Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock

Patients with cirrhosis are susceptible to bacterial infection, which can result in circulatory dysfunction, renal failure, hepatic encephalopathy, and a decreased survival rate. Severe sepsis is frequently associated with adrenal insufficiency, which may lead to hemodynamic instability and a poor prognosis. We evaluated adrenal function using short corticotropin stimulation test (SST) in 101 critically ill patients with cirrhosis and severe sepsis. Adrenal insufficiency occurred in 51.48% of patients. The patients with adrenal insufficiency had a higher hospital mortality rate when compared with those with normal adrenal function (80.76% vs. 36.7%, P < .001). The cumulative rates of survival at 90 days were 15.3% and 63.2% for the adrenal insufficiency and normal adrenal function groups, respectively (P < .0001). The hospital survivors had a higher cortisol response to corticotropin (16.2 +/- 8.0 vs. 8.5 +/- 5.9 microg/dL, P < .001). The cortisol response to corticotropin was inversely correlated with various disease severity, Model for End-Stage Liver Disease, and Child-Pugh scores. Acute physiology, age, chronic health evaluation III score, and cortisol increment were independent factors to predict hospital mortality. Mean arterial pressure on the day of SST was lower in patients with adrenal insufficiency (60 +/- 14 vs. 74.5 +/- 13 mm Hg, P < .001), and a higher proportion of these patients required vasopressors (73% vs. 24.48%, P < .001). Mean arterial pressure, serum bilirubin, vasopressor dependency, and bacteremia were independent factors that predicted adrenal insufficiency. In conclusion, adrenal insufficiency is common in critically ill patients with cirrhosis and severe sepsis. It is related to functional liver reserve and disease severity and is associated with hemodynamic instability, renal dysfunction, and increased mortality.     

Update on adrenal insufficiency in patients with liver cirrhosis

Liver cirrhosis is a major cause of mortality worldwide,often with severe sepsis as the terminal event.Over the last two decades,several studies have reported that in septic patients the adrenal glands respond inappropriately to stimulation,and that the treatment with corticosteroids decreases mortality in such patients.Both cirrhosis and septic shock share many hemodynamic abnormalities such as hyperdynamic circulatory failure,decreased peripheral vascular resistance,increased cardiac output,hypo-responsiveness to vasopressors,increased levels of proinflammatory cytokines [interleukine(IL)-1,IL-6,tumor necrosis factor-alpha] and it has,consequently,been reported that adrenal insufficiency(AI) is common in critically ill cirrhotic patients.AI may also be present in patients with stable cirrhosis without sepsis and in those undergoing liver transplantation.The term hepato-adrenal syndrome defines AI in patients with advanced liver disease with sepsis and/or other complications,and it suggests that it could be a feature of liver disease per se,with a dif-ferent pathogenesis from that of septic shock.Relative AI is the term given to inadequate cortisol response to stress.More recently,another term is used,namely "critical illness related corticosteroid insufficiency" to define "an inadequate cellular corticosteroid activity for the severity of the patient’s illness".The mechanisms of AI in liver cirrhosis are not completely understood,although decreased levels of high-density lipoprotein cholesterol and high levels of proinflammatory cytokines and circulatory endotoxin have been suggested.The prevalence of AI in cirrhotic patients varies widely according to the stage of the liver disease(compensated or decompensated,with or without sepsis),the diagnostic criteria defining AI and the methodology used.The effects of corticosteroid therapy on cirrhotic patients with septic shock and AI are controversial.This review aims to summarize the existing published information regarding AI in patients with liver cirrhosis.     

Adrenal insufficiency in patients with decompensated cirrhosis

Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary-adrenal(HPA) axis are causes for adrenal insufficiency(AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI in cirrhotics aswell. Both stable cirrhotics and liver transplant patients(early and later after transplantation) have been reported to present AI. The mechanisms leading to reduced cortisol production in cirrhotics are the combination of low cholesterol levels(the primary source of cortisol), the increased cytokines production that overstimulate and exhaust HPA axis and the destruction of adrenal glands due to coagulopathy. AI has been recorded in 10%-82% cirrhotics depending on the test used to evaluate adrenal function and in 9%-83% stable cirrhotics. The similarity of those proportions support the assumption that AI is an endogenous characteristic of liver disease. However, the lack of a gold standard method for AI assessment and the limitation of precise thresholds in cirrhotics make difficult the recording of the real prevalence of AI. This review aims to summarize the present data over AI in stable, critically ill cirrhotics and liver transplant recipients. Moreover, it provides information about the current knowledge in the used diagnostic tools and the possible effectiveness of corticosteroids administration in critically ill cirrhotics with AI.     

