Improved Outcomes of Cardiopulmonary Resuscitation in Rats Treated With Vagus Nerve Stimulation and Its Potential Mechanism

Abstract

Studies have demonstrated that vagus nerve stimulation (VNS) reduces ischemia/reperfusion injury. In this study, we investigated the protective effects of VNS in a rat model of cardiopulmonary resuscitation (CPR). We further investigated whether the beneficial effects of VNS were dependent on the alpha 7 nicotinic acetylcholine receptor (α7nAChR). Forty animals were randomized into four groups and all underwent CPR (n = 10 each): CPR alone (control); VNS during CPR; α7nAChR antagonist methyllycaconitine citrate (MLA) with VNS; α7nAChR agonist 3-(2, 4-dimethoxybenzylidene) anabaseine (GTS-21 dihydrochloride) without VNS. The right vagus nerve was exteriorized in all animals. Ventricular fibrillation was induced and untreated for 8 min. Defibrillation was attempted after 8 min of CPR. VNS was initiated at the beginning of precordial chest compressions and continued for 4 h after return of spontaneous circulation (ROSC) in both the VNS and MLA groups. Hemodynamic measurements and myocardial function, including ejection fraction and myocardial performance index, were assessed at baseline, 1 and 4 h after ROSC. The neurological deficit score was measured at 24-h intervals for a total of 72 h. The heart rate was reduced in the VNS and MLA groups, while no difference was found in mean arterial pressure between the four groups. Better post-resuscitation myocardial and cerebral function and longer duration of survival were observed in the VNS-treated animals. The protective effects of VNS could be abolished by MLA and imitated by GTS-21. In addition, VNS decreased the number of electrical shocks and the duration of CPR required. VNS improves multiple outcomes after CPR.

A Rodent Model for Long-Term Vagus Nerve Stimulation Experiments

“…Applications of VNS-based targeted neuroplasticity training have been studied in rodent models of tinnitus [11], stroke [12] and post-traumatic stress disorder [13] with the potential for clinical translation [14]. Since VNS can have an impact on multiple organ systems, long-term assessment of VNS using animal models provides a deeper understanding of the mechanisms of action and associated off-target effects that will ultimately improve therapeutic outcomes [15][16][17][18][19][20][21].…”

“…Also, anticonvulsive effects of VNS were first characterized using electroencephalography (EEG) experiments from rodent models of epilepsy, that later resulted in implantable devices to control seizures [15,18]. While rodent models have been informative, majority of VNS experiments have been limited to acute timelines [19][20][21][22][23][24][25][26][27]. Factors such as small animal size, early device failure, device migration and difficult access to electrode connectors can impact the experiment duration in rodents [20][21][22][23][24][25][26][27][28][29][30][31][32].…”

Vagus Nerve Stimulation and the Cardiovascular System

“…Preclinical studies have been undertaken to assess whether VNS could be used to facilitate resuscitation attempts in rats with induced cardiac arrest (Sun et al 2018). It was found that when VNS was used in conjunction with CPR in rodents, success rates for return of spontaneous circulation (ROSC) were 90.91% when compared to CPR alone at 83.33% (Sun et al 2018). Results also indicated that VNS reduced the duration of CPR by preventing arrhythmias independent of the heart slowing mechanism expected in VNS (Sun et al 2018).…”

“…It was found that when VNS was used in conjunction with CPR in rodents, success rates for return of spontaneous circulation (ROSC) were 90.91% when compared to CPR alone at 83.33% (Sun et al 2018). Results also indicated that VNS reduced the duration of CPR by preventing arrhythmias independent of the heart slowing mechanism expected in VNS (Sun et al 2018). In addition to its effect on CPR, VNS also reduced the number of electrical shocks required to achieve ROSC (Sun et al 2018).…”

Ultrasound improves the outcomes of cardiopulmonary resuscitation in rats by stimulating the cholinergic anti‑inflammatory pathway

“…Vagus nerve stimulation (VNS) may exert a protective effect against acute cerebral, cardiac and kidney ischemia reperfusion injury (IRI) by suppressing inflammation and apoptosis via the alpha 7 nicotinic acetylcholine receptor (α7nAChR) (3–5). It has recently been demonstrated that VNS may improve survival in rat models of cardiopulmonary resuscitation (CPR) (6), indicating that VNS may be an alternative therapeutic strategy for CPR with a neural interface approach.…”