This is the first study of the pyrrole etomidate analogue carboetomidate in a model of sepsis. It defined the effects of carboetomidate on plasma ACTH, corticosterone, and cytokine concentrations and compared them to the effects of etomidate and vehicle alone following an LPS challenge in rats. Our results reveal that carboetomidate and etomidate differentially affect the inflammatory response that results from LPS administration. This difference was most pronounced in studies using multiple anesthetic doses administered over a prolonged period of time as etomidate significantly reduced plasma corticosterone concentrations and increased peak plasma concentrations of the pro-inflammatory cytokines IL-1β, IL-6 and the anti-inflammatory cytokine IL-10 whereas carboetomidate only increased plasma concentrations of IL-10.
Several animal models of sepsis have been used to replicate either the signs and symptoms or the laboratory findings observed in human sepsis (37
). These include bacterial infusion models, polymicrobial peritonitis models, and endotoxin models. Each model replicates certain aspects of clinical sepsis but also has its own limitations. For example, bacterial infusion models are not exactly analogous to clinical situations where there is commonly a focus of infection providing continuous dissemination of bacteria that colonize and replicate (38
). Bacterial peritonitis models closely resemble the clinical scenario of sepsis following bowel perforation, but the model has wide variability in terms of the host inflammatory and physiological responses, and the level of bacteremia and mortality rates (40
). We chose the endotoxin model in the present study because the model is highly reproducible and mimics the hyperinflammatory response that often occurs in patients in septic shock, while acknowledging that it differs from clinical sepsis because it lacks an infectious focus and produces larger and more transient cytokine responses.
Numerous cytokines have been identified that play important roles in the pathophysiology of sepsis (42
). The pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 have been shown to both modulate and to be modulated by the hypothalamic-pituitary-adrenal axis (32
). Such crosstalk suggests that drugs known to inhibit adrenocortical function (e.g. etomidate, but not carboetomidate) might alter the production of these cytokines. In contrast, IL-10 possesses strong anti-inflammatory properties that may counteract some of the actions of these pro-inflammatory cytokines and improve survival (45
Our results demonstrate that etomidate inhibits LPS-stimulated corticosterone production in vivo
. Following LPS injection, a single intravenous etomidate dose significantly reduced plasma corticosterone concentrations (relative to vehicle controls) for 60–120 min. This duration of adrenocortical suppression is shorter than that observed in humans (20
), which may reflect the presence of an aliesterase found in rat blood that rapidly metabolizes etomidate (49
). With multiple etomidate doses, plasma corticosterone concentrations initially decreased after LPS administration. This likely reflects the combined effects of metabolism of existing plasma corticosterone along with inhibition of new corticosterone synthesis during prolonged etomidate administration. Etomidate reduced plasma corticosterone concentrations without impacting the ACTH response to LPS injection, consistent with etomidate’s known direct inhibitory action on 11β-hydroxylase activity (18
Carboetomidate’s affect on the adrenocortical response to an LPS challenge was significantly less than that of etomidate and not different from that of vehicle alone even when multiple doses were administered over a nearly two-hour time period. This implys that carboetomidate does not significantly inhibit 11β-hydroxylase activity and is consistent with our previous observation that carboetomidate does not suppress the adrenocortical response to exogenously administered ACTH (30
In addition to differences between etomidate and carboetomidate with respect to the adrenocortical response to LPS injection, we also observed differences in their impact on cytokine production as peak plasma IL-1β and IL-6 concentrations were significantly higher following administration of etomidate versus carboetomidate (or vehicle control). These differences between etomidate and carboetomidate may relate to their differential effects on adrenocortical function as glucocorticoids reduce pro-inflammatory cytokine synthesis. For example, dexamethasone administration reduces the serum IL-1 concentration of mice challenged with LPS (51
) and hydrocortisone infusion reduces plasma levels of IL-6 in patients in septic shock (34
). Similarly, reducing glucocorticoid synthesis by either surgical adrenalectomy (32
) or pharmacological adrenalectomy with mifepristone (44
) increases plasma concentrations of IL-6 after LPS administration.
Although there have been few clinical studies defining the effects of etomidate on cytokine production, they suggest a link between etomidate-induced adrenocortical suppression and increased pro-inflammatory cytokine production. Jameson et al. (52
) showed that compared to thiopentone, etomidate reduced plasma cortisol concentrations and increased plasma IL-6 concentrations in women undergoing hysterectomies. In pediatric patients with meningococcal sepsis, Den Brinker et al (53
) showed that plasma IL-6 concentrations were inversely related to the cortisol:ACTH ratios and increased in patients who had received etomidate. Yeager et al. (54
) found that perioperative hydrocortisone replacement therapy administered to patients who received etomidate for cardiac surgery dose-dependently reduced postoperative plasma IL-6 concentrations.
In summary, our studies demonstrate that carboetomidate has lesser effects than etomidate on the adrenocortical and pro-inflammatory cytokine responses to LPS administration. This suggests that unlike etomidate, carboetomidate may be useful as an anesthetic maintenance agent in patients with sepsis.