Eva Boonen

Reduced Cortisol Metabolism during Critical Illness

BACKGROUND Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism. METHODS In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes. RESULTS Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons). CONCLUSIONS During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).

Endocrine Responses to Critical Illness: Novel Insights and Therapeutic Implications

CONTEXT Critical illness, an extreme form of severe physical stress, is characterized by important endocrine and metabolic changes. Due to critical care medicine, survival from previously lethal conditions has become possible, but many patients now enter a chronic phase of critical illness. The role of the endocrine and metabolic responses to acute and prolonged critical illness in mediating or hampering recovery remains highly debated. EVIDENCE ACQUISITION The recent literature on changes within the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-adrenal axis and on hyperglycemia in relation to recovery from critical illness was critically appraised and interpreted against previous insights. Possible therapeutic implications of the novel insights were analyzed. Specific remaining questions were formulated. EVIDENCE SYNTHESIS In recent years, important novel insights in the pathophysiology and the consequences of some of these endocrine responses to acute and chronic critical illness were generated. Acute endocrine adaptations are directed toward providing energy and substrates for the vital fight-or-flight response in a context of exogenous substrate deprivation. Distinct endocrine and metabolic alterations characterize the chronic phase of critical illness, which seems to be no longer solely beneficial and could hamper recovery and rehabilitation. CONCLUSIONS Important novel insights reshape the current view on endocrine and metabolic responses to critical illness and further clarify underlying pathways. Although many issues remain unresolved, some therapeutic implications were already identified. More work is required to find better treatments, and the optimal timing for such treatments, to further prevent protracted critical illness, to enhance recovery thereof, and to optimize rehabilitation.

Reduced nocturnal ACTH-driven cortisol secretion during critical illness

Recently, during critical illness, cortisol metabolism was found to be reduced. We hypothesize that such reduced cortisol breakdown may suppress pulsatile ACTH and cortisol secretion via feedback inhibition. To test this hypothesis, nocturnal ACTH and cortisol secretory profiles were constructed by deconvolution analysis from plasma concentration time series in 40 matched critically ill patients and eight healthy controls, excluding diseases or drugs that affect the hypothalamic-pituitary-adrenal axis. Blood was sampled every 10 min between 2100 and 0600 to quantify plasma concentrations of ACTH and (free) cortisol. Approximate entropy, an estimation of process irregularity, cross-approximate entropy, a measure of ACTH-cortisol asynchrony, and ACTH-cortisol dose-response relationships were calculated. Total and free plasma cortisol concentrations were higher at all times in patients than in controls (all P < 0.04). Pulsatile cortisol secretion was 54% lower in patients than in controls (P = 0.005), explained by reduced cortisol burst mass (P = 0.03), whereas cortisol pulse frequency (P = 0.35) and nonpulsatile cortisol secretion (P = 0.80) were unaltered. Pulsatile ACTH secretion was 31% lower in patients than in controls (P = 0.03), again explained by a lower ACTH burst mass (P = 0.02), whereas ACTH pulse frequency (P = 0.50) and nonpulsatile ACTH secretion (P = 0.80) were unchanged. ACTH-cortisol dose response estimates were similar in patients and controls. ACTH and cortisol approximate entropy were higher in patients (P ≤ 0.03), as was ACTH-cortisol cross-approximate entropy (P ≤ 0.001). We conclude that hypercortisolism during critical illness coincided with suppressed pulsatile ACTH and cortisol secretion and a normal ACTH-cortisol dose response. Increased irregularity and asynchrony of the ACTH and cortisol time series supported non-ACTH-dependent mechanisms driving hypercortisolism during critical illness.

Impact of Duration of Critical Illness on the Adrenal Glands of Human Intensive Care Patients

