Abstract
Background:
Cytokines have been proposed as mediators of neonatal brain injury via neuroinflammatory pathways triggered by hypoxia-ischemia. Limited data are available on cytokine profiles in larger cohorts of newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH).
Methods:
Serum cytokines interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, tumor necrosis factor-α, and interferon-γ were measured in newborns with HIE at 24 and 72 h of TH. Differences between infants with favorable (survivors with mild/no magnetic resonance imaging (MRI) injury) vs. adverse outcome (death or moderate/severe MRI injury) were compared using mixed models to adjust for covariates.
Results:
Data from 36 term newborns with HIE (favorable outcome: n = 20, adverse outcome: n = 16) were evaluated. Cytokines IL-1β, IL-2, IL-6, IL-8, IL-10, and IL-13 were elevated in the adverse relative to favorable outcome group at 24 h. IL-6 remained significantly elevated in the adverse outcome group at 72 h. IL-6 and IL-10 remained significantly associated with outcome group after controlling for covariates.
Conclusion:
Inflammatory cytokines are elevated in HIE newborns with brain injury by MRI. In particular, IL-6 and IL-10 were associated with adverse outcomes after controlling for baseline characteristics and severity of presentation. These data suggest that cytokine response may identify infants in need of additional neuroprotective interventions.
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References
Liu L, Johnson HL, Cousens S, et al.; Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2012;379:2151–61.
Dilenge ME, Majnemer A, Shevell MI. Long-term developmental outcome of asphyxiated term neonates. J Child Neurol 2001;16:781–92.
Perlman JM, Wyllie J, Kattwinkel J, et al.; Neonatal Resuscitation Chapter Collaborators. Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Pediatrics 2010;126:e1319–44.
Shankaran S, Laptook AR, Ehrenkranz RA, et al.; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574–84.
Arvin B, Neville LF, Barone FC, Feuerstein GZ. The role of inflammation and cytokines in brain injury. Neurosci Biobehav Rev 1996;20:445–52.
Wang X, Feuerstein GZ. Role of immune and inflammatory mediators in CNS injury. Drug News Perspect 2000;13:133–40.
Dammann O, O’Shea TM. Cytokines and perinatal brain damage. Clin Perinatol 2008;35:643–63, v.
Jenkins DD, Rollins LG, Perkel JK, et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab 2012;32:1888–96.
Chalak LF, Sánchez 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;164:468–74.e1.
Yanagawa Y, Kawakami M, Okada Y. Moderate hypothermia alters interleukin-6 and interleukin-1alpha reactions in ischemic brain in mice. Resuscitation 2002;53:93–9.
Diestel A, Roessler J, Berger F, Schmitt KR. Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells. Cryobiology 2008;57:216–22.
Johnston MV, Fatemi A, Wilson MA, Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011;10:372–82.
Shalak LF, Laptook AR, Jafri HS, Ramilo O, Perlman JM. Clinical chorioamnionitis, elevated cytokines, and brain injury in term infants. Pediatrics 2002;110:673–80.
Bartha AI, Foster-Barber A, Miller SP, et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res 2004;56:960–6.
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;40:215–26.
Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001;7:56–64.
Silveira RC, Procianoy RS. Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic-ischemic encephalopathy. J Pediatr 2003;143:625–9.
Chiesa C, Pellegrini G, Panero A, et al. Umbilical cord interleukin-6 levels are elevated in term neonates with perinatal asphyxia. Eur J Clin Invest 2003;33:352–8.
Tekgul H, Yalaz M, Kutukculer N, et al. Value of biochemical markers for outcome in term infants with asphyxia. Pediatr Neurol 2004;31:326–32.
Wintermark P, Boyd T, Gregas MC, Labrecque M, Hansen A. Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia. Am J Obstet Gynecol 2010;203:579.e1–9.
Strunk T, Härtel C, Temming P, Matzke N, Zimmer J, Schultz C. Erythropoietin inhibits cytokine production of neonatal and adult leukocytes. Acta Paediatr 2008;97:16–20.
Barkovich AJ, Hajnal BL, Vigneron D, et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol 1998;19:143–9.
Rutherford M, Ramenghi LA, Edwards AD, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol 2010;9:39–45.
Shankaran S, Barnes PD, Hintz SR, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2012;97:F398–404.
Cheong JL, Coleman L, Hunt RW, et al.; Infant Cooling Evaluation Collaboration. Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med 2012;166:634–40.
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976;33:696–705.
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Orrock, J., Panchapakesan, K., Vezina, G. et al. Association of brain injury and neonatal cytokine response during therapeutic hypothermia in newborns with hypoxic-ischemic encephalopathy. Pediatr Res 79, 742–747 (2016). https://doi.org/10.1038/pr.2015.280
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DOI: https://doi.org/10.1038/pr.2015.280
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