Etomidate, Adrenal Insufficiency and Mortality Associated With Severity of Illness: A Meta-Analysis.

PURPOSE: Etomidate causes adrenal insufficiency. Yet in critically ill patients, it is controversial whether it increases mortality rates above that of comparator anesthetic induction agents. We postulated that etomidate would increase relative mortality rates correspondingly to the severity of illness as defined by SAPS or APACHE scores. MATERIALS AND METHODS: A literature search was performed on Pub Med, SCOPUS, and Cochrane Reviews for human studies, regardless of language, between 1983 and February 2020. The search strategy used keywords, "etomidate," "adrenal insufficiency," "glucocorticoid," and "intensive care." Both authors reviewed electronic data search titles, abstracts and extracted data, which were checked by the other reviewer. Primary outcome was 28-day survival. Secondary outcome was adrenal insufficiency. RESULTS: There were 29 trials of etomidate versus comparators in 8584 patients. Etomidate was associated with adrenal insufficiency (risk ratio (rr) = 1·54, 95% CI; 1·42, 1·67, p < 0.001) and increased overall relative mortality rates (rr = 1.09, CI;1.04,1.16, p = 0.001). Meta-regression showed that with etomidate there was a continuous progressive relative risk of mortality associated with increasing severity of illness (predefined in each article by standard critical illness scores). In those patients who had a predicted mortality rate > the median for this analysis (predicted mortality 44%) the relative mortality rate (rr) = 1.20, Ci;1.12,1.29, p < 0.001, the absolute risk difference (rd) = 0.08, CI;0.05,0.11, p < 0.0001 and the number needed to harm (1/rd) was 12.5. In those with a calculated predicted mortality <44% there was no increase in relative mortality rate. CONCLUSIONS: Whereas etomidate causes adrenal insufficiency, it was not shown to increase mortality in many analyzed here in ICU settings. However, etomidate associated relative mortality rates increased progressively and correlated with the severity of critical illness scores. Intensivists should anticipate the need for glucocorticoid supplementation after etomidate in those with severe critical illness and in those with acute deterioration of vital signs.

Adrenal function/dysfunction in critically ill patients: a concise narrative review of recent novel insights.

The "fight or flight" response to critical illness relies on increased cortisol availability, traditionally attributed to several-fold-increased cortisol production via hypothalamus-pituitary-adrenal-axis activation. Recent studies provided evidence against this concept with clinical implications. First, high cortisol availability during critical illness is driven by suppressed cortisol binding and reduced cortisol breakdown rather than increased cortisol production. This implies reduction of hydrocortisone doses when prescribed in ICU. Second, plasma ACTH is low, explained by feedback inhibition by peripherally driven high free cortisol and/or other central glucocorticoid-receptor ligands. Third, ICU patients have elevated plasma concentrations of the ACTH-precursor hormone, pro-opiomelanocortin, because of impaired pituitary processing into ACTH, and pro-opiomelanocortin could drive some adrenocortical cortisol production in face of low ACTH. Fourth, in prolonged critically ill patients, endogenously suppressed ACTH, aggravated by exogenous corticosteroids, associates with poor outcome. In long-stay ICU patients, central adrenal insufficiency may occur due to lack of trophic ACTH signaling. Finally, the Cosyntropin test is not suitable to assess adrenocortical reserve in ICU patients as the test is confounded by increased cortisol distribution volume. These insights necessitate further research focusing on the need, if any, of treating ICU patients with corticosteroids, and timing thereof, outside indications for pharmacological anti-inflammatory drugs.

Including Relative Adrenal Insufficiency in Definition and Classification of Acute-on-Chronic Liver Failure.