CONTEXT Adrenal insufficiency is considered to be prevalent during critical illness, although the pathophysiology, diagnostic criteria, and optimal therapeutic strategy remain controversial. During critical illness, reduced cortisol breakdown contributes substantially to elevated plasma cortisol and low plasma ACTH concentrations. OBJECTIVE Because ACTH has a trophic impact on the adrenal cortex, we hypothesized that with a longer duration of critical illness, subnormal ACTH adrenocortical stimulation predisposes to adrenal insufficiency. DESIGN, SETTING AND PARTICIPANTS Adrenal glands were harvested 24 hours or sooner after death from 13 long intensive care unit (ICU)-stay patients, 27 short ICU-stay patients, and 13 controls. Prior glucocorticoid treatment was excluded. MAIN OUTCOME AND MEASURE(S): Microscopic adrenocortical zonational structure was evaluated by hematoxylin and eosin staining. The amount of adrenal cholesterol esters was determined by Oil-Red-O staining, and mRNA expression of ACTH-regulated steroidogenic enzymes was quantified. RESULTS The adrenocortical zonational structure was disturbed in patients as compared with controls (P < .0001), with indistinguishable adrenocortical zones present only in long ICU-stay patients (P = .003 vs. controls). Adrenal glands from long ICU-stay patients, but not those of short ICU-stay patients, contained 21% less protein (P = .03) and 9% more fluid (P = .01) than those from controls, whereas they tended to weigh less for comparable adrenal surface area. There was 78% less Oil-Red-O staining in long ICU-stay patients than in controls and in short-stay patients (P = .03), the latter similar to controls (P = .31). The mRNA expression of melanocortin 2 receptor, scavenger-receptor class B, member 1, 3-hydroxy-3-methylglutaryl-CoA reductase, steroidogenic acute regulatory protein, and cytochrome P450 cholesterol side-chain cleavage enzyme was at least 58% lower in long ICU-stay patients than in controls (all P ≤ .03) and of melanocortin 2 receptor, scavenger-receptor class B, member 1, steroidogenic acute regulatory protein, and cytochrome P450 cholesterol side-chain cleavage enzyme at least 53% lower than in short ICU-stay patients (all P ≤ .04), whereas gene expression in short ICU-stay patients was similar to controls. CONCLUSION AND RELEVANCE Lipid depletion and reduced ACTH-regulated gene expression in prolonged critical illness suggest that sustained lack of ACTH may contribute to the risk of adrenal insufficiency in long-stay ICU patients.

New insights into the controversy of adrenal function during critical illness

Critical illness represents a life-threatening disorder necessitating recruitment of defence mechanisms for survival. Herein, the hypothalamic-pituitary-adrenal axis is essential. However, the relevance of a relative insufficiency of the hypothalamic-pituitary-adrenal axis in critical illness, which is diagnosed by a suppressed cortisol response to exogenous adrenocorticotropic hormone (ACTH) irrespective of the plasma cortisol concentration, is controversial. Findings from several studies have provided insights that clarify at least part of this controversy. Rather than an activated hypothalamic-pituitary-adrenal axis, ACTH-independent regulators have been reported to contribute to increased cortisol availability during critical illness. One of these regulators is reduced cortisol breakdown, mediated by suppressed expression and activity of cortisol metabolising enzymes in the liver and kidneys. This downstream mechanism increases concentrations of plasma cortisol, but the ensuing feedback-inhibited ACTH release, when sustained for more than 1 week, has been shown to negatively affect adrenocortical integrity and function. Reduced adrenocortical ACTH signalling could explain reduced cortisol responses to exogenous ACTH. Whether such reduced cortisol responses in the presence of raised plasma (free) cortisol identifies adrenal failure needing treatment is unlikely. Additionally, reduced cortisol breakdown affects the optimum dose of hydrocortisone treatment during critical illness. Identification of patients with an insufficient hypothalamic-pituitary-adrenal axis response and the optimum treatment for this disorder clearly need more well designed preclinical and clinical studies.

Novel insights in the HPA-axis during critical illness

Abstract Critical illness represents a major challenge for the human body, implicating that an adequate stress response is indispensable for survival. Therefore, for a long time, activation of the hypothalamic pituitary adrenal axis was assumed to be increased to respond to this stressful situation. Recent novel insights, however, provided evidence that the HPA-axis is regulated differently during critical illness. Cortisol metabolism was shown to be reduced which contributed to hypercortisolism in an energy efficient way without increasing cortisol production dramatically. Yet, the concomitant low ACTH levels, explained by negative feedback inhibition, could lead to an understimulation of the adrenal gland and affect adrenal structure and function, given the crucial role of ACTH for adrenal gland maintenance. This side-effect could negatively affect outcome predominantly in the prolonged phase of critical illness and could explain the increased incidence of adrenal failure in these patients. Altogether, novel findings represent a paradigm shift in our current understanding of HPA-axis regulation during critical illness and redirect future research perspectives with an urgent need to well-designed clinical trials to further explore HPA-axis functioning during critical illness.

Drug-induced HPA axis alterations during acute critical illness: a multivariable association study

Critical illness is hallmarked by low plasma ACTH in the face of high plasma cortisol. We hypothesized that frequently used drugs could play a role by affecting the hypothalamic–pituitary–adrenal axis.

