Polyvagal and Global Cytokine Theory of Safety and Threat Covid-19 – Plan B

David Hanscom, David Roger Clawson, Stephen W. Porges, Ray Bunnage, Les Aria, Steve Lederman, James Taylor, C. Sue Carter

Abstract


We are presenting this document to medical providers as a systematic approach to improve outcomes of patients with COVID-19. The following variables are considered: Autonomic nervous system viewed from the perspective of the Polyvagal Theory; Timing of interventions in terms of phase of the body’s defense (Fight, Flight, Freeze, Faint); The nervous system considered the context of a “One System” perspective; Protein/Enzyme function; Immune system; Cytokine load - activity, inflammation and metabolic response; Viral load; Angiotensin 2 load.

The ARDS and multi-system organ failure of the COVID-19 is a complex problem. This approach acknowledges the complexity and presents a structure where the variables are systematically addressed.

1. The common risk factors for death are associated with baseline elevations of pro-inflammatory cytokines. Measures can be taken to lower them before being exposed to the virus–Plan A.

2. Strategies to optimize the body’s defenses should be assessed and optimized. These include nutrition, vitamins, and trace elements, sleep, exercise, and minimizing threat.

3. The body’s own resources are utilized through recruiting the autonomic nervous system to counteract elevated pro-inflammatory cytokines. The interventions are implemented in the context of what stage of defense the body is in–fight, flight, freeze, or faint.

4. Progressive pharmacological interventions are considered with the early interventions being those with minimal risk.

We are asking the following:

  • This approach is viewed as the foundation for clinical interventions. They should be implemented in a systematic and stepwise manner.
  • Most of the treatments are already medically proven with minimal or no risk.
  • All basic treatments are in place before more aggressive interventions are implemented.
  • That this process be considered a framework to test clinical protocols and novel therapies. Much work needs to be done regarding dosing and timing.
  • We are particularly interested in the potential of the following interventions, which do need to be looked at in a protocol.
    • o Allowing ketosis in the Mid and Late Phases of the illness.
    • o Considering the use of ketone bodies instead of glucose for fuel in Mid and Late Phases of illness.
    • o Eliminating glucocorticosteroids in the Early and Mid-Phases the use of steroids.
    • o Utilizing the anti-inflammatory cholinergic nervous system (vagal stimulation, nicotine patches, etc.).
    • o Closer monitoring of IL-6 to in real time deliver the most appropriate interventions.

 

Doi: 10.28991/SciMedJ-2020-02-SI-2

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Keywords


Covid-19; Polyvagal Theory; Cytokine Theory; Coronavirus.

References


PORGES, S. W. (1995). Orienting in a defensive world: Mammalian modifications of our evolutionary heritage. A Polyvagal Theory. Psychophysiology, 32(4), 301–318. doi:10.1111/j.1469-8986.1995.tb01213.x.

Porges, S. W. (2007). The polyvagal perspective. Biological Psychology, 74(2), 116–143. doi:10.1016/j.biopsycho.2006.06.009.

Porges, S. W. (2011). The polyvagal theory: neurophysiological foundations of emotions, attachment, communication, and self-regulation (Norton Series on Interpersonal Neurobiology). WW Norton & Company.

Barrett, L. F. (2014). The Conceptual Act Theory: A Précis. Emotion Review, 6(4), 292–297. doi:10.1177/1754073914534479.

Porges, S. (2009). Polyvagal Theory 1: Basic Principles (Phylogny, Neoception, Dissolution, Social Engagement System). Lecture recorded at NSW Service for the Treatment and Rehabilitation of Torture and Trauma Survivors, New South Wales.

Jackson, J. H. (1884). The Croonian Lectures on Evolution and Dissolution of the Nervous System. BMJ, 1(1215), 703–707. doi:10.1136/bmj.1.1215.703.

Heffner, Kathi L. “Neuroendocrine Effects of Stress on Immunity in the Elderly: Implications for Inflammatory Disease.” Immunology and Allergy Clinics of North America 31, no. 1 (February 2011): 95–108. doi:10.1016/j.iac.2010.09.005.

Zambelli, V., Grassi, A., & Bellani, G. (2012). Role of the Renin-Angiotensin System in ARDS. Annual Update in Intensive Care and Emergency Medicine 2012, 171–181. doi:10.1007/978-3-642-25716-2_17.

Youm, Y.-H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., … Dixit, V. D. (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nature Medicine, 21(3), 263–269. doi:10.1038/nm.3804.

Tracey, K. J. (2002). The inflammatory reflex. Nature, 420(6917), 853–859. doi:10.1038/nature01321.

Porges, S. W., & Dana, D. A. (2018). Clinical Applications of the Polyvagal Theory: The Emergence of Polyvagal-Informed Therapies (Norton Series on Interpersonal Neurobiology). WW Norton & Company.

