To determine whether systemic inflammation-modulating cytokine expression is related to heart rate variability (HRV) in newborns with hypoxic-ischemic encephalopathy (HIE).
The data from 30 newborns with HIE were analyzed. Cytokine levels (IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-1β, TNF-α, IFN-λ) were measured either at 24 h of cooling (n=5), 72 h of cooling (n=4) or at both timepoints (n=21). The following HRV metrics were quantified in the time domain: alpha_S, alpha_L, root mean square (RMS) at short time scales (RMS_S), RMS at long time scales (RMS_L), while low-frequency power (LF) and high-frequency power (HF) were quantified in the frequency domain. The relationships between HRV metrics and cytokines were evaluated using mixed-models.
IL-6, IL-8, IL-10, and IL-13 levels were inversely related to selected HRV metrics.
Inflammation-modulating cytokines may be important mediators in the autonomic dysfunction observed in newborns with HIE.
Subscribe to Journal
Get full journal access for 1 year
only $20.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Shankaran S, Woldt E, Koepke T, Bedard MP, Nandyal R . Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 1991; 25 (2): 135–148.
Dilenge ME, Majnemer A, Shevell MI . Long-term developmental outcome of asphyxiated term neonates. J Child Neurol 2001; 16 (11): 781–792.
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. The N Engl J Med 2005; 353 (15): 1574–1584.
Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361 (14): 1349–1358.
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365 (9460): 663–670.
Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011; 165 (8): 692–700.
Massaro AN, Govindan RB, Al-Shargabi T, Andescavage NN, Metzler M, Chang T et al. Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia. J Perinatol 2014; 34 (11): 836–841.
Fairchild KD, Srinivasan V, Moorman JR, Gaykema RP, Goehler LE . Pathogen-induced heart rate changes associated with cholinergic nervous system activation. Am J/ Physiol Regul Integr Comp Physiol 2011; 300 (2): R330–R339.
Fairchild KD, Saucerman JJ, Raynor LL, Sivak JA, Xiao Y, Lake DE et al. Endotoxin depresses heart rate variability in mice: cytokine and steroid effects. Am J Physiol Regul Integr Comp Physiol 2009; 297 (4): R1019–R1027.
Malave HA, Taylor AA, Nattama J, Deswal A, Mann DL . Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure. Chest 2003; 123 (3): 716–724.
Griffin MP, Lake DE, Bissonette EA, Harrell FE Jr., O'Shea TM, Moorman JR . Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 2005; 116 (5): 1070–1074.
Tateishi Y, Oda S, Nakamura M, Watanabe K, Kuwaki T, Moriguchi T et al. Depressed heart rate variability is associated with high IL-6 blood level and decline in the blood pressure in septic patients. Shock 2007; 28 (5): 549–553.
Raynor LL, Saucerman JJ, Akinola MO, Lake DE, Moorman JR, Fairchild KD . Cytokine screening identifies NICU patients with Gram-negative bacteremia. Pediatr Res 2012; 71 (3): 261–266.
Orrock JE, Panchapakesan K, Vezina G, Chang T, Harris K, Wang Y et al. Association of brain injury and neonatal cytokine response during therapeutic hypothermia in newborns with hypoxic-ischemic encephalopathy. Pediatr Res 2016; 79 (5): 742–747.
Ulusar UD, Govindan RB, Wilson JD, Lowery CL, Preissl H, Eswaran H . Adaptive rule based fetal QRS complex detection using hilbert transform. Conf Proc IEEE Eng Med Biol Soc 2009; 1: 4666–4669.
Govindan RB, Al-Shargabi T, Metzler M, Andescavage NN, Joshi R, Du Plessis A . A spike correction approach for variability analysis of heart rate in sick infants. Physica A 2016; 444: 35–42.
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.
Massaro AN, Govindan RB, Al-Shargabi T, Andescavage NN, Metzler M, Chang T et al. Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia. J Perinatol 2013; 34 (11): 836–841.
Cerutti S, Baselli G, Civardi S, Ferrazzi E, Marconi AM, Pagani M et al. Variability analysis of fetal heart rate signals as obtained from abdominal electrocardiographic recordings. J Perinat Med 1986; 14 (6): 445–452.
Govindan RB, Massaro AN, Al-Shargabi T, Andescavage NN, Chang T, Glass P et al. Detrended fluctuation analysis of non-stationary cardiac beat-to-beat interval of sick infants. EPL (Europhys/ Lett) 2014; 108: 40005–p40001-p40006.
