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

Abstract

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 ms(2) 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 ms(2) 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.

Keywords: biomarker; necrotizing enterocolitis; vagal tone.

Figure 1

Raw data (upper) and histogram summary (lower) of cardiac interbeat interval (IBI) in 4 representative healthy premature infants (upper traces) who remained healthy throughout the study duration. The lower traces show the raw data (upper) and summary histogram (lower) of IBI in 4 healthy premature infants who developed NEC (using Bell’s stage II+ criteria) 0.5-20 days later. Note that the healthy premature infants had a larger IBI variability and a broader distribution of events whereas premature healthy infants that went on to develop NEC had much less IBI variability and sharper event distribution even before NEC was clinically diagnosed. All the “healthy” infants which later developed NEC were identified by the lower IBI variability and HF-power. The representative subjects selected for comparison (“healthy” and “healthy prior to NEC”) were matched for gestational age and morbidity index at birth.

Figure 2

Graphical summary of the differences in A) time domain (IBI) and B) frequency domain (HF power) analyses of HRV in healthy premature infants who remained healthy throughout the study duration [Healthy, NEC (−), N=61] and “healthy premature infants” prior to the development of NEC [NEC (+), N=9]. Note that even before NEC was clinically diagnosed, susceptible premature infants showed a decrease in both IBI and HF power, *p<0.05, NEC(−) vs. NEC(+). Graphical summary showing measures of HF power taken at 8-14 days intervals (C). Note that HF power in healthy infants increased over time and was higher than in infants that developed NEC; conversely, the HF power in infants that later developed NEC did not increase significantly over time, *p>0.05.

Figure 3

The receiver operating characteristic (ROC) curve was generated for HF-HRV mean values obtained from the two cohorts of infants (28-35 weeks post menstrual age; N=70).The graph represents each cut-off point of sensitivity (true positive rate) on the vertical axis, against 1-specificity (false positive rate) on the horizontal axis. The highest plot on the left represents the point which maximizes the area under the curve (AUC). The optimum cutoff value of HF-HRV for use as a diagnostic criterion of NEC-risk in this cohort is 4.68ms². The AUC is 0.9 ± 0.04 with asymptotic 95% confidence intervals at 0.81 and 0.992 as lower and higher bound, respectively.