Cortisol breakdown impaired during critical illness

The breakdown and clearance of cortisol are impaired during critical illness, which may account in part for the abnormally high blood levels of cortisol often observed in ICU patients, according to a report published online March 19 in the New England Journal of Medicine.

Hypercortisolemia often accompanies critical illness, but until now it usually has been attributed to increased cortisol production driven by stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, some researchers posited that another possible contributor to hypercortisolemia in this setting might be suppression of the removal of cortisol.

"We hypothesized that cortisol metabolism is reduced during critical illness, contributing to sustained hypercortisolemia with enhanced negative-feedback inhibition of corticotropin," said Dr. Eva Boonen of the clinical division and laboratory of intensive care medicine, Catholic University of Leuven (Belgium), and her associates.

To test their hypothesis, the investigators studied 158 consecutive adults treated for critical illness in a single ICU and 64 demographically matched but not critically ill control subjects. They measured five aspects of cortisol metabolism: daily corticotropin and cortisol levels; plasma cortisol levels reflecting the clearance, metabolism, and production of cortisol during an infusion of deuterium-labeled tracers; plasma clearance of a therapeutic 100-mg IV bolus of hydrocortisone; urinary levels of cortisol metabolites; and levels of major cortisol-metabolizing enzymes in liver and adipose tissue.

Their findings demonstrated that "elevated cortisol levels in critically ill patients were only partially explained by an increase of 83% in cortisol production, as compared with controls." In addition, impaired breakdown and clearance of cortisol contributed to hypercortisolemia, the investigators reported. They found a reduction of more than 50% in cortisol clearance after administration of the 100 mg of hydrocortisone (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMoa1214969]).

The clinical implications of these study results are important because the findings markedly change "our understanding of the stress response. Reduced inactivation of cortisol may be important not only to increase circulating levels but also to potentiate cortisol levels and activity within the vital tissues that express inactivating enzymes.

"More pragmatically, the data suggest that ‘stress doses’ of hydrocortisone, which are advocated to replace cortisol production in critically ill patients who are presumed to have adrenal failure, are at least 3 times too high," Dr. Boonen and her colleagues said.

The data also suggest that "a low cortisol response to corticotropin stimulation does not necessarily reflect adrenal failure, since cortisol production in critically ill patients is not subnormal, and the suppressed clearance maintains hypercortisolemia. Our results may therefore help to explain why studies investigating the effect of the daily administration of 200 mg of hydrocortisone in patients with sepsis ... have had conflicting results," they added.

This study was supported by the Belgian Fund for Scientific Research, the British Heart Foundation, the Flemish government\'s Methusalem Program, and the European Research Council. No relevant conflicts of interest were reported.

The breakdown and clearance of cortisol are impaired during critical illness, which may account in part for the abnormally high blood levels of cortisol often observed in ICU patients, according to a report published online March 19 in the New England Journal of Medicine.

Hypercortisolemia often accompanies critical illness, but until now it usually has been attributed to increased cortisol production driven by stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, some researchers posited that another possible contributor to hypercortisolemia in this setting might be suppression of the removal of cortisol.

"We hypothesized that cortisol metabolism is reduced during critical illness, contributing to sustained hypercortisolemia with enhanced negative-feedback inhibition of corticotropin," said Dr. Eva Boonen of the clinical division and laboratory of intensive care medicine, Catholic University of Leuven (Belgium), and her associates.

To test their hypothesis, the investigators studied 158 consecutive adults treated for critical illness in a single ICU and 64 demographically matched but not critically ill control subjects. They measured five aspects of cortisol metabolism: daily corticotropin and cortisol levels; plasma cortisol levels reflecting the clearance, metabolism, and production of cortisol during an infusion of deuterium-labeled tracers; plasma clearance of a therapeutic 100-mg IV bolus of hydrocortisone; urinary levels of cortisol metabolites; and levels of major cortisol-metabolizing enzymes in liver and adipose tissue.

