Relative Adrenal Insufficiency In Patients Research Articles

Endocrinology for the hepatologist.

INTRODUCTION The liver and endocrine system are inextricably linked, with the liver responsible for the metabolism of a variety of hormones (Figure 1). The complex feedback mechanism between the liver and the endocrine axes has been implicated in various forms of endocrine abnormalities and liver disease. The aim of this article is to review the current literature on the association of chronic liver disease and selected endocrine abnormalities, including thyroid dysfunction, adrenal insufficiency, type 2 diabetes, and osteoporosis.FIGURE 1: The liver plays a key role in the metabolism of multiple different hormones. Hepatic dysfunction is associated with impaired synthesis of hormones and proteins, thus leading to the development of several endocrine abnormalities. Abbreviations: CBG, cortisol-binding globulin; TBG, thyroid-binding globulin.LIVER DISEASE AND THYROID DISORDERS The liver is responsible for the peripheral conversion of T4 to its biologically active form, T3.1 In addition, the liver serves an important role in the synthesis of thyroid-binding globulin and allows for biliary excretion of thyroid hormone metabolites. Thus, variations in serum thyroid levels can be observed in patients with cirrhosis. Previous studies have reported a strong correlation between decreased levels of serum T3 and severity of hepatic dysfunction in patients with cirrhosis.2 Low serum T4 has also been associated with increased intrahepatic lipid content in subclinical and overt hypothyroid patients.3,4 Thyroid hormones play a significant role in cholesterol metabolism as they regulate lipogenesis and cholesterol synthesis. Hypothyroidism has been associated with dyslipidemia and shares several clinical features of the metabolic syndrome, including a strong bidirectional relationship with the development of NAFLD. Thyroid dysfunction is associated with autoimmune-mediated liver diseases such as primary biliary cholangitis (PBC), autoimmune hepatitis, and primary sclerosing cholangitis.1,5 Diagnosis of thyroid disease in cirrhosis Patients with cirrhosis, especially in those with autoimmune-mediated liver disease, should be screened for thyroid disorders. Thyroid tests may be difficult to interpret in patients with concomitant liver disease due to impaired hepatic synthetic function. The most consistent thyroid hormone profile seen in patients with cirrhosis includes a low total and free T3 and an elevated reverse T3 in the setting of normal thyroid-stimulating hormone, otherwise known as sick euthyroid syndrome.1 Management of hypothyroidism in cirrhosis In patients with NAFLD, levothyroxine replacement therapy has been associated with improved serum lipid levels and reduced body mass index.4 Treatment with levothyroxine has also been shown to reduce the prevalence of NAFLD in patients with subclinical hypothyroidism and dyslipidemia.6 In addition, administration of levothyroxine in euthyroid patients with NAFLD having diabetes mellitus decreases intrahepatic lipid content.7 In patients with cirrhosis, higher doses of levothyroxine may be needed due to malabsorption. Because of the complex interplay between thyroid hormones and NAFLD, therapeutics that modulate the thyroid hormone receptor (THR) have garnered increased interest. Agents such as resmetirom, a selective THR-β agonist, have shown promise as potential therapeutics in decreasing hepatic steatosis and NASH severity.4 ADRENAL INSUFFICIENCY IN CIRRHOSIS Relative adrenal insufficiency (RAI) is characterized by inadequate cortisol production when compared with organ demand. RAI is relatively common and under-recognized in patients with cirrhosis with a prevalence estimated between 15% and 72%.8 The hypothalamic-pituitary-adrenal axis is disrupted in patients with cirrhosis, as there is impaired metabolism of cortisol and decreased synthesis of corticosteroid-binding globulin and albumin. In addition, patients with cirrhosis are observed to have a delay in the morning secretion of cortisol, particularly in those who are decompensated. The pathophysiology of RAI is complex and multifactorial, as outlined in Figure 2. Besides the impaired production of apolipoprotein A1 and lecithin-cholesterol acyltransferase enzyme, several other mechanisms by which RAI develops in cirrhosis have been proposed, including impaired vascular tone leading to adrenal hypoperfusion, deficient adrenal enzymatic activity, and the effect of proinflammatory cytokines on the hypothalamic-pituitary-adrenal axis.FIGURE 2: Adrenal steroidogenesis is dependent on activation of protein (StAR). Activation of StAR requires ApoA1 and LCAT, both of which are produced in the liver and therefore their synthesis is impaired in the setting of cirrhosis, leading to adrenal insufficiency. Abbreviations: ApoA1, apolipoprotein A; LCAT, lecithin-cholesterol acyltransferase enzyme; StAR, steroidogenic acute regulatory.RAI in cirrhosis has important consequences. In a cohort of 101 patients with cirrhosis and severe sepsis, just over 50% of patients had RAI with a significant increase in 90-day mortality.9 In another cohort of Italian inpatients admitted with acutely decompensated cirrhosis, almost 50% of patients had RAI, resulting in a higher risk of sepsis, shock, organ dysfunction, and 90-day mortality.10 Diagnosis of RAI in patients with cirrhosis The diagnosis of RAI in the setting of cirrhosis is challenging because of the overlap of symptoms and shortcomings in our diagnostic tools. Patients with RAI may present with hemodynamic lability, electrolyte derangements, such as hyponatremia, fatigue, and abdominal pain, all symptoms that can also be seen in patients with cirrhosis. Although RAI is most frequently seen in patients with acutely decompensated cirrhosis and acute liver failure, it can also be observed in patients with compensated cirrhosis. Because of its association with increased mortality and poor prognosis, prompt recognition of RAI is imperative and screening for RAI should be initiated in patients with hemodynamic compromise refractory to resuscitation, unexplained abdominal pain, and persistent hyponatremia that is out of proportion to the underlying acute illness or liver disease. The diagnosis of RAI in cirrhosis is based on measurements of total cortisol (TC) levels at baseline and after stimulation with either cosyntropin or synacthen, otherwise known as an adrenocorticotropic hormone (ACTH) stimulation test. An impaired response to ACTH stimulation is diagnostic of RAI.11 Alternatively, morning TC of <5 μg/dL can also be used in cases where ACTH stimulation test is unavailable. However, measurement of TC in patients with cirrhosis has diagnostic limitations. More than 90% of serum cortisol is bound to cortisol-binding globulin and albumin,8 both of which are produced by the liver. Thus, serum TC can be falsely low in patients with cirrhosis and may lead to the overestimation of RAI. Additional tests such as free cortisol level and salivary cortisol level are alternatives; however, they are often impractical and expensive with limited use in daily clinical practice. Treatment of RAI in patients with cirrhosis The treatment of RAI in patients with cirrhosis and concomitant critical illness remains debatable with conflicting data in the literature. In patients with cirrhosis and septic shock, hydrocortisone replacement was associated with reduced vasopressor requirements, septic shock reversal, and decrease mortality.12 On the other hand, in a randomized control trial comparing the administration of hydrocortisone versus placebo in patients with cirrhosis and septic shock, administration of hydrocortisone led to an increased risk of infections and gastrointestinal bleeding without survival benefit.9 Therefore, glucocorticoid replacement should be used cautiously with a high index of suspicion for the development of infection and bleeding. Clinicians should consider using a physiological dose of i.v. hydrocortisone (200–300 mg/d in 3–4 divided doses), with a slow taper depending on the patient’s clinical course. On the other hand, in patients with RAI and compensated cirrhosis, steroid replacement therapy is not recommended except in certain circumstances. No randomized trials have studied the use of steroids in concomitant RAI and cirrhosis in a noncritical care setting. However, in the presence of persistent hypotension, abdominal pain, or hyponatremia, empiric use of steroids may be considered on a case-by-case basis weighing the risk of potential complications. DIABETES AND LIVER DISORDERS Type 2 diabetes mellitus (T2DM) is common in patients with chronic liver disease and associated with increased morbidity