As part of a fictitious consideration of the potential effects of the 2019 coronavirus pandemic (SARS), it is hypothesised that neural therapy with local anaesthetics could be able to mitigate the adverse effects associated with the pandemic and its post-SARS phase

COVID 19 (SARS-COV2) epidemic, which does not have an effective treatment method yet, that started in Wuhan, China in December 2019 and continues to threaten the world as a global pandemic. Human CoV infections are caused by α- and β -CoVs and can cause diseases in human respiratory, enteric, hepatic and neurological systems [1,2] . 

COVID-19 is considered a self-limiting highly contagious infectious disease. It is estimated that most cases with mild symptoms can recover within 1-2 weeks and the average incubation period is 2-5 days. Emerging as an acute respiratory infection disease (ARDS), COVID-19 spreads primarily through the respiratory tract via droplets, respiratory secretions, and direct contact. With recent studies, it has also been shown that it can be transmitted through oral-fecal and blood with the binding of the virus S-protein to the ACE-2 receptor in the respiratory epithelium [3-5]. Clinical findings occur in lung parenchyma, vascular endothelium, kidney cells, liver and small intestine cells. Due to widespread alveolar damage, a microvascular circulation disorder, susceptibility to thromboembolism, capillary micro embolism, increased proinflammatory cytokines, and chemokines are seen in the lungs. As a result of neurological involvement, headache, nausea, vomiting, encephalitis, loss of taste, and anosmia due to olfactory nerve involvement. Conjunctivitis and burning in the eyes can be seen as a result of mucosal inflammation. The virus exerts its effect on CNS through synaptic connections and via trans-synaptic way from peripheral nerve endings. Cytokine storm is encountered when endothelial and, epithelial damage worsens with the invasion of the virus into the cell and the spread of inflammation in the surrounding tissues Due to impaired tissue and organ perfusion, endothelial inflammation, and thromboembolism have been reported to cause multiple organ failure [6-12]. 

The risk of mortality is increased in patients with multimorbid diseases such as diabetes mellitus, hypertension, heart disease, immune deficiency, immunosuppressive drug users, kidney failure, obesity, and smokers [13-15].

Pathogens may play a key role in numerous respiratory diseases interacting with the human peripheral immune system. However, despite the insufficient data regarding virobiota, it has been reported that the viruses might have an effect on the immune system through the peripheral immune response and that the disease can spread from peripheral nerve endings in the extracellular matrix [16,17]. 

COVID 19 may cause infection in the brain stem of nucleus solitari and nucleus ambiguus that effects the innervation of airway smooth muscles, glands and blood vessels. Clinical findings of myocarditis, coronary ischemia, which occurs in critically ill patients, supports the suggestion of endothelial damage through perfusion disorder, thromboembolism and vagus nerve exposure due to neural involvement [18-21]. 

The basic regulatory system of the extracellular matrix represents the most fundamental and oldest regulatory and information system in the organism, with a phylogenetically older history than the hormone and nervous systems. Furthermore, the ECM is considered to be the site of complex interactions between invading pathogens, host tissues, and immune cells. Additionally, the ECM is a fundamental component of the host cellular microenvironment where the majority of events leading to infection, disease, and tissue repair occur. It also serves as a reservoir for diverse and tissue-specific signals (cytokines, growth factors, and other bioactive degradation products, or matrikines) that contribute to immunological pathways. 

Treatment algorithms may vary, based on the health authorities of countries and of clinical findings of the patients, and personal/social isolation precautions are options to combat the pandemic. With the effects of systemic application of local anesthetics and also neural therapy on ANS seems to support the hypothesis that it may be effective both in preventive medicine and therapeutically, for the regulation of immune system responses, perfusion problems and neural spread in the process of the disease [22].

