Light shed on stress response in critically ill
medwireNews: A large part of the hypercortisolemia seen in critically ill patients is down to reduced breakdown of cortisol, say researchers.
The findings "change our understanding of the stress response," write study author Greet Van den Berghe (KU Leuven, Belgium) and colleagues in The New England Journal of Medicine.
"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," they say.
"More pragmatically, the data suggest that the 'stress doses' of hydrocortisone (200 mg per day), which are advocated to replace cortisol production in critically ill patients who are presumed to have adrenal failure, are at least three times too high."
The team reports that plasma cortisol levels in 158 patients in the intensive care unit were 3.5 times higher than in 64 demographically matched controls. This was only partly accounted for by differences in cortisol production, which was 1.83-fold higher in patients than controls.
However, using stable isotope tracers, the researchers found that plasma clearance of cortisol was reduced by 53% in patients relative to controls, and the same was true for supraphysiologic levels, with clearance 60% lower in patients versus controls after administration of hydrocortisone 100 mg.
The reduced cortisol clearance seemed to be caused by suppressed activity of cortisol-metabolizing enzymes, with analysis of the ratios of various cortisol metabolites suggesting significantly reduced activity of 11β-HSD enzymes and A-ring reductases. In line with this, there was reduced expression and activity of A-ring reductases in the patients' liver biopsy samples. Notably, serum levels of bile acids, which are thought to inhibit cortisol-metabolizing enzymes, were elevated 2.4-fold in patients versus controls.
Patients' reduced cortisol clearance was also related to their response to corticotropin. The clearance rate in patients with a response indicative of adrenal insufficiency (<21 µg/dL) was about half of that in patients with a normal corticotropin response. Cortisol production in patients with adrenal insufficiency was similar to that in controls, whereas those with a normal corticotropin response had elevated production.
"Our data 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," say the researchers.
This may explain why trials assessing the relationship between patients' corticotropin response and the effects of hydrocortisone treatment have produced mixed results, they suggest.
By Eleanor McDermid, Senior medwireNews Reporter