Regulation of acute reflectory hyperinflammation in viral and other diseases by means of stellate ganglion block. A conceptual view with a focus on Covid-19

Lorenz Fischer, Hans Barop, Sabina Maria Ludin, Hans-Georg Schaible, Lorenz Fischer, Hans Barop, Sabina Maria Ludin, Hans-Georg Schaible

Abstract

Whereas the autonomic nervous system (ANS) and the immune system used to be assigned separate functions, it has now become clear that the ANS and the immune system (and thereby inflammatory cascades) work closely together. During an acute immune response (e. g., in viral infection like Covid-19) the ANS and the immune system establish a fast interaction resulting in "physiological" inflammation. Based on our knowledge of the modulation of inflammation by the ANS we propose that a reflectory malfunction of the ANS with hyperactivity of the sympathetic nervous system (SNS) may be involved in the generation of acute hyperinflammation. We believe that sympathetic hyperactivity triggers a hyperresponsiveness of the immune system ("cytokine storm") with consecutive tissue damage. These reflectory neuroimmunological and inflammatory cascades constitute a general reaction principle of the organism under the leadership of the ANS and does not only occur in viral infections, although Covid-19 is a typical current example therefore. Within the overreaction several interdependent pathological positive feedback loops can be detected in which the SNS plays an important part. Consequently, there is a chance to regulate the hyperinflammation by influencing the SNS. This can be achieved by a stellate ganglion block (SGB) with local anesthetics, temporarily disrupting the pathological positive feedback loops. Thereafter, the complex neuroimmune system has the chance to reorganize itself. Previous clinical and experimental data have confirmed a favorable outcome in hyperinflammation (including pneumonia) after SGB (measurable e. g. by a reduction in proinflammatory cytokines).

Keywords: Autonomic nervous system; Covid-19; Cytokine storm; Hyperinflammation; Local anesthetics; Stellate ganglion block.

Conflict of interest statement

None.

Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Overview of affected systems, e. g. following a virus infection like Covid-19. The grey area symbolizes that the autonomic nervous system (ANS) is integrated in the communication of all systems and has a coordinating function. The black arrows symbolize that the systems are connected to each other via neuronal and non-neuronal feedback loops and are therefore interdependent. The same neuronal and non-neuronal substances can have both activating and inhibiting effects, depending on the current state of the system as well as on the point in time. (For literature, see text). Interestingly, the reactions in this system take place in principle in the same way, regardless of whether the initial stimulus was a viral infection, mechanical trauma, psychological stress, or other cause. The clinical picture – the disease – is then determined by the organ or organ system mainly affected (see text). In our opinion, the consequences of acute hyperinflammation such as ARDS, endothelial dysfunction, microcirculation disturbance, and coagulopathy are not different entities in a viral infection, but an expression of a malfunction of the ANS with sympathetic hyperactivity.
Fig. 2
Fig. 2
Autonomic nervous system and immune system: central and peripheral communication (more details in Fig. 3). Positive feedback loops exist between AND within the central and peripheral communication. Example: Elements of peripheral communication sensitize each other: Thus, immune cells AND nerve fibers produce cytokines and substance P (SP), which in turn induce the immune cells and nerve fibers to produce even more cytokines and SP (positive feedback loop). The brain is then informed of the cytokine and SP concentration; it knows via the afferent nerve fibers the site of tissue damage and the incipient inflammation. Now, this information is processed (central communication) and the resulting output is then communicated to the periphery by means of the efferents shown here (communication between center and periphery).
Fig. 3
Fig. 3
Schematic and simplified overview of the autonomic nervous system and immune system and influence of the stellate ganglion block (direct and indirect) on several systems simultaneously (blue fields; see Section 3). Representation of different levels of the “crosstalk” between nervous system and immune system (described step by step in the text). Each “part” is dependent on the whole system, and the function of the “parts” can hardly be considered in isolation. In addition to negative feedback loops, several positive feedback loops (iterations) are formed so that the system gets a high complexity. The “reset” by means of stellate ganglion block not only affects the fibers of the autonomic nervous system, but also the subsequent reactions triggered by it, such as the regulation of the immune and inflammatory system and thus, cytokine production, too (see Table 1). CP: Celiac plexus; HPA: hypothalamic-pituitary-adrenal; RVLM: rostral ventrolateral medulla; SGB: stellate ganglion block. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
The stellate ganglion block (SGB) simultaneously regulates the systems linked to the autonomic nervous system (ANS).

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