Should Patients With Cirrhosis and Variceal Hemorrhage Receive Glucocorticoid Therapy? The impact of critical illness–related corticosteroid insufficiency (CIRCI) on the outcomes of patients with cirrhosis and variceal hemorrhage remains unknown. Therefore this study prospectively evaluated adrenal function using short corticotropin stimulation test in 143 patients with variceal hemorrhage. CIRCI occurred in 29.9% of patients. The patients with CIRCI had significantly higher rates of treatment failure and 6-week mortality. Hypovolemic shock, high-density lipoprotein, platelet count, and bacterial infection at inclusion were independent predictors of CIRCI, whereas CIRCI, MELD score, hypovolemic shock, hepatocellular carcinoma, and active bleeding at endoscopy were independent predictors of treatment failure. Multivariate analysis identified MELD score, hypovolemic shock, and bacterial infection at inclusion as independent predictors of 6-week mortality. This study shows that CIRCI is common in cirrhotic patients with variceal hemorrhage and is an independent predictor of 5-day treatment failure.
Comment Major stresses such as hemorrhage may be associated with hypercortisolemia that correlates with the severity of illness. This finding is classically explained by stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis and increased corticotropinelicited cortisol production. Adequate levels of cortisol are necessary to overcome critical illness by increasing cardiac output and vascular tonus and decreasing the release of tissue-damaging proinflammatory cytokines. However, stress-induced activation of the HPA axis may not be sufficient in patients with relative adrenal insufficiency, also known as critical illness–related corticosteroid insufficiency (CIRCI). In the context of severe stress, patients with CIRCI may have excessive proinflammatory production that results in shock and multiorgan failure. In critically ill patients CIRCI may be due to structural damage caused by hemorrhage and necrosis, although for most survivors CIRCI is reversible. Diagnostic criteria of CIRCI recommended by a consensus1 are based on measurement of serum total cortisol before and after stimulation with a short corticotropin (250 mg) stimulation test. However, these criteria are arbitrary and controversial.1 Nevertheless, glucocorticoid therapy has been shown to improve systemic hemodynamics and reduce the vasopressor requirement in patients with severe sepsis and septic shock. Unfortunately, recent international multicenter randomized trials did not find a significant effect of hydrocortisone therapy on survival in patients with severe sepsis and septic shock. 1758
Some critically ill patients do not exhibit stressinduced activation of the HPA axis. These patients have dissociation between plasma corticotropin levels and cortisol levels, marked by suppressed corticotropin levels and elevated plasma cortisol levels. Corticotropin suppression is probably a result of a negative feedback loop stimulated by elevated cortisol levels. If this is the case, what would explain hypercortisolemia in critically ill patients? Stresses may stimulate production of proinflammatory cytokines that induce a direct, HPA axis–independent cortisol secretion by the adrenal glands. Hypercortisolemia may also result from a reduction in cortisol breakdown due to underexpression and underactivity of cortisol-metabolizing enzymes. Critically ill patients have elevated levels of circulating bile acids that are known to inhibit the expression and activity of cortisol-metabolizing enzymes.2 Variceal hemorrhage is a complication in patients with cirrhosis. Although it has been shown that CIRCI may develop in patients without cirrhosis but with hemorrhage, little is known about the prevalence of CIRCI and its prognostic significance in patients with cirrhosis who bleed. Any evidence of a role of CIRCI in mortality of the bleeding episode would raise the question of whether hydrocortisone therapy should be used in patients with variceal bleeding and CIRCI. In a recent study published in Critical Care Medicine, Tsai et al. investigated CIRCI in a large prospective cohort of patients with cirrhosis and variceal hemorrhage.3 The presence of CIRCI was assessed using recommended criteria1; it was defined by a baseline serum cortisol level
Comment Major stresses such as hemorrhage may be associated with hypercortisolemia that correlates with the severity of illness. This finding is classically explained by stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis and increased corticotropinelicited cortisol production. Adequate levels of cortisol are necessary to overcome critical illness by increasing cardiac output and vascular tonus and decreasing the release of tissue-damaging proinflammatory cytokines. However, stress-induced activation of the HPA axis may not be sufficient in patients with relative adrenal insufficiency, also known as critical illness–related corticosteroid insufficiency (CIRCI). In the context of severe stress, patients with CIRCI may have excessive proinflammatory production that results in shock and multiorgan failure. In critically ill patients CIRCI may be due to structural damage caused by hemorrhage and necrosis, although for most survivors CIRCI is reversible. Diagnostic criteria of CIRCI recommended by a consensus1 are based on measurement of serum total cortisol before and after stimulation with a short corticotropin (250 mg) stimulation test. However, these criteria are arbitrary and controversial.1 Nevertheless, glucocorticoid therapy has been shown to improve systemic hemodynamics and reduce the vasopressor requirement in patients with severe sepsis and septic shock. Unfortunately, recent international multicenter randomized trials did not find a significant effect of hydrocortisone therapy on survival in patients with severe sepsis and septic shock. 1758
Some critically ill patients do not exhibit stressinduced activation of the HPA axis. These patients have dissociation between plasma corticotropin levels and cortisol levels, marked by suppressed corticotropin levels and elevated plasma cortisol levels. Corticotropin suppression is probably a result of a negative feedback loop stimulated by elevated cortisol levels. If this is the case, what would explain hypercortisolemia in critically ill patients? Stresses may stimulate production of proinflammatory cytokines that induce a direct, HPA axis–independent cortisol secretion by the adrenal glands. Hypercortisolemia may also result from a reduction in cortisol breakdown due to underexpression and underactivity of cortisol-metabolizing enzymes. Critically ill patients have elevated levels of circulating bile acids that are known to inhibit the expression and activity of cortisol-metabolizing enzymes.2 Variceal hemorrhage is a complication in patients with cirrhosis. Although it has been shown that CIRCI may develop in patients without cirrhosis but with hemorrhage, little is known about the prevalence of CIRCI and its prognostic significance in patients with cirrhosis who bleed. Any evidence of a role of CIRCI in mortality of the bleeding episode would raise the question of whether hydrocortisone therapy should be used in patients with variceal bleeding and CIRCI. In a recent study published in Critical Care Medicine, Tsai et al. investigated CIRCI in a large prospective cohort of patients with cirrhosis and variceal hemorrhage.3 The presence of CIRCI was assessed using recommended criteria1; it was defined by a baseline serum cortisol level