Relative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome)

AimRelative adrenal insufficiency (RAI) has been reported in critically ill patients with cirrhosis. We evaluated the prevalence of RAI and its relationship to clinical course in non-septic cirrhosis patients with ascites.MethodsThe study included 66 consecutive non-septic cirrhosis patients with ascites. RAI was defined by a delta cortisol lower than 9 μg/dL and/or a peak cortisol lower than 18 μg/dL.ResultsSixty-six patients with cirrhosis and ascites were studied. The mean Child-Turcotte-Pugh (CTP) and model for end stage liver disease (MELD) scores were 10.6 ± 1.9 and 21.5 ± 7.3, respectively. The prevalence of RAI in patients with cirrhosis and ascites was 47% (31/66). The prevalence of RAI in patients with and without spontaneous bacterial peritonitis, renal failure and type 1 hepatorenal syndrome (HRS) was comparable. Baseline hyponatremia was common in RAI (42% versus 17%, p = 0.026). There was a significant correlation of prevalence of RAI with prothrombin time, international normalized ratio, MELD scores and CTP class. During follow-up, there was no association between RAI and the risk to develop new infections, severe sepsis, type 1 HRS and death.ConclusionsRAI is common in non-septic cirrhotic patients with ascites and its prevalence increases with severity of liver disease. However, it does not affect the short-term outcome in these patients.     

Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods

CONTEXT: Activation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated, such as the definition of normal adrenal response, the concept of relative adrenal insufficiency, and the use of glucocorticoids in the setting of critical illness. OBJECTIVES: The primary objective was to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and provide alternative approaches in that setting. DESIGN: This was a critical review of relevant data from the literature with inclusion of previously published as well as unpublished observations by the author. Data on HPA function during three different forms of critical illnesses were reviewed: experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units. SETTING: The study was conducted at an academic medical center. PATIENTS/PARTICIPANTS: Participants were critically ill subjects. Intervention: There was no intervention. MAIN OUTCOME MEASURE: The main measure was to provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements. RESULTS: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 microg/dl or more in most critically ill patients, irrespective of their serum binding proteins. Because the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens' method) and determining the free cortisol index (ratio of serum cortisol to transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continue to provide reliable assessment of adrenal function in critically ill patients, in whom a random serum total cortisol would be expected to be 15 microg/dl or more in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 microg/dl or more in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients. CONCLUSIONS: The routine use of glucocorticoids during critical illness is not justified except in patients in whom adrenal insufficiency was properly diagnosed or others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as low-dose hydrocortisone leads to excessive elevation in serum cortisol to values severalfold greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally insufficient subjects.     

Relative adrenal failure in intensive care: an identifiable problem requiring treatment?

Adequate adrenocortical function is essential to survive critical illness. Most critically ill patients display an elevated plasma cortisol level, reflecting activation of the pituitary-adrenal axis, which is considered to be a homeostatic adaptation. In the setting of critical illness, the failure of an appropriate neuroendocrine response can lead to the picture of vasopressor-dependent refractory hypotension. This state of relative or functional adrenal insufficiency is characterized by an inadequate production of cortisol in relation to an increased demand during periods of severe stress, particularly prolonged critical illness such as multi-organ failure. This clinical entity, however, lacks clear-cut diagnostic criteria. What are the appropriate cortisol concentrations in the critically ill? Should base-line and adrenocorticotropic hormone-stimulated cortisol concentrations be assessed? The classical adrenocorticotropic hormone stimulation test is often used, but there are problems with interpreting its results. Other diagnostic tools, such as the low-dose adrenocorticotropic hormone test and relative eosinophilia, are promising but also lack proper criteria. A prompt response to hydrocortisone treatment is a major clue to the diagnosis. Recent studies with stress doses of hydrocortisone in sepsis and septic shock have shown a marked haemodynamic improvement, but whether patients with relative adrenal dysfunction benefit most from this treatment and whether there is definitely an effect on outcome is still undecided.     

