Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation




Pharmacology and Nutritional Sciences

First Advisor

Xiang-an Li


Sepsis is a leading cause of death in children. Glucocorticoid (GC) therapy had been strongly recommended for the pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020 due to weak evidence. Relative adrenal insufficiency (RAI) is a condition characterized by impaired inducible glucocorticoid (iGC) production in response to stress. It develops in 32.8% of pediatric septic patients. Unfortunately, little is known about the pathogenesis of RAI in pediatric sepsis, and whether GC therapy should be based on the status of RAI is controversial. In this study, we utilized 21-day-old SF1CreSRBIfl/fl mice as the first pediatric RAI mouse model to assess the pathogenesis of RAI and evaluate GC therapy. RAI mice were susceptible to both cecal ligation and puncture (CLP) and cecal slurry induced septic death, with a survival of 88.9% in SRBIfl/fl mice versus 15.4% in SF1CreSRBIfl/fl mice in CLP model; 33% SRBIfl/fl mice versus 0% in SF1CreSRBIfl/fl mice in cecal slurry model. SF1CreSRBIfl/fl mice featured persistent inflammatory responses, and they were effectively rescued by GC therapy. RNA-seq analysis revealed that RAI leads to persistent inflammatory responses mainly due to transcriptional dysregulation of AP-1 and NF-κB, and cytokine-induced secondary inflammatory response. Furthermore, we identified that a number of prognostic biomarkers reported in pediatric septic patients were also identified in RAI mice. Our findings support a precision medicine approach to guide GC therapy for pediatric patients – use of GC based on the status of RAI. Additionally, our study indicates that the status of RAI is age-dependent.

RAI is commonly diagnosed by the ACTH stimulation test with an increase in total cortisol of < 9 g/dL. This diagnosis was first introduced in the 2004 Surviving Campaign guidelines and GC therapy was recommended for patients with RAI, which is supported by a large clinical trial that showed a beneficial effect of corticosteroid treatment in septic shock patients with RAI. However, another large trial failed to validate these findings in a less severe group of septic patients with RAI. Due to the controversial results, this diagnosis was abandoned in the 2008 Surviving Sepsis Campaign guidelines. But a task force of experts in critical care medicine recommended using the ACTH test to diagnose critical-illness-related corticosteroid insufficiency (CIRCI) in 2008, a health condition including RAI. However, the current sepsis guideline (2021) does not mention RAI or CIRCI, raising questions about the validity of the ACTH stimulation test for diagnosing RAI in septic patients. Our hypothesis is that since ACTH tests adrenal stress responses that may be valid for normal people, but not for septic patients because they are already in high-stress states, therefore may not further respond to the ACTH stimulation. To test this hypothesis, we evaluated the ACTH stimulation test in C57BL/6J mice and RAI mice during sepsis. Indeed, the results showed that the ACTH stimulation test fails to accurately diagnose RAI in acute phase of sepsis. Additionally, ACTH test is harmful during this phase, as evidenced by increased inflammatory cytokine production and mortality rate in both wildtype and RAI mice. The further mechanistic study showed that ACTH induces IL-6 mRNA expression in the adrenal gland mainly through transcriptional regulation of AP-1. Further study indicated that inadequate total GC levels and excessive production of IL-6 could potentially be used as markers for diagnosing RAI, which is associated with the worse outcome of sepsis. It’s important to note that abnormally high total GC levels are also linked to a high-risk death from sepsis.

Overall, our results support that RAI is a risk in pediatric sepsis and the use of GC based on the status of RAI could save more lives. Additionally, we found that the ACTH stimulation test is not an effective diagnostic method for diagnosing RAI in patients with sepsis

Digital Object Identifier (DOI)

Funding Information

NIH R01GM121796 and NIH 1R35GM141478 (X-A Li)

Available for download on Saturday, May 10, 2025