Porges SW. (2020) The COVID-19 Pandemic is a paradoxical challenge to our nervous system: a Polyvagal Perspective. Clin Neuropsychiatry 17, 135–8. doi: 10.36131/CN20200220.

Porges, SW. (2020). U.S. Patent No. 10,661,046. Washington, DC: U.S. Patent and Trademark Office.

Chovatiya, R., & Medzhitov, R. (2014). Stress, Inflammation, and Defense of Homeostasis. Molecular Cell, 54(2), 281–288. doi:10.1016/j.molcel.2014.03.030.

Kiecolt-Glaser, J. K., and Glaser, R. (1991). Stress and Immune Function in Humans. Psychoneuroimmunology, 849–867. doi:10.1016/b978-0-12-043780-1.50038-5.

Reiche, E. M. V., Nunes, S. O. V., & Morimoto, H. K. (2004). Stress, depression, the immune system, and cancer. The Lancet Oncology, 5(10), 617–625. doi:10.1016/s1470-2045(04)01597-9.

Reznikov, L. R., Grillo, C. A., Piroli, G. G., Pasumarthi, R. K., Reagan, L. P., & Fadel, J. (2007). Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment. European Journal of Neuroscience, 25(10), 3109–3114. doi:10.1111/j.1460-9568.2007.05560.x.

Nakao, M. (2019). Special series on “effects of board games on health education and promotion” board games as a promising tool for health promotion: a review of recent literature. BioPsychoSocial medicine, 13(1), 5. doi:10.1186/s13030-019-0146-3.

Nakao, M. (2019). Heart Rate Variability and Perceived Stress as Measurements of Relaxation Response. Journal of Clinical Medicine, 8(10), 1704. doi:10.3390/jcm8101704.

Brown, Richard P., and Patricia L. Gerbarg. “Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part I—Neurophysiologic Model.” The Journal of Alternative and Complementary Medicine 11, no. 1 (February 2005): 189–201. doi:10.1089/acm.2005.11.189.

Jerath, R., Edry, J. W., Barnes, V. A., & Jerath, V. (2006). Physiology of long pranayamic breathing: Neural respiratory elements may provide a mechanism that explains how slow deep breathing shifts the autonomic nervous system. Medical Hypotheses, 67(3), 566–571. doi:10.1016/j.mehy.2006.02.042.

Naik, G. S., Gaur, G. S., & Pal, G. K. (2018). Effect of modified slow breathing exercise on perceived stress and basal cardiovascular parameters. International journal of yoga, 11(1), 53. doi:10.4103/ijoy.IJOY_41_16

Telles, S., Gupta, R. K., Yadav, A., Pathak, S., & Balkrishna, A. (2017). Hemisphere specific EEG related to alternate nostril yoga breathing. BMC Research Notes, 10(1). doi:10.1186/s13104-017-2625-6.

Chin, M. S., & Kales, S. N. (2019). Understanding mind–body disciplines: A pilot study of paced breathing and dynamic muscle contraction on autonomic nervous system reactivity. Stress and Health, 35(4), 542–548. doi:10.1002/smi.2887.

Gerritsen, R. J. S., & Band, G. P. H. (2018). Breath of Life: The Respiratory Vagal Stimulation Model of Contemplative Activity. Frontiers in Human Neuroscience, 12. doi:10.3389/fnhum.2018.00397.

Radaelli, A., Raco, R., Perfetti, P., Viola, A., Azzellino, A., Signorini, M. G., & Ferrari, A. U. (2004). Effects of slow, controlled breathing on baroreceptor control of heart rate and blood pressure in healthy men. Journal of Hypertension, 22(7), 1361–1370. doi:10.1097/01.hjh.0000125446.28861.51.

Bilo, G., Revera, M., Bussotti, M., Bonacina, D., Styczkiewicz, K., Caldara, G., … Parati, G. (2012). Effects of Slow Deep Breathing at High Altitude on Oxygen Saturation, Pulmonary and Systemic Hemodynamics. PLoS ONE, 7(11), e49074. doi:10.1371/journal.pone.0049074.

Byeon, K., Choi, J.-O., Yang, J. H., Sung, J., Park, S. W., Oh, J. K., & Hong, K. P. (2012). The Response of the Vena Cava to Abdominal Breathing. The Journal of Alternative and Complementary Medicine, 18(2), 153–157. doi:10.1089/acm.2010.0656.

Dick, T. E., Mims, J. R., Hsieh, Y.-H., Morris, K. F., & Wehrwein, E. A. (2014). Increased cardio-respiratory coupling evoked by slow deep breathing can persist in normal humans. Respiratory Physiology & Neurobiology, 204, 99–111. doi:10.1016/j.resp.2014.09.013.