Hypothalamic-pituitary adrenal function in end-stage non-alcoholic liver disease

Abstract Patients with end-stage liver disease have significant mortality often associated with intercurrent episodes of bleeding or sepsis. Intact adrenal function is essential in such situations. In order to test the hypothesis that adrenal insufficiency might be present in severe liver disease, hypothalamic-pituitary adrenal function was evaluated in patients with end-stage liver disease awaiting transplantation. The study had a prospective, open comparative design with patients restricted to those having non-alcoholic liver disease in order to avoid the confounding direct effects of alcohol on adrenocortical function. Fifty-one consecutive patients with end-stage, non-alcoholic liver disease undergoing evaluation for liver transplantation and 40 healthy controls were studied. Patients who had used corticosteroids (n= 8) or who were unable to complete the investigations (n= 5) were excluded leaving 38 patients eligible for analysis. Adrenal function was evaluated under basal conditions by single morning measurements of plasma total and free cortisol, corticosteroid-binding globulin, dehydroepiandrosterone sulfate and by adrenal stimulation indirectly using insulin-induced (0.1 U/kg, i.v.) hypoglycaemia and/or directly by adrenocorticotrophic hormone (ACTH); 250 μg tetracosactrin, i.v.) stimulation. Compared with healthy controls, patients with liver disease had a 64% reduction in maximal increments of plasma cortisol to indirect adrenal stimulation via insulin-induced hypoglycaemia and a 39% reduction to direct adrenal stimulation by ACTH (all P < 0.001). There was a significant negative correlation between the severity of underlying liver disease as assessed by Child-Pugh scores and peak control responses to ACTH (r= -0.647, P < 0.0001) and insulin-induced hypoglycaemia (r= -0.597, P < 0.0001). Patients with liver disease also exhibited significantly blunted and delayed hypoglycaemic responses to insulin (0.1 U/kg), brisker growth hormone responses of reduced magnitude and decreased corticosteroid-binding globulin levels. Baseline morning cortisol, free cortisol and dehydroepiandrosterone sulfate levels were unchanged compared with healthy controls. Patients on spironolactone had lower basal and peak cortisol responses to ACTH and hypoglycaemia, but the reductions were unrelated to spironolactone dose. Although insulin resistance and spironolactone therapy are confounding factors, it can be concluded that hypothalamic-pituitary regulation of adrenal function is defective in end-stage non-alcoholic liver disease. It is therefore possible that functional central adrenal insufficiency might contribute to the mortality of patients with end-stage liver disease and raises the question of the need for controlled studies of adrenocortical replacement therapy during acute deteriorations (sepsis and haemorrhage) in severe hepatic disease.     

Diagnosis of adrenal insufficiency in severe sepsis and septic shock

RATIONALE: Diagnosis of adrenal insufficiency in critically ill patients has relied on random or cosyntropin-stimulated cortisol levels, and has not been corroborated by a more accurate diagnostic standard. OBJECTIVE: We used the overnight metyrapone stimulation test to investigate the diagnostic value of the standard cosyntropin stimulation test, and the prevalence of sepsis-associated adrenal insufficiency. METHODS: This was an inception cohort study. MEASUREMENTS AND RESULTS: In two consecutive septic cohorts (n = 61 and n = 40), in 44 patients without sepsis and in 32 healthy volunteers, we measured (1) serum cortisol before and after cosyntropin stimulation, albumin, and corticosteroid-binding globulin levels, and (2) serum corticotropin, cortisol, and 11beta-deoxycortisol levels before and after an overnight metyrapone stimulation. Adrenal insufficiency was defined by postmetyrapone serum 11beta-deoxycortisol levels below 7 microg/dl. More patients with sepsis (31/61 [59% of original cohort with sepsis] and 24/40 [60% of validation cohort with sepsis]) met criteria for adrenal insufficiency than patients without sepsis (3/44; 7%) (p < 0.001 for both comparisons). Baseline cortisol (< 10 microg/dl), Delta cortisol (< 9 microg/dl), and free cortisol (< 2 microg/dl) had a positive likelihood ratio equal to infinity, 8.46 (95% confidence interval, 1.19-60.25), and 9.50 (95% confidence interval, 1.05-9.54), respectively. The best predictor of adrenal insufficiency (as defined by metyrapone testing) was baseline cortisol of 10 microg/dl or less or Delta cortisol of less than 9 microg/dl. The best predictors of normal adrenal response were cosyntropin-stimulated cortisol of 44 microg/dl or greater and Delta cortisol of 16.8 microg/dl or greater. CONCLUSIONS: In sepsis, adrenal insufficiency is likely when baseline cortisol levels are less than 10 microg/dl or delta cortisol is less than 9 microg/dl, and unlikely when cosyntropin-stimulated cortisol level is 44 microg/dl or greater or Delta cortisol is 16.8 microg/dl or greater.     