and mortality. Between 30% and 60% of patients with cirrhosis have T2DM, with the highest prevalence in patients with NAFLD.13 Although the highest prevalence of T2DM is seen in patients with cirrhosis due to NAFLD, it is also commonly seen in patients with alcohol-associated liver disease, cryptogenic cirrhosis, hepatitis C, and HCC.14 T2DM in patients with cirrhosis can develop because of impaired glucose metabolism, a term referred to as hepatogenous diabetes. In addition, T2DM is an independent risk factor for the development of NASH and advanced hepatic fibrosis.5 Although it is difficult to differentiate between intrinsic T2DM and hepatogenous diabetes, there are significant clinical implications as patients with hepatogenous diabetes are less likely to have a family history of T2DM, less likely to experience cardiovascular-related death, and have a decreased incidence of diabetic retinopathy. The liver serves a critical role in maintaining glucose homeostasis.15 Several mechanisms by which T2DM develops in patients with cirrhosis have been proposed; however, the most important factor appears to be the role of insulin resistance. T2DM leads to progressive hepatic fibrosis through a variety of different mechanisms and pathways as outlined in Figure 3.FIGURE 3: Type 2 diabetes mellitus occurs in the setting of insulin resistance and hyperinsulinemia. Hyperglycemia stimulates the release of FFA from adipose tissue. The intrahepatic accumulation of FFA leads to oxidative stress and inflammation, which can stimulate hepatic stellate cells. In addition, insulin resistance leads to apoptosis, which in turn activates stellate cells. The stimulation of stellate cells results in increased extracellular matrix production and is key to the development of hepatic fibrosis. Hyperglycemia and insulin resistance also stimulate angiogenesis, which promotes the development of fibrosis. Abbreviation: FFA, free fatty acids.Diagnosis of diabetes in cirrhosis The diagnosis of T2DM in patients with cirrhosis is challenging given the decreased sensitivity of common biochemical markers in the presence of hepatic insufficiency. In the early stages of cirrhosis, fasting plasma glucose and hemoglobin A1c (HbA1c) may be within normal range, and a 2-hour plasma glucose may be required for diagnosis.16 HbA1c is the gold standard for diagnosing T2DM and monitoring glycemic control; however, it needs to be used with caution in patients with cirrhosis. Values of HbA1c can be falsely low in patients with cirrhosis due to high red blood cell turnover, which may occur in the setting of hypersplenism, bleeding, and vitamin deficiency.14 Fructosamine is a measurement of total plasma glycated proteins and may be useful to assess glycemic control in patients with cirrhosis. Some studies have suggested that fructosamine may be more accurate than HbA1c17,18; however, levels may be falsely elevated in patients with cirrhosis,19,20 and therefore, the use of fructosamine is not routinely recommended for glycemic monitoring in patients with chronic liver disease. Management of diabetes in cirrhosis The choice of antidiabetic agents in patients with cirrhosis should be based on the degree of liver dysfunction and the presence of comorbidities. Secretagogues, such as sulfonylureas (eg, glimepiride), are metabolized in the liver and associated with a significant risk of hypoglycemia and are therefore not generally used in patients with cirrhosis. In general, with the exception of secretagogues, noninsulin agents can be safely used in patients with compensated cirrhosis. However, in patients with decompensated cirrhosis, insulin remains the mainstay of therapy. Metformin has been shown to decrease the risk of HCC, increase survival, and reduce all-cause mortality among patients with cirrhosis and T2DM.21 The risk of developing lactic acidosis in the absence of renal dysfunction is rare and therefore should not discourage providers. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs; eg, liraglutide and semaglutide) have emerged as a promising treatment for NASH as they are associated with weight loss and decreased hepatic steatosis.22 Of note, most studies on the pharmacokinetics of GLP-1 RA included patients with Child-Pugh A and B cirrhosis, and therefore, their use in patients with advanced cirrhosis needs to be studied further. The use of GLP-1 RA should be avoided in patients who are malnourished or in those with renal dysfunction.23 Sodium-glucose cotransporter 2 inhibitors (eg, empagliflozin, canagliflozin, and dapagliflozin) enhance urinary excretion of sodium and glucose and are known for their cardiovascular benefits. These agents are metabolized by the liver and should be used with caution in patients with Child-Pugh B cirrhosis and avoided in patients with Child-Pugh C cirrhosis. OSTEOPOROSIS IN PATIENTS WITH CHRONIC LIVER DISEASE Osteoporosis is frequently observed in patients with chronic liver disease. It is characterized by the aberrant microarchitecture of bone resulting in reduced bone mass that leads to an increased risk of fragility fractures. Approximately 30% of patients with chronic liver disease develop osteoporosis, with a higher prevalence reported in patients with cholestatic liver disease.24 Although best reported in patients with PBC, osteoporosis is a well-described complication of hereditary hemochromatosis and NAFLD. Several risk factors for osteoporosis have been described, including the duration of cholestatic disease, postmenopausal state, decreased body mass index, and advanced age. The mechanism of bone loss in liver disease is multifactorial and dependent on the etiology of cirrhosis. The primary mechanism by which osteoporosis develops is reduced bone formation due to osteoblast dysfunction in the presence of retained products of cholestasis and sclerostin.25 Increased bone resorption has also been implicated as another potential mechanism due to hyperparathyroidism and abnormalities in the RANKL/osteoprotegerin system. Additional risk factors for the development of osteoporosis include a malnourished state, alcohol intake, hypogonadism, steroid use, and hormonal dysregulation. Screening for osteoporosis in chronic liver disease There are limited guidelines for screening for osteoporosis in patients with chronic liver disease. In general, evaluation of bone mineral density (BMD) should be conducted in patients with a history of fragility fractures, long-term use of corticosteroids, and as part of the evaluation for liver transplant. In addition, patients with PBC have a higher prevalence of osteopenia and osteoporosis in comparison with age-matched and sex-matched controls.24 Therefore, baseline screening with bone densitometry and regular screening every 1–2 years should be considered in this patient population. Similarly, in patients with cirrhosis, BMD screening should be performed every 2–3 years with a shorter screening interval in patients with significant risk factors (Figure 4).FIGURE 4: Screening intervals for osteoporosis in patients with chronic liver disease. BMD, bone mineral density.Management of osteoporosis in cirrhosis The approach to treatment of osteoporosis in chronic liver disease should focus on mitigation of risk factors, treatment of the underlying liver disease, and optimization of nutritional status. Supplementation with vitamin D and calcium should be considered in all patients with chronic liver disease as primary prevention. In addition, in perimenopausal and postmenopausal women with PBC, vitamin D levels should be monitored annually. Bisphosphonates are considered the first-line treatment in patients with osteoporosis or low BMD with fragility fractures.24 In patients with PBC, both monthly ibandronate and weekly alendronate were comparable in efficacy and safety in improvement of bone mass.26 The use of oral bisphosphonates is generally avoided in patients with severe esophagitis and esophageal varices, with parenteral bisphosphonate as an alternative therapy. Raloxifene, a selective estrogen receptor agonist, has shown some benefits in improving BMD in patients with PBC; however, there are limited data on its efficacy and safety in patients with advanced fibrosis.27 In general, hormone replacement therapy is avoided in patients with cirrhosis owing to potential adverse effects. More recently, the use of denosumab, a RANK ligand inhibitor, has emerged as a potential agent in the treatment of osteoporosis in chronic liver disease.28 CONCLUSIONS The liver serves an important role in the endocrine system. Hepatologists need to be aware of the various endocrine abnormalities that coexist with chronic liver disease as well as an understanding of the diagnosis and management of these abnormalities.