Therapeutic local anesthetic (neural therapy) application has influences mostly on ANS for pain and inflammation with local and segmental subcutaneous infiltrations, of structures within the segment (with myotome, sclerotome, neurotome, angiotome connections) with local and segmental subcutaneous and ganglion injections. For these effects, using a low concentration of procaine (0.5-1%) or lidocaine (0.5-1%), allow healthy functioning of organs and systems with their pharmacological effects on the ANS. In neural therapy, the aim is to regulate the neuroimmunological processes of the organism in connection with the interaction of the sympathetic and parasympathetic nervous system using neuroanatomical connections and to provide neurovegetative regulation using the possibilities of reaction. Neural therapy achieves these effects mostly by regulating the sympathetic nervous system [23-33]. 

Local anesthetic agents have been in clinical use for over a century, primarily due to their nerve-blocking properties. However, an increasing body of evidence suggests that local anesthetics can also act on non-neuronal tissues. It appears that local anesthetic effects on non-excitable cells, including monocytes, neutrophils and mast cells, may contribute to a prolonged therapeutic effect beyond the pharmacological half-life of the [34-38]. 

Local anesthetics have been demonstrated to induce Gq-protein-complex-mediated intracellular anti-inflammatory mechanisms, deactivate overactive granulocytes, inhibit the signaling of human NMDA receptors, induce vasodilatation, exhibit antimicrobial properties and exert a sympatholytic effect. Furthermore, they have been shown to affect the synthesis and release of inflammatory mediators, including eicosanoids, histamine, prostaglandins and cytokines [39,40]. 

Wind-up mechanisms, central sensitization, and neuroplasticity can be defined for the continuity of inflammation. The sympathetic nervous system plays a very special role in the development and settlement of inflammation [41-46]. 

There is growing body of literature that supports the hyperactivity of the sympathetic nervous system, and also chronic stimulation of Nerves vagus, in several well-known pain syndromes and inflammation. The sympathetic nervous system has been shown to have a pro or anti-inflammatory effect, depending on the inflammatory process and time. In this case, the sympathetic nervous system has an important feature both the progress and combat of inflammation [47-50]. It is known that peripheral immune cells, which is considered as the first step of ANS in the development of inflammation that is located in the extracellular matrix, where the immune system is regulated, send signals to the central nervous system (CNS) for the release of proinflammatory cytokines. These newly formed cytokines have key roles in neural control of peripheral inflammation process [51-59]. 

With the application of neural therapy, the release of pro-inflammatory neuropeptides from sympathetic fibers is blocked, vasomotor system-related inflammation is regulated and the development of inflammation is prevented by disrupting the communication between the sympathetic nervous system and the immune system. The effects of local anesthetics used in neural therapy are not dose-dependent but regulate the stimuli of sympathetic ganglia, reduce sympathetic sprouting and by diminishing sympathetic activity in WDR neurons which helps temporarily resetting positive neuronal feedback cycles that create a vicious circle at the spinal-supraspinal level, allowing the organization of related organs and systems to be reorganized [60-66].

Recent studies have shown regulatory functions and anti-inflammatory activities of vagus nerve on the cardiovascular system and internal organs. It has been stated that these above-mentioned effects occur through the hypothalamic pituitary adrenal pathway, cholinergic anti-inflammatory pathway, and splenic sympathetic anti-inflammatory pathway. Vagus nerve may have anti-inflammatory efficacy through these specified pathways in the treatment of systemic inflammatory response and sepsis. In cases of inflammation, severe stress, and vigorous sympathetic system activity lead to sympathetic dominance in the ANS. Organizing sympathetic activation in case of serious inflammation becomes important for the treatment of patients. It is known that stellate ganglion blockade (SGB) may regulate the imbalance in the ANS by reducing the sympathetic hyperactivity by activating these pathways with Vagus nerve connection [67-77]. 

