Despite advanced, aggressive ICU management of the septic patient, lethality rates remain at 40-60% for patients in septic shock . Multiple promising experimental approaches have failed to show a successful therapeutic translation into humans . Initially, these failures might have been attributable to an overly simplified theoretical understanding of sepsis as a merely proinflammatory state . Subsequently, this notion has been challenged , requiring a careful reconsideration and revisiting our current concept of the pathophysiology behind the sepsis syndrome [1, 29].
Triggered by the septic inflammatory response, endogenous glucocorticoids are being released, presumably in an attempt to modulate and counterbalance the synthesis and release of inflammatory mediators on a cellular level . However, vascular and ischemic damage, inflammation, and apoptosis within the HPA-axis itself  can severely impair the HPA-axis and prompt adrenal insufficiency, a well-described complication during sepsis . Glucocorticoid insufficiency may result in an imbalanced T-cell response with uncontrolled systemic inflammation . If unrecognized and untreated, impaired HPA axis function may result in a lethal outcome [33, 34]. Thus, current recommendations advocate the use of corticosteroids in critically ill patients with adrenal insufficiency . However, in a large clinical trial, high-dose corticosteroids significantly increased morbidity and is therefore considered obsolete for the treatment of severe sepsis and septic shock . As a result, current recommendations suggest the use of moderate doses of corticosteroids in septic patients . Nonetheless, glucocorticoid substitution in the septic patient remains a matter of lively debate , as previous studies used different methodology (± ACTH test or not), and study group characteristics (sepsis vs. septic shock). This is likely due to the fact that sepsis-induced adrenal insufficiency seems to be highly multifactorial and is associated with a very complex and poorly understood pathophysiology.
In the present study, we investigated the function of the HPA-axis as a function of time after experimental, CLP-induced sepsis. Focusing on ACTH, corticosterone, and the mineralocorticoid aldosterone, we assessed the dynamic changes of these HPA-axis hormones. In addition, we sought to assess the changes in plasma electrolyte homeostasis following CLP. We describe bell-shaped plasma levels of both, corticosterone and aldosterone (Figures 1B, C). In septic patients, initial hypercortisolism during the early stages of sepsis also has been described and is usually followed by cortisol insufficiency . Although there is evidence that, in septic patients, a clear dissociation between ACTH and cortisol levels exists , our present data imply that, in rodents, the physiologic feed-back loops of the HPA-axis may be intact during the early course of experimental sepsis (Figures 1A, B). However, during the later course of CLP, there is likely breakdown of the blood-brain barrier with ensuing pituitary dysfunction, resulting in dissociation of the HPA axis . Such a breakdown of physiologic barriers will result in extravasation of inflammatory markers and cells, bacteria, ultimately disrupting the classic HPA feedback mechanisms. Previous reports have described sepsis-induced plasma alterations of ACTH and corticosterone concentrations only during the late stages of sepsis [39, 40]. Clinical studies describe persistent hypercortisolism despite low ACTH levels in septic humans, which may reflect breakdown of feedback mechanisms in humans and/or neuronal or mediator-induced hormonal changes. Our discordant findings may represent one of the disconnects observed between rodents and men . For instance, rats are known to produce glucocorticoids in extra-adrenal organs as well, which may result in a different steroid response in experimental sepsis .
Sepsis and septic shock are important risk factors for acute renal failure (ARF) and represent the most important trigger for ARF in the ICU [43, 44]. Twenty percent of patients with severe sepsis and 50% of patients with septic shock have been shown exhibit ARF . In addition, ARF has previously been described in rats following CLP . In the current study, we found severe plasma electrolyte disturbances. Animals displayed significant hypernatremia following CLP (Figure 2A). Sepsis has been shown recently to be associated with hypernatremia, which seemed to serve as an independent predictor for higher mortality in these patients . It remains to be determined whether the alterations of especially sodium and potassium levels observed in our study are indeed a result of ARF or rather represent a downstream effect of the significantly increased aldosterone levels found in septic animals (Figure 1C). In the present study, septic rats also exhibited severe hypomagnesemia (Figure 2D), which also has been described in up to 65% of ICU patients [48, 49]. More importantly, magnesium deficiency in the ICU is associated with prolonged hospitalization , two- to threefold higher mortality rates, and the development of sepsis . An experimental study revealed that magnesium administration reduced the severity of septic encephalopathy , which represents a serious complication of sepsis in the ICU with high morbidity and mortality . In this study, animals treated with magnesium sulfate displayed attenuated blood-brain barrier breakdown and reduced brain edema compared with vehicle-treated septic littermates .
Our study has several shortcomings. First, the animal model did not use any resuscitative measure or antibiotic coverage but only studied the natural course of disease. This limits the transferability of our findings into the human setting even more in addition to the traditional, well-described disconnect between humans and rodents . Second, we did not provide a true hormonal time-course for sham controls. However, plasma samples were obtained exactly at the same time of the day for all experiments to account for the circadian rhythm of HPA axis hormones. Thus, it was assumed that sham animals maintained an intact HPA axis. In addition, our study is merely descriptive and fails to unravel any molecular mechanisms involved in the breakdown of the HPA axis in sepsis. Complement C5a may play an important role in the pathogenesis of the HPA disturbance . Nevertheless, our study provides novel insights into the sepsis-induced disturbance of the HPA axis.