Increasing Blood Pressure by Greater Splanchnic Nerve Stimulation: a Feasibility Study

Abstract

The splanchnic vascular compartment is the major reservoir for intravascular blood volume, and dysregulation of the compartment was implicated in a series of cardiovascular conditions. We explored feasibility and effectiveness of an implantable cuff system on the greater splanchnic nerve (GSN) in healthy canines for short- and long-term neuromodulation to affect the circulation. Five mongrel hounds underwent minimally invasive right-sided unilateral GSN cuff placement. All animals underwent same day GSN stimulation and repeat stimulation at 9–30 days. Stimulation parameter optimization was conducted both acutely and chronically. Parameters ranged from 1–250 Hz, 0.25 mA–35 mA, 0.1–0.5 ms, and 30-s pulse duration. Two animals were survived for 9 days and 3 animals for 30 days. Stimulation of the right GSN increased mean arterial blood pressure by 36.9 mmHg ± 13.4 (p < 0.0001), central venous pressure by 6.9 mmHg ± 1.7 (p < 0.0001), and mean pulmonary arterial pressure by 6.3 mmHg ± 2.0 (p < 0.0001). Peak effects were observed within 30 s, and magnitude of effects was comparable between stimulation cycles (p = 0.4). Stimulation-induced changes in hemodynamics were independent of afferent nerve fibers (pain response) or the adrenal gland. Necropsy showed no evidence of nerve damage on histologic studies up to 30 days after implantation. GSN stimulation via an implanted nerve cuff provided a reproducible and rapid method to increase arterial, central venous, and pulmonary arterial pressures. The neuromodulation cuff was well tolerated and elicited a response up to 30 days after implantation. The clinical application of GSN stimulation as a tool to change central and peripheral cardiovascular hemodynamics needs to be explored.

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References

  1. 1.

    Magder, S. (2016). Volume and its relationship to cardiac output and venous return. Critical Care, 20, 271.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Gelman, S. (2008). Venous function and central venous pressure: a physiologic story. Anesthesiology, 108(4), 735–748.

    PubMed  Article  Google Scholar 

  3. 3.

    Barnes, R. J., Bower, E. A., & Rink, T. J. (1986). Haemodynamic responses to stimulation of the splanchnic and cardiac sympathetic nerves in the anaesthetized cat. The Journal of Physiology, 378, 417–436.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Greenway, C. V. (1991). Blockade of reflex venous capacitance responses in liver and spleen by hexamethonium, atropine, and surgical section. Canadian Journal of Physiology and Pharmacology, 69(9), 1284–1287.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Carneiro, J. J., & Donald, D. E. (1977). Change in liver blood flow and blood content in dogs during direct and reflex alteration of hepatic sympathetic nerve activity. Circulation Research, 40(2), 150–158.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Greenway, C. V. (1983). Role of splanchnic venous system in overall cardiovascular homeostasis. Federation Proceedings, 42(6), 1678–1684.

    CAS  PubMed  Google Scholar 

  7. 7.

    Fudim, M., et al. (2017). Raising the pressure: hemodynamic effects of splanchnic nerve stimulation. Journal of Applied Physiology (Bethesda, MD: 1985), jap 00069 2017.

  8. 8.

    Fudim, M., Hernandez, A. F., & Felker, G. M. (2017). Role of volume redistribution in the congestion of heart failure. Journal of the American Heart Association, 6(8).

  9. 9.

    Diedrich, A., & Biaggioni, I. (2004). Segmental orthostatic fluid shifts. Clinical Autonomic Research, 14(3), 146–147.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Fallick, C., Sobotka, P. A., & Dunlap, M. E. (2011). Sympathetically mediated changes in capacitance: redistribution of the venous reservoir as a cause of decompensation. Circulation. Heart Failure, 4(5), 669–675.

    PubMed  Article  Google Scholar 

  11. 11.

    Fudim, M., et al. (2018). Splanchnic nerve block for acute heart failure. Circulation.

  12. 12.

    Radlinsky, M. G., et al. (2002). Thoracoscopic visualization and ligation of the thoracic duct in dogs. Vet Surg, 31(2), 138–46.

  13. 13.

    Parker, R. H., E. A. Kahn, & Iob V. (1953) Thoracic duct ligation during supradiaphragmatic splanchnic section; effect on hypertension and lipid transport. Med Bull (Ann Arbor), 19(11), 291–301.