Cardiac dysfunction in cirrhosis – does adrenal function play a role? A hypothesis

Cirrhotic cardiomyopathy (CCM), a condition of unknown pathogenesis, is characterized by suboptimal ventricular contractile response to stress, diastolic dysfunction and QT interval prolongation. It is most often found in patients with advanced cirrhosis. It is clinically relevant during stressful conditions, such as sepsis, bleeding and surgery. CCM reverses after liver transplantation and potentially has a role in the pathogenesis of hepatorenal syndrome. In adrenal insufficiency (AI), cardiac dysfunction is a feature with low ejection fraction, decreased left ventricular chamber size and electrocardiographic abnormalities, including QT interval prolongation. With optimal diagnostic tests, AI is present in approximately 10% of patients with cirrhosis, particularly in those with advanced disease. Down-regulation and decreased number of beta-adrenergic receptors, and high catecholamine levels are common to both cardiac conditions. Thus, AI may play a role in CCM. Steroid replacement therapy reverses cardiac changes in AI, and may do so for CCM, with important therapeutic implications; this needs formal evaluation.     

Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality

CONTEXT: Adequate adrenal function is pivotal to survive meningococcal sepsis. OBJECTIVES: The objective of the study was to evaluate adrenocortical function in meningococcal disease. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a university-affiliated pediatric intensive care unit. PATIENTS: Sixty children with meningococcal sepsis or septic shock participated in the study. MAIN OUTCOME MEASURES: The differences in adrenal function between nonsurvivors (n = 8), shock survivors (n = 43), and sepsis survivors (n = 9) on pediatric intensive care unit admission were measured. RESULTS: Nonsurvivors had significantly lower median cortisol to ACTH ratio than shock survivors and sepsis survivors. Because cortisol binding globulin and albumin levels did not significantly differ among the groups, bioavailable cortisol levels were also significantly lower in nonsurvivors than sepsis survivors. Nonsurvivors had significantly lower cortisol to 11-deoxycortisol ratios but not lower 11-deoxycortisol to 17-hydroxyprogesterone ratios than survivors. Using multiple regression analysis, decreased cortisol to ACTH ratio was significantly related to higher IL-6 levels and intubation with etomidate (one single bolus), whereas decreased cortisol to 11-deoxycortisol ratio was significantly related only to intubation with etomidate. Aldosterone levels tended to be higher in nonsurvivors than shock survivors, whereas plasma renin activity did not significantly differ. CONCLUSIONS: Our study shows that the most severely ill children with septic shock had signs of adrenal insufficiency. Bioavailable cortisol levels were not more informative on adrenal function than total cortisol levels. Besides disease severity, one single bolus of etomidate during intubation was related to decreased adrenal function and 11beta-hydroxylase activity. Decreased adrenal function was not related to decreased 21-hydroxylase activity. Based on our results, it seems of vital importance to take considerable caution using etomidate and consider combining its administration with glucocorticoids during intubation of children with septic shock.     

The Effect of Adrenal Replacement Therapy on Rates of Fungal Colonization and Mortality in Critically Ill Patients Awaiting Liver Transplantation

Background

The effect of adrenal replacement therapy (ART) with hydrocortisone on critical endpoints such as infection and mortality in critically ill patients with cirrhosis remains unclear. We evaluated our indications for ART in patients with cirrhosis with clinical symptoms of adrenal insufficiency (AI), and examined the rate of peri-transplant fungal colonization and mortality associated with ART.

