Elsevier

The Journal of Pediatrics

Volume 164, Issue 3, March 2014, Pages 468-474.e1
The Journal of Pediatrics

Original Article
Biomarkers for Severity of Neonatal Hypoxic-Ischemic Encephalopathy and Outcomes in Newborns Receiving Hypothermia Therapy

https://doi.org/10.1016/j.jpeds.2013.10.067Get rights and content

Objective

To evaluate serum neuronal and inflammatory biomarkers to determine whether measurements of umbilical cords at birth can stratify severity of hypoxic-ischemic encephalopathy (HIE), whether serial measurements differ with hypothermia-rewarming, and whether biomarkers correlate with neurological outcomes.

Study design

This is a prospective cohort of inborn term newborns with varying degrees of HIE by neurological assessment. Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and inflammatory cytokines were measured in serum from umbilical artery at 6-24, 48, 72, and 78 hours of age. Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales) were performed at 15-18 months.

Results

Twenty neonates had moderate (n = 17) or severe (n = 3) HIE and received hypothermia; 7 had mild HIE and were not cooled. At birth, serum GFAP and ubiquitin carboxyl-terminal hydrolase L1 increased with the severity of HIE (P < .001), and serial GFAP remained elevated in neonates with moderate to severe HIE. Interleukin (IL)-6, IL-8, and vascular endothelial growth factor were greater at 6-24 hours in moderate to severe vs mild HIE (P < .05). The serial values were unaffected by hypothermia-rewarming. Elevated GFAP, IL-1, IL-6, IL-8, tumor necrosis factor, interferon, and vascular endothelial growth factor at 6-24 hours were associated with abnormal neurological outcomes.

Conclusions

The severity of the hypoxic-ischemic injury can be stratified at birth because elevated neuronal biomarkers in cord serum correlated with severity of HIE and outcomes.

Section snippets

Methods

This prospective cohort pilot study included all inborn infants ≥36 weeks of gestation and birth weight ≥1800 g who were admitted to the neonatal intensive care unit at Parkland Memorial Hospital, Dallas, TX, from June 2010 to June 2011 and had perinatal asphyxia with metabolic acidosis. Exclusion criteria included the presence of congenital anomalies or if comfort care was planned. The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center.

Results

Of 14 000 inborn neonates, 100 (0.7%) had perinatal acidosis and were admitted to the neonatal intensive case unit for neurologic assessment of encephalopathy. Twenty-two infants, 1.6 per 1000 live births, had moderate to severe encephalopathy and were treated with hypothermia. One patient with severe HIE was excluded because he died within hours of birth, and there was no parental consent for another newborn. The hypothermia study group was composed of 20 newborns (17 with moderate and 3 with

Discussion

This pilot cohort study examined an array of neuronal specific serum biomarkers and circulating inflammatory cytokines known to be involved in the excitatory-oxidative cascade of brain injury in infants with HIE. Key findings were: (1) a concentration-dependent relationship between serum GFAP at birth and the severity of encephalopathy; (2) the absence of a surge in any serum biomarkers after rewarming; and (3) evidence that a panel of inflammatory and neuronal biomarkers measured at 6-24 hours

References (47)

  • A.J. Gunn et al.

    Hypothermic neuroprotection

    NeuroRx

    (2006)
  • S. Shankaran et al.

    Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy

    N Engl J Med