As a result of sympathetic activation caused by stellate ganglion stimulation, a decrease in lung compliance, an increase in alveolar surface tension, and cholesterol level were detected. It was stated that increased sympathetic stimulation triggers a rise in the levels of IL-1B and TNF-a in alveolar macrophages and also a decrease in nitric oxide release [78-80]. Local anesthetics themselves also have a positive effect on acute lung injury and ARDS. This effect takes place in regulating vascular inflammation via TNFα, by decreasing microvascular endothelial damage, and inflammatory hyperpermeability. It was observed that with the interactions arising in these pathways with SGB application, it is possible to regulate the immune response by increasing both in the lymphocyte subgroups and naturel killer cell activity. In addition, a significant increase in lung functions and respiratory values has been observed clinically. This anti-inflammatory result of SGB was observed by the effect of Vagus nerve with increased perfusion in the pulmonary vascular bed, a relief in the bronchial system, and vasodilation. The reduction of pulmonary oxidative stress responses with cervical sympathetic ganglion blocks can also be explained by the increased perfusion and vasodilation, which may result in the improvement of hypoxia. 

In recent studies, micro embolism is remarkable in COVID 19 pneumonia. The inflammation and alveolar edema, that appeared before micro embolism indicates sympathetic predominance in that region, with increased pulmonary vascular resistance and decreased lung compliance. An increase in vascular resistance and development of thrombosis in pulmonary vessels can lead to changes similar to the pathology of pulmonary arterial hypertension. These changes were evaluated in connection with the sympathetic nervous system dominance [81]..

In the light of these evidences, it can be predicted that the progress of inflammation will diminish, that lung perfusion will increase, and alveolar tension will decrease and may help to improve the hypoxemia with the neural therapy aimed to the lung segments and SGB, at the early stages of the lung injury. There is sympathetic dominance in the pulmonary vascular system and is regulated by the first 5 thoracic ganglia, including the stellate ganglion. As a local treatment, the T2-T9 segments, where sympathetic innervation of the lung is provided, and C3-5 segments for the diaphragm-phrenic nerve connection for respiratory mechanics are applied. And also, Neural Therapeutic local anesthetics may hinder the involvement of CNS by acting on synaptic connections and trans-synaptic way from peripheral nerve endings in the extracellular matrix [82].

Gut-lung immunity has a cross-interacting system. The intestinal microbiota plays a protective role against bacterial and viral lung infections by regulating innate and adaptive immune responses. It is stated that disruptions in the intestinal microbiota are associated with increased susceptibility to airway diseases and infections, including allergies, by modifying the immune responses [16-18]. 

The high rate of GI symptoms seen in COVID-19 patients and increased mortality rates in these patients seems like evidence of deterioration in the intestinal-pulmonary immune axis. From the holistic point of view, it shows that it is important to make a treatment planning for regulating the mucosal immune system and also for the gut-lung axis, in this group of patients [83].

It has also been reported that the stellate ganglion and cervical ganglia are associated with efferent innervation of the intestines through the Vagus nerve. It is anticipated that the treatment to be applied in these patients, it may support both the mucosal immunity and the regression of the inflammatory process in the lung.

Neural therapy can be administered by expert neural therapists for gut-lung axis to the local, segmental and ganglia that associated with gut segments as it is described in textbooks of neural therapy both for preventative medicine and in patients for gut-lung axis.

Since 1905, when the local anesthetics were first discovered, its systemic use began with procaine and continues with the addition of Lidocaine in the 1960s. Local anesthetics can be used systemically for pain, inflammation, vasodilation, bronchodilation, and to increase perfusion in circulatory disorders and for general physical health. 

Local anesthetic agent of procaine prevents the development of arterial vasospasm and thrombosis. In recent studies, it has been published that local anesthetics have positive effects on coagulation, fibrinolysis, inflammation, platelet aggregation and microcirculation. It is known that local anesthetics perform strong anti-inflammatory effects through various immune system cells such as monocytes, macrophages, and neutrophils. Local anesthetics increase the survival rate in case of sepsis. This effect is achieved by preventing ischemia-reperfusion damage in vital organs such as heart, lung, and liver [78-81]. 

