Changes in Autonomic Tone in Premature Infants Developing Necrotizing Enterocolitis

Tareq Al-Shargabi; Daniel Reich; R. B. Govindan; Somya Shankar; Marina Metzler; Caitlin Cristante; Robert McCarter; Anthony D. Sandler; Mariam Said; Adre du Plessis

doi:10.1055/s-0038-1639339

American Journal of Perinatology, Table of Contents

Am J Perinatol 2018; 35(11): 1079-1086
DOI: 10.1055/s-0038-1639339

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Changes in Autonomic Tone in Premature Infants Developing Necrotizing Enterocolitis

Tareq Al-Shargabi

¹Division of Fetal and Transitional Medicine, Children's National Health System, Washington, District of Columbia

,

Daniel Reich

¹Division of Fetal and Transitional Medicine, Children's National Health System, Washington, District of Columbia

,

R. B. Govindan

¹Division of Fetal and Transitional Medicine, Children's National Health System, Washington, District of Columbia

,

Somya Shankar

¹Division of Fetal and Transitional Medicine, Children's National Health System, Washington, District of Columbia

,

Marina Metzler

¹Division of Fetal and Transitional Medicine, Children's National Health System, Washington, District of Columbia

,

Caitlin Cristante

¹Division of Fetal and Transitional Medicine, Children's National Health System, Washington, District of Columbia

,

Robert McCarter

²Division of Biostatistics and Informatics, Children's National Health System, Washington, District of Columbia

,

Anthony D. Sandler

³Division of General and Thoracic Surgery, Children's National Health System, Washington, District of Columbia

,

Mariam Said

⁴Division of Neonatology, Children's National Health System, Washington, District of Columbia

,

Adre du Plessis

¹Division of Fetal and Transitional Medicine, Children's National Health System, Washington, District of Columbia

› Author Affiliations

Abstract

Background Necrotizing enterocolitis (NEC) is a complication of prematurity with a high mortality rate. Currently, there are no reliable biomarkers capable of identifying infants at risk for developing NEC. We sought to determine the autonomic nervous system antecedents of NEC in premature infants, using heart rate variability (HRV).

Materials and Methods HRV was quantified by retrieving archived electrocardiogram (EKG) data from 30 premature infants from 4 days prior, through 4 days after, the clinical NEC diagnosis. HRV metrics were compared with those on the diagnosis day using the receiver operating characteristic (ROC) analysis.

Results HRV metrics showed a depression of autonomic tone that preceded the clinical NEC diagnosis by 2 days, and which recovered to baseline by 2 days after diagnosis (area under the curve [AUC] < 0.7). The pattern of HRV change was significantly associated with the clinical severity of NEC (stage II vs. stage III).

Conclusion Our studies suggest that readily accessible metrics of autonomic depression might expedite the diagnosis of NEC and its severity in a clinically meaningful manner. Clearly, these studies need to be extended prospectively to determine the diagnostic utility of this approach.

Keywords

preemie - heart rate variability - autonomic nervous system - necrotizing enterocolitis