Relative Adrenal Insufficiency in Patients with Alcoholic Hepatitis

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. 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. 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). RAI is a common entity in patients with severe AH, and it is related with the severity of disease.

Relative Adrenal Insufficiency in Patients with Cirrhosis: A Systematic Review and Meta-Analysis.

Relative adrenal insufficiency (RAI) is frequently observed in patients with cirrhosis. We sought to identify evidence in the literature regarding the impact of RAI on clinical outcomes in cirrhotic patients. We conducted a systematic review (SR) and meta-analysis (MA) using the Ovid-MEDLINE, EMBASE, and Cochrane Library databases to identify relevant studies in the literature. Of the 182 studies identified, 16 were eligible according to our inclusion criteria. The prevalence of RAI was 49.4% (744/1507), and cirrhotic patients with acute critical illnesses such as sepsis were more likely to have RAI compared to those without critical illnesses (P<0.001). With respect to clinical outcomes, patients with RAI had poorer survival rates and an increased risk of complications such as bleeding and hepatorenal syndrome compared to those without RAI. Corticosteroid therapy had a beneficial effect on critically ill cirrhotic patients in terms of hospital survival rate. Based on this SR and MA, critically ill patients with cirrhosis have a high risk of RAI, and the presence of RAI is related to a poor prognosis and occurrence of cirrhotic complications.

Adrenal insufficiency: an uncommon presentation of non-small cell lung cancer

Metastasis to the adrenal gland has been observed in several malignancies; however, adrenal insufficiency as the presenting sign seems rare in these patients. This is a case of a patient presenting with nausea, vomiting, generalized fatigue, and hyponatremia. CT scan demonstrated left upper lobe opacity and bilateral adrenal masses. A biopsy of the adrenal gland revealed non-small cell lung cancer (NSCLC) with metastatic involvement of the adrenal glands. The non-specific symptoms and relative adrenal insufficiency in patients with lung masses should heighten the suspicion for metastatic involvement of the adrenals.

ASSESSMENT OF ADRENOCORTICAL DYSFUNCTION IN PATIENTS WITH STABLE LIVER CIRRHOSIS.

Relative adrenal insufficiency (RAI) is common in the setting of critical illness as well as in hemodynamically instable cirrhotic patients with sepsis. Several studies have also shown that RAI is frequent in patients with stable cirrhosis without sepsis. The aim of this study was to prospectively assess the incidence of RAI in patients with stable cirrhosis. Forty-seven patients with hemodynamically stable liver cirrhosis without sepsis were prospectively included. RAI, assessed by using low dose-short Synacthen test (LD-SST), was defined as either a basal total cortisol concentration below 3.6 µg/dL or a peak total serum cortisol ≤ 16 µg/dL at 30 min after stimulation. RAI was present in 10 (21.3%) of 47 cirrhotic patients. Peak cortisol level was negatively correlated with the severity of cirrhosis evaluated by Child-Turcotte-Pugh (CTP) (r=-0.46; P=0.001) and Model for End-Stage Liver Disease (MELD) (r=-0.51; P=0.001) scores. The frequency of RAI increased from CTP-A (10%) to CTP-B (30%) to CTP-C (60%). RAI diagnosed by LD-SST is frequent in patients with stable cirrhosis and is related to the severity of liver disease. Further studies are needed to define clinical importance of RAI in stable cirrhotic patients.

Relative adrenal insufficiency in cirrhotic patients.

Relative adrenal insufficiency (RAI) was demonstrated in patients with cirrhosis and liver failure. A relationship appears to exist between the severity of the liver disease and the presence of RAI. Neither the mechanism nor the exact prevalence of RAI is fully understood. There is though a hypothesis that low high-density lipoprotein (HDL) levels in this group of patients may be responsible for the insufficiency of cortisol. Several questions also arise about the way and the kind of cortisol (total cortisol, free cortisol, or even salivary cortisol) that should be measured. The presence of RAI in patients with cirrhosis is unquestionable, but still several studies should come up in order to properly define it and fully understand it.

Interaction between etomidate and beta tumoral necrosis factor on hemodynamic response after cardiac surgery

The use of etomidate is a risk factor for relative adrenal insufficiency in patients undergoing cardiopulmonary bypass (CPB) [1]. The objective was to determine the possible interaction between etomidate and beta tumoral necrosis factor (TNFβ) polymorphism on hemodynamics after CPB.

Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial

Recent studies have reported a high prevalence of relative adrenal insufficiency in patients with liver cirrhosis. However, the effect of corticosteroid replacement on mortality in this high-risk group remains unclear. We examined the effect of low-dose hydrocortisone in patients with cirrhosis who presented with septic shock. We enrolled patients with cirrhosis and septic shock aged 18 years or older in a randomized double-blind placebo-controlled trial. Relative adrenal insufficiency was defined as a serum cortisol increase of less than 250 nmol/L or 9 μg/dL from baseline after stimulation with 250 μg of intravenous corticotropin. Patients were assigned to receive 50 mg of intravenous hydrocortisone or placebo every six hours until hemodynamic stability was achieved, followed by steroid tapering over eight days. The primary outcome was 28-day all-cause mortality. The trial was stopped for futility at interim analysis after 75 patients were enrolled. Relative adrenal insufficiency was diagnosed in 76% of patients. Compared with the placebo group (n = 36), patients in the hydrocortisone group (n = 39) had a significant reduction in vasopressor doses and higher rates of shock reversal (relative risk [RR] 1.58, 95% confidence interval [CI] 0.98-2.55, p = 0.05). Hydrocortisone use was not associated with a reduction in 28-day mortality (RR 1.17, 95% CI 0.92-1.49, p = 0.19) but was associated with an increase in shock relapse (RR 2.58, 95% CI 1.04-6.45, p = 0.03) and gastrointestinal bleeding (RR 3.00, 95% CI 1.08-8.36, p = 0.02). Relative adrenal insufficiency was very common in patients with cirrhosis presenting with septic shock. Despite initial favourable effects on hemodynamic parameters, hydrocortisone therapy did not reduce mortality and was associated with an increase in adverse effects. (Current Controlled Trials registry no. ISRCTN99675218.).

Relative Adrenal Insufficiency in Patients With Chronic Liver Disease

In Brief The objective of this overview is to examine the prevalence, pathophysiology, diagnosis, and treatment of relative adrenal insufficiency (RAI) in patients with chronic liver disease. Several studies have demonstrated a high prevalence of RAI in this population, especially with advanced liver disease and during critical illness. The mechanisms of RAI include dysfunction of the hypothalamic-pituitary-adrenal axis, changes in circulating hormones, and peripheral glucocorticoid resistance. These are due, at least in part, to the increased levels of proinflammatory cytokines and lipopolysaccharides observed in this population. There is continued controversy about the best diagnostic test for RAI, because of the limitations of the current case definitions. Only a few studies examined the effect of hydrocortisone therapy in patients with liver disease and showed improvement in hemodynamic abnormalities. However, the effect on survival was not consistent in these studies. Further research in this area is needed to identify the best diagnostic and therapeutic approach to this important entity. Relative adrenal insufficiency has increasingly been recognized in patients with chronic liver disease especially those who are critically ill, opening new potential therapeutic frontiers. The objective of this review is to examine the prevalence, pathophysiology, diagnosis, and treatment of this important entity.

A Prospective Study on the Incidence and Predictive Factors of Relative Adrenal Insufficiency in Korean Critically-Ill Patients

This study was undertaken to evaluate the incidence and risk factors associated with relative adrenal insufficiency (RAI) in Korean critically-ill patients. All patients who were admitted to the Medical Intensive Care Unit (MICU) of Samsung Medical Center between January 1, 2006 and April 30, 2007 were prospectively evaluated using a short corticotropin stimulation test on the day of admission. RAI was defined as an increase in the serum cortisol level of <9 µg/dL from the baseline after administration of 250 µg of corticotropin. In all, 123 patients were recruited and overall the incidence of RAI was 44% (54/123). The presence of septic shock (P=0.001), the Simplified Acute Physiology Score (SAPS) II (P=0.003), the Sequential Organ Failure Assessment (SOFA) score (P=0.001), the mean heart rate (P=0.040), lactate levels (P=0.001), arterial pH (P=0.047), treatment with vasopressors at ICU admission (P=0.004), and the 28-day mortality (P=0.041) were significantly different between patients with and without RAI. The multivariate analysis showed that the SOFA score was an independent predictor of RAI in critically-ill patients (odd ratio=1.235, P=0.032). Our data suggest that RAI is frequently found in Korean critically-ill patients and that a high SOFA score is an independent predictor of RAI in these patients.

Insuficiência adrenal relativa no choque séptico: comparação da resposta ao tratamento com hidrocortisona em pacientes diagnosticados através de dosagem única do cortisol plasmático versus teste da corticotropina

The incidence of relative adrenal insufficiency (RAI) in patients with septic shock is high and has a significant impact on survival. The purpose of this study was to determine whether a random cortisol concentration < 25 mg/dL was as good as a low dose (1 mg) corticotrophin stimulation test in the diagnosis of RAI in patients with septic shock as assessed by the hemodynamic response to hydrocortisone. Patients were randomized to a single cortisol determination or to a low dose corticotrophin stimulation test. After blood collection to cortisol determinations, hydrocortisone (100 mg every 8 hrs) was administered for all patients in the first 36 hours. RAI was defined by a random cortisol concentration < 25 mg/dL or a D cortisol concentration < 9 mg/dL in the corticotrophin test. Sixty patients (G1 = 30; G2 = 30) were included in the analysis and were comparable regarding to demographic data, nosologies and disease severity. The time to norepinephrin withdrawal in group 1 patients with RAI diagnostic criteria was not different from the patients with cortisol > 25 mg/dL. In group 2 patients with D cortisol < 9 mg/dL had a shorter time of norepinephrin infusion (3 days) compared to patients with D cortisol > 9 (6 days). This study suggests that 1 mg corticotrophin test is better than a random cortisol determination < 25 mg/dL to the diagnosis of relative adrenal insufficiency in septic shock patients.