Their findings demonstrated that "elevated cortisol levels in critically ill patients were only partially explained by an increase of 83% in cortisol production, as compared with controls." In addition, impaired breakdown and clearance of cortisol contributed to hypercortisolemia, the investigators reported. They found a reduction of more than 50% in cortisol clearance after administration of the 100 mg of hydrocortisone (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMoa1214969]).

The clinical implications of these study results are important because the findings markedly change "our understanding of the stress response. Reduced inactivation of cortisol may be important not only to increase circulating levels but also to potentiate cortisol levels and activity within the vital tissues that express inactivating enzymes.

"More pragmatically, the data suggest that ‘stress doses’ of hydrocortisone, which are advocated to replace cortisol production in critically ill patients who are presumed to have adrenal failure, are at least 3 times too high," Dr. Boonen and her colleagues said.

The data also suggest that "a low cortisol response to corticotropin stimulation does not necessarily reflect adrenal failure, since cortisol production in critically ill patients is not subnormal, and the suppressed clearance maintains hypercortisolemia. Our results may therefore help to explain why studies investigating the effect of the daily administration of 200 mg of hydrocortisone in patients with sepsis ... have had conflicting results," they added.

This study was supported by the Belgian Fund for Scientific Research, the British Heart Foundation, the Flemish government\'s Methusalem Program, and the European Research Council. No relevant conflicts of interest were reported.

The breakdown and clearance of cortisol are impaired during critical illness, which may account in part for the abnormally high blood levels of cortisol often observed in ICU patients, according to a report published online March 19 in the New England Journal of Medicine.

Hypercortisolemia often accompanies critical illness, but until now it usually has been attributed to increased cortisol production driven by stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, some researchers posited that another possible contributor to hypercortisolemia in this setting might be suppression of the removal of cortisol.

"We hypothesized that cortisol metabolism is reduced during critical illness, contributing to sustained hypercortisolemia with enhanced negative-feedback inhibition of corticotropin," said Dr. Eva Boonen of the clinical division and laboratory of intensive care medicine, Catholic University of Leuven (Belgium), and her associates.

To test their hypothesis, the investigators studied 158 consecutive adults treated for critical illness in a single ICU and 64 demographically matched but not critically ill control subjects. They measured five aspects of cortisol metabolism: daily corticotropin and cortisol levels; plasma cortisol levels reflecting the clearance, metabolism, and production of cortisol during an infusion of deuterium-labeled tracers; plasma clearance of a therapeutic 100-mg IV bolus of hydrocortisone; urinary levels of cortisol metabolites; and levels of major cortisol-metabolizing enzymes in liver and adipose tissue.

Their findings demonstrated that "elevated cortisol levels in critically ill patients were only partially explained by an increase of 83% in cortisol production, as compared with controls." In addition, impaired breakdown and clearance of cortisol contributed to hypercortisolemia, the investigators reported. They found a reduction of more than 50% in cortisol clearance after administration of the 100 mg of hydrocortisone (N. Engl. J. Med. 2013 March 19 [doi: 10.1056/NEJMoa1214969]).

The clinical implications of these study results are important because the findings markedly change "our understanding of the stress response. Reduced inactivation of cortisol may be important not only to increase circulating levels but also to potentiate cortisol levels and activity within the vital tissues that express inactivating enzymes.

"More pragmatically, the data suggest that ‘stress doses’ of hydrocortisone, which are advocated to replace cortisol production in critically ill patients who are presumed to have adrenal failure, are at least 3 times too high," Dr. Boonen and her colleagues said.

The data also suggest that "a low cortisol response to corticotropin stimulation does not necessarily reflect adrenal failure, since cortisol production in critically ill patients is not subnormal, and the suppressed clearance maintains hypercortisolemia. Our results may therefore help to explain why studies investigating the effect of the daily administration of 200 mg of hydrocortisone in patients with sepsis ... have had conflicting results," they added.

This study was supported by the Belgian Fund for Scientific Research, the British Heart Foundation, the Flemish government\'s Methusalem Program, and the European Research Council. No relevant conflicts of interest were reported.