Diminished vagal tone is a predictive biomarker of necrotizing enterocolitis-risk in preterm infants

Background: Necrotizing enterocolitis (NEC) is an acute neonatal inflammatory disease which may lead to intestinal necrosis, multisystem failure, and death. Currently, NEC is diagnosed by a combination of laboratory and radiographic tests conducted a posteriori i.e., when NEC is already clinically significant. Given the acute onset and rapid progression of NEC, a non-invasive biomarker that allows early detection of patients at risk is required as a matter of urgency. We evaluated whether the high frequency (HF) component of heart rate variability (HRV), a measure of vagal efferent tonic cholinergic activity may be used as a predictive biomarker for NEC-risk before the onset of clinical disease. Methods: In this prospective study, stable preterm (gestational age 28-35 weeks) infants had HRV power spectra analyzed from surface electrocardiogram waveforms taken at rest on day 5-8 of life. We used regression modeling to determine the utility of HF-HRV in predicting NEC. Key Results: HF-HRV power was 21.5 ± 2.7 and 3.9 ± 0.81 ms² in infants that remained healthy and those that later developed stage 2+ NEC, respectively (p < 0.001). Nine of 70 enrolled infants developed NEC. The ROC discriminated a HF-HRV value of 4.68 ms² predictive for developing NEC with a sensitivity and specificity of 89% and 87%, and positive and negative predictive value of 50% and 98%, respectively. With predictive regression modeling, the risk (odds ratio) of developing NEC was 10 per every one SD decrease in HF-HRV. Conclusions & Inferences: Our preliminary data indicate that HF-HRV may serve as a potential, non-invasive predictive biomarker of NEC-risk in NICU infants. Prognostic identification of infants at risk for necrotizing enterocolitis (NEC) is required as a matter of urgency. We tested the hypothesis that the high frequency (HF) component of heart rate variability (HRV) representative of vagal tone and the cholinergic anti-inflammatory reflex may be used in infants as a predictive biomarker for NEC-risk before the onset of clinical NEC. Spectral analysis of surface electrocardiogram was done in 'healthy' preterm infants at rest on day 5-8 of life and associated with later diagnosis of NEC. The risk (odds ratio) of developing NEC 0.5-20 days in advance of clinical symptoms was 10 per every one SD decrease in HF-HRV (vagal tone). Our preliminary data indicate that HF-HRV may serve as a potential, non-invasive predictive biomarker of NEC-risk in NICU infants.