Effect of Early Parenteral Nutrition on the HPA Axis and on Treatment With Corticosteroids in Intensive Care Patients.

BACKGROUND Nutrition can affect the hypothalamus-pituitary-adrenal axis. We hypothesized that early administration of parenteral nutrition (PN) during critical illness reduces plasma ACTH and cortisol concentrations and thereby increases the use of corticosteroids. METHODS This is a preplanned substudy of a randomized controlled trial (EPaNIC) that compared early PN with late PN in 4640 critically ill patients. We investigated the effect of early vs late PN on any steroid treatment and on treatment for ≥ 5 days to capture patients with clinical suspicion of adrenal insufficiency, and assessed whether this was related to an effect on septic shock. Also, in a propensity score-matched subgroup (n=174) of patients not receiving steroids, plasma ACTH and (free) cortisol were quantified. RESULTS Compared with late PN, more patients on early PN received treatment with corticosteroids (26.2% vs 23.8%; P = .05) and with corticosteroids for ≥ 5 days (14.0% vs 11.9%; P = .03). However, plasma ACTH and (free) cortisol concentrations were unaffected and thus could not explain the higher use of corticosteroids with early PN. Instead, more patients developed new septic shock with early PN (17.0%) than with late PN (14.2%) (P = .01). In multivariate logistic regression analysis, new septic shock was an independent determinant for ≥ 5 days steroid treatment (odds ratio, 6.25; 95% confidence interval, 4.93-7.94; P < .0001), statistically explaining the effect of early PN on steroid treatment. CONCLUSIONS Early PN did not affect plasma concentrations of ACTH and (free) cortisol, but increased the incidence of septic shock, which statistically explained why more patients on early PN received corticosteroids.

Ridotto metabolismo del cortisolo in corso di malattia critica

N Engl J Med 2013 March 19 as doi: 10.1056/NEJMoa1214969 La malattia critica, come lo stress fisico acuto intenso, è spesso associata a ipercortisolemia di entità proporzionale alla gravità della malattia. Tradizionalmente l’ipercortisolemia è attribuita all’attivazione dell’asse ipotalamo-ipofsi-surrene, con conseguente aumento della produzione di cortisolo ACTH-dipendente, tuttavia è stato riportato anche una ridotta concentrazione di ACTH nel corso di ipercortisolismo. In questo studio gli autori ipotizzano che l’ipercortisolismo sia dovuto ad un ridotto metabolismo del cortisolo con conseguente effetto di feedback negativo sull’ACTH. Per verificare questa ipotesi sono stati esaminati 158 soggetti ricoverati in terapia intensiva e 64 controlli sani; 5 aspetti del metabolismo del cortisolo sono stati considerati: le concentrazioni ematiche giornaliere di cortisolo e ACTH, la clearance plasmatica del cortisolo, il metabolismo e la sua produzione durante l’infusione di steroidi marcati, la clearance plasmatica di 100 mg di idrocortisone, le concentrazioni urinarie dei metaboliti del cortisolo e la concentrazione di mRNA e di proteine dei principali enzimi coinvolti nel metabolismo del cortisolo in biopsie del fegato e del tessuti adiposo in 44 soggetti deceduti. I risultati di questo studio evidenziavano concentrazioni plasmatiche di cortisolo libero più elevate nei pazienti critici rispetto ai soggetti di controllo, mentre le concentrazioni dell’ACTH erano ridotte. Vi era una riduzione del 50% della clearance del cortisolo dopo infusione di idrocortisone, che si correlava con una ridotta risposta allo stimolo corticotropinico; la riduzione del metabolismo del cortisolo valutato attraverso il rapporto tra gli steroidi urinari, la cinetica del cortisolo marcato e la valutazione delle biopsie epatiche si associava a una ridotta inattivazione dello stesso a livello del fegato e del rene, per una ridotta espressione della 5 alfa reduttasi e della 11 beta idrossisteroidodeidrogenasi tipo 2 Lo studio di Boonen e coll. dimostra che la genesi dell’ipercortisolemia nel paziente critico non dipende dall’attivazione dell’asse ipotalmo-ipofisi-surrene ma da un ridotto metabolismo periferico del cortisolo. Le citochine pro-infiammatorie, che raggiungono concentrazioni plasmatiche elevate nel paziente critico, possono essere considerate il principale fattore di riduzione della clearance metabolica del cortisolo e della sua sintesi surrenalica. Questo studio potrebbe contribuire a cambiare le conoscenze sulla risposta allo stress nel paziente critico e a modificarne la gestione terapeutica.