Relative Adrenal Insufficiency Is a Risk Factor for Pediatric Sepsis: A Proof-of-Concept Study

Area of Science:

• Pediatric critical care
• Endocrinology
• Immunology

Background:

• Glucocorticoid (GC) therapy recommendations for pediatric sepsis have shifted due to weak evidence.
• Relative adrenal insufficiency (RAI) affects approximately 32.8% of pediatric sepsis patients.
• The role of RAI status in guiding GC therapy for pediatric sepsis remains controversial.

Purpose of the Study:

• To establish the first pediatric RAI mouse model using SF1CreSRBIfl/fl mice.
• To investigate the pathogenesis of RAI in pediatric sepsis.
• To evaluate the efficacy of GC therapy in pediatric RAI sepsis.

Main Methods:

• Utilized a novel 21-day-old SF1CreSRBIfl/fl mouse model for pediatric RAI.
• Induced sepsis using cecal ligation and puncture (CLP) and cecal slurry (CS) models.
• Performed RNA sequencing to analyze inflammatory responses and transcriptional pathways.

Main Results:

• RAI mice demonstrated significantly higher mortality rates during sepsis.
• RAI mice exhibited persistent inflammatory responses.
• GC therapy effectively rescued RAI mice and mitigated sepsis-induced mortality.
• RNA sequencing identified dysregulation of AP-1 and NF-κB pathways in RAI mice, contributing to persistent inflammation.

Conclusions:

• The study supports a precision medicine strategy for GC therapy in pediatric sepsis, guided by RAI status.
• RAI is a critical factor influencing sepsis outcomes and GC treatment response.
• This pediatric RAI mouse model provides a valuable platform for future research into sepsis pathogenesis and treatment.