CIRMI-a new term for a concept worthy of further exploration: a narrative review

Abstract

Background and objective: Critical illness-related corticosteroid insufficiency (CIRCI) describes hypothalamic-pituitary-axis impairment during critical illness associated with three major pathophysiological events; dysregulation of the hypothalamic-pituitary-axis, altered cortisol metabolism, and tissue corticosteroid resistance. Similar changes are evident with regard to mineralocorticoid dysfunction in critical illness. Hyperreninemic hypoaldosteronism describes a sub-population of critically ill patients with an impaired adrenal aldosterone response to increased levels of renin. In the light of the recent demonstration of significant mortality improvements associated with adjunctive glucocorticoid treatment in combination with fludrocortisone in septic shock, and the suggestion that angiotensin II is effective in treating vasodilatory shock, the clinical relevance of mineralocorticoid dysfunction in critical illness requires further exploration. This interpretative review considers hyperreninemic hypoaldosteronism, a concept worth re-examining in the light of the potential mortality benefit of mineralocorticoid supplementation in critical illness. We compare the pathophysiological and clinical characteristics of CIRCI and hyperreninemic hypoaldosteronism, two syndromes that represent corticosteroid and mineralocorticoid dysfunction in critical illness. We highlight gaps in the literature and give novel insights into the limitations of assessment, diagnosis and treatment.

Methods: English language abstracts and articles published before June 2021 were identified through PubMed and Google Scholar. Randomized trials, observational studies, basic sciences studies, systematic and narrative reviews were considered. Reference lists of articles were searched for further relevant material.

Key content and findings: Difficulties are encountered in interpreting measures of gluco- and mineralo-corticoid activity in critical illness. Aldosterone levels, like cortisol, have been shown to be increased in sepsis and hemorrhagic shock. The finding of hyperreninemia and hyperaldosteronism with an aldosterone/plasma renin activity ratio below 2 should prompt consideration of hyperreninemic hypoaldosteronism, a finding, which likely signifies the loss of negative feedback control of the renin-angiotensin-aldosterone system.

Conclusions: As there is evidence to suggest that in acute critical illness, hyperreninemic hypoaldosteronism, is associated with poor outcomes, co-administration of hydrocortisone with fludrocortisone in patients with septic shock should be considered. In keeping with the concept of CIRCI, we suggest the term critical illness-related mineralocorticoid insufficiency as a more appropriate description of the impaired aldosterone response to increased levels of renin seen in this group of patients.

Keywords: Adrenal insufficiency; corticosteroid insufficiency; critical illness; glucocorticoids; mineralocorticoids.

Figure 1

The hypothalamic-pituitary-adrenal axis during acute critical illness. CRH mediates the release of ACTH from the pituitary in response to stress and/or inflammation. ACTH, in turn, results in increased cortisol production from the adrenal gland. The increase in pro-inflammatory mediators during acute inflammation results in a reduction in CBG and plasma albumin and/or downregulation of hepatic GR, with a subsequent increase in free cortisol levels (33-35). CRH, Corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; CBG, cortisol binding globulin; GR, glucocorticoid receptors.

Figure 2

Renin Angiotensin Aldosterone System. Angiotensin I, a result of the conversion of angiotensinogen by the action of renin, is converted to angiotensin II through the action of angiotensin converting enzyme (ACE). Further peptides and receptors have since been demonstrated to be involved in the cascade that regulates aldosterone release. ACE, angiotensin converting enzyme; ADH, antidiuretic hormone; APA, aminopeptidase A; PCP, prolyl carboxypeptidase; Mas, mitochondrial assembly receptor; AT₁ receptor, angiotensin II type 1 receptor; AT₂ receptor, angiotensin II type 2 receptor; K⁺, potassium; Mg²⁺, magnesium.

Figure 3

Aldosterone action; genomic and non-genomic effects of aldosterone and cortisol. Classical slow genomic actions mediated through the MR result in gene transcription and the production of effector proteins. Fast actions mediated through a surface receptor, which interact with the classic genomic actions, have been recently described to be mediated through the G-protein coupled receptor GPR30(GPER) and/or possibly through a membrane bound mineralocorticoid receptor. Aldosterone action through GPR30(GPER) is currently understood to be specific for aldosterone. GPR30, G protein-coupled receptor 30; PI3-K, Phosphatidylinositol 3-kinase; ERK1/2, extracellular-signal regulated kinase 1/2; JNK, c-Jun NH2-terminal kinase; c-SRC, non-receptor tyrosine kinase c-SRC protein; BP, blood pressure; MR, mineralocorticoid receptor.

Figure 4

Proposed schematic representation of the hypothalamic-pituitary axis and key mechanisms in hyperreninemic hypoaldosteronism. Renin-angiotensin-aldosterone system activation occurs through the classical pathway of aldosterone secretion. Additional corticotrophin independent pathways include effects of cytokines and vasopressin, which trigger corticotrophin release, independent of hypothalamic control. Critical illness triggers release of corticotrophin-releasing hormone from the hypothalamus. Corticotrophin-releasing hormone stimulates the anterior pituitary to release adrenocorticotropic hormone, which stimulates the release of cortisol and to a lesser extent, aldosterone from the adrenal cortex. In a subset of critically ill patients, the loss of regulatory negative feedback mechanisms results in the dissociation of renin and aldosterone (hyperreninemic hypoaldosteronism) which is characterized by hyperreninemia in the face of inappropriately low aldosterone and is associated with a higher mortality. HPA, hypothalamic-pituitary-adrenal; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; RAAS, renin-angiotensin-aldosterone system; CIRCI, critical illness-related corticosteroid insufficiency; CIRMI, critical illnessrelated mineralocorticoid insufficiency.