BACKGROUND & AIMS: Relative adrenal insufficiency (RAI) is defined by insufficient production of cortisol relative to organ demand. RAI is observed frequently in hospitalized patients with cirrhosis, but there is disagreement over the clinical effects of RAI in these patients. We evaluated the prevalence and the clinical effects of RAI in hospitalized patients with cirrhosis. METHODS: We performed a prospective study of 160 patients admitted to a hospital in Italy for acute decompensation of cirrhosis from May 2011 through September 2016. Patients were followed up until death, liver transplantation, or a maximum of 90 days. Serum and salivary levels of cortisol were measured before and after a 1-hour Short Synacthen Test. A diagnosis of RAI was given to patients with an increase in serum cortisol of less than 9 µg/dL, after Synacthen administration, in patients with baseline serum levels of cortisol less than 35 µg/dL. We collected blood samples before the Synacthen test and analyzed them for blood cell counts, liver and renal function, levels of C-reactive protein, and lipid profiles (total cholesterol, high-density lipoprotein cholesterol, apolipoprotein-A1). RESULTS: A diagnosis of RAI was made for 78 patients (49%). Age (odds ratio [OR], 0.95; P = .030), number of leukocytes (OR, 3.10; P = .006), and levels of high-density lipoprotein cholesterol (OR, 0.30; P = .039) were associated independently with RAI. Patients with RAI had a significantly higher risk of developing bacterial infections (hazard ratio [HR], 1.60; P = .038), sepsis (HR, 2.95; P = .001), septic shock (HR, 4.94; P = .038), new organ failures (HR, 2.45; P = .014), and acute-on-chronic liver failure (HR, 2.27; P = .037) than patients without RAI. RAI was associated independently with death within 90 days of diagnosis (subdistribution HR, 4.83; P = .001). Patients with RAI and mild renal dysfunction or hepatic encephalopathy had no significant difference in cumulative incidence of 28-day mortality vs patients with acute-on-chronic liver failure grade 1 (25% vs 22%). CONCLUSIONS: We found RAI to occur in almost half of patients admitted to a hospital for acute decompensation of cirrhosis. RAI was associated with a deficit of substrates for steroidogenesis and an increase in markers of inflammation. Patients with RAI have a high risk of developing sepsis, septic shock, organ failure, and death within 90 days. RAI has similar prognostic value to nonrenal organ failures.

SNARE-ing the Reason for Post-Cardiac Surgery Critical Illness-Related Corticosteroid Insufficiency.

Critical illness-related corticosteroid insufficiency (CIRCI) can cause hemodynamic instability in neonates after congenital heart surgery with manifestations that increase morbidity and potential mortality. We retrospectively reviewed neonates who underwent cardiac surgery between August 2018 and July 2020 at a freestanding children's hospital, had next-generation sequencing performed, and had their cortisol levels drawn as standard clinical care after cardiac surgery. The groups were defined as CIRCI (with a cortisol level ≤ 4.5 mcg/dL) and non-CIRCI (level > 4.5 mcg/dL). The CIRCI group (n = 8) had a 100% incidence of heterozygous gene mutation on STX1A with splicing or loss of function, and this mutation was not found in the non-CIRCI group (n = 8). Additional gene mutations were found in the CIRCI group on RAB6A, ABCA3, SIDT2, and LILRB3, with no incidence in the non-CIRCI group. Three additional mutations were found across the CIRCI group in INPPL1 and FAM189A2 (both splicing and missense), with 12-25% of patients in the non-CIRCI group also displaying these mutations. Novel genetic abnormalities were seen in neonates with symptoms of CIRCI with potential cardiac implications from a gene mutation for STX1A. Compounding effects of additional gene mutations need to be confirmed and explored for potential predisposition to hemodynamic instability during times of stress.

Changes in Cortisol Secretion and Corticosteroid Receptors in COVID-19 and Non COVID-19 Critically Ill Patients with Sepsis/Septic Shock and Scope for Treatment.

