J Korean Neurosurg Soc.  2023 Nov;66(6):618-631. 10.3340/jkns.2023.0061.

The Unique Relationship between Neuro-Critical Care and Critical Illness-Related Corticosteroid Insufficiency : Implications for Neurosurgeons in Neuro-Critical Care

• Choo YH
• Kim M
• Kim JH
• Jeon H
• Jung HW
• Ha EJ
• Oh J
• Shim Y
• Kim SB
• Jung HG
• Park SH
• Kim JO
• Kim J
• Kim H
• Lee S

• KMID: 2547456
• DOI: http://doi.org/10.3340/jkns.2023.0061

Abstract

The brain houses vital hormonal regulatory structures such as the hypothalamus and pituitary gland, which may confer unique susceptibilities to critical illness-related corticosteroid insufficiency (CIRCI) in patients with neurological disorders. In addition, the frequent use of steroids for therapeutic purposes in various neurological conditions may lead to the development of steroid insufficiency. This abstract aims to highlight the significance of understanding these relationships in the context of patient care and management for physicians. Neurological disorders may predispose patients to CIRCI due to the role of the brain in hormonal regulation. Early recognition of CIRCI in the context of neurological diseases is essential to ensure prompt and appropriate intervention. Moreover, the frequent use of steroids for treating neurological conditions can contribute to the development of steroid insufficiency, further complicating the clinical picture. Physicians must be aware of these unique interactions and be prepared to evaluate and manage patients with CIRCI and steroid insufficiency in the context of neurological disorders. This includes timely diagnosis, appropriate steroid administration, and careful monitoring for potential adverse effects. A comprehensive understanding of the interplay between neurological disease, CIRCI, and steroid insufficiency is critical for optimizing patient care and outcomes in this complex patient population.

Keyword

Critical illness; Adrenal insufficiency; Intracranial pressure; Traumatic brain injury; Hypotension

Figure

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  Fig. 1. Hypothalamic-pituitary-adrenal (HPA) axis regulation. This schematic diagram illustrates the key components and interactions within the HPA axis, highlighting the regulatory role of the hypothalamus, pituitary gland, and adrenal cortex in stress response and hormonal balance. The figure demonstrates the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which triggers the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. Subsequently, ACTH stimulates the adrenal cortex to produce cortisol, the primary stress hormone. The HPA axis is regulated through a negative feedback loop, where increased cortisol levels inhibit the release of both CRH and ACTH, maintaining hormonal homeostasis.

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  Fig. 2. Steroidogenesis in the adrenal gland. This schematic diagram provides an overview of the key enzymatic processes involved in steroidogenesis within the adrenal gland, focusing on the synthesis of mineralocorticoids, glucocorticoids, and adrenal androgens. The figure depicts the conversion of cholesterol to pregnenolone, serving as the initial and rate-limiting step in steroidogenesis. It further illustrates the specific enzymatic pathways and intermediate compounds leading to the production of aldosterone (mineralocorticoid), cortisol (glucocorticoid), and dehydroepiandrosterone (DHEA; adrenal androgen). Additionally, the figure emphasizes the distinct functional zones of the adrenal cortex, highlighting the zona glomerulosa (mineralocorticoid production), zona fasciculata (glucocorticoid production), and zona reticularis (adrenal androgen production). Adopted from Arlt and Stewart [3] with permission. 3 ß HSD : 3-beta (ß)-hydroxysteroid dehydrogenase (HSD), P450c21 : human cytochrome P450c21 (steroid 21-hydroxylase, CYP21A2), CYP11B2 : aldosterone synthase (previously known as corticosterone methyloxidase), P450c17 : steroid 17 alphahydroxylase/17,20 lyase, CYP11B : steroid 11β-hydroxylase, SULT2A1 : dehydroepiandrosterone sulfotransferase.

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  Fig. 3. . Glucocorticoid synthesis at rest and stress [4]. This graphical representation compares the rate and regulation of glucocorticoid synthesis, specifically cortisol, under resting conditions and during stress. The figure highlights the role of the hypothalamic-pituitary-adrenal (HPA) axis in modulating cortisol production in response to various stressors. Under resting conditions, the HPA axis maintains basal cortisol levels through a tightly regulated negative feedback loop. In contrast, during stress, the HPA axis is activated, resulting in increased secretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), ultimately leading to elevated cortisol production by the adrenal cortex. The figure emphasizes the crucial role of cortisol in mediating physiological adaptations to stress, such as mobilizing energy reserves and modulating the immune response. Adopted from Annane et al. [1] with permission. AVP : arginine vasopressin, TLR : Toll-like receptor, ANS : autonomic nervous system, DAMPs : damage-associated molecular patterns, PAMPs : pathogen-associated molecular patterns.

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  Fig. 4. Activity of the hypothalamic-pituitary-adrenal (HPA) axis under different conditions [7]. This three-panel figure illustrates the activity of the HPA axis under normal conditions (A), during an appropriate response to stress (B), and during an inappropriate response to critical illness (C). (A) demonstrates the basal activity of the HPA axis under normal conditions, with the hypothalamus releasing corticotropin-releasing hormone (CRH), stimulating the anterior pituitary to secrete adrenocorticotropic hormone (ACTH), which in turn triggers the adrenal cortex to produce cortisol. A negative feedback loop maintains hormonal homeostasis. (B) shows an appropriate response to stress, where the HPA axis is activated, resulting in increased secretion of CRH and ACTH, and subsequently, elevated cortisol production. This adaptive response enables the body to cope with the stressor by mobilizing energy reserves, modulating immune response, and maintaining homeostasis. (C) depicts an inappropriate response to critical illness, characterized by a blunted or dysregulated HPA axis. This may lead to inadequate cortisol production, contributing to poor outcomes such as persistent inflammation, immune dysregulation, and multi-organ dysfunction. This panel highlights the potential need for exogenous glucocorticoid administration to counteract the detrimental effects of HPA axis dysfunction during critical illness. Adopted from Cooper and Stewart [8] with permission. HIV : human immunodeficiency virus.

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  Fig. 5. Pathophysiology of glucocorticoid induced hypothalamic-pituitary-adrenal (HPA) axis suppression [5]. This schematic diagram illustrates the pathophysiological mechanisms underlying glucocorticoid-induced HPA axis suppression, focusing on the negative feedback loop triggered by exogenous glucocorticoid administration. The figure demonstrates that exogenous glucocorticoids, when administered in pharmacological doses, result in elevated systemic cortisol levels. This increase in cortisol suppresses the production and release of corticotropin-releasing hormone (CRH) from the hypothalamus and adrenocorticotropic hormone (ACTH) from the anterior pituitary gland, effectively inhibiting the normal activity of the HPA axis. Consequently, the adrenal cortex produces lower amounts of endogenous cortisol, leading to adrenal insufficiency and a reduced ability to respond to stressors. The figure highlights the importance of recognizing and managing glucocorticoid-induced HPA axis suppression to prevent complications, such as adrenal crisis, during withdrawal or rapid tapering of exogenous glucocorticoids. Adopted from Prete and Bancos [19] with permission. GC : glucocorticoid, IV : intravenous, IM : intramuscular.

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