Systemic local anesthetic infusion is effective in the peripheral and CNS. Experimental evidence indicates that these effects are produced by reduced ectopic signals, suppressed inflammatory processes, and regulated the inhibitor-excitatory neural conduction [82]. 

The intravenous administration of procaine, which is used effectively in neural therapy, has also some systemic therapeutic effects. It has a high solubility ratio, short half-life, and low toxicity due to its destruction by plasma esterase. Its therapeutic effects on capillary perfusion, inhibition of inflammation, anti-oxidative, and fat-reducing effects are important both in therapeutic and preventative approach. Procaine degradation products are also responsible for all above mentioned effects via its active molecules. Unlike other local anesthetic agents, procaine causes vasodilation in the arteries and capillaries. Therefore, in the case of inflammation and pain, it is possible to reach the tissues with impaired perfusion and shows therapeutic effect in the most appropriate way. Local anesthetics also show their anti-inflammatory effects via intra-cellular G-q protein complex, affecting the synthesis and release of inflammatory mediators (i.e. TNF-α), block granulocyte activity. It has been stated that adding bicarbonate to intravenous procaine infusions can prevent low pH, which may create more effective response on the tissue permeability [76, 81-91]. 

According to the scientific evidence mentioned above and also in recent studies [92-95]; regarding the systemic local anesthetic and intravenous procaine-lidocaine infusions, it is predicted that these modalities might show positive effects on the treatment of acute and chronic inflammation through decreased endothelial inflammation and vasoconstriction and make significant contributions in terms of increased perfusion in the pulmonary vascular capillary bed, protection of organ systems and decreased thromboembolic predisposition.

The treatment of generalized dysfunctions occurring on the tissue and organ systems and in the management of lung complications following COVID-19 infection; the neuraltherapeutic approaches might be considered as a promising method with the regulation effects on the ANS.

Considering the available evidence, it can be predicted that the systemic uses of local anesthetics may have a positive effect against the onset and advanced processes of the inflammatory process-for tissue perfusion and thromboembolic phenomena.

The authors would like to thank Assoc. Prof. Dr. Cüneyt Can Tamam, and Prof. Dr. Yusuf Tamam for their contributions to this work.

The Authors declares that there is no conflict of interest.

This research received no specific grant from any funding agency in the public, commercial, or not for profit sectors.

All authors have contributed to the paper and stated that have never submitted the manuscript, in whole or in part, to other journals.

