Glucocorticoids in Sepsis: To Be or Not to Be

Abstract

Sepsis is a highly lethal syndrome resulting from dysregulated immune and metabolic responses to infection, thereby compromising host homeostasis. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequently adrenocortical glucocorticoid (GC) production during sepsis are important regulatory processes to maintain homeostasis. Multiple preclinical studies have proven the pivotal role of endogenous GCs in tolerance against sepsis by counteracting several of the sepsis characteristics, such as excessive inflammation, vascular defects, and hypoglycemia. Sepsis is however often complicated by dysfunction of the HPA axis, resulting from critical-illness-related corticosteroid insufficiency (CIRCI) and GC resistance. Therefore, GCs have been tested as an adjunctive therapy in sepsis and septic shock in different randomized clinical trials (RCTs). Nonetheless, these studies produced conflicting results. Interestingly, adding vitamin C and thiamin to GC therapy enhances the effects of GCs, probably by reducing GC resistance, and this results in an impressive reduction in sepsis mortality as was shown in two recent preliminary retrospective before-after studies. Multiple RCTs are currently underway to validate this new combination therapy in sepsis.

Keywords: HAT therapy; HPA axis dysfunction; glucocorticoid resistance; glucocorticoids; sepsis.

Figure 1

Schematic representation of the hypothalamic–pituitary–adrenal (HPA) axis. Upon circadian rhythm, stress, and inflammatory cytokines, the hypothalamus secretes corticotropin-releasing hormone (CRH), stimulating the pituitary to release adrenocorticotropic hormone (ACTH), which in turn induces cortisol (human) or corticosterone (rodents) by the adrenal cortex. These glucocorticoids in turn negatively regulate the activity of the HPA axis via the paraventricular nucleus (PVN) of the hypothalamus and the anterior pituitary, or indirectly by decreasing the expression of inflammatory cytokines. Figure created with BioRender.com.

Figure 2

The essential roles of glucocorticoids to tolerate sepsis. In sepsis patients, the immune system is activated to eliminate the infectious agents; however, if not properly balanced, pathogen eradication is associated with excessive inflammation and endothelial barrier dysfunction leading to organ failure. Dysregulated immune responses are also accompanied with changes in metabolism, such as hypoglycemia. Glucocorticoids are induced upon infections to maintain homeostasis and tolerate the life-threatening impact of sepsis on the host.

Figure 3

Mechanisms of glucocorticoid resistance (GCR) in sepsis. Pro-inflammatory cytokines and oxidative stress have shown to interfere with the GC signaling pathway at multiple levels. This leads to an inadequate response of the GR to both endogenous (cortisol/corticosterone) and exogenous GCs to tolerate collateral damage induced by sepsis. Vitamin C has been shown to restore the GR function by reverting the effect of oxidative stress on GR's ligand- and DNA-binding capacity. TF-BS, transcription factor binding site; GRE, GC-responsive element; NTL, nuclear translocation.

Figure 4

HAT therapy. The function or levels of hydrocortisone, ascorbic acid, and thiamin are reduced in sepsis. Administering one of these agents as monotherapy has shown favorable but limited outcomes. Combination of these three agents in the so-called HAT therapy may work synergistically to combat sepsis.