Relative adrenal insufficiency in patients with severe acute pancreatitis

Relative adrenal insufficiency in patients with severe acute pancreatitis

Managing Septic Shock in Patients With Cirrhosis: The Role of Adrenal Insufficency

Fernández J, Escorsell A, Zabalza M, et al. (Liver Unit, Hospital Clinic, Barcelona, Spain). Adrenal insufficiency in patients with cirrhosis and septic shock: effect of treatment with hydrocortisone on survival. Hepatology 2006;44:1288–1295.Bacterial infection continues to be a major cause of death among patients with cirrhosis. The demonstrated survival benefit of prophylactic antibiotic therapy in cirrhotic patients with gastrointestinal hemorrhage underscores the significant impact that bacterial sepsis has in this patient population (Hepatology 1999;29:1655–1661). Currently, management of patients with sepsis centers on supportive care. Many areas of uncertainty remain and strategies for management of sepsis need to be prospectively evaluated in patients with advanced liver disease.Relative adrenal insufficiency (RAI) has been linked to refractory shock, resistance to vasoconstrictor medications, and increased mortality in patients with sepsis (N Engl J Med 2003;348:727–734). A recent meta-analysis of data from multiple clinical trials demonstrates a significant survival benefit from stress-dose steroid replacement in patients with septic shock not necessarily associated with cirrhosis (BMJ 2004;329:480–489). In this setting, Fernández et al prospectively assessed the impact of hydrocortisone treatment in cirrhotic patients with septic shock and abnormal short corticotropin test responses (Hepatology 2006;44:1288–1295).Twenty-five consecutive cirrhotic patients with a diagnosis of septic shock admitted to a specialized liver intensive care unit (ICU) from June 2004 to January 2006 were assessed for adrenal insufficiency with a short corticotropin test within 24 hours of ICU admission. Immunocompromised patients, those with advanced hepatocellular carcinoma, and those with a history of steroid therapy within the past 6 months were excluded. Patients with RAI—defined as a baseline cortisol concentration <15 μg/dL and/or increase of plasma cortisol concentration of <9 μg/dL 1 hour after corticotrophin administration in patients with a baseline cortisol concentration <35 μg/dL—were treated with 50 mg of intravenous hydrocortisone every 6 hours. Hydrocortisone was tapered once vasopressor medications were no longer required. Patients in the prospective cohort were compared with a historical control group of the last 50 consecutive patients with cirrhosis and sepsis in whom adrenal function was not assessed and no steroid therapy was given. All patients were treated with a standard protocol that differed only in the assessment of adrenal function and included antibiotic therapy, central venous and urinary catheterization, goal-directed plasma volume expansion and vasopressor therapy, albumin administration in cases of spontaneous bacterial peritonitis, and continuous venovenous hemofiltration and mechanical ventilation as indicated.Within the prospective cohort, 17 of 25 patients had RAI. A trend toward higher rates of RAI in patients with Child–Pugh class C cirrhosis was noted (P = .08), although no statistically significant differences in clinical characteristics were identified between patients with and without adrenal insufficiency. Compared with historical controls, patients in the prospective cohort had similar baseline clinical characteristics, except for a statistically significant lower serum albumin concentration (2.3 ± 5 g/dL vs 2.7 ± 5 g/dL; P < .05). Clinically important outcomes were improved in the prospective cohort compared with controls, including resolution of shock (96% vs 58%; P = .001), time to shock resolution (48% vs 18% within 48 hours of ICU admission; P =.01), ICU and hospital survival (68% vs 38% [P = .03]; 64% vs 32% [P = .003], respectively). Two patients treated with hydrocortisone died of fungal infection; no other serious adverse events were reported in the hydrocortisone treatment group.CommentThe sepsis syndrome is a major precipitant for acute-on-chronic liver failure, thereby leading to hypotension, worsening hepatic function, hepatorenal syndrome, multisystem organ failure, and death (Gut 2005;54:718–725). Broad-spectrum antibiotic therapy and early goal-directed therapy (with target values for targets for central venous oxygen saturation, central venous pressure, and mean arterial pressure) have been demonstrated to improve short-term survival in patients with sepsis not necessarily associated with cirrhosis (N Engl J Med 2001;345:1368–1377). Strategies for the management of septic shock need to be prospectively evaluated in patients with liver disease, among whom infection remains a major cause of death.The hemodynamic derangements of cirrhosis mirror those of septic shock and adrenal insufficiency. Recent data have emerged regarding the association of RAI in patients with liver dysfunction and sepsis. In patients with acute liver failure, RAI was present in 62% of patients and was associated with lower transplant-free survival (Hepatology 2002;36:395–402). A series of cirrhotic patients with septic shock revealed that RAI was present in 51.5% of patients and was associated with significantly higher ICU and hospital mortality rates. Cumulative 90-day survival rates were 15.3% and 63.2% in adrenal-insufficient and normal adrenal function groups, respectively (Hepatology 2006;43:673–681).The rates of RAI reported by Fernández et al were similar to, if not higher than, previously reported rates. In concordance with prior reports, RAI was more common in patients with more advanced liver disease. Whether this is directly related to impaired hepatic cholesterol synthesis and steroid metabolism, the proinflammatory cytokine milieu, or whether adrenal insufficiency is simply a marker of multisystem organ failure remains unclear. That RAI is frequently present in patients with acute liver failure without evidence of sepsis (Hepatology 2002;36:395–402) suggests that hepatocellular dysfunction may play a significant role. Notably, a specific bacterial etiology for the sepsis syndrome was not identified in 36% and 24% of patients in the prospective and control groups, respectively. The role of RAI and steroid therapy in cirrhotic patients with noninfectious precipitants for the systemic inflammatory response syndrome (such as gastrointestinal hemorrhage or surgery) remains to be determined.Although the overall mortality rate was improved in patients receiving steroid therapy, 2 of 17 patients receiving hydrocortisone therapy developed fatal fungal infections. The site of infection and portal of entry was not reported by the authors. A prior study utilizing higher doses of steroid replacement (hydrocortisone 300 mg/d) reported an increased rate of resistant bacterial infections (Liver Int 2003;23:71–77). No resistant bacterial infections were noted in the current study.The major limitation of the current study is the absence of a contemporary, blinded, placebo-controlled arm. Although the use of clinical management protocols in a single, specialized liver ICU minimized the variability in care between the prospective and historical cohorts, it is possible that the improved survival in the contemporary (prospective) cohort may be due to an unidentified factor other than adrenal replacement therapy. Although this study provides valuable insight into the care of the septic cirrhotic patient, the results need to be validated in a larger, multicenter, placebo-controlled trial before routine use of hydrocortisone for RAI in cirrhotic patients with sepsis can be recommended. Fernández J, Escorsell A, Zabalza M, et al. (Liver Unit, Hospital Clinic, Barcelona, Spain). Adrenal insufficiency in patients with cirrhosis and septic shock: effect of treatment with hydrocortisone on survival. Hepatology 2006;44:1288–1295. Bacterial infection continues to be a major cause of death among patients with cirrhosis. The demonstrated survival benefit of prophylactic antibiotic therapy in cirrhotic patients with gastrointestinal hemorrhage underscores the significant impact that bacterial sepsis has in this patient population (Hepatology 1999;29:1655–1661). Currently, management of patients with sepsis centers on supportive care. Many areas of uncertainty remain and strategies for management of sepsis need to be prospectively evaluated in patients with advanced liver disease. Relative adrenal insufficiency (RAI) has been linked to refractory shock, resistance to vasoconstrictor medications, and increased mortality in patients with sepsis (N Engl J Med 2003;348:727–734). A recent meta-analysis of data from multiple clinical trials demonstrates a significant survival benefit from stress-dose steroid replacement in patients with septic shock not necessarily associated with cirrhosis (BMJ 2004;329:480–489). In this setting, Fernández et al prospectively assessed the impact of hydrocortisone treatment in cirrhotic patients with septic shock and abnormal short corticotropin test responses (Hepatology 2006;44:1288–1295). Twenty-five consecutive cirrhotic patients with a diagnosis of septic shock admitted to a specialized liver intensive care unit (ICU) from June 2004 to January 2006 were assessed for adrenal insufficiency with a short corticotropin test within 24 hours of