Methods

Seventy-eight patients with cirrhosis admitted to our institution''s surgical intensive care unit (ICU) over a 4-year period met criteria for AI by vasopressor requirement and baseline cortisol levels. Outcomes included disposition at 90-days, fungal colonization, and fungal infection in the presence or absence of ART.

Results

In total, 56 patients received hydrocortisone (HC+) while 22 did not (HC−). The HC+ and HC− groups had comparable median Model for End-stage Liver Disease (MELD) scores (26.5 vs. 25, respectively; p=0.93), median ICU lengths of stay (23 vs. 20 days, respectively; p=0.54) and median cortisol levels (18 μg/dL for both, p=0.87). Fungal cultures (FC) from blood, urine or bronchoalveolar lavage/sputum were positive for 44% of HC+, and 40.9% of HC− (p=0.77) had mortality rates between HC+ and HC− groups that were not significantly different (60.7% vs. 50%, respectively; p=0.39; α=0.05). The 90-day outcomes for HC+ vs. HC− (39.3% vs. 50% discharged, respectively; p=0.39; α=0.05) and those surviving to transplant (17.9% vs. 36.4%, respectively; p=0.08; α=0.05) were not significantly different between the two groups.

Conclusion

In this small single-center series, we found that steroid administration for AI does not affect the rate of fungal colonization/infection or mortality. Further prospective studies are required to determine the utility of ART and factors affecting the rate of FC and mortality in these patients.     

Serum cortisol levels in patients admitted to the department of medicine: Prognostic correlations and effects of age, infection, and comorbidity

BACKGROUND: In contrast to healthy adults or critically ill patients, data on serum cortisol levels in noncritically ill patients admitted to general internal medicine wards has not been well characterized. We aimed to describe the distribution and range of serum cortisol levels in patients admitted to the department of medicine, to discover whether old age, severe infections, or comorbidity induced a blunted hypothalamic-pituitary-adrenal (HPA) response and whether initial serum cortisol value had a prognostic significance. METHODS: Morning (8 am) serum cortisol level together with epidemiologic, clinical, and laboratory data were analyzed for 252 consecutive adult (age > or = 18 yrs) patients admitted to the department of internal medicine during a 6-weeks period. RESULTS: The mean serum cortisol level (541 +/- 268 nmol/L) was within the normal range. Only one patient had a low serum cortisol level of 72 nmol/L, whereas the majority of patients had either normal (80%) or increased (19%) serum cortisol levels. Older age, sepsis, prolonged duration of fever, higher comorbidity score, and higher serum creatinine level were each associated with significantly higher serum cortisol level. In addition, a higher serum cortisol level was significantly related to longer hospitalization and higher in-hospital mortality rate. CONCLUSIONS: Serum cortisol level positively correlated with age, disease severity, and outcome. All admitted patients, except one, had normal to high serum cortisol. Whether this increased cortisol level is an adequate HPA response or less than required for the disease-induced stress should be investigated in further studies.     

Acute respiratory failure complicating advanced liver disease

Advanced liver disease is associated with hypoxemia and respiratory failure by various mechanisms. Patients with cirrhosis are especially prone to episodes of decompensation requiring intensive care unit admission and management. Such patients may already be in acute liver failure or have decompensated due to a concurrent illness such as spontaneous bacterial peritonitis, sepsis, encephalopathy, varices, or hepatorenal syndrome. Acute respiratory distress syndrome is one of the main reasons for intensive care unit admission and mortality. Overall, critically ill cirrhotic patients frequently progress to multiorgan failure requiring mechanical ventilation. Caring for such patients is therefore understandably complex and extremely challenging. Patients with end-stage liver disease are especially at risk for developing acute respiratory failure and hypoxemia secondary to hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. They should therefore be screened for these conditions because failure to recognize and adequately treat these serious complications of cirrhosis may have devastating consequences. This article is based on a review of the current literature on how to approach and manage acute respiratory failure in advanced liver disease, which is important to intensivists, anesthesiologists, and physicians as a whole.     