Sepsis is associated with dysregulated cortisol secretion, leading to abnormal levels of cortisol in the blood. In the early stages of the condition, cortisol levels are typically elevated due to increased secretion from the adrenal glands. However, as the disease progresses, cortisol levels may decline due to impaired adrenal function, leading to relative adrenal insufficiency. The latter is thought to be caused by a combination of factors, including impaired adrenal function, decreased production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and pituitary gland, and increased breakdown of cortisol. The dysregulation of cortisol secretion in sepsis is thought to contribute to the pathophysiology of the disease by impairing the body's ability to mount an appropriate inflammatory response. Given the dysregulation of cortisol secretion and corticosteroid receptors in sepsis, there has been considerable interest in the use of steroids as a treatment. However, clinical trials have yielded mixed results and corticosteroid use in sepsis remains controversial. In this review, we will discuss the changes in cortisol secretion and corticosteroid receptors in critically ill patients with sepsis/septic shock. We will also make special note of COVID-19 patients, who presented a recent challenge for ICU management, and explore the scope for corticosteroid administration in both COVID-19 and non-COVID-19 septic patients.

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

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.

Low Baseline but Not Delta Cortisol Relates to 28-Day Transplant-Free Survival in Acute and Acute-on-Chronic Liver Failure.

Background and Aims: The clinical, prognostic, and therapeutic impact of adrenal insufficiency in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) remains controversial and exact diagnostic criteria are lacking. We sought to determine the diagnostic and therapeutic value of cortisol measurement and glucocorticoid (GC) treatment in ALF and ACLF. Methods: 28-day transplant-free survival (TFS) was studied in relation to absolute cortisol concentrations and to GC treatment in ALF (n = 30) and ACLF (n = 34) patients. Cortisol concentrations and short synacthen test were assessed by chemiluminescence immunoassay and liquid chromatography-mass spectrometry. Clinicians decided independently on GC treatment. In relation, phenotypic and functional characteristics of circulating monocytes were assessed. Results: In ALF, baseline cortisol concentrations <387 nmol/L predicted TFS (sensitivity 83%, specificity 53%). In ACLF, baseline cortisol <392 nmol/L correlated with TFS (sensitivity 80%, specificity 61%). In both, ALF and ACLF, GC treatment did not influence 28-day TFS in patients with low baseline cortisol. However, in patients with baseline cortisol exceeding 387 and 392 nmol/L, respectively, TFS was higher if they had been treated with GC. High baseline cortisol was associated with low HLA-DR expression on monocytes. Conclusion: Our data suggest a prognostic value of baseline cortisol measurement in ALF and ACLF. Overall, strong activation of the hypothalamic-pituitary-adrenal axis indicated poor prognosis. Furthermore, baseline cortisol deserves prospective evaluation as a guide for GC treatment decision-making.

Critical Illness-induced Corticosteroid Insufficiency: What It Is Not and What It Could Be.

Critical illnesses are hallmarked by increased systemic cortisol availability, a vital part of the stress response. Acute stress may trigger a life-threatening adrenal crisis when a disease of the hypothalamic-pituitary-adrenal (HPA) axis is present and not adequately treated with stress doses of hydrocortisone. Stress doses of hydrocortisone are also used to reduce high vasopressor need in patients suffering from septic shock, in the absence of adrenal insufficiency. Research performed over the last 10 years focusing on the HPA axis during critical illness has led to the insight that neither of these conditions can be labeled "critical illness-induced corticosteroid insufficiency" or CIRCI. Instead, these data suggested using the term CIRCI for a condition that may develop in prolonged critically ill patients. Indeed, when patients remain dependent on vital organ support for weeks, they are at risk of acquiring central adrenal insufficiency. The sustained increase in systemic glucocorticoid availability, mainly brought about by suppressed circulating cortisol-binding proteins and suppressed hepatic/renal cortisol metabolism, exerts negative feedback inhibition at the hypothalamus/pituitary, while high levels of other glucocorticoid receptor ligands, such as bile acids, and drugs, such as opioids, may further suppress adrenocorticotropic hormone (ACTH) secretion. The adrenal cortex, depleted from ACTH-mediated trophic signaling for weeks, may become structurally and functionally impaired, resulting in insufficient cortisol production. Such a central HPA axis suppression may be maladaptive by contributing to lingering vasopressor need and encephalopathy, hence preventing recovery. Here, we review this concept of CIRCI and we advise on how to recognize and treat this poorly understood condition.

Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies.

BACKGROUND: Reduced glucocorticoid-receptor (GR) expression in blood suggested that critically ill patients become glucocorticoid-resistant necessitating stress-doses of glucocorticoids. We hypothesised that critical illness evokes a tissue-specific, time-dependent expression of regulators of GR-action which adaptively guides glucocorticoid action to sites of need. METHODS: We performed a prospective, observational, cross-sectional human study and two translational mouse studies. In freshly-isolated neutrophils and monocytes and in skeletal muscle and subcutaneous adipose tissue of 137 critically ill patients and 20 healthy controls and in skeletal muscle and adipose tissue as well as in vital tissues (heart, lung, diaphragm, liver, kidney) of 88 septic and 26 healthy mice, we quantified gene expression of cortisone-reductase 11ß-HSD1, glucocorticoid-receptor-isoforms GRα and GRß, GRα-sensitivity-regulating-co-chaperone FKBP51, and GR-action-marker GILZ. Expression profiles were compared in relation to illness-duration and systemic-glucocorticoid-availability. FINDINGS: In patients' neutrophils, GRα and GILZ were substantially suppressed (p≤0·05) throughout intensive care unit (ICU)-stay, while in monocytes low/normal GRα coincided with increased GILZ (p≤0·05). FKBP51 was increased transiently (neutrophils) or always (monocytes,p≤0·05). In patients' muscle, 11ß-HSD1 and GRα were low-normal (p≤0·05) and substantially suppressed in adipose tissue (p≤0·05); FKBP51 and GILZ were increased in skeletal muscle (p≤0·05) but normal in adipose tissue. GRß was undetectable. Increasing systemic glucocorticoid availability in patients independently associated with further suppressed muscle 11ß-HSD1 and GRα, further increased FKBP51 and unaltered GILZ (p≤0·05). In septic mouse heart and lung, 11ß-HSD1, FKBP51 and GILZ were always high (p≤0·01). In heart, GRα was suppressed (p≤0·05), while normal or high in lung (all p≤0·05). In diaphragm, 11ß-HSD1 was high/normal, GRα low/normal and FKBP51 and GILZ high (p≤0·01). In kidney, 11ß-HSD1 transiently increased but decreased thereafter, GRα was normal and FKBP51 and GILZ high (p≤0·01). In liver, 11ß-HSD1 was suppressed (p≤0·01), GRα normal and FKBP51 high (p≤0·01) whereas GILZ was transiently decreased but elevated thereafter (p≤0·05). Only in lung and diaphragm, treatment with hydrocortisone further increased GILZ. INTERPRETATION: Tissue-specific, time-independent adaptations to critical illness guided GR-action predominantly to vital tissues such as lung, while (partially) protecting against collateral harm in other cells and tissues, such as neutrophils. These findings argue against maladaptive generalised glucocorticoid-resistance necessitating glucocorticoid-treatment. FUNDING: Research-Foundation-Flanders, Methusalem-Program-Flemish-Government, European-Research-Council, European-Respiratory-Society.

Prognostic Factors Related to the Mortality Rate of Acute-on-Chronic Liver Failure Patients.

