Mechanism of adrenal insufficiency following trauma and severe hemorrhage - Role of hepatic 11 beta-hydroxysteroid dehydrogenase

Background: Although adrenal insufficiency may not occur with moderate hypo tension, it does occur with severe hemorrhage. Since hepatocellular functio n is depressed following severe hemorrhage, it remains unknown whether the liver plays any role in regulating adrenal function after trauma and hemorr hagic shock. Hypothesis: Hepatic 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), a m icrosomal enzyme responsible for the degradation of bioactive corticosteron e, plays a major role in the development of adrenal insufficiency following trauma and severe hemorrhage. Design, Interventions, and Main Outcome Mea sures: Male rats underwent lapa rotomy to induce trauma before hemorrhage. They were then bled to and maint ained at a blood pressure of 40 mm Hg until 40% of the maximal bleed-out vo lume was returned in the form of Ringer lactate. The rats were then resusci tated with 4 times the volume of maximal bleed-out with Ringer lactate duri ng a 60-minute period. Plasma levels of corticosterone and corticotropin we re measured at various intervals. In additional groups, corticotropin-induc ed corticosterone release, adrenal contents of corticosterone and cyclic ad enosine monophosphate (cAMP), hepatic 11 beta-HSD activity, and plasma leve ls of corticosterone-binding globulin were determined at 1.5 hours after re suscitation. Moreover, a model of moderate hypotension (blood pressure, 80 mm Hg) was used to determine whether adrenal function is depressed under su ch conditions. Results: At the time of maximal bleed-out, plasma corticosterone and cortic otropin levels increased by 245% (P<.001) and 293% (P<.001), respectively. Despite corticotropin levels being similar to those of the animals undergoi ng sham operation after resuscitation, corticosterone levels in hemorrhaged animals remained elevated up to 4 hours after resuscitation (by 158%-207%; P<.001). In addition, corticotropin-induced corticosterone release decreas ed by 78% at 1.5 hours after resuscitation (P = .009). In contrast, moderat e hypotension did not reduce corticotropin-induced corticosterone release. Adrenal corticosterone content and cAMP levels tie, the second messenger of corticotropin action) decreased by 55% (P<.001) and 25% (P = .03), respect ively. Hepatic 11 beta-HSD activity decreased significantly at 1.5 hours af ter resuscitation (P<.001). Conclusions: Sustained increase in plasma corticosterone levels following h emorrhage and resuscitation may be, in part, due to the decreased hepatic 1 1 beta-HSD activity. The high level of corticosterone negatively regulates corticotropin release, further reducing adrenal responsiveness to corticotr opin stimulation. Thus, the liver appears to play an important role in regu lating adrenal function following trauma and severe hemorrhage.