Vagal Tone and Proinflammatory Cytokines Predict Feeding Intolerance and Necrotizing Enterocolitis Risk

Abstract

Background: Necrotizing enterocolitis (NEC) is the leading cause of death due to gastrointestinal disease in preterm neonates; yet, clinicians lack reliable and noninvasive predictive tools.

Purpose: We aimed to test that diminished high-frequency heart rate variability (HF-HRV) and elevated levels of proinflammatory cytokines would have utility in NEC prediction.

Methods: In this multisite prospective study, we enrolled 250 preterm (26-34 weeks' postmenstrual age [PMA]) neonates with physiological stability at 72 hours of life. HRV was measured noninvasively using electrocardiograhic data from standardized cardiorespiratory monitors at postnatal week 1 of life and weekly thereafter until 35 weeks' PMA or discharge; blood was collected for cytokines at postnatal weeks 1 and 3. NEC was diagnosed via Modified Bell's Staging Criteria.

Results: HF-HRV was decreased at weeks 1 and 2 in neonates (47% females) who developed feeding intolerance or stage 2+ NEC. In addition, these neonates displayed elevated levels of IL-8 at week 1 and increased levels of IL-1β, IL-6, TNF-α, and IL-8 at week 3 of life. Low HF-HRV was associated with elevated IL-6 or IL-8 levels at weeks 1 and 3 of life. Logistic regression indicated that only HF-HRV was a significant predictor of feeding intolerance or NEC development.

Implications for practice and research: HRV is a promising noninvasive modality for NEC risk detection. The association of low HF-HRV with elevated proinflammatory cytokines provides evidence for a putative role of the vagal cholinergic pathway in NEC pathogenesis. Future studies should focus on application of these techniques to test clinical therapeutics.Video Abstract available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?autoPlay=false&videoId=54.

Figure 1:. HF-HRV at Weeks 1, 2, and 3 of Life.

Neonates who later develop NEC show significantly decreased HF-HRV (Vagal Tone) at week one of life (*p<0.05 vs. controls), but not at weeks two or three (p>0.05 vs. controls).

Figure 2:. Mean Cytokine Levels at Weeks 1 and 3 of Life.

All neonates showed similar levels of the cytokines TNF-α, IL-6, IFN-γ, IL-1β, and IL-10 at postnatal day 5–8 of life (p>0.05 vs. controls). The levels of IL-8, however, were significantly higher at day 5–8 in neonates who would later develop any stage of NEC; in these neonates the levels of TNF-α, IL-6, IL-8, and IL-1β, but not IFN-γ and IL-10, were significantly increased at week 3 of life (*p<0.05 vs. controls).