disclosure information not submitted.
Xiangan Li, PhD
professor
University of Kentucky Medical Center, United States
Disclosure information not submitted.
Title: Use of Precision Medicine to Guide Corticosteroids Therapy for Pediatric Sepsis
Background:
Previous Sepsis Campaign Guidelines recommended timely corticosteroids (CS) therapy for septic children with fluid-refractory, catecholamine-resistant shock and suspected or proven absolute adrenal insufficiency (grade 1A). However, last year, the recommendation was changed to "either IV hydrocortisone or no hydrocortisone may be used if adequate fluid resuscitation and vasopressor therapy are not able to restore hemodynamic stability" (grade 2C). This change in recommendation indicates a lack of evidence to address whether adrenal insufficiency is a risk factor and if CS therapy is beneficial for pediatric sepsis. The use of an adrenal insufficiency animal model will provide evidence to address these questions.
Methods and Results:
SR-BI is a well-established high density lipoprotein (HDL) receptor. It mediates cholesterol uptake from HDL, which provides cholesterol for CS synthesis in adrenal gland. SF1CreSR-BIfl/fl knockout mice exhibited specific depletion of SR-BI in adrenal gland, resulting in a lack of induced corticosteroids (iCS) in response to ACTH without affecting basal GC levels – a status of relative adrenal insufficiency (RAI). Using SF1CreSR-BIfl/fl mice as a RAI model, we tested our hypothesis in two sepsis models: cecal ligation and puncture (CLP)- or cecal slurry-induced sepsis. We found that 21-day old SF1Cre SR-BIfl/fl young mice are susceptible to sepsis (86.67 % survival in SR-BIfl/fl mice versus 12.5% in SF1CreSRBIfl/fl mice, p=0.001 in CLP-induced sepsis; 33% survival in SR-BIfl/fl mice versus 0% in SF1CreSRBIfl/fl mice, p< 0.05 in cecal slurry-induced sepsis). Supplementation of hydrocortisone significantly improved the survival rate in CLP-treated SF1Cre SR-BIfl/fl mice, but had no effect on CLP-treated SR-BIfl/fl mice. Further mechanistic study revealed that iCS production is an essential host response for effectively controlling immune response.
Conclusions:
Using SF1CreSR-BIfl/fl mice as a unique RAI mouse model, we demonstrate that iGC production is an essential host response to control immune response and a deficiency in iCS production – a status of RAI, is a risk factor for pediatric sepsis; our finding provides a proof of concept to support the use of a precision medicine approach for CS therapy – selectively using CS therapy for pediatric septic patients with RAI.