Intensive care of the patient with cirrhosis

Acute deterioration of patients with cirrhosis manifests as multiple organ failure requiring admission to an intensive care unit. Precipitating events may be viral hepatitis, typically in Asia, and drug or alcoholic hepatitis and variceal hemorrhage in the West. Patients with cirrhosis in the intensive care unit have a high mortality, and each admission is associated with a mean charge of US $116,200. Prognosis is determined by the number of organs failing (sequential organ failure assessment [SOFA] score), the presence of infection, and the degree of liver dysfunction (Child-Turcotte-Pugh or Model for End-Stage Liver Disease scores). The most common organ failing is the kidney; sepsis is associated with further deterioration in liver function by compromise of the microcirculation. Care of these critically ill patients with impending multiple organ failure requires a team approach with expertise in both hepatology and critical care. Treatment is aimed at preventing further deterioration in liver function, reversing precipitating factors, and supporting failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. Treatment is futile in some patients, but it is difficult to identify these patients a priori. Artificial and bioartificial liver support systems have thus far not demonstrated significant survival benefit in these patients.     

Algorithm for Screening of Adrenal Function in Stable Patients with Cirrhosis

Introduction and aimsAdrenal insufficiency (AI) is common in patients with cirrhosis. We aimed to assess the presence of AI in stable patients with cirrhosis using the gold-standard insulin tolerance test (ITT) and to propose an algorithm for screening AI in these patients.Material and methodsWe studied 40 stable patients with cirrhosis. We determined the basal total (BTC) and peak cortisol (PTC) levels. Using the ITT, we defined AI as a serum PTC < 18 ng/dL at 30 min after insulin-induced hypoglycemia. We assessed the diagnostic accuracy of BTC in different stages of liver disease to discriminate between those with NAF and AI.ResultsOf the 40 patients, 24 (60%) presented with AI. Child-Pugh and MELD scores differed between the NAF and AI groups (Child-Pugh: NAF 7.2 ± 1.7 vs. AI 8.8 ± 2.4, p = 0.024 and MELD: NAF 9.9 ± 2.5 vs. AI 14.9 ± 6.3, p = 0.001). The BTC level was lower in patients with AI than in those with NAF (7.2 ± 2.4 vs. 12.5 ± 5.2, p < 0.001). A BTC value <10.0 |ig/dL had a 96% sensitivity (negative predictive value: 90%) for identifying AI. This cutoff value (BTC <10.0 |ig/dL) provided 100% specificity (positive predictive value: 100%) in patients with advanced liver disease (Child-Pugh >9 or MELD >12).ConclusionAn algorithm including the use of BTC and the severity of liver disease may be a useful and simple method for assessing adrenal function in stable patients with cirrhosis.     

Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy necessary?

Patients undergoing pituitary adenomectomy are usually given glucocorticoid therapy, although there are no data to document the need for such therapy. We prospectively studied hypothalamic-pituitary-adrenal axis (HPA) function in 88 consecutive pituitary adenoma patients before and after selective adenomectomy, excluding those with corticotroph adenomas. Preoperatively, 5 patients had adrenal insufficiency (AI); they were treated with glucocorticoids and excluded from the analysis. The remaining 83 patients had normal HPA function preoperatively and were not given glucocorticoids before, during, or immediately after surgery, but were closely monitored, and their serum cortisol levels were measured in the immediate postoperative period. Two patients were clinically suspected to have AI postoperatively and were treated accordingly. The remaining 81 patients had no clinical manifestations of AI and received no glucocorticoid therapy. Their serum cortisol levels in the immediate postoperative period were appropriately elevated. The mean serum cortisol level was 40.5 +/- 11.1 (+/- SD) micrograms/dL (1117 +/- 306 nmol/L) 6 h after surgery; serum cortisol levels decreased gradually thereafter. Morning serum cortisol levels were within the normal range on the fourth, fifth, and sixth days after surgery: day 4, 15.1 +/- 7.0 micrograms/dL (417 +/- 193 nmol/L); day 5, 16.4 +/- 5.6 micrograms/dL (453 +/- 155 nmol/L); and day 6, 16.3 +/- 5.7 micrograms/dL (450 +/- 157 nmol/L). When tested 3 months after surgery, all 81 patients had normal HPA function. We conclude that HPA function is rarely compromised after selective pituitary adenomectomy. Close observation and serum cortisol measurements in the immediate postoperative period can reliably predict the integrity of the HPA after surgery. Routine glucocorticoid therapy is not needed in patients undergoing selective adenomectomy whose preoperative adrenal function is normal.     