Giardino, N. D., Glenny, R. W., Borson, S., & Chan, L. (2003). Respiratory sinus arrhythmia is associated with efficiency of pulmonary gas exchange in healthy humans. American Journal of Physiology-Heart and Circulatory Physiology, 284(5), H1585–H1591. doi:10.1152/ajpheart.00893.2002.

Hayano, J., Yasuma, F., Okada, A., Mukai, S., & Fujinami, T. (1996). Respiratory Sinus Arrhythmia. Circulation, 94(4), 842–847. doi:10.1161/01.cir.94.4.842.

Ito, S., Sasano, H., Sasano, N., Hayano, J., Fisher, J. A., & Katsuya, H. (2006). Vagal nerve activity contributes to improve the efficiency of pulmonary gas exchange in hypoxic humans. Experimental Physiology, 91(5), 935–941. doi:10.1113/expphysiol.2006.034421.

Aeschbacher, S., Schoen, T., Dörig, L., Kreuzmann, R., Neuhauser, C., Schmidt-Trucksäss, A., … Conen, D. (2016). Heart rate, heart rate variability and inflammatory biomarkers among young and healthy adults. Annals of Medicine, 49(1), 32–41. doi:10.1080/07853890.2016.1226512.

Tsuji, J. (1996). Innovations in organic synthesis. Angewandte Chemie-German Edition, 108(18), 2291.

Eckberg, D. L. (2003). The human respiratory gate. The Journal of Physiology, 548(2), 339–352. doi:10.1113/jphysiol.2002.037192.

Hering, H. E. (1910). A functional test of heart vagi in man. Menschen Munchen Medizinische Wochenschrift, 57, 1931-1933.

Ilie, P. C., Stefanescu, S., & Smith, L. (2020). The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental Research, 32(7), 1195–1198. doi:10.1007/s40520-020-01570-8.

Harshman, S. G., & Shea, M. K. (2016). The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis. Current Nutrition Reports, 5(2), 90–98. doi:10.1007/s13668-016-0162-x.

Kashiouris, M. G., L’Heureux, M., Cable, C. A., Fisher, B. J., Leichtle, S. W., & Fowler, A. A. (2020). The Emerging Role of Vitamin C as a Treatment for Sepsis. Nutrients, 12(2), 292. doi:10.3390/nu12020292.

Sugimoto, J., Romani, A. M., Valentin-Torres, A. M., Luciano, A. A., Ramirez Kitchen, C. M., Funderburg, N., … Bernstein, H. B. (2012). Magnesium Decreases Inflammatory Cytokine Production: A Novel Innate Immunomodulatory Mechanism. The Journal of Immunology, 188(12), 6338–6346. doi:10.4049/jimmunol.1101765.

Foster, M., & Samman, S. (2012). Zinc and Regulation of Inflammatory Cytokines: Implications for Cardiometabolic Disease. Nutrients, 4(7), 676–694. doi:10.3390/nu4070676.

Prasad, A. S., Beck, F. W., Bao, B., Fitzgerald, J. T., Snell, D. C., Steinberg, J. D., & Cardozo, L. J. (2007). Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. The American Journal of Clinical Nutrition, 85(3), 837–844. doi:10.1093/ajcn/85.3.837.

Cabrera, Á. J. R. (2015). Zinc, aging, and immunosenescence: an overview. Pathobiology of Aging & Age-Related Diseases, 5(1), 25592. doi:10.3402/pba.v5.25592.

Neghaiwi, BH., 2020, Roche test receives FDA emergency use approval for COVID-19 patients. Reuters Available online: https://www.reuters.com/article/us-roche-hldg-elecsys/roche-test-receives-fda-emergency-use-approval-for-covid-19-patients-idUSKBN23B0IC (accessed on 3 June 2020).

Gibbs, J. (1999). Preoperative Serum Albumin Level as a Predictor of Operative Mortality and Morbidity. Archives of Surgery, 134(1), 36. doi:10.1001/archsurg.134.1.36.

Bernard, G. R., Luce, J. M., Sprung, C. L., Rinaldo, J. E., Tate, R. M., Sibbald, W. J., … Brigham, K. L. (1987). High-Dose Corticosteroids in Patients with the Adult Respiratory Distress Syndrome. New England Journal of Medicine, 317(25), 1565–1570. doi:10.1056/nejm198712173172504.

Krady, J. K., Basu, A., Allen, C. M., Xu, Y., LaNoue, K. F., Gardner, T. W., & Levison, S. W. (2005). Minocycline Reduces Proinflammatory Cytokine Expression, Microglial Activation, and Caspase-3 Activation in a Rodent Model of Diabetic Retinopathy. Diabetes, 54(5), 1559–1565. doi:10.2337/diabetes.54.5.1559.

