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.

PurposeFor patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus–pituitary–adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival.MethodsPatients still in ICU on day 7 (N = 392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 µg) performed weekly, repeated 1 week after ICU discharge on the regular ward.ResultsIn all patients free of glucocorticoid treatment up until ICU day 28 (N = 347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P ≤ 0.002) explained by reduced binding proteins (P ≤ 0.02) and suppressed cortisol breakdown (P ≤ 0.001). Beyond ICU day 28 (N = 64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P ≤ 0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P ≤ 0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N = 45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol.ConclusionsIrrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test.Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5366-7) contains supplementary material, which is available to authorized users.

International audienceArabica coffee is a major agricultural commodity worldwide, representing 60 % of the world’s coffee production. Arabica coffee is cultivated in more than 36 countries and is a key cash crop for many developing countries. Despite the coffee’s huge economic importance, there is very limited knowledge on the association of arbuscular mycorrhizal fungi with coffee roots. Therefore, we assessed the mycorrhizal diversity and community composition in Arabica coffee (Coffea arabica L.), using 454 pyrosequencing, in its Ethiopian center of origin. We studied the five most common coffee management systems in Ethiopia. Using pyrosequencing, we retrieved 10,061 mycorrhizae sequences across 30 samples, generating 36 operational taxonomic units from the four mycorrhizae orders: Glomerales, Diversisporales, Archaeosporales, and Paraglomerales; and eight families. Our results show that mycorrhizal diversity strongly differed between natural forest coffee systems and the other management systems. Furthermore, 13 operational taxonomic units were uniquely found in natural forest coffee. Finally, the mycorrhizal community composition in shade coffee plantations was different from the community composition in the other managed systems and the natural forest coffee systems. This is the first in depth study of mycorrhizal communities in wild coffee in its Ethiopian region of origin. Furthermore, we show for the first time the major differences in mycorrhizal communities in coffee between natural coffee forest and more intensively managed coffee systems. We, therefore, provide evidence of the conservation value of natural coffee forest systems as they harbor a unique mycorrhizal diversity, with possible future applications in low input coffee agriculture

For decades, elevated plasma cortisol concentrations in critically ill patients were exclusively ascribed to a stimulated hypothalamus-pituitary-adrenal axis with increased circulating adrenocorticotropic hormone (ACTH) inferred to several-fold increase adrenal cortisol synthesis. However, 'ACTH-cortisol dissociation' has been reported during critical illness, referring to low circulating ACTH coinciding with elevated circulating cortisol. It was recently shown that metabolism of cortisol is significantly reduced in critically ill patients explained by a suppression of the activity and expression of cortisol metabolizing enzymes in kidney and liver. This reduced cortisol breakdown determines hypercortisolemia, much more than increased cortisol production, in the critically ill. Although the low plasma ACTH concentrations, evoked by the elevated plasma cortisol via feedback inhibition, are part of this adaptation, they may negatively affect adrenocortical structure and function in the prolonged phase of critical illness. These new insights have implications for diagnosis and treatment of adrenal insufficiency in critically ill patients.

PurposeLow plasma ACTH in critically ill patients may be explained by shock/inflammation-induced hypothalamus-pituitary damage or by feedback inhibition exerted by elevated plasma free cortisol. One can expect augmented/prolonged ACTH-responses to CRH injection with hypothalamic damage, immediately suppressed responses with pituitary damage, and delayed decreased responses in prolonged critical illness with feedback inhibition.MethodsThis randomized, double-blind, placebo-controlled crossover cohort study, compared ACTH responses to 100 µg IV CRH and placebo in 3 cohorts of 40 matched patients in the acute (ICU-day 3–6), subacute (ICU-day 7–16) or prolonged phase (ICU-day 17–28) of critical illness, with 20 demographically matched healthy subjects. CRH or placebo was injected in random order on two consecutive days. Blood was sampled repeatedly over 135 min and AUC responses to placebo were subtracted from those to CRH.ResultsPatients had normal mean ± SEM plasma ACTH concentrations (25.5 ± 1.6 versus 24.8 ± 3.6 pg/ml in healthy subjects, P = 0.54) but elevated free cortisol concentrations (3.11 ± 0.27 versus 0.58 ± 0.05 µg/dl in healthy subjects, P < 0.0001). The order of the CRH/placebo injections did not affect the ACTH responses, hence results were pooled. Patients in the acute phase of illness had normal mean ± SEM ACTH responses (5149 ± 848 pg/mL min versus 4120 ± 688 pg/mL min in healthy subjects; P = 0.77), whereas those in the subacute (2333 ± 387 pg/mL min, P = 0.01) and prolonged phases (2441 ± 685 pg/mL min, P = 0.001) were low, irrespective of sepsis/septic shock or risk of death.ConclusionsSuppressed ACTH responses to CRH in the more prolonged phases, but not acute phase, of critical illness are compatible with feedback inhibition exerted by elevated free cortisol, rather than by cellular damage to hypothalamus and/or pituitary.Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5427-y) contains supplementary material, which is available to authorized users.