Vagus Nerve Stimulation Regulates Hemostasis in Swine

Abstract

The central nervous system regulates peripheral immune responses via the vagus nerve, the primary neural component of the cholinergic anti-inflammatory pathway. Electrical stimulation of the vagus nerve suppresses pro-inflammatory cytokine release in response to endotoxin, I/R injury, and hypovolemic shock and protects against lethal hypotension. To determine the effect of vagus nerve stimulation on coagulation pathways, anesthetized pigs were subjected to partial ear resection before and after electrical vagus nerve stimulation. We observed that electrical vagus nerve stimulation significantly decreased bleeding time (pre-electrical vagus nerve stimulation = 1033 ± 210 s versus post-electrical vagus nerve stimulation = 585 ± 111 s; P < 0.05) and total blood loss (pre-electrical vagus nerve stimulation = 48.4 ± 6.8 mL versus post-electrical vagus nerve stimulation = 26.3 ± 6.7 mL; P < 0.05). Reduced bleeding time after vagus nerve stimulation was independent of changes in heart rate or blood pressure and correlated with increased thrombin/antithrombin III complex generation in shed blood. These data indicate that electrical stimulation of the vagus nerve attenuates peripheral hemorrhage in a porcine model of soft tissue injury and that this protective effect is associated with increased coagulation factor activity.

The Inflammatory Reflex and Neural Tourniquet: Harnessing the Healing Power of the Vagus Nerve

“…Using rotational thromboelastography, we observed that electrical VNS significantly reduces reaction (r) time of systemic blood compared with baseline values [46]. Thrombin generation studies revealed that compared with baseline values, blood from the injury site has significantly higher TAT concentrations in vagus nerve stimulated animals versus sham-stimulated animals [46].…”

“…To explain these improvements in hemostasis, hemodynamic parameters and measures of circulating cells and clotting function in systemic blood and shed blood from the injury site were analyzed via thromboelastography, platelet aggregometry and ELISA for thrombin-antithrombin (TAT) complexes [46]. Despite an initial concern for vagal parasympathetic effects on the heart, electrical VNS had no appreciable effect on either heart rate or blood pressure.…”

“…We first developed an ear laceration and hemorrhage model in swine, a commonly utilized species to study bleeding [46]. 2-to 5-month-old male and female pigs weighing 25-30 kg received general anesthesia and then underwent a standardized ear laceration of 3 cm wide and 1.5 cm long with a scalpel.…”

Baroreflex impairment and morbidity after major surgery

“…In experimental soft tissue injury, haemorrhage is reduced after vagal nerve stimulation. 41 Diminished efferent (parasympathetic) activity, which contributes to baroreflex dysfunction, is promoted by inflammatory mediators, opiates, and anaesthetic agents. 42 43 Further loss of parasympathetic neural activity triggered by haemorrhage, reperfusion, and consequent inflammation during major surgery may therefore be particularly detrimental.…”

Reflex Principles of Immunological Homeostasis

“…Although this study was not designed to prove causality of diminished vagus activity in lethal outcomes, the functional importance for intrinsic anti-inflammatory activity mediated by vagus nerve signaling is strongly supported by experimental evidence that vagotomy in animal sepsis models increases mortality and worsens tissue damage secondary to uncontrolled cytokine release (30, 31). Moreover, experimentally activating the cholinergic anti-inflammatory pathway in preclinical studies of sepsis by vagus nerve stimulation or administration of selective or universal α7 nAChR agonists improves survival, reduces proinflammatory cytokine levels (including HMGB1, implicated as a necessary and sufficient mediator of lethal sepsis in rodent models), and prevents the development of disseminated intravascular coagulation (24, 25, 30, 32, 33) (Figure 4). …”