Evaluación y manejo de emergencias en el paciente con cirrosis

The approach to and management of critically ill patients is one of the most versatile themes in emergency medicine. Patients with cirrhosis of the liver have characteristics that are inherent to their disease that can condition modification in acute emergency treatment. Pathophysiologic changes that occur in cirrhosis merit the implementation of an analysis as to whether the overall management of a critically ill patient can generally be applied to patients with cirrhosis of the liver or if they should be treated in a special manner. Through a review of the medical literature, the available information was examined, and the evidence found on the special management required by those patients was narratively synthesized, selecting the most representative decompensations within chronic disease that require emergency treatment.     

New determinants of prognosis in bacterial infections in cirrhosis

Despite major advances in the knowledge and management of liver diseases achieved in recent decades, decompensation of cirrhosis still carries a high burden of morbidity and mortality. Bacterial infections are one of the main causes of decompensation. It is very important for clinical management to be aware of the population with the highest risk of poor outcome. This review deals with the new determinants of prognosis in patients with cirrhosis and bacterial infections reported recently. Emergence of multiresistant bacteria has led to an increasing failure rate of the standard empirical antibiotic therapy recommended by international guidelines. Moreover, it has been recently reported that endothelial dysfunction is associated with the degree of liver dysfunction and, in infected patients, with the degree of sepsis. It has also been reported that relative adrenal insufficiency is frequent in the non-critically ill cirrhotic population and it is associated with a higher risk of developing infection, severe sepsis, hepatorenal syndrome and death. We advise a change in the standard empirical antibiotic therapy in patients with high risk for multiresistant infections and also to take into account endothelial and adrenal dysfunction in prognostic models in hospitalized patients with decompensated cirrhosis.     

Cosyntropin-stimulated salivary cortisol in hospitalized patients with hypoproteinemia

Analysis of adrenocortical function in acutely ill, hospitalized patients can be challenging due to changes in plasma binding proteins. This study used dynamic testing of salivary cortisol levels to evaluate adrenal function in hospitalized patients with low/low-normal plasma protein concentration in whom adrenal insufficiency was suspected. Twenty-eight patients with low serum albumin and proteins hospitalized for acute illness were evaluated for decreased adrenocortical function because of clinical presentations suspicious for adrenal insufficiency. Baseline and post cosyntropin-stimulated levels of serum total and salivary cortisol levels were assessed. Data were gathered by a retrospective analysis of medical records. Eight patients had normal peak serum total and salivary cortisol responses, consistent with intact adrenocortical function. Five patients had abnormal peak serum total and salivary cortisol responses indicating decreased adrenocortical function. Fifteen patients had subnormal peak serum total cortisol, but normal peak salivary cortisol responses indicating normal adrenal function. Salivary cortisol testing can identify hospitalized patients with apparently intact adrenal function in whom low serum protein confounded interpretation of serum total cortisol measurements. Salivary cortisol is a clinically useful surrogate for serum free cortisol in dynamic testing of adrenocortical function.     

Upregulation of TLR2 and TLR4 in the human adrenocortical cells differentially modulates adrenal steroidogenesis

Rapid activation of adrenal steroid release plays a pivotal role in an organism's first line of defense during sepsis. Adrenal gland function is often suppressed in critically ill patients and negatively impacts the overall survival rate. Increasingly, experimental and clinical evidence suggests that Toll-like receptors (TLRs), components of the innate immune system, play a key role in the mediation of systemic responses to invading pathogens during sepsis. In the present study, we aimed to elucidate the effect of TLR2, TLR4 and CD14 upregulation on adrenocortical cell steroidogenesis. We found that TLR4 and CD14 but not TLR2 overexpression in NCI-H295R cells inhibited basal and acute cortisol and aldosterone production. This effect could be partially explained by reduced expression of enzymes involved in the synthesis of latter steroids--CYP11B1 and CYP11B2. Together, these data suggest that TLR upregulation in the steroid producing cells may be involved in the adrenal gland dysfunction during sepsis.