BACKGROUND: Critical illness-related corticosteroid insufficiency (CIRCI) is known to be a common complication in patients with acute-on-chronic liver failure (ACLF). However, factors that predict the survival rate of ACLF patients remain unclear. The present study aims to determine the prognostic factors that impinge on the survival rate of ACLF patients. METHODS: A total of 90 patients with ACLF at different stages, with or without CIRCI, were prospectively evaluated. RESULTS: Various clinical factors were found to be significantly different among patients at early, mid and late stages of ACLF, as well as between the same population of patients with and without CIRCI. Specifically, patients at later stages of ACLF and patients with CIRCI had significantly higher Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD) and ACLF Research Consortium (AARC)-ACLF scores. CIRCI was observed in 20% of the enrolled patients (18 out of 90). In addition, the 90-day mortality rate was higher in mid- and late-stage ACLF patients, as well as patients with CIRCI. CONCLUSION: ACLF stage and CIRCI predict early mortality in patients with ACLF and could be actively monitored in these patients for prioritized liver transplantation.

Critical illness-related corticosteroid insufficiency during difficult weaning from mechanical ventilation.

BACKGROUND: Critical illness-related corticosteroid insufficiency (CIRCI) is common during critical illness and is usually associated with poor outcomes, as prolonged duration of mechanical ventilation (MV) and higher mortality. CIRCI may alter cardiac and vascular functions. Weaning-induced pulmonary oedema (WiPO) is a major mechanism of weaning failure. The aim of this study was to evaluate the role of CIRCI in patients with difficult ventilator weaning and its possible relation with WiPO. METHODS: This is a prospective study conducted in the intensive care of a university hospital in France. Patients under MV for more than 24 h, meeting weaning criteria and having failed the first spontaneous breathing trial (SBT) underwent a corticotropin stimulation test, with assessment of total blood cortisol levels immediately before (T0) 0.25 mg iv of tetracosactrin and 30 and 60 min afterward. Δmax was defined as the difference between the maximal value after the test and T0. CIRCI was defined as T0 < 10 µg/dL (276 nmol/L) and/or Δmax < 9 µg/dL (248 nmol/L) and inadequate adrenal reserve as Δmax < 9 µg/dL. Biomarkers (natriuretic peptide and protidemia) sampling and echocardiograms were performed during the second SBT and were used to diagnose WiPO, which was defined according to two definitions (one liberal and one conservative) derived from recent publications on the topic. Successful extubation was defined as patient alive without reintubation 7 days after extubation. A competing risk analysis was used to assess extubation failure and mortality. RESULTS: Seventy-six consecutive patients (63 ± 14 years; 49 men) with difficult weaning were enrolled. CIRCI and inadequate adrenal reserve occurred in 25 (33%) and 17 (22%) patients, respectively. The probability of successful extubation was significantly decreased in patients with CIRCI or inadequate adrenal reserve, as compared to their counterparts, and this association persisted after adjustment on severity (SOFA score at first SBT). WiPO occurred in 44 (58%) and 8 (11%) patients, according to the liberal and conservative definition, respectively. WiPO was not associated with CIRCI nor with inadequate adrenal reserve. CONCLUSION: CIRCI was common during difficult weaning and was associated with its prolongation. We did not find a significant association between CIRCI and WiPO.

Decreased maximal cortisol secretion rate in patients with cirrhosis: Relation to disease severity.

BACKGROUND & AIMS: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins. METHODS: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61). RESULTS: Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSRmax was negatively correlated with CP score (r = -0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min-1) compared with that in the CP ≤8 group (0.21 ± 0.21 min-1), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p <0.001) was observed. CONCLUSIONS: CSRmax and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSRmax estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis. LAY SUMMARY: We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis.

Glucocorticoid metabolism in critically ill dogs (Canis lupus familiaris).