ICU admission. Immunocompromised patients, those with advanced hepatocellular carcinoma, and those with a history of steroid therapy within the past 6 months were excluded. Patients with RAI—defined as a baseline cortisol concentration <15 μg/dL and/or increase of plasma cortisol concentration of <9 μg/dL 1 hour after corticotrophin administration in patients with a baseline cortisol concentration <35 μg/dL—were treated with 50 mg of intravenous hydrocortisone every 6 hours. Hydrocortisone was tapered once vasopressor medications were no longer required. Patients in the prospective cohort were compared with a historical control group of the last 50 consecutive patients with cirrhosis and sepsis in whom adrenal function was not assessed and no steroid therapy was given. All patients were treated with a standard protocol that differed only in the assessment of adrenal function and included antibiotic therapy, central venous and urinary catheterization, goal-directed plasma volume expansion and vasopressor therapy, albumin administration in cases of spontaneous bacterial peritonitis, and continuous venovenous hemofiltration and mechanical ventilation as indicated. Within the prospective cohort, 17 of 25 patients had RAI. A trend toward higher rates of RAI in patients with Child–Pugh class C cirrhosis was noted (P = .08), although no statistically significant differences in clinical characteristics were identified between patients with and without adrenal insufficiency. Compared with historical controls, patients in the prospective cohort had similar baseline clinical characteristics, except for a statistically significant lower serum albumin concentration (2.3 ± 5 g/dL vs 2.7 ± 5 g/dL; P < .05). Clinically important outcomes were improved in the prospective cohort compared with controls, including resolution of shock (96% vs 58%; P = .001), time to shock resolution (48% vs 18% within 48 hours of ICU admission; P =.01), ICU and hospital survival (68% vs 38% [P = .03]; 64% vs 32% [P = .003], respectively). Two patients treated with hydrocortisone died of fungal infection; no other serious adverse events were reported in the hydrocortisone treatment group. CommentThe sepsis syndrome is a major precipitant for acute-on-chronic liver failure, thereby leading to hypotension, worsening hepatic function, hepatorenal syndrome, multisystem organ failure, and death (Gut 2005;54:718–725). Broad-spectrum antibiotic therapy and early goal-directed therapy (with target values for targets for central venous oxygen saturation, central venous pressure, and mean arterial pressure) have been demonstrated to improve short-term survival in patients with sepsis not necessarily associated with cirrhosis (N Engl J Med 2001;345:1368–1377). Strategies for the management of septic shock need to be prospectively evaluated in patients with liver disease, among whom infection remains a major cause of death.The hemodynamic derangements of cirrhosis mirror those of septic shock and adrenal insufficiency. Recent data have emerged regarding the association of RAI in patients with liver dysfunction and sepsis. In patients with acute liver failure, RAI was present in 62% of patients and was associated with lower transplant-free survival (Hepatology 2002;36:395–402). A series of cirrhotic patients with septic shock revealed that RAI was present in 51.5% of patients and was associated with significantly higher ICU and hospital mortality rates. Cumulative 90-day survival rates were 15.3% and 63.2% in adrenal-insufficient and normal adrenal function groups, respectively (Hepatology 2006;43:673–681).The rates of RAI reported by Fernández et al were similar to, if not higher than, previously reported rates. In concordance with prior reports, RAI was more common in patients with more advanced liver disease. Whether this is directly related to impaired hepatic cholesterol synthesis and steroid metabolism, the proinflammatory cytokine milieu, or whether adrenal insufficiency is simply a marker of multisystem organ failure remains unclear. That RAI is frequently present in patients with acute liver failure without evidence of sepsis (Hepatology 2002;36:395–402) suggests that hepatocellular dysfunction may play a significant role. Notably, a specific bacterial etiology for the sepsis syndrome was not identified in 36% and 24% of patients in the prospective and control groups, respectively. The role of RAI and steroid therapy in cirrhotic patients with noninfectious precipitants for the systemic inflammatory response syndrome (such as gastrointestinal hemorrhage or surgery) remains to be determined.Although the overall mortality rate was improved in patients receiving steroid therapy, 2 of 17 patients receiving hydrocortisone therapy developed fatal fungal infections. The site of infection and portal of entry was not reported by the authors. A prior study utilizing higher doses of steroid replacement (hydrocortisone 300 mg/d) reported an increased rate of resistant bacterial infections (Liver Int 2003;23:71–77). No resistant bacterial infections were noted in the current study.The major limitation of the current study is the absence of a contemporary, blinded, placebo-controlled arm. Although the use of clinical management protocols in a single, specialized liver ICU minimized the variability in care between the prospective and historical cohorts, it is possible that the improved survival in the contemporary (prospective) cohort may be due to an unidentified factor other than adrenal replacement therapy. Although this study provides valuable insight into the care of the septic cirrhotic patient, the results need to be validated in a larger, multicenter, placebo-controlled trial before routine use of hydrocortisone for RAI in cirrhotic patients with sepsis can be recommended. The sepsis syndrome is a major precipitant for acute-on-chronic liver failure, thereby leading to hypotension, worsening hepatic function, hepatorenal syndrome, multisystem organ failure, and death (Gut 2005;54:718–725). Broad-spectrum antibiotic therapy and early goal-directed therapy (with target values for targets for central venous oxygen saturation, central venous pressure, and mean arterial pressure) have been demonstrated to improve short-term survival in patients with sepsis not necessarily associated with cirrhosis (N Engl J Med 2001;345:1368–1377). Strategies for the management of septic shock need to be prospectively evaluated in patients with liver disease, among whom infection remains a major cause of death. The hemodynamic derangements of cirrhosis mirror those of septic shock and adrenal insufficiency. Recent data have emerged regarding the association of RAI in patients with liver dysfunction and sepsis. In patients with acute liver failure, RAI was present in 62% of patients and was associated with lower transplant-free survival (Hepatology 2002;36:395–402). A series of cirrhotic patients with septic shock revealed that RAI was present in 51.5% of patients and was associated with significantly higher ICU and hospital mortality rates. Cumulative 90-day survival rates were 15.3% and 63.2% in adrenal-insufficient and normal adrenal function groups, respectively (Hepatology 2006;43:673–681). The rates of RAI reported by Fernández et al were similar to, if not higher than, previously reported rates. In concordance with prior reports, RAI was more common in patients with more advanced liver disease. Whether this is directly related to impaired hepatic cholesterol synthesis and steroid metabolism, the proinflammatory cytokine milieu, or whether adrenal insufficiency is simply a marker of multisystem organ failure remains unclear. That RAI is frequently present in patients with acute liver failure without evidence of sepsis (Hepatology 2002;36:395–402) suggests that hepatocellular dysfunction may play a significant role. Notably, a specific bacterial etiology for the sepsis syndrome was not identified in 36% and 24% of patients in the prospective and control groups, respectively. The role of RAI and steroid therapy in cirrhotic patients with noninfectious precipitants for the systemic inflammatory response syndrome (such as gastrointestinal hemorrhage or surgery) remains to be determined. Although the overall mortality rate was improved in patients receiving steroid therapy, 2 of 17 patients receiving hydrocortisone therapy developed fatal fungal infections. The site of infection and portal of entry was not reported by the authors. A prior study utilizing higher doses of steroid replacement (hydrocortisone 300 mg/d) reported an increased rate of resistant bacterial infections (Liver Int 2003;23:71–77). No resistant bacterial infections were noted in the current study. The major limitation of the current study is the absence of a contemporary, blinded, placebo-controlled arm. Although the use of clinical management protocols in a single, specialized liver ICU minimized the variability in care between the prospective and historical cohorts, it is possible that the improved survival in the contemporary (prospective) cohort may be due to an unidentified factor other than adrenal replacement therapy. Although this study provides valuable insight into the care of the septic cirrhotic patient, the results need to be validated in a larger, multicenter, placebo-controlled trial before routine use of hydrocortisone for RAI in cirrhotic patients with sepsis can be recommended.

