Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
, 17 (1), 150

Transvenous Vagus Nerve Stimulation Does Not Modulate the Innate Immune Response During Experimental Human Endotoxemia: A Randomized Controlled Study

Affiliations
Randomized Controlled Trial

Transvenous Vagus Nerve Stimulation Does Not Modulate the Innate Immune Response During Experimental Human Endotoxemia: A Randomized Controlled Study

Matthijs Kox et al. Arthritis Res Ther.

Abstract

Introduction: Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia.

Methods: We performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5-C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0-10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg(-1) Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation.

Results: No serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS.

Conclusions: tVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia.

Trial registration: Clinicaltrials.gov NCT01944228. Registered 12 September 2013.

Figures

Fig. 1
Fig. 1
Schematic overview of the study procedures. LPS lipopolysaccharide, tVNS transvenous vagus nerve stimulation
Fig. 2
Fig. 2
Hemodynamic parameters, temperature, and symptoms. a Heart rate (HR). b Mean arterial pressure (MAP). c Temperature. d Score of self-reported symptoms. Data are expressed as mean and SEM of 10 subjects per group. The gray box indicates the period in which the (sham) stimulation took place. Within-group changes over time were all highly significant (p < 0.0001 for all parameters in both groups, calculated using repeated measures one-way ANOVA). p-values depicted indicate differences between groups over time calculated using repeated measures two-way ANOVA (interaction term). AU arbitrary units, LPS lipopolysaccharide, tVNS transvenous vagus nerve stimulation
Fig. 3
Fig. 3
Plasma concentrations of inflammatory cytokines. a Tumor necrosis factor (TNF)-α. b Interleukin (IL)-6. c IL-8 (d) IL-10. Data are expressed as medians of 10 subjects per group. Inserted bar graphs depict median and interquartile range of area under curve of cytokine time courses. Within-group changes over time were all highly significant (p < 0.0001 for all cytokines in both groups, calculated using Friedman tests). p-values depicted were calculated using Mann-Whitney U-tests. LPS lipopolysaccharide, tVNS transvenous vagus nerve stimulation
Fig. 4
Fig. 4
Cytokine production of leukocytes stimulated ex vivo with lipopolysaccharide (LPS). a Tumor necrosis factor (TNF)-α. b Interleukin (IL)-6. Data expressed as mean and SEM of 10 subjects per group. Within-group changes over time were all highly significant (p < 0.0001 for all parameters in both groups, calculated using repeated measures one-way ANOVA). p-values depicted indicate differences between groups over time calculated using repeated measures two-way ANOVA (interaction term). tVNS transvenous vagus nerve stimulation
Fig. 5
Fig. 5
Neutrophil phagocytosis capacity. a Representative example of gating of neutrophils in the leukocyte population using forward side-scatter characteristics. b Representative example of gating of phRodo positive-neutrophils (phycoerythrin (PE) channel) within the neutrophil gate. c Phagocytic index calculated using the formula: pHrodo positive neutrophils × MFI of pHrodo-positive neutrophils. Data in panel c are expressed as mean and SEM of 10 subjects per group. Within-group changes over time were not significant (p = 0.38 and p = 0.14 for the sham and tVNS groups, respectively, calculated using repeated measures one-way ANOVA). p-values depicted indicate differences between groups over time calculated using repeated measures two-way ANOVA (interaction term). AU arbitrary units, FS forward scatter, LPS lipopolysaccharide, SS side scatter, tVNS transvenous vagus nerve stimulation

Similar articles

See all similar articles

Cited by 10 PubMed Central articles

See all "Cited by" articles

References

    1. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907–16. doi: 10.1056/NEJM200103223441207. - DOI - PubMed
    1. Buch MH, Emery P. New therapies in the management of rheumatoid arthritis. Curr Opin Rheumatol. 2011;23:245–51. doi: 10.1097/BOR.0b013e3283454124. - DOI - PubMed
    1. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov. 2010;9:325–38. doi: 10.1038/nrd3003. - DOI - PubMed
    1. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62. doi: 10.1038/35013070. - DOI - PubMed
    1. van Westerloo DJ, Giebelen IA, Meijers JC, Daalhuisen J, de Vos AF, Levi M, et al. Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats. J Thromb Haemost. 2006;4:1997–2002. doi: 10.1111/j.1538-7836.2006.02112.x. - DOI - PubMed

Publication types

Substances

Associated data

Feedback