The clinical potential of GDF15 as a "ready-to-feed indicator" for critically ill adults.

BACKGROUND: Circulating growth-differentiation factor-15 (GDF15), a cellular stress marker, abruptly increases during critical illness, but its later time course remains unclear. GDF15 physiologically controls oral intake by driving aversive responses to nutrition. Early parenteral nutrition (PN) in ICU patients has overall been shown not beneficial. We hypothesized that low GDF15 can identify patients who benefit from early PN, tolerate enteral nutrition (EN), and resume spontaneous oral intake. METHODS: In secondary analyses of the EPaNIC-RCT on timing of PN initiation (early PN versus late PN) and the prospective observational DAS study, we documented the time course of circulating GDF15 in ICU (N = 1128) and 1 week post-ICU (N = 72), compared with healthy subjects (N = 65), and the impact hereon of randomization to early PN versus late PN in propensity score-matched groups (N = 564/group). Interaction between upon-admission GDF15 and randomization for its outcome effects was investigated (N = 4393). Finally, association between GDF15 and EN tolerance in ICU (N = 1383) and oral intake beyond ICU discharge (N = 72) was studied. RESULTS: GDF15 was elevated throughout ICU stay, similarly in early PN and late PN patients, and remained high beyond ICU discharge (p < 0.0001). Upon-admission GDF15 did not interact with randomization to early PN versus late PN for its outcome effects, but higher GDF15 independently related to worse outcomes (p ≤ 0.002). Lower GDF15 was only weakly related to gastrointestinal tolerance (p < 0.0001) and a steeper drop in GDF15 with more oral intake after ICU discharge (p = 0.05). CONCLUSION: In critically ill patients, high GDF15 reflected poor prognosis and may contribute to aversive responses to nutrition. However, the potential of GDF15 as "ready-to-feed indicator" appears limited. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00512122, registered 31 July 2007, https://www.clinicaltrials.gov/ct2/show/NCT00512122 (EPaNIC trial) and ISRCTN, ISRCTN 98806770, registered 11 November 2014, http://www.isrctn.com/ISRCTN98806770 (DAS trial).

Adrenal function and dysfunction in critically ill patients.

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 into the response of the hypothalamic-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.

ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study.

PURPOSE: Low 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. METHODS: This 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. RESULTS: Patients 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. CONCLUSIONS: Suppressed 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.

Adrenocortical function during prolonged critical illness and beyond: a prospective observational study.

PURPOSE: For 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. METHODS: Patients 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. RESULTS: In 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. CONCLUSIONS: Irrespective 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.

Adrenocortical Stress Response during the Course of Critical Illness.

Critically ill patients have elevated plasma cortisol concentrations, in proportion to illness severity. This was traditionally attributed exclusively to a central activation of the hypothalamus-pituitary axis. However, low rather than high plasma ACTH concentrations have been reported in critically ill patients, with loss of diurnal ACTH and cortisol rhythm. Low ACTH together with high cortisol is referred to as "ACTH-cortisol dissociation." Although cortisol production is somewhat increased with inflammation, a reduced cortisol breakdown explains to a larger extent the hypercortisolism during critical illness. Inflammation-driven decrease in cortisol binding proteins further increase the active free cortisol fraction. Several drugs administered to ICU patients suppress plasma cortisol in a dose-dependent manner. Sustained low circulating ACTH might contribute to adrenal atrophy and dysfunction in the prolonged phase of critical illness. In the acute phase of sepsis or septic shock, a condition referred to as "relative adrenal insufficiency" has been suggested to ensue from glucocorticoid resistance and insufficiently elevated circulating cortisol to overcome such resistance, with pathological changes possibly occurring at every level of the HPA axis. However, it remains highly controversial whether tissue-specific glucocorticoid resistance is adaptive or maladaptive, how to diagnose "relative" adrenal insufficiency, and how it should be treated. Large RCTs, investigating the effect of 200 mg/d hydrocortisone treatment for sepsis or septic shock have shown conflicting, mainly negative, results. Not taking into account the reduced cortisol breakdown, which increases the risk of overdosing hydrocortisone, might have played a role. Further research on diagnostic, therapeutic and dosing aspects is urgently warranted. Compr Physiol 8:283-298, 2018.

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

OBJECTIVE: 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. DESIGN: Observational association study. PATIENTS: A total of 156 medical-surgical critically ill patients. MEASUREMENTS: Plasma concentrations of ACTH and total/free cortisol were quantified upon ICU admission and throughout the first 3 ICU days. The independent associations between drugs administered 24 h prior to ICU admission and plasma ACTH and cortisol concentrations upon ICU admission were quantified with use of multivariable linear regression analyses. RESULTS: Upon ICU admission, compared with healthy subjects, patients had low mean±SEM plasma ACTH concentrations (2·7 ± 0·6 pmol/l vs 9·0 ± 1·6 pmol/l, P < 0·0001) in the face of unaltered total plasma cortisol (336·7 ± 30·4 nmol/l vs 300·8 ± 16·6 nmol/l, P = 0·3) and elevated free plasma cortisol concentrations (41·4 ± 5·5 nmol/l vs 5·5 ± 0·8 nmol/l, P = 0·04). Plasma ACTH concentrations remained low (P < 0·001) until day 3, whereas plasma (free) cortisol concentrations steeply increased and remained high (P < 0·001). No independent correlations with plasma ACTH were found. In contrast, the total admission plasma cortisol concentration was independently and negatively associated with the cumulative opioid (P = 0·001) and propofol (P = 0·02) dose, the use of etomidate (P = 0·03), and positively with the cumulative dobutamine dose (P = 0·0007). CONCLUSIONS: Besides the known suppressive effect of etomidate, opioids and propofol may also suppress and dobutamine increases plasma cortisol in a dose-dependent manner. The observed independent associations suggest drug effects not mediated centrally via ACTH, but rather peripherally by a direct or indirect action on the adrenal cortex.

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.