Adrenal function and dysfunction in critically ill patients

Abstract

Critical illnesses are characterized by increased systemic cortisol availability, which is a vital part of the stress response. 'Relative adrenal failure' (later termed critical illness-related corticosteroid insufficiency; CIRCI) is a condition in which the systemic availability of cortisol is assumed to be insufficiently high to face the stress of the illness, and is most typically thought to occur in the acute phase of septic shock. Researchers suggested that CIRCI could be diagnosed by a suppressed incremental cortisol response to an injection of adrenocorticotropic hormone, irrespective of the baseline plasma cortisol. This concept triggered several randomized clinical trials on the impact of large "stress doses" of hydrocortisone to treat CIRCI, which gave conflicting results. Recent novel insights in the response of the hypothalamus-pituitary-adrenal axis to acute and prolonged critical illnesses challenge the concept of CIRCI, as currently defined, as well as the current practice guidelines for diagnosis and treatment. In this Review, these novel insights are integrated within a novel conceptual framework that can be used to re-appreciate adrenocortical function and dysfunction in the context of critical illness. This framework opens new avenues for further research and for preventive and/or therapeutic innovations. KEY POINTS • The amount of cortisol that is produced by patients during critical illness is not much higher, if at all, than that produced during health. • Increased systemic cortisol availability during critical illness is largely driven by decreased cortisol binding proteins in the circulation, by the reduced binding affinity of these proteins, and by suppressed cortisol breakdown.

COVID-19 infection and glucocorticoids: update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency

“…Additionally, as previously mentioned, the HPA axis plays a significant role in stress-priming the immune response and the lack of physiological increase in GC secretion in AI patients during mild illness intuitively exposes them to higher risk of progressing to more critical stages, especially if replacement therapy is not properly administered. Moreover, as noted in other critical illnesses, COVID-19 pneumonia can affect residual adrenal function [20] through cytokine release, worsening the outcome of patients with secondary AI. This is true also for tertiary adrenal insufficiency, the commonest cause for AI in the general population, resulting from long-term (more than 4 weeks) steroid treatment (equal or more than 5 mg of prednisolone per day), especially if administered in a noncircadian fashion (e.g., night doses).…”

“…In fact, if in one hand, supraphysiological dose of exogenous GCs have been shown to exerts detrimental effects in the early phase (by increasing the plasma viral load), one can argue the possibility to restrain the cytokine storm of the second, and more harmful, phase suppressing the immune overreaction by steroid treatment [19]. Moreover, in critically ill patients, the HPA axis may be unable to produce sufficient amount of corticosteroids, leading to critical illness-related corticosteroid insufficiency (CIRCI) [20]. Although the pathological features and clinical progression of COVID-19 resemble those seen in other coronavirus infections for which various standardised steroid protocols have been proposed, recent WHO guidance on the clinical management of COVID-19 advises against corticosteroids, unless indicated for another reason [21].…”

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…Critical illness-related corticosteroid insufficiency is a term used to define the central role played by the HPA-axis and the activated GRα complex in the pathogenesis of dysregulated systemic inflammation in critical illness (17). Three major pathophysiologic events account for the neuroendocrine decompensation observed in CIRCI: (i) multi-level dysregulation of the HPA-axis correlating with circulating inflammatory cytokine levels; (ii) altered cortisol metabolism [reviewed in (122)], and (iii) secondary generalized circulating and tissue specific reduction in GRα number/function with observed multifactorial tissue resistance to endogenous glucocorticoids (17). The role of mitochondrial oxidative stress in reducing GRα number/function is reviewed later (see section Oxidative Stress and CIRCI).…”

Subphenotypes in Patients with Septic Shock Receiving Vitamin C, Hydrocortisone, and Thiamine: A Retrospective Cohort Analysis

“…Low-dose corticosteroids have been used as an adjuvant therapy for septic shock, as it downregulates the dysfunctional proinflammatory response and limits the anti-inflammatory response [4,5], increases adrenergic responsiveness [6], and preserves the endothelial glycocalyx [7]. Meanwhile, doses of corticosteroid in current guidelines do not consider the increased half-life of cortisol in the critically ill and may further increase central adrenocortical inhibition [8]. Two large randomized controlled trials have recently examined the effects of low-dose corticosteroids on mortality after septic shock [9,10], albeit with conflicting results.…”