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

Endocrinology for the hepatologist.

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.

Relative Adrenal Insufficiency in Patients with Alcoholic Hepatitis

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.

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 (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.

To review the criteria for diagnosing and treating adrenal insufficiency in patients with septic shock. Articles published in Brazilian and foreign journals selected through these publicationś websites and Medline, as well as references cited in key articles. The literature reports a range betwen 17 and 54% for the finding of adrenal insufficiency in patients with septic shock. There is no consensus for diagnosing adrenal insufficiency in patients suffering from critical diseases, particularly in patients with septic shock. The presence of volume-refractory and catecholamine-resistant septic shock suggests this condition, while basal cortisol under 25 micro g/dl is a diagnostic criterion indicating adrenal insufficiency. The adrenal stimulation test is a useful resource for identifying patients with relative adrenal insufficiency. Our testing option for adrenal stimulation in children is the use of corticotropin in low doses (0.5 micro g/1,73 m(2)). An increase of less than 9 micro g/dl in the value of postcorticotropin-stimulated cortisol suggests the presence of occult (relative) adrenal insufficiency. In patients with septic shock presenting adrenal insufficiency, either suspected or confirmed, the administration of hydrocortisone in shock or stress doses can be vital for a favorable clinical outcome. The existing data, although controversial, already provides a basis to determine when to begin hormone replacement therapy, the serum level of cortisol accepted as adequate, and the choice of corticotropin doses for performing the adrenal stimulation test and diagnosing occult or relative adrenal insufficiency in patients with septic shock.

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.

IntroductionEtomidate blocks adrenocortical synthesis when it is administered intravenously as a continuous infusion or a single bolus. The influence of etomidate administration on the incidence of relative adrenal insufficiency in patients with septic shock has not been formally investigated. The objective of this study was to determine the incidence of relative adrenal insufficiency in patients with septic shock after etomidate administration compared with patients with septic shock who did not receive etomidate.MethodsIn this retrospective study, 152 adults with septic shock who had a consyntropin stimulation test between March 2002 and August 2003 in a tertiary medical center were included. Relative adrenal insufficiency was defined as a rise in serum cortisol ≤ 9 μg/dl after the administration of 250 μg of consyntropin. Patients were divided into those who did and those who did not receive etomidate before the stimulation test. The proportion of patients with relative adrenal insufficiency in these two groups was compared using Fischer's exact test. A P of value < 0.05 was considered statistically significant.ResultsThe mean age of the patients was 64 years, 59% of patients were male, 97% of patients were white and their hospital mortality rate was 57%. Thirty-eight patients (25%) received etomidate before the cosyntropin stimulation test, and the median (interquartile range) time interval between the administration of the drug and the test was 7 (4–10) hours. The incidence of relative adrenal insufficiency was 76% in the patients who received etomidate compared with 51% in the patients who did not (P = 0.0077).ConclusionThe incidence of relative adrenal insufficiency in patients with septic shock is increased when the stimulation test is performed after the administration of etomidate.

Prognostic value of relative adrenal insufficiency in patients with severe alcohol-associated hepatitis-A prospective clinical study.

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.

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.

To assess the prevalence of relative adrenal insufficiency in patients successfully resuscitated after cardiac arrest, and its prognostic role in post-resuscitation disease. A prospective observational single-center study in a medical intensive care unit. 64 patients hospitalised in the intensive care unit after successful resuscitation for out-of-hospital cardiac arrest. A corticotropin-stimulation test was performed between 12 and 24 h following admission: serum cortisol level was measured before and 60 min after administration of tetracosactide 250 microg. Patients with an incremental response less than 9 microg/dl were considered to have relative adrenal insufficiency (non-responders). Variables were expressed as medians and interquartile ranges. 33 patients (52%) had relative adrenal insufficiency. Baseline cortisol level was higher in non-responders than in responders (41 [27.2-55.5] vs. 22.8 [15.7-35.1] microg/dl respectively, P=0.001). A long interval before initiation of cardiopulmonary resuscitation was associated with relative adrenal insufficiency (5 [3-10] vs. 3 [3-5] min, P=0.03). Of the 38 patients with post-resuscitation shock, 13 died of irreversible multiorgan failure. The presence of relative adrenal insufficiency was identified as a poor prognostic factor of shock-related mortality (log-rank P=0.02). A trend towards higher mortality in non-responders was identified in a multivariate logistic regression analysis (odds ratio 6.77, CI 95% 0.94-48.99, P=0.058). Relative adrenal insufficiency occurs frequently after successful resuscitation of out-of-hospital cardiac arrest, and appears to be associated with a poor prognosis in cases of post-resuscitation shock. The role of corticosteroid supplementation should be evaluated in this setting.

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.

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