Proof of Concept—How to Bridge Proof with Concept and Linked to Reality

We read the article by Avramescu et al. published in Anesthesiology with great interest.¹  The authors investigated the effect of interleukin-1β on the γ-aminobutyric acid (GABA) inhibitory currents in hippocampal and cortical neurons after exposure to etomidate or isoflurane in vitro. They arrived at their findings with the use of a mice model of sepsis consisting of intraperitoneal lipopolysaccharide injection. They were able to show some interaction between lipopolysaccharide and some, not all, measures of behavioral effectiveness of two anesthetics. Overall, results described seem to offer insight on the potential relationship between inflammation and the amount of anesthetic needed in mouse models to achieve the desired anesthesia. In conclusion, the authors extrapolated the results of their study to clinically relevant scenarios of sepsis.

The authors picked one in vitro and one in vivo model of inflammation to test the effect lipopolysaccharide has on anesthetics mechanisms. In vitro part consisted of the stimulation of neurons with interleukin-1β at the concentration of 60 ng/ml determined to be an approximation of the cytokine environment in sepsis. But in sepsis, several cytokines are released concomitantly with interleukin-6 correlating the best with clinical outcomes. Moreover, the production of interleukin-1β by leukocytes stimulated by lipopolysaccharide can be significantly suppressed.²  The concentration of interleukin-1β in serum or cerebrospinal fluid is not known despite an excellent opportunity presented by the in vitro part of the study. Furthermore, the presented article examines single exposure to interleukin-1β. This may be true for surgical procedures but not for the clinical scenarios with sustained and repetitive exposure to insulting agents like lipopolysaccharide and other pathogen mediators.

There is a long tradition of the study of inflammatory processes, most notably sepsis, and seemingly clinically relevant animal models. However, it has been almost uniformly shown that animal models consistently fail to mimic the immunologic environment as seen in human victims of septic shock.³  This is frequently cited as one of the reasons for repetitive failures in translation of clinical drugs from animal platforms into the clinical realm.⁴  Out of several available models (cecal ligation and puncture, interperitoneal bacteria injection), intraperitoneal lipopolysaccharide injections are especially very distant from clinical reality.⁵  The dose of lipopolysaccharide was chosen to induce systemic inflammation with increase of interleukin-1β while preserving hemodynamic stability. This lack of measuring the hemodynamic changes induced by lipopolysaccharide injections prohibits accurate studying of this effect. Measuring serum interleukin-6 in sepsis has been shown to correlate with the magnitude of inflammatory response and mortality.⁶  Therefore, measuring serum interleukin-6 and endotoxemia together is of particular importance since lipopolysaccharide itself can cause behavioral changes. This would help to address the question whether behavioral changes are related to systemic hemodynamically oriented changes versus generalized inflammation versus central neuroinflammation.

The choice of the anesthetic was dictated by selectivity for GABA receptor (etomidate) and popularity for use (isoflurane). However, the use of etomidate has decreased in sepsis and other systemic inflammatory response syndrome conditions because of the potential for adrenal suppression and associated mortality.⁷  Etomidate does provide superb hemodynamic stability, but in this particular situation, the dose of lipopolysaccharide was chosen for its ability to keep hemodynamic stability and avoidance of profound septic shock, so it is unclear whether etomidate would be an appropriate agent in such clinical scenarios. Along with being as popular an agent as isoflurane, propofol has the intriguing benefit of certain immunomodulatory properties. For example, an article published in the same issue of Anesthesiology showed the positive effects of total intravenous anesthesia and cancer recurrence,⁸  but it was not chosen by Avramescu et al.¹  Along with being frequently recommended as an appropriate agent to induce anesthesia in septic patients, ketamine has been shown to decrease interleukin-1β levels in the hippocampus.⁹  Yet neither of these drugs were included in the study.

Furthermore, this article reports that although lipopolysaccharide did potentiate the immobilizing properties of etomidate, it did not do the same for isoflurane. This highlights the fact that the effect anesthetics have on the cerebral cortex and surrounding neurologic areas cannot solely be attributed to their action at GABA receptors. Similarly, their effects on the immune system are much more complex.

I applaud the investigators and authors on a well-designed experiment and a thorough, concise article. The results described seem to offer insight on the potential relationship between inflammation and the amount of anesthetic needed in mouse models to achieve the desired anesthesia. However, these results cannot be translated into clinical practice considering multiple obstacles in interpreting the results presented in the article in context of clinical context. In fact, altering the way clinical anesthesia is performed based on these results would not only be imprudent, but potentially detrimental to the patient.

The authors declare no competing interests.