Piao, W.-H., Campagnolo, D., Dayao, C., Lukas, R. J., Wu, J., & Shi, F.-D. (2009). Nicotine and inflammatory neurological disorders. Acta Pharmacologica Sinica, 30(6), 715–722. doi:10.1038/aps.2009.67.

Keller, M. J., Kitsis, E. A., Arora, S., Chen, J.-T., Agarwal, S., Ross, M. J., … Southern, W. (2020). Effect of Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients With COVID-19. Journal of Hospital Medicine, 15(8), 489–493. doi:10.12788/jhm.3497.

Mikkelsen, K., Stojanovska, L., Prakash, M., & Apostolopoulos, V. (2017). The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas, 96, 58–71. doi:10.1016/j.maturitas.2016.11.012.

Horowitz, R. I., Freeman, P. R., & Bruzzese, J. (2020). Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respiratory Medicine Case Reports, 30, 101063. doi:10.1016/j.rmcr.2020.101063.

Akbari, M., Ostadmohammadi, V., Tabrizi, R., Mobini, M., Lankarani, K. B., Moosazadeh, M., … Asemi, Z. (2018). The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Nutrition & Metabolism, 15(1). doi:10.1186/s12986-018-0274-y.

Sánchez-López, A. L., Ortiz, G. G., Pacheco-Moises, F. P., Mireles-Ramírez, M. A., Bitzer-Quintero, O. K., Delgado-Lara, D. L. C., … Velázquez-Brizuela, I. E. (2018). Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Archives of Medical Research, 49(6), 391–398. doi:10.1016/j.arcmed.2018.12.004.

Hardeland, R. (2019). Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks. International Journal of Molecular Sciences, 20(5), 1223. doi:10.3390/ijms20051223.

Deng, X., Song, Y., Manson, J. E., Signorello, L. B., Zhang, S. M., Shrubsole, M. J., … Dai, Q. (2013). Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Medicine, 11(1). doi:10.1186/1741-7015-11-187.

Pinto, A., Bonucci, A., Maggi, E., Corsi, M., & Businaro, R. (2018). Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease. Antioxidants, 7(5), 63. doi:10.3390/antiox7050063.

Yamaguchi, K., Kumakura, S., Someya, A., Iseki, M., Inada, E., & Nagaoka, I. (2017). Anti-inflammatory actions of gabapentin and pregabalin on the substance P-induced mitogen-activated protein kinase activation in U373 MG human glioblastoma astrocytoma cells. Molecular Medicine Reports, 16(5), 6109–6115. doi:10.3892/mmr.2017.7368.

Papagianni, E. P., & Stevenson, C. W. (2019). Cannabinoid Regulation of Fear and Anxiety: an Update. Current Psychiatry Reports, 21(6). doi:10.1007/s11920-019-1026-z.

Liu, C., Ma, H., Slitt, A. L., & Seeram, N. P. (2020). Inhibitory Effect of Cannabidiol on the Activation of NLRP3 Inflammasome Is Associated with Its Modulation of the P2X7 Receptor in Human Monocytes. Journal of Natural Products. doi:10.1021/acs.jnatprod.0c00138.s001.

Tanasescu, R., & Constantinescu, C. S. (2010). Cannabinoids and the immune system: An overview. Immunobiology, 215(8), 588–597. doi:10.1016/j.imbio.2009.12.005.

Meyer, M., Huaux, F., Gavilanes, X., van den Brûle, S., Lebecque, P., Lo Re, S., … Leal, T. (2009). Azithromycin Reduces Exaggerated Cytokine Production by M1 Alveolar Macrophages in Cystic Fibrosis. American Journal of Respiratory Cell and Molecular Biology, 41(5), 590–602. doi:10.1165/rcmb.2008-0155oc.

Roschewski, M., Lionakis, M. S., Sharman, J. P., Roswarski, J., Goy, A., Monticelli, M. A., … Wilson, W. H. (2020). Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Science Immunology, 5(48), eabd0110. doi:10.1126/sciimmunol.abd0110.

Diep, P. T., Buemann, B., Uvnäs-Moberg, K., & Marazziti, D. (2020). Oxytocin, a possible treatment for COVID-19? Everything to gain, nothing to lose. Clinical Neuropsychiatry, 17(3). doi:10.36131/CNEPUB20201703.

Abbas, A.K.; Lichtman, A.H. (2005) Cellular and Molecular Immunology, 5th ed.; Elsevier Saunders: Philadelphia, PA, USA.

Zhou, X., Fragala, M. S., McElhaney, J. E., & Kuchel, G. A. (2010). Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research. Current Opinion in Clinical Nutrition and Metabolic Care, 13(5), 541–547. doi:10.1097/mco.0b013e32833cf3bc.


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DOI: 10.28991/SciMedJ-2020-02-SI-2

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