title: Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01944228. Registered 12 September 2013.
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. matthijs.kox@radboudumc.nl.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. lucas.vaneijk@radboudumc.nl.
authors.forename: Lucas T
authors.initials: LT
authors.lastname: van Eijk
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. tim_verhaak@hotmail.com.
authors.forename: Tim
authors.initials: T
authors.lastname: Verhaak
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. tim.frenzel@radboudumc.nl.
authors.forename: Tim
authors.initials: T
authors.lastname: Frenzel
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. dorien.kiers@radboudumc.nl.
authors.forename: Harmke D
authors.initials: HD
authors.lastname: Kiers
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. jelle.gerretsen@radboudumc.nl.
authors.forename: Jelle
authors.initials: J
authors.lastname: Gerretsen
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. hans.vanderhoeven@radboudumc.nl.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.affiliation: Medtronic Inc., Endepolsdomein 5, 6229, GW, Maastricht, The Netherlands. lilian.kornet@medtronic.com.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kornet
authors.affiliation: Medtronic Inc., 8200 Coral Sea St NE, Mounds View, MN, 55112, USA. avram.scheiner@medtronic.com.
authors.forename: Avram
authors.initials: A
authors.lastname: Scheiner
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Geert Grooteplein 10, 6500, HB, Nijmegen, The Netherlands. peter.pickkers@radboudumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D019446:Endotoxemia / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D055536:Vagus Nerve Stimulation / Q000379:methods*; D055815:Young Adult
chemical_list: D008070:Lipopolysaccharides