Relative Adrenal Insufficiency in Patients with Acute Spinal Cord Injury

Relative adrenal insufficiency has been shown to occur in the settings of critical illness and septic shock, impairing the body's ability to respond to stress. Studies have demonstrated that the treatment of adrenal insufficiency (AI) results in shock reversal, hemodynamic stability, and a subsequent decrease in mortality. Endocrine changes and AI have been reported in patients with spinal cord injuries during their extended courses of rehabilitation. We describe two cases of patients with cervical spine injuries who presented with acute adrenal insufficiency following their injuries. With the addition of low-dose corticosteroids, each patient had symptom resolution and demonstrated clinical improvement. Patients with spinal cord injuries are at risk for AI, both in the acute and chronic settings following injury prompting the need for an increased awareness of this condition. Although variability exists in the exact criteria for the diagnosis of AI, the combination of clinical symptoms, depressed serum cortisol concentrations, and responsiveness to exogenous steroid therapy should all contribute to the diagnosis of this condition.

In reply

Dr. McConachie’s concerns regarding potentially significant adrenal suppression with etomidate have, as he notes, been raised many times.1Oglesby A.J. Should etomidate be the induction agent of choice for rapid sequence intubation in the emergency department?.Emerg Med J. 2004; 21: 655-659Crossref PubMed Scopus (61) Google Scholar, 2Absalom A. Pledger D. Kong A. Adrenocrotical function in critically ill patients 24h after a single dose of etomidate.Anaesthesia. 1999; 54: 861-867Crossref PubMed Scopus (206) Google Scholar, 3Shirley P.J. McAuley D.F. Etomidate–misused or misunderstood?.Anaesthesia. 2006; 61: 190Crossref PubMed Scopus (2) Google Scholar, 4Jones D. Hayes M. Webb S. et al.Relative adrenal insufficiency in etomidate-naïve patients with septic shock.Anaesth Intesive Care. 2006; 34: 599-605PubMed Google Scholar, 5Mohammad Z. Afessa B. Finkielman J.D. The incidence of relative adrenal insufficiency in patients with septic shock after the administration of etomidate.Crit Care. 2006; 10: R105Crossref PubMed Scopus (67) Google Scholar Indeed, we noted as a limitation that our study design6Jacoby J. Heller M. Nicholas J. et al.Etomidate versus midazolam for out-of-hospital intubation: a prospective, randomized trial.Ann Emerg Med. 2006; 47: 542-544Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar did not allow us to assess the clinical significance of this well-known pharmacologic characteristic. Unfortunately, as Zed et al noted recently, “It is uncertain if this transient adrenal insufficiency results in significant clinical manifestations, as it is still poorly studied.”7Zed P.J. Mabasa V.H. Slavik R.S. et al.Etomidate for rapid sequence intubation in the emergency department: is adrenal suppression a concern?.Can J Emerg Med. 2006; 8: 347-350Google Scholar We agree with Dr. McConachie that “the emergency department, the operating theatre and the ICU should all work together in the interest of the patient” and we heartily support a clinical study that could resolve this issue. We do not agree with the contention that “…all papers discussing etomidate should include…” a discussion of adrenal suppression. Dr. McConachie’s concerns regarding potentially significant adrenal suppression with etomidate have, as he notes, been raised many times.1Oglesby A.J. Should etomidate be the induction agent of choice for rapid sequence intubation in the emergency department?.Emerg Med J. 2004; 21: 655-659Crossref PubMed Scopus (61) Google Scholar, 2Absalom A. Pledger D. Kong A. Adrenocrotical function in critically ill patients 24h after a single dose of etomidate.Anaesthesia. 1999; 54: 861-867Crossref PubMed Scopus (206) Google Scholar, 3Shirley P.J. McAuley D.F. Etomidate–misused or misunderstood?.Anaesthesia. 2006; 61: 190Crossref PubMed Scopus (2) Google Scholar, 4Jones D. Hayes M. Webb S. et al.Relative adrenal insufficiency in etomidate-naïve patients with septic shock.Anaesth Intesive Care. 2006; 34: 599-605PubMed Google Scholar, 5Mohammad Z. Afessa B. Finkielman J.D. The incidence of relative adrenal insufficiency in patients with septic shock after the administration of etomidate.Crit Care. 2006; 10: R105Crossref PubMed Scopus (67) Google Scholar Indeed, we noted as a limitation that our study design6Jacoby J. Heller M. Nicholas J. et al.Etomidate versus midazolam for out-of-hospital intubation: a prospective, randomized trial.Ann Emerg Med. 2006; 47: 542-544Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar did not allow us to assess the clinical significance of this well-known pharmacologic characteristic. Unfortunately, as Zed et al noted recently, “It is uncertain if this transient adrenal insufficiency results in significant clinical manifestations, as it is still poorly studied.”7Zed P.J. Mabasa V.H. Slavik R.S. et al.Etomidate for rapid sequence intubation in the emergency department: is adrenal suppression a concern?.Can J Emerg Med. 2006; 8: 347-350Google Scholar We agree with Dr. McConachie that “the emergency department, the operating theatre and the ICU should all work together in the interest of the patient” and we heartily support a clinical study that could resolve this issue. We do not agree with the contention that “…all papers discussing etomidate should include…” a discussion of adrenal suppression. Etomidate Controversies in Emergency MedicineAnnals of Emergency MedicineVol. 50Issue 2PreviewThere seems to be a growing interest in the use of the anaesthetic induction agent, etomidate, in locations other than the operating room and administered by nonanaesthesia personnel. Indeed, Annals of Emergency Medicine has published 3 papers recently examining uses of etomidate in scenarios commonly experienced by emergency medicine personnel. It is not necessarily my place to comment on papers exploring the relative merits of etomidate versus midazolam for intubation or procedural sedation in the emergency department (ED) or in the field. Full-Text PDF