Hüseyin Nazlikul: Writing, Data collecting, Editing

Mehmet Ali Elmacioglu: Writing, Data collecting, Editing

Fatma Gülcin Ural Nazlikul: Writing, Data collecting, Editing

1. Zhu N, Zhang D, Wang W, Li X, Yang B, et al.  (2020) A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 382: 727-733.
2. Li Q, Guan X, Wu P, Wang X, Zhou L, et al. (2020) Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med 382: 1199-1207.
3. Lee PI, Hsueh PR (2020) Emerging threats from zoonotic coronaviruses-from SARS and MERS to 2019-nCoV. J Microbiol Immunol Infect 53: 365-367.
4. Zhang W, Du RH, Li B, Zheng XS, Yang XL, et al. (2020)  Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect 9: 386-389.
5. https://www.science.org/content/article/how-does-coronavirus-kill-clinicians-trace-ferocious-rampage-through-body-brain-toes
6. Liu J, Zheng X, Tong Q, Li W, Wang B, et al. (2020) Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol 92: 491-494.
7. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, et al. (2020) Endothelial cell infection and endotheliitis in COVID-19. Lancet 395: 1417-1418.
8. Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, et al. (2020) Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence. J Clin Med 9: 1417.
9. https://chemrxiv.org/engage/chemrxiv/article-details/60c74f63567dfe3814ec567f
10. Li YC, Bai WZ, Hashikawa T (2020) The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 92: 552-555.
11. Pan L, Mu M, Yang P, Sun Y, Wang R, et al. (2020) Clinical Characteristics of COVID-19 Patients with Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study. Am J Gastroenterol 115: 766-773.
12. https://www.medscape.com/viewarticle/929092?form=fpf
13. Weiss P, Murdoch DR (2020) Clinical course and mortality risk of severe COVID-19. Lancet 395: 1014-1015.
14. Cho I, Blaser MJ (2020) The human microbiome: at the interface of health and disease. Nat Rev Genet 13: 260-270.
15. Mitchell AB, Glanville AR (2018) Introduction to Techniques and Methodologies for Characterizing the Human Respiratory Virome. Methods Mol Biol 1838: 111-123.
16. Matsuda K, Park CH, Sunden Y, Kimura T, Ochiai K, et al. (2004) The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice. Vet Pathol 41: 101-107.
17. Machado C, DeFina PA, Chinchilla M, Machado Y, Machado Y (2020) Brainstem Dysfunction in SARS-COV2 Infection Can Be a Potential Cause of Respiratory Distress. Neurol India 68: 989-993.
18. https://issuu.com/nobeltipkitabevi/docs/9789754207336
19. https://www.huseyinnazlikul.com/icerik/noralterapi-enjeksiyonlarinda-dikkat-edilmesi-gereken-hususlar-318
20. https://ignh.de/buecher/w-dosch-lehrbuch-der-neuraltherapie-nach-huneke-regulationstherapie-mit-lokalanaesthetika/
21. https://www.neuraltherapie.at/wp-content/uploads/2022/05/2005_Fischer_etal_Health_Technology_Assessment_Neuraltherapie_nach_Huneke.pdf
22. https://link.springer.com/article/10.1016/j.dza.2013.09.002
23. Egli S, Pfister M, Ludin SM, Puente de la Vega K, Busato A, et al. (2015) Long-term results of therapeutic local anesthesia (neural therapy) in 280 referred refractory chronic pain patients. BMC Complement Altern Med 15: 200.
24. Richardson JD, Vasko MR (2002) Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302: 839-845.
25. Steinhoff M, Ständer S, Seeliger S, Ansel JC, Schmelz M, et al. (2003) Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 139: 1479-1488.
26. Meggs WJ (1995) Neurogenic switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity. Environ Health Perspect 103: 54-56.
27. Bellinger DL, Lorton D (2018) Sympathetic Nerve Hyperactivity in the Spleen: Causal for Nonpathogenic-Driven Chronic Immune-Mediated Inflammatory Diseases (IMIDs)?. Int J Mol Sci 19: 1188.