  14. 14.

    Kahn, E. A. (1954). Twenty years’ experience with the surgery of hypertension. The New England Journal of Medicine, 251(16), 633–638.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Fudim, M., et al. (2018). Splanchnic nerve block for decompensated chronic heart failure: splanchnic-HF. European Heart Journal.

  16. 16.

    Brooksby, G. A., & Donald, D. E. (1971). Dynamic changes in splanchnic blood flow and blood volume in dogs during activation of sympathetic nerves. Circulation Research, 29(3), 227–238.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Martin, S. J., Burstein, C. L., & Rovenstine, E. A. (1942). Stimulation of the celiac plexus in the dog: I. Cardiovascular and respiratory effects. Archives of Surgery, 44(5), 943–952.

    Article  Google Scholar 

  18. 18.

    Pan, H. L., Zeisse, Z. B., & Longhurst, J. C. (1996). Role of summation of afferent input in cardiovascular reflexes from splanchnic nerve stimulation. The American Journal of Physiology, 270(3 Pt 2), H849–H856.

    CAS  PubMed  Google Scholar 

  19. 19.

    Pan, H. L., et al. (2001). Differential responses of regional sympathetic activity and blood flow to visceral afferent stimulation. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 280(6), R1781–R1789.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Greenway, C. V., & Innes, I. R. (1980). Effects of splanchnic nerve stimulation on cardiac preload, afterload, and output in cats. Circulation Research, 46(2), 181–189.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Rea, R. F., & Thames, M. D. (1993). Neural control mechanisms and vasovagal syncope. Journal of Cardiovascular Electrophysiology, 4(5), 587–595.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Kaufmann, H. (1997). Neurally mediated syncope and syncope due to autonomic failure: differences and similarities. Journal of Clinical Neurophysiology, 14(3), 183–196.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Shen, W. K., et al. (2017). 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology, 70(5), 620–663.

    PubMed  Article  Google Scholar 

  24. 24.

    Stewart, J. M., et al. (2004). Relation of postural vasovagal syncope to splanchnic hypervolemia in adolescents. Circulation, 110(17), 2575–2581.

    PubMed  Article  Google Scholar 

  25. 25.

    Denq, J. C., et al. (1997). Efficacy of compression of different capacitance beds in the amelioration of orthostatic hypotension. Clinical Autonomic Research, 7(6), 321–326.

  26. 26.

    Tanaka, H., Yamaguchi, H., & Tamai, H. (1997). Treatment of orthostatic intolerance with inflatable abdominal band. Lancet, 349(9046), 175.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Breslow, M. J., et al. (1987). Effect of vasopressors on organ blood flow during endotoxin shock in pigs. The American Journal of Physiology, 252(2 Pt 2), H291–H300.

    CAS  PubMed  Google Scholar 

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Funding

This research was funded by NIH Grant 1R44HL132656-01A1.

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Correspondence to Marat Fudim.

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Conflict of Interest

AB is an employee at Coridea LLC, INC, serves as consultant to Axon Therapies and supported by R44-HL132656-02 grant.

ZE is an employee at Coridea LLC, INC, serves as consultant to Axon Therapies and supported by R44-HL132656-02 grant.

MF is supported by an American Heart Association Grant 17MCPRP33460225, and serves as a consultant to Coridea, Axon Therapies, Galvani and Daxor.

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Statement of Clinical Relevance

Splanchnic vascular compliance has been suggested to be central to the pathophysiology of heart failure. Splanchnic nerve stimulation via an implanted nerve cuff provided a reproducible and rapid method to increase arterial, central venous, and pulmonary arterial pressures. The present research opens up numerous avenues of splanchnic nerve modulation for the treatment of diseases such as neurally mediated syncope.

Associate Editor Enrique Lara-Pezzi oversaw the review of this article

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Bapna, A., Adin, C., Engelman, Z.J. et al. Increasing Blood Pressure by Greater Splanchnic Nerve Stimulation: a Feasibility Study. J. of Cardiovasc. Trans. Res. 13, 509–518 (2020). https://doi.org/10.1007/s12265-019-09929-7

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Keywords

  • Splanchnic nerve
  • Neuromodulation
  • Hemodynamics