Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis

Abstract

Objectives: To investigate the potential benefits of vagus nerve stimulation in a clinically-relevant large animal model of progressive sepsis. Design: Prospective, controlled, randomized trial. Setting: University animal research laboratory. Subjects: Twenty-five domestic pigs were divided into three groups: 1) sepsis group (eight pigs), 2) sepsis + vagus nerve stimulation group (nine pigs), and 3) control sham group (eight pigs). Interventions: Sepsis was induced by cultivated autologous feces inoculation in anesthetized, mechanically ventilated, and surgically instrumented pigs and followed for 24 hours. Electrical stimulation of the cervical vagus nerve was initiated 6 hours after the induction of peritonitis and maintained throughout the experiment. Measurements and Main Results: Measurements of hemodynamics, electrocardiography, biochemistry, blood gases, cytokines, and blood cells were collected at baseline (just before peritonitis induction) and at the end of the in vivo experiment (24 hr after peritonitis induction). Subsequent in vitro analyses addressed cardiac contractility and calcium handling in isolated tissues and myocytes and analyzed mitochondrial function by ultrasensitive oxygraphy. Vagus nerve stimulation partially or completely prevented the development of hyperlactatemia, hyperdynamic circulation, cellular myocardial depression, shift in sympathovagal balance toward sympathetic dominance, and cardiac mitochondrial dysfunction, and reduced the number of activated monocytes. Sequential Organ Failure Assessment scores and vasopressor requirements significantly decreased after vagus nerve stimulation. Conclusions: In a clinically-relevant large animal model of progressive sepsis, vagus nerve stimulation was associated with a number of beneficial effects that resulted in significantly attenuated multiple organ dysfunction and reduced vasopressor and fluid resuscitation requirements. This suggests that vagus nerve stimulation might provide a significant therapeutic potential that warrants further thorough investigation.

The Pathogenesis of Sepsis and Potential Therapeutic Targets

“…Upon interaction with ACh, α7 nAChR causes a decrease in the level of pro-inflammatory factors, reduces the expression of chemokines and adhesion molecules, alters the differentiation and activation of immune cells, and regulates homeostasis [72]; thus, it acts as an “effector” to exert anti-inflammatory effects in CAP. After the vagus nerve is severed, the susceptibility to endotoxic shock is increased [74,75]. Therefore, systemic inflammatory response can be alleviated by stimulating the efferent vagus nerve or activating α7 nAChR.…”

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs

“…In addition, large animal models can reveal biological effects previously not studied in rodent models. For example, it has been demonstrated by our group and others, that SpN or VN neuromodulation promotes cardiovascular protection in endotoxemia models in pigs via a mechanism independent of cytokine modulation (4,22), suggestive of regulation of additional pathways beyond cytokine production.…”

The Vagal Autonomic Pathway of COVID-19 at the Crossroad of Alzheimer’s Disease and Aging: A Review of Knowledge

“…Of interest, when considering the COVID-19 pandemic, VNS could impact not only on systemic inflammation but also on the coagulant-anticoagulant balance, as suggested by VNS application in endotoxemia rats [104]. In a clinically relevant porcine model of progressive sepsis, VNS significantly attenuated multiple organ dysfunctions (with partial or complete prevention of hyperlactatemia, hyperdynamic circulation, cellular myocardial depression, shift in sympathova-gal balance toward sympathetic dominance, cardiac myocardial dysfunction and reduction of activated monocytes), thus reducing vasopressor and fluid resuscitation requirements [105].…”

“…HRV, a biomarker for efferent vagal activation [108], is easier to assess with taVNS than with cervical tVNS [107]. taVNS is mostly used in pharmaco-resistant epilepsy, depression, hypertension, and other diseases [93,[105][106][107]. A recent study has validated the use of taVNS to inhibit both peripheral and central inflammation and suggested a link between taVNS suppression of inflammation and effectiveness in reducing depression severity [109].…”