28. Kronenberg RM, Ludin SM, Fischer L (2018) Severe Case of Chronic Pelvic Pain Syndrome: Recovery after Injection of Procaine into the Vesicoprostatic Plexus-Case Report and Discussion of Pathophysiology and Mechanisms of Action. Case Rep Urol 26: 9137215.
29. Teague HL, Ahlman MA, Alavi A, Wagner DD, Lichtman AH, et al. (2017) Unraveling Vascular Inflammation: From Immunology to Imaging. J Am Coll Cardiol 70: 1403-1412.
30. Liao CD, Tsauo JY, Liou TH, Chen HC, Rau CL (2016) Efficacy of Noninvasive Stellate Ganglion Blockade Performed Using Physical Agent Modalities in Patients with Sympathetic Hyperactivity-Associated Disorders: A Systematic Review and Meta-Analysis. PLoS One 11: e0167476.
31. Jänig W (2006) The integrative action of the autonomic nervous system. Cambridge: Cambridge University Press.
32. Straub RH, Wiest R, Strauch UG, Härle P, Schölmerich J (2006) The role of the sympathetic nervous system in intestinal inflammation. Gut 55 :1640-1649.
33. Zegarska B, Leli?ska A, Tyrakowski T (2006) Clinical and experimental aspects of cutaneous neurogenic inflammation. Pharmacol Rep 58: 13-21.
34. Davinelli S, Maes M, Corbi G, Zarrelli A, Willcox DC, et al. (2016) Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges. Immun Ageing 13: 16.
35. Katoh M (2018) Multi?layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β?catenin signaling activation (Review). Int J Mol Med 42: 713-725.
36. Boyd DF, Thomas PG (2017) Towards integrating extracellular matrix and immunological pathways. Cytokine 98: 79-86.
37. Sorokin L (2010) The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10(10):712-723.
38. Puente de la Vega Costa K, Gómez Perez MA, Roqueta C, Fischer L (2016) Effects on hemodynamic variables and echocardiographic parameters after a stellate ganglion block in 15 healthy volunteers. Autonomic Neuroscience: Basic & Clinical 197: 46-55. 
39. Nazlikul H, Babacan A (2019) Nöralterapi ve enjeksiyonlardaki rolü. Babacan A, editör. Agri ve Enjeksiyonlar. 1. Baski Ankara: Türkiye Klinikleri 110-117.
40. Weinschenk S, Brocker K, Hotz L, Strowitzki T, Joos S (2013) Successful therapy of vulvodynia with local anesthetics: a case report. Forsch Komplementmed 20: 138-143.
41. Bonaz B, Sinniger V, Pellissier S (2020) Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19? Bioelectron Med 29: 6:15.
42. Chavan SS, Tracey KJ (2017) Essential Neuroscience in Immunology. J Immunol 198 :3389-3397.
43. Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117: 289-296.
44. Fernandez R, Nardocci G, Navarro C, Reyes EP, Acuña-Castillo C, et al. (2014) Neural reflex regulation of systemic inflammation: potential new targets for sepsis therapy. Front Physiol 5: 489.
45. Liu Y, Tao T, Li W, Bo Y (2017) Regulating autonomic nervous system homeostasis improves pulmonary function in rabbits with acute lung injury 17: 98.
46. Bergren DR, Beckman DL (1979) Lung compliance and cholesterol during stellate ganglion stimulation. Respir Physiol 38: 11-22.
47. Broug-Holub E, Persoons JH, Schornagel K, Mastbergen SC, Kraal G (1998) Effects of stress on alveolar macrophages: a role for the sympathetic nervous system. Am J Respir Cell Mol Biol 19: 842-848.
48. Yokoyama M, Nakatsuka H, Itano Y, Hirakawa M (2000) Stellate ganglion block modifies the distribution of lymphocyte subsets and natural-killer cell activity. Anesthesiology 92: 109-115.
49. Parris WC, Lin S, Frist W Jr (1988) Use of stellate ganglion blocks for chronic chest pain associated with primary pulmonary hypertension. Anesth Analg 67: 993-995.