Yanagawa Y, Kawakami M, Okada Y . Moderate hypothermia alters interleukin-6 and interleukin-1alpha reactions in ischemic brain in mice. Resuscitation 2002; 53 (1): 93–99.
Diestel A, Roessler J, Berger F, Schmitt KR . Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells. Cryobiology 2008; 57 (3): 216–222.
Tekgul H, Yalaz M, Kutukculer N, Ozbek S, Kose T, Akisu M et al. Value of biochemical markers for outcome in term infants with asphyxia. Pediatr Neurol 2004; 31 (5): 326–332.
Bartha AI, Foster-Barber A, Miller SP, Vigneron DB, Glidden DV, Barkovich AJ et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res 2004; 56 (6): 960–966.
Chalak LF, Sanchez PJ, Adams-Huet B, Laptook AR, Heyne RJ, Rosenfeld CR . Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J Pediatr 2014; 164 (3): 468–474 e461.
Ramaswamy V, Horton J, Vandermeer B, Buscemi N, Miller S, Yager J . Systematic review of biomarkers of brain injury in term neonatal encephalopathy. Pediatr Neurol 2009; 40 (3): 215–226.
Jenkins DD, Rollins LG, Perkel JK, Wagner CL, Katikaneni LP, Bass WT et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood flow Metab 2012; 32 (10): 1888–1896.
Arvin B, Neville LF, Barone FC, Feuerstein GZ . The role of inflammation and cytokines in brain injury. Neurosci Biobehav Rev 1996; 20 (3): 445–452.
Wang X, Feuerstein GZ . Role of immune and inflammatory mediators in CNS injury. Drug News Perspect 2000; 13 (3): 133–140.
Massaro AN, Govindan RB, Al-Shargabi T, Andescavage NN, Metzler M, Chang T et al. Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia. J Perinatol 2014; 34: 836–4.
Johnston MV, Fatemi A, Wilson MA, Northington F . Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011; 10 (4): 372–382.
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405 (6785): 458–462.
Bernik TR, Friedman SG, Ochani M, DiRaimo R, Susarla S, Czura CJ et al. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J Vasc Surg 2002; 36 (6): 1231–1236.
Peterson CY, Krzyzaniak M, Coimbra R, Chang DC . Vagus nerve and postinjury inflammatory response. Arch Surg 2012; 147 (1): 76–80.
Bellinger DL, Millar BA, Perez S, Carter J, Wood C, ThyagaRajan S et al. Sympathetic modulation of immunity: relevance to disease. Cell Immunol 2008; 252 (1-2): 27–56.
Akiho H, Khan WI, Al-Kaabi A, Blennerhassett P, Deng Y, Collins SM . Cytokine modulation of muscarinic receptors in the murine intestine. Am J Physiol Gastrointesti Liver Physiol 2007; 293 (1): 12.
Barnes PJ, Haddad EB, Rousell J . Regulation of muscarinic M2 receptors. Life Sci 1997; 60 (13-14): 1015–1021.
Moreno L, Jacoby DB, Fryer AD . Dexamethasone prevents virus-induced hyperresponsiveness via multiple mechanisms. American journal of physiology Lung cellular and molecular physiology 2003; 285 (2): 25.
Cooper TM, McKinley PS, Seeman TE, Choo TH, Lee S, Sloan RP . Heart rate variability predicts levels of inflammatory markers: Evidence for the vagal anti-inflammatory pathway. Brain, Behav Immunity 2015; 49: 94–100.
We would like to thank Ms. Sophie Wohlers for her editorial assistance. We also thank Karuna Panchapakesan and Susan Knobloch for their assistance with cytokine determinations. This work was supported by the Clinical and Translational Science Institute at Children’s National (UL1TR000075 and 1KL2RR031987-01), the Intellectual and Developmental Disabilities Research Consortium (NIH P30HD040677), and the NCMRR-DC Molecular and Functional Outcome Measures in Rehabilitation Medicine Core (NICHD/NINDS 5R24HD050846-08).
The authors declare no conflict of interest.
About this article
Cite this article
Al-Shargabi, T., Govindan, R., Dave, R. et al. Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy. J Perinatol 37, 668–672 (2017). https://doi.org/10.1038/jp.2017.15
Enquiring beneath the surface: can a gene expression assay shed light into the heterogeneity among newborns with neonatal encephalopathy?
Pediatric Research (2020)
Experimental Biology and Medicine (2019)
Neurogastroenterology & Motility (2019)
Physiological Reports (2019)