Aspects of the Neuroendocrine Stress Response in Patients with Severe Sepsis or Trauma

Abstract

This thesis investigated the pathophysiology and clinical implications of adrenal insufficiency (AI) in the context of systemic inflammation with a particular focus on the interplay between the renin-angiotensin-aldosterone system (RAAS), cortisol metabolism, and glucocorticoid sensitivity. Through a series of observational studies and narrative reviews, a comprehensive analysis of hormonal alterations, their impact on critical care management, and the potential for targeted therapeutic strategies in critically ill patients is provided. The first study examined the profiles of pro- and anti-inflammatory cytokines and total cortisol levels in patients with severe sepsis and septic shock. Elevated levels of interleukin (IL)-6 and tumour necrosis factor receptor 1 (TNFR1) were identified as significant predictors of mortality in this population, while the independent role of cortisol in predicting outcomes remains less definitive. IL-1 receptor antagonist (Ra) showed a significant median reduction from day 1 to day 7, with a significant association with an increased mortality ratio, suggesting its potential role as a marker of immune resolution and recovery in the current cohort. This study is the first to explore the trajectory of these biomarkers in a South African cohort with severe sepsis and septic shock. The findings highlight the importance of IL-6, TNFR1, ILRa and total cortisol in characterising disease severity, progression, and outcomes, emphasising their potential utility in risk stratification for critically ill patients. A related investigation evaluated the free cortisol response to synacthen and glucocorticoid sensitivity in patients with traumatic brain injury (TBI). Findings from this study highlight altered glucocorticoid sensitivity and responsiveness in TBI. Significant variability in 9 measures of glucocorticoid sensitivity attributed to receptor-level changes and impaired hypothalamic-pituitary-adrenal (HPA) axis function was observed. These findings suggest that in traumatic brain injury, the sensitivity and responsiveness to glucocorticoids are altered with mechanistic and therapeutic implications. To establish a baseline for understanding glucocorticoid receptor dynamics in critical illness, the thesis extended this investigation to glucocorticoid sensitivity in healthy volunteers to provide a baseline for interpreting cortisol metabolism and receptor activity in critically ill states. This comparative analysis established the extent to which critical illness modifies glucocorticoid receptor function. Moreover, the concept of critical illness-related mineralocorticoid insufficiency is introduced, challenging the conventional focus on glucocorticoid insufficiency alone and advocating for a more comprehensive and nuanced approach to adrenal pathophysiology and support in critical illness. Finally, the thesis critically evaluated adjunctive corticosteroid therapy in septic shock. To integrate these findings into clinical practice, the thesis provides a narrative review of adjunctive corticosteroid therapy, particularly the use of adjunctive hydrocortisone with or without fludrocortisone in septic shock. The biochemical and molecular basis of corticosteroid action, the potential benefits of dual therapy targeting both glucocorticoid and mineralocorticoid pathways, and the limitations of current treatment protocols are discussed. In summary, this thesis advances the understanding of adrenal insufficiency in critical illness by elucidating the complex interactions between cortisol production, RAAS dysregulation, and glucocorticoid and mineralocorticoid receptor dynamics. The integrated approach taken 10 here—spanning observational studies and comprehensive reviews—offers a holistic view of adrenal dysfunction and proposes actionable insights with the potential to refine current understanding, with the aim to improve outcomes for patients with septic shock and traumatic injury.