Full Text

References

References
1 Bell MJ, Ternberg JL, Feigin RD. , et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187 (01) 1-7
2 Kliegman RM, Walsh MC. Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of illness. Curr Probl Pediatr 1987; 17 (04) 213-288
3 Walsh MC, Kliegman RM, Hack M. Severity of necrotizing enterocolitis: influence on outcome at 2 years of age. Pediatrics 1989; 84 (05) 808-814
4 Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enterocolitis among neonates in the United States. J Perinatol 2003; 23 (04) 278-285
5 Samuels N, van de Graaf RA, de Jonge RCJ, Reiss IKM, Vermeulen MJ. Risk factors for necrotizing enterocolitis in neonates: a systematic review of prognostic studies. BMC Pediatr 2017; 17 (01) 105
6 Eaton S. Necrotizing enterocolitis symposium: epidemiology and early diagnosis. J Pediatr Surg 2017; 52 (02) 223-225
7 Doheny KK, Palmer C, Browning KN. , et al. Diminished vagal tone is a predictive biomarker of necrotizing enterocolitis-risk in preterm infants. Neurogastroenterol Motil 2014; 26 (06) 832-840
8 Fairchild KD, Saucerman JJ, Raynor LL. , et al. Endotoxin depresses heart rate variability in mice: cytokine and steroid effects. Am J Physiol Regul Integr Comp Physiol 2009; 297 (04) R1019-R1027
9 Fairchild KD, O'Shea TM. Heart rate characteristics: physiomarkers for detection of late-onset neonatal sepsis. Clin Perinatol 2010; 37 (03) 581-598
10 Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 2003; 9 (5-8): 125-134
11 Blakely ML, Lally KP, McDonald S. , et al; NEC Subcommittee of the NICHD Neonatal Research Network. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005; 241 (06) 984-989 , discussion 989–994
12 Stone ML, Tatum PM, Weitkamp JH. , et al. Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis. J Perinatol 2013; 33 (11) 847-850
13 Kota S, Swisher CB, Al-Shargabi T, Andescavage N, du Plessis A, Govindan RB. Identification of QRS complex in non-stationary electrocardiogram of sick infants. Comput Biol Med 2017; 87: 211-216
14 Govindan RB, Al-Shargabi T, Metzler M. , et al. A spike correction approach for variability analysis of heart rate in sick infants. Physica A 2016; 444: 35-42
15 Welch PD. The use of fast Fourier transform for the estimation of power spectra: a method based on time averaging over short, modified periodograms. IEEE Trans Audio Electroacoust 1967; AU-15: 70-73
16 Govindan RB, Massaro AN, Niforatos N, du Plessis A. Mitigating the effect of non-stationarity in spectral analysis-an application to neonate heart rate analysis. Comput Biol Med 2013; 43 (12) 2001-2006
17 Govindan RB, Massaro AN, Al-Shargabi T. , et al. Detrended fluctuation analysis of non-stationary cardiac beat-to-beat interval of sick infants. Europhysics Letters 2014; 108: 40005
18 Lange S, Van Leeuwen P, Schneider U. , et al. Heart rate features in fetal behavioural states. Early Hum Dev 2009; 85 (02) 131-135
19 Liu HL, Garzoni L, Herry C. , et al. Can monitoring fetal intestinal inflammation using heart rate variability analysis signal incipient necrotizing enterocolitis of the neonate?. Pediatr Crit Care Med 2016; 17 (04) e165-e176
20 Borovikova LV, Ivanova S, Nardi D. , et al. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci 2000; 85 (1-3): 141-147
21 Borovikova LV, Ivanova S, Zhang M. , et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405 (6785): 458-462
22 Martelli D, McKinley MJ, McAllen RM. The cholinergic anti-inflammatory pathway: a critical review. Auton Neurosci 2014; 182: 65-69
23 Martin CR, Walker WA. Intestinal immune defences and the inflammatory response in necrotising enterocolitis. Semin Fetal Neonatal Med 2006; 11 (05) 369-377
24 Frost BL, Jilling T, Caplan MS. The importance of pro-inflammatory signaling in neonatal necrotizing enterocolitis. Semin Perinatol 2008; 32 (02) 100-106
25 Benkoe T, Baumann S, Weninger M. , et al. Comprehensive evaluation of 11 cytokines in premature infants with surgical necrotizing enterocolitis. PLoS One 2013; 8 (03) e58720
26 Franklin AL, Said M, Cappiello CD. , et al. Are immune modulating single nucleotide polymorphisms associated with necrotizing enterocolitis?. Sci Rep 2015; 5: 18369
27 Fairchild G, Passamonti L, Hurford G. , et al. Brain structure abnormalities in early-onset and adolescent-onset conduct disorder. Am J Psychiatry 2011; 168 (06) 624-633
28 Lear CA, Davidson JO, Galinsky R. , et al. Subclinical decelerations during developing hypotension in preterm fetal sheep after acute on chronic lipopolysaccharide exposure. Sci Rep 2015; 5 (16201): 16201