Critical illness due to sepsis is a major global health concern associated with a high burden of mortality and cost. Glucocorticoid dysregulation in human sepsis is associated with poorer outcomes. This study examines glucocorticoid metabolism in septic canine patients to delineate elements of cellular dysregulation in common with critically ill humans and explore potential differences. This was a prospective case-control study conducted in the veterinary specialist critical care departments of two University teaching hospitals. Critically ill canine patients with naturally occurring sepsis or septic shock were compared with an in-hospital control population. Serum total, bound, and free cortisol concentrations were increased in septic shock (P < 0.001), and higher bound cortisol was associated with nonsurvival (P = 0.026). Urinary Gas Chromatography-Tandem Mass Spectrometry was performed to assess urinary glucocorticoid metabolites and estimate intracellular glucocorticoid metabolism. Decreased renal 11ß-hydroxysteroid dehydrogenase 2 (11ßHSD2) activity inferred from increased urinary cortisol-to-cortisone ratio was observed in critically ill dogs (P < 0.001). Decreased 11ßHSD2 activity (P = 0.019) and increased A-ring reduction of cortisone (P = 0.001) were associated with nonsurvival within the critically ill dogs. Intriguingly, two dogs were identified with low circulating total cortisol (<2 mg/dL) associated with increased A-ring reduction of cortisol, not previously described. Investigation of spontaneous canine sepsis and septic shock reveals dysregulation of cortisol to cortisone conversion similar to that observed in human patients, but with differences in A-ring reduction compared with those reported in humans. In addition, two dogs with high levels of cortisol inactivation associated with low circulating cortisol concentrations were identified.

Cortisol and adrenocorticotropic hormone concentrations in horses with systemic inflammatory response syndrome.

BACKGROUND: Plasma adrenocorticotropic hormone (ACTH) and serum cortisol concentrations increase with illness-associated stress. Dynamics of plasma ACTH and serum cortisol concentrations in adult horses with systemic illness are undocumented. HYPOTHESIS/OBJECTIVE: To determine whether ACTH and cortisol concentrations and the ACTH/cortisol ratio vary with survival, the presence of systemic inflammatory response syndrome (SIRS), or ischemic gastrointestinal lesions at admission, or throughout hospitalization. ANIMALS: One hundred fifty-one adult horses. METHODS: Prospective study measuring serum cortisol and plasma ACTH at admission and on days 2, 4, and 6 of hospitalization. Horses were grouped by outcome (survival, SIRS status, number of SIRS criteria [SIRS score], SIRS severity group, and the presence of an ischemic lesion). Differences between groups and over time for ACTH, cortisol, and ACTH/cortisol ratio were investigated with a mixed effect model. Receiving operator characteristic curves and odds ratios were calculated for survival and ischemia. RESULTS: In all groups, ACTH, cortisol, and ACTH/cortisol ratio significantly decreased over time (P < .0001). ACTH, cortisol, and ACTH/cortisol ratio were higher at admission in nonsurvivors, and ACTH and cortisol were higher in horses with ischemic lesions (P < .01). Horses with ACTH above reference interval at admission were 6.10 (2.73-13.68 [95% confidence interval]) times less likely to survive (P < .0001). No significant difference in ACTH, cortisol, and ACTH/cortisol ratio between horses with different SIRS status, scores, or groups were detected, although nonsurvivors had a higher SIRS score (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Pituitary and adrenal responses are altered in nonsurviving horses and those with an ischemic gastrointestinal lesion.

Determination of salivary cortisol to assess time-related changes of the adrenal response to stress in critically ill patients.

BACKGROUND: The value of salivary cortisol measurement to study stress-related adrenal response is controversial. The study aim was to assess the role of salivary cortisol measurement to detect time-related changes of adrenal response in critically ill patients. PATIENTS AND METHODS: Patients with organ failure, sepsis or trauma were prospectively recruited in the Emergency Department. Serum and salivary cortisol were measured at baseline (T0) and after 48 h (T48). In 33 patients ACTH test was also done. RESULTS: Fifty-five patients were studied and classified as septic (22) or non-septic (33). We found a significant correlation between serum and salivary cortisol at T0 and T48. No patient had baseline serum cortisol < 276 nmol/L and salivary cortisol significantly decreased at T48 in almost all patients. A delta serum cortisol < 250 nmol/L after ACTH was found in only 4 patients who showed elevated baseline cortisol levels. CONCLUSION: We found that reduced baseline and post-ACTH cortisol levels are uncommon in our samples. In patients able to provide adequate saliva samples, salivary cortisol may be used to check the degree of stress-induced response and appears as a suitable tool for multiple measurements over time.