Relative adrenal insufficiency in patients with severe acute pancreatitis

Inadequate cortisol levels and adrenal dysfunction may play a role in the pathophysiology of severe acute pancreatitis. This study aimed to analyse the incidence of relative adrenal insufficiency (RAI) in these patients, to identify factors associated with RAI and to describe how adrenal responsiveness affects outcome. Prospective observational multicenter study. Twenty-five patients with severe acute pancreatitis. A short Synacthen test (SST) was performed within 5 days after admission to the hospital. The incidence of RAI, defined as an increment after SST of less than 9 microg/dl was the primary endpoint of the study. Serum cortisol was measured at baseline and at 30 and 60 min after administration of 250 microg adrenocorticotropic hormone. Median baseline cortisol level was 26.6 microg/dl, and increased to 43.2 microg/dl and 48.8 microg/dl after 30 min and 60 min respectively. RAI was found in 16% of all patients and in 27% of patients with organ dysfunction. Patients with RAI were more severely ill and had higher SOFA scores from days 4 to 7 after admission. All patients with RAI developed pancreatic necrosis, and all of them needed surgical intervention. Twenty-eight-day mortality was significantly higher in patients with RAI (75% vs. 5%, p =0.007). Patients who died had a lower increment in cortisol levels after the SST than patients who survived. RAI is frequent in patients with severe acute pancreatitis and organ dysfunction. It occurs in patients with more severe pancreatitis and is associated with increased mortality.

Relative adrenal insufficiency in patients with severe acute pancreatitis

Objective Inadequate cortisol levels and adrenal dysfunction may play a role in the pathophysiology of severe acute pancreatitis. This study aimed to analyse the incidence of relative adrenal insufficiency (RAI) in these patients, to identify factors associated with RAI and to describe how adrenal responsiveness affects outcome.

Relative adrenal insufficiency in patients with septic shock; a close look to practice patterns

Purpose To assess patterns of practice in our institution specifically regarding corticosteroid deficiency diagnosis in patients with septic shock. Methods Consecutive adult patients with vasopressor-dependent septic shock admitted to the medical intensive care unit between January 2002 and September 2003 were studied. Relative adrenal insufficiency (RAI) was diagnosed by a random serum cortisol level ≤15 μg/dL or by a random cortisol level between 15 and 34 μg/dL and an increase in response to cosyntropin stimulation test (250 μg) ≤9 μg/dL. Results Ninety-two patients were included in the study. Mean (±SD) age was 59 ± 18 years. Overall mortality was 53%. Relative adrenal insufficiency was suspected in 44 (48%) patients and confirmed in 25 (57%). Maximal doses of vasopressors were comparable between groups but more patients in whom AI was suspected were on phenylephrine and/or vasopressin and more were treated with activated protein C ( P < .05). Diagnosis of RAI was confirmed by a low basal cortisol (<15 μg/dL) in 12 (48%) patients, whereas a diagnosis of RAI was made by a lack of response to the stimulation test in the rest. Conclusions Relative adrenal insufficiency was diagnosed in half of the patients investigated. Patients with presumed RAI were more likely to be on phenylephrine or vasopressin infusions and treated with activated protein C and had a longer intensive care unit stay but no difference in intensive care unit survival.

Relative Adrenal Insufficiency in Patients With Septic Shock: Comparison of Low-Dose and Conventional Corticotropin Tests

Relative Adrenal Insufficiency in Patients With Septic Shock: Comparison of Low-Dose and Conventional Corticotropin Tests

Relative adrenal insufficiency in patients with septic shock: Comparison of low-dose and conventional corticotropin tests*

To compare a low-dose (1 microg) corticotropin stimulation test with the more standard (250 microg) test for the diagnosis of relative adrenal insufficiency. Diagnostic study. Thirty-one-bed mixed medico-surgical department of intensive care. Forty-six consecutive patients with septic shock. Corticotropin stimulation tests (low-dose test, 1 microg, and standard 250-microg test), performed consecutively at an interval >4 hrs. In each test, serum cortisol levels were measured before (T0) and 30 (T30), 60 (T60), and 90 (T90) mins after corticotropin injection. The maximal increase in cortisol (Deltamax) was calculated as the difference between T0 and the highest cortisol value at T30, T60, or T90 and considered as adequate if >9 microg/dL (250 nmol/L). Nonresponders to the low-dose test had a lower survival rate than responders to both tests (27 vs. 47%, p = .06; Kaplan Meier curves). Interestingly, nonresponders to high-dose test received hydrocortisone treatment and had a similar survival to responders. Multivariable logistic regression disclosed that the response to the combined low-dose test and high-dose test was an independent predictor of survival (odds ratio 28.91, 95% confidence interval 1.81-462.70, p = .017), whereas basal or maximal cortisol levels in both tests were not. The low-dose test identified a subgroup of patients in septic shock with inadequate adrenal reserve who had a worse outcome and would have been missed by the high-dose test. These patients may also benefit from glucocorticoid replacement therapy.