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      Vagus nerve stimulation in postoperative thoracic surgery: the obstacle is the path

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          Abstract

          In the realm of surgical innovation, the quest to minimize complications and improve patient outcomes is an ongoing and challenging journey. The evolution from conventional thoracotomy (CT) to minimally invasive techniques, including robotic surgery (RS), has propelled the field of cardiothoracic surgery forward, but novel approaches beyond surgical techniques hold the potential to further revolutionize clinical practice. Notably, systemic inflammation, measured with C-reactive protein (CRP) and interleukin (IL)-6, has been shown to be crucial in the pathogenesis of postoperative complications (1). Vagus nerve stimulation (VNS), an innovative therapeutic technique involving electrical stimulation of the vagus nerve, has captured the medical community’s attention due to its ability to modulate various human body functions. The vagus nerve, a critical component of the parasympathetic nervous system, plays a pivotal role in regulating cardiac, pulmonary, and gastrointestinal functions, and even inflammation (2). By harnessing the power of VNS, we unlock a promising avenue for addressing a spectrum of conditions, including—but limited to—epilepsy, depression, and inflammatory disorders. As the landscape of VNS research continues to unfold, it holds the potential to revolutionize the way we approach and manage a variety of medical conditions. The recent study by Carvalho et al. (3) sheds light on VNS in the context of postoperative inflammatory responses following thoracic surgery. This preclinical study explores the use of VNS to reduce the systemic inflammatory response syndrome (SIRS) and clinical complications associated with CT and RS in a pig model which is comparable to human physiology, histology, and immune response (4). Their results indicate that VNS led to a more stable heart rate during the postoperative period and reduced cardiac complications, making it a potential non-pharmacological tool for mitigating the inflammatory response and complications, particularly in aggressive surgical procedures. While applauding the authors’ dedication to advancing surgical outcomes, several key points deserve further discussion and clarification. The application of VNS in the reduction of proinflammatory cytokines like IL-6 levels after thoracic surgery is attractive. However, human studies have already established the potential of autonomic neuromodulation, including VNS, in reducing IL-6 levels post-cardiac surgery (5). Therefore, it is of utmost clinical significance to explore the effect of VNS on clinical outcomes beyond surrogate inflammatory biomarkers and physiological responses. Clinical endpoints, such as the incidence of postoperative atrial fibrillation, infection rates, recovery duration, and mortality rates are essential for assessing the translational potential of this approach in clinical practice. Furthermore, the invasive nature of mediastinal VNS, involving electrode implantation, raises concerns about its impact on surgery duration and potential complications, such as vascular and neurological injuries (6). These considerations may outweigh the perceived benefits of VNS in the postoperative period. Exploring less invasive alternatives, like transcutaneous auricular VNS, which has yet to prove equivalent to cervical or mediastinal VNS, might hold promise. Moreover, the authors found that the pigs that have undergone CT benefited the most from the VNS. As CT has been to a significant extent replaced by minimally invasive approaches, the applicability of mediastinal VNS in routine thoracic surgery becomes less feasible and practical, warranting the exploration of alternative methods, including but not limited to noninvasive VNS. Last, although this study’s findings demonstrated a reduction in the postoperative inflammatory response, it’s worth noting that the study did not delve into the underlying mechanisms responsible for this anti-inflammatory effect. Overall, prior work has described the action of VNS via the anti-inflammatory pathway at the spleen, further mechanistic studies within the specific context of postoperative thoracic surgery are essential. Specific aspects of postoperative complications such as postoperative atrial fibrillation have been recently elucidated, and these could serve as the basis for future work on this condition (6). In conclusion, the investigation into VNS as a means to mitigate postoperative inflammatory responses in thoracic surgery is a commendable endeavor. However, a comprehensive approach that incorporates existing knowledge, delves into mechanistic insights, prioritizes clinical outcomes, and elucidates the feasibility of VNS in practical surgical settings will enhance the impact and relevance of this research. Addressing these key points will undoubtedly bolster the advancement of surgical techniques and, most importantly, enhance the well-being of patients undergoing thoracic surgery. Supplementary The article’s supplementary files as 10.21037/atm-23-1889

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          The inflammatory reflex.

          Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.
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            Postoperative atrial fibrillation: mechanisms, manifestations and management

            Postoperative atrial fibrillation (POAF) complicates 20-40% of cardiac surgical procedures and 10-20% of non-cardiac thoracic operations. Typical features include onset at 2-4 days postoperatively, episodes that are often fleeting and a self-limited time course. Associated adverse consequences of POAF include haemodynamic instability, increased risk of stroke, lengthened hospital and intensive care unit stays and greater costs. Underlying mechanisms are incompletely defined but include intraoperative and postoperative phenomena, such as inflammation, sympathetic activation and cardiac ischaemia, that combine to trigger atrial fibrillation, often in the presence of pre-existing factors, making the atria vulnerable to atrial fibrillation induction and maintenance. A better understanding of the underlying mechanisms might enable the identification of new therapeutic targets. POAF can be prevented by targeting autonomic alterations and inflammation. β-Blocker prophylaxis is the best-established preventive therapy and should be started or continued before cardiac surgery, unless contraindicated. When POAF occurs, rate control usually suffices, and routine rhythm control is unnecessary; rhythm control should be reserved for patients who develop haemodynamic instability or show other indications that rate control alone will be insufficient. In this Review, we summarize the epidemiological and clinical features of POAF, the available pathophysiological evidence from clinical and experimental investigations, the results of prophylactic and therapeutic approaches and the consensus recommendations of various national and international societies.
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              The pig as a model for immunology research

              The pig is an omnivorous, monogastric species with many advantages to serve as an animal model for human diseases. There are very high similarities to humans in anatomy and functions of the immune system, e g., the presence of tonsils, which are absent in rodents. The porcine immune system resembles man for more than 80% of analyzed parameters in contrast to the mouse with only about 10%. The pig can easily be bred, and there are less emotional problems to use them as experimental animals than dogs or monkeys. Indwelling cannulas in a vein or lymphatic vessel enable repetitive stress-free sampling. Meanwhile, there are many markers available to characterize immune cells. Lymphoid organs, their function, and their role in lymphocyte kinetics (proliferation and migration) are reviewed. For long-term experiments, minipigs (e.g., Göttingen minipig) are available. Pigs can be kept under gnotobiotic (germfree) conditions for some time after birth to study the effects of microbiota. The effects of probiotics can be tested on the gut immune system. The lung has been used for extracorporeal preservation and immune engineering. After genetic modifications are established, the pig is the best animal model for future xenotransplantation to reduce the problem of organ shortage for organ transplantation. Autotransplantation of particles of lymphnodes regenerates in the subcutaneous tissue. This is a model to treat secondary lymphedema patients. There are pigs with cystic fibrosis and severe combined immune deficiency available.
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                Author and article information

                Journal
                Ann Transl Med
                Ann Transl Med
                ATM
                Annals of Translational Medicine
                AME Publishing Company
                2305-5839
                2305-5847
                30 October 2023
                20 December 2023
                : 11
                : 12
                : 406
                Affiliations
                [1 ]deptInstitute for Bioelectronic Medicine , Feinstein Institutes for Medical Research , Manhasset, NY, USA;
                [2 ]Elmezzi Graduate School of Molecular Medicine, Northwell Health , Manhasset, NY, USA
                Author notes
                Correspondence to: Stefanos Zafeiropoulos, MD, MS, PhD. Elmezzi Graduate School of Molecular Medicine, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA; Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA. Email: szafeiropoul@ 123456northwell.edu .
                Article
                atm-11-12-406
                10.21037/atm-23-1889
                10777229
                8c99697b-bd14-49d7-9ba4-3054e0992aa7
                2023 Annals of Translational Medicine. All rights reserved.

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

                History
                : 09 October 2023
                : 19 October 2023
                Categories
                Editorial | Emerging Therapeutics

                vagus nerve stimulation (vns),postoperative inflammation,thoracic surgery

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