The neonatal sepsis is diminished by cervical vagus nerve stimulation and tracked non-invasively by ECG: a preliminary report in the piglet model with cervical vagus electroneurograms

<b>Background</b>: Vagus nerve stimulation (VNS) reduces inflammation induced by lipopolysaccharide (LPS) in an adult rat sepsis model. Multi-dimensional heart rate variability (HRV) index reliably tracks the inflammatory profile in the near-term sheep fetuses. The effects of VNS on neonates are not known. First, in the piglet model of sepsis, we aimed at evaluating the effect of VNS on the systemic inflammatory response induced by a high dose of LPS to mimic late-onset neonatal sepsis. Second, we aimed at validating our derived HRV inflammatory index in piglet to test its performance in this different species, older developmental stage and a stronger degree of sepsis. Third, we recorded, for the first time, neonatal piglet's vagus electroneurogram (VENG), as proof of concept to test whether the inflammatory response captured by cytokine and HRV measurements is also reflected directly in the VENG properties over time. This repository contains the VENG dataset.<b>Methods</b>: Three neonatal piglets of 7-14 days of age with 2.4-4 kg in body weight were used in this study. Following anesthesia, electrodes were attached to the left vagus nerve to allow stimulation (VNS). ECG, blood pressure (BP) and VENG were recorded for the duration of the experiment. We provide a readme document of the exact VENG recordings available. After baseline recording, the piglets were administered LPS as 2 mg/kg IV bolus. In the VNS treated piglet, the vagus nerve was stimulated for 10 minutes prior to and 10 min after the injection of LPS. In both groups, every 15 min post LPS, the arterial blood sample was drawn for blood gas, lactate, and glucose as well as the inflammatory cytokines measured by a quantitative ELISA multiplex panel. At the end of the experiment, the piglets were euthanized. BP and ECG-derived HRV were calculated.<b>Results</b>: The piglets developed a potent inflammatory response to the LPS injection with TNF-alpha, IL-1beta, IL-6 and IL-8 peaking between 45 and 90 min post-injection. VNS diminished the LPS-induced systemic inflammatory response varying across the measured cytokines from two to ten-fold. In the accompanying manuscript we present the low-cost, easy-to-implement design of the VNS/VENG probe and a signal-analytical framework to analyze VENG in response to LPS. The HRV index tracked accurately the cytokines’ temporal profile. <b>Discussion</b>: We present a novel method to model, manipulate and track neonatal sepsis. Our findings suggest that 1) the HRV index of inflammatory response applies across species pre- and postnatally, 2) the HRV index performs well at different degrees of sepsis (i.e., nanogram and milligram doses of LPS), and 3) the present VNS paradigm suppresses LPS-induced inflammation, even at high doses of LPS, and notably is also reflected by changes in the HRV composite measure and VENG patterns. The presented method lays the foundation for larger studies investigating the mechanisms and the therapeutic potential of early postnatal VNS intervention to counteract sepsis progression and of HRV monitoring to early detect and track neonatal inflammatory response.