Anterior pituitary function in critical illness.

Critical illness is hallmarked by major changes in all hypothalamic-pituitary-peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness by analogy with the fasting state. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body toward a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic-pituitary-peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones or strategies to overcome resistance to anabolic stimuli failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well-controlled RCTs to corroborate these findings are needed.

Relative Adrenal Insufficiency in Patients with Alcoholic Hepatitis.

BACKGROUND/AIMS: Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with high morbidity and mortality. Treatment with steroids is known to decrease short-term mortality in severe AH patients. Hence, we hypothesize that adrenal insufficiency can be associated with severe AH and affects prognosis. The aim of this study was (1) to evaluate relative adrenal insufficiency (RAI) in patients with AH and (2) to Compare RAI with the severity of AH. METHODS: Newly diagnosed cases of AH hospitalized in SMS Medical College and Hospital, Department of Gastroenterology were, enrolled. All patients of AH were classified as mild and severe AH on the basis of Maddrey discriminant function (DF). After baseline serum cortisol, 25 IU ACTH (Adreno Corticotrophic Hormone) was injected intramuscularly and blood sample was collected after 1 h and assessed for serum cortisol. RAI was defined as <7 µg increase in the cortisol level from baseline. RAI was compared with severity of AH. RESULTS: Of 120 patients of AH, 58 patients fulfilled the inclusion criteria, in which 48 patients were diagnosed as severe AH and 10 patients were diagnosed as mild AH. In patients with severe AH, the baseline mean serum cortisol level was significantly high as compared with mild AH; 26 patients (54.16 %) of 48 patients with severe AH showed RAI (P ≤ 0.001).Whereas in patients with mild AH, none of patients showed RAI. RAI also showed negative correlation with DF. There was no difference in RAI with respect to acute kidney injury (AKI). CONCLUSION: RAI is a common entity in patients with severe AH, and it is related with the severity of disease.

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.

Measurement of the glucocorticoid receptor: relevance to the diagnosis of critical illness-related corticosteroid insufficiency in children.

Diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in children continues to remain difficult and controversial in that no consensus for either exists among pediatric critical care physicians. Critical illness-related corticosteroid insufficiency is defined as a corticosteroid response that is inadequate for the severity of the illness experienced by the patient. Critical illness-related corticosteroid insufficiency manifests as an insufficient corticosteroid mediated down-regulation of proinflammatory cytokines, due to either corticosteroid tissue resistance and/or inadequate circulating levels of cortisol. The tissue resistance is likely due to alterations in the functionality of the intracellular receptor for corticosteroids, the glucocorticoid receptor (GR). This article details the role of the GR during critical illness with a focus upon the measurement of the GR, as a potentially important means by which to clinically assess the level of corticosteroid tissue-resistant in patients suspected of CIRCI. Measurement of the GR may be particularly useful as a means by which to determine the judicious administration of steroids, maximizing their therapeutic potential, whereas minimizing the morbidity that can be associated with their use.

Current Use of Steroids in Critical Care.

Septic shock is characterized by an uncontrolled systemic inflammatory response that contributes to organ dysfunction, failure and eventually death. The importance of the adrenal glands for survival under conditions of physiologic stress has been known since the early 20th century. Clinical studies explored the potential therapeutic role of corticosteroids in the treatment of sepsis and septic shock. Despite controversies on the benefit-to-risk ratio, they are widely used. The longstanding adoption of corticosteroids in the treatment of severe sepsis likely relies on the prompt reversal of septic shock often seen at the bedside. This current review was designed to provide readers with a clear understanding and rationale for using corticosteroids, while presenting a review of the Surviving Sepsis Guidelines and the results from the implementation of the Surviving Sepsis Campaign.