50. Vaillancourt M, Chia P, Sarji S, Nguyen J, Hoftman N, et al. (2017) Autonomic nervous system involvement in pulmonary arterial hypertension. Respir Res 18: 201.
51. Casey K, Iteen A, Nicolini R, Auten J (2020) COVID-19 pneumonia with hemoptysis: Acute segmental pulmonary emboli associated with novel coronavirus infection [published online ahead of print, 2020 Apr 8]. Am J Emerg Med 38: 1544.e1-1544.e3.
52. Chen J, Wang X, Zhang S (2020) Findings of acute pulmonary embolism in COVID-19 patients. SSRN Electron J.
53. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med 382 :e38.
54. Kummer W (2011) Pulmonary vascular innervation and its role in responses to hypoxia: size matters!. Proc Am Thorac Soc 8: 471-476.
55. Liu SF, Barnes PJ (1997) Neural control of pulmonary vascular tone. In: Crystal RG, West JB, Weibel ER, Barnes PJ, editors. The lung: scientific foundations, 2nd ed. Philadelphia: Lippincott – Raven Publishers 1457–1472.
56. Chen Y, Guo L, Lang H, Hu X , Jing S, et al. Effect of a Stellate Ganglion Block on Acute Lung Injury in Septic Rats. Inflammation 41: 1601-1609.
57. Zhao Y, Xiang R, Peng X, Dong Q, Li D, et al. Transection of the cervical sympathetic trunk inhibits the progression of pulmonary arterial hypertension via ERK-1/2 Signalling. Respir Res 20: 121.
58. Yokoyama M, Nakatsuka H, Itano Y, Hirakawa M (2000) Stellate ganglion block modifies the distribution of lymphocyte subsets and natural-killer cell activity. Anesthesiology 92: 109-115.
59. Nazlikul H, Bilgin MD (2022) What is Neural Therapy? The Effect of Neural Therapy on Chronic Inflammatory Diseases (Chronic Inflammatory Bowel Diseases) - Nöralterapi nedir? Kronik Inflamatuar Iastaliklarda (Kronik Inflamatuar Bagirsak Hastaliklari) Nöralterapi Etkinligi. Babacan CA, editör. Ozon ve Nöralterapi. 1. Baski . Ankara: Türkiye Klinikleri 36- 44.
60. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, et al. (2011) Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci USA 108: 5354-5359.
61. Keely S, Talley NJ, Hansbro PM (2012) Pulmonary-intestinal cross talk in mucosal inflammatory disease. Mucosal Immunol 5: 7-18.
62. Chen LW, Chen PH, Hsu CM (2011) Commensal microflora contribute to host defense against Escherichia coli pneumonia through Toll-like receptors. Shock 36: 67-75.
63. Schuijt TJ, Lankelma JM, Scicluna BP, de Sousa e Melo F, Roelofs JJ, et al. (2016) The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut 65: 575-583.
64. Skalski JH, Limon JJ, Sharma P, Gargus MD, Nguyen C, et al. (2018) Expansion of commensal fungus Wallemia mellicola in the gastrointestinal mycobiota enhances the severity of allergic airway disease in mice. PLoS Pathog 14: e1007260.
65. Enaud R, Prevel R, Ciarlo E, Beaufils F, Wieërs G, et al. (2020) The Gut-Lung Axis in Health and Respiratory Diseases: A Place for Inter-Organ and Inter-Kingdom Crosstalks. Front Cell Infect Microbiol 10: 9.
66. Marsland BJ, Trompette A, Gollwitzer ES (2015) The Gut-Lung Axis in Respiratory Disease. Ann Am Thorac Soc 2: S150-S156.
67. McAleer JP, Kolls JK (2018) Contributions of the intestinal microbiome in lung immunity. Eur J Immunol 48: 39-49.
68. Lundberg JM, Dahlström A, Larsson I, Petterson G, Ahlman H, et al. (1978) Efferent innervation of the small intestine by adrenergic neurons from the cervical sympathetic and stellate ganglia, studied by retrograde transport of peroxidase. Acta Physiol Scand 104: 33-42.
69. BARTLETT EE, HUTSERANI O (1961) Xylocaine for the relief of postoperative pain. Anesth Analg 40: 296-304.
70. Aslan A (1960) Procaine Therapy in Old Age and other Disorders (Novocaine Factor H₃). Geront clin 2: 148-176.
71. Grittain GJ (1949) Intravenous Procaine Hydrochloride. Anesthesiology 10: 514.
72. Reviews of Educational Materials (1961) Bronchial Procaine Block. Anesthesiology 22: 1029.
73. Mushin WW, Rendell BL (1942) Intravenous Procaine: A Review. Anesthesiology 11: 511.
74. Leriche R (1942) Intraarterial and intravenous injection of novocaine as general method of vasodilatation caused by action on endothelium. Proges med 70: 443.
75. GRAUBARD DJ, PETERSON MC (1949) The therapeut?c uses of intravenous procaine. Anesthesiology 10: 175-187.
76. Reuter URM, Oettmeier R, Nazlikul H (2017) Procaine and Procaine-Base-Infusion: A Review of the Safety and Fields of Application after Twenty Years of Use. Clin Res Open Access 002: 1-8
77. Hahn-Godeffroy J (2011) D: Procain-Reset: Ein Therapiekonzept zur Behandlung chronischer Erkrankungen. Schweiz Z Ganzheitsmed 23: 291-296.
78. Howland WJ, Curry JL (1967) Wheeler PP. Intra-arterial administration of procaine hydrochloride after arteriography. Potential value in preventing arteriospasm and thrombosis. JAMA 201: 813-816.
79. Gallos G, Jones DR, Nasr SH, Emala CW, Lee HT (2004) Local anesthetics reduce mortality and protect against renal and hepatic dysfunction in murine septic peritonitis. Anesthesiology 101: 902-911.
80. Caracas HC, Maciel JV, Martins PM, de Souza MM, Maia LC (2009) The use of lidocaine as an anti-inflammatory substance: a systematic review. J Dent 37: 93-97.
81. Hahnenkamp K, Theilmeier G, Van Aken HK, Hoenemann CW (2002) The effects of local anesthetics on perioperative coagulation, inflammation, and microcirculation. Anesth Analg 94: 1441-1447.
82. Hermanns H, Hollmann MW, Stevens MF, Lirk P, Brandenburger T, et al. (2019) Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review. Br J Anaesth 123: 335-349.
83. Cassuto J, Sinclair R, Bonderovic M (2006) Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiol Scand 50: 265-282.
84. Hollmann MW, Gross A, Jelacin N, Durieux ME (2001) Local anesthetic effects on priming and activation of human neutrophils. Anesthesiology 95: 113-122.
85. Hollmann MW, Durieux ME, Graf BM (2001) Novel local anaesthetics and novel indications for local anaesthetics. Curr Opin Anaesthesiol 14: 741-749.
86. Bailey M, Corcoran T, Schug S, Toner A (2018) Perioperative lidocaine infusions for the prevention of chronic postsurgical pain: a systematic review and meta-analysis of efficacy and safety. Pain 159: 1696-1704.
87. Bicket MC, Cohen SP (2018) Lidocaine infusions and preventative analgesia: can the answer to our prayers be hiding right under our noses? Pain 159: 1677-1678.
88. Hollmann MW, Durieux ME (2000) Local anesthetics and the inflammatory response: a new therapeutic indication?. Anesthesiology 93: 858-875.
89. Schotes S, Saha FJ Dobos G (2018) Intraarterielle Procaingabe bei peripherer arterieller Verschlusskrankheit. Schmerz 32: 468-470.
90. Piegeler T, Votta-Velis EG, Bakhshi FR, Mao M, Carnegie G, et al. (2014) Endothelial barrier protection by local anesthetics: ropivacaine and lidocaine block tumor necrosis factor-α-induced endothelial cell Src activation. Anesthesiology 120: 1414-1428.
91. Nishina K, Mikawa K, Takao Y, Shiga M, Maekawa N, et al. (1998) Intravenous lidocaine attenuates acute lung injury induced by hydrochloric acid aspiration in rabbits. Anesthesiology 88: 1300-1309.
92. Finnerty DT, Buggy DJ (2020) A novel role for lidocaine in COVID-19 patients?. Br J Anaesth 125: e391-e394.
93. Ali ZA, El-Mallakh RS (2020) Nebulized Lidocaine in COVID-19, An Hypothesis. Med Hypotheses 144: 109947.
94. https://www.clinicaltrials.gov/ct2/show/NCT04609865
95. Maab H, Mustafa F, Arshad Ali S (2020) Anti-inflammatory aspects of Lidocaine: a neglected therapeutic stance for COVID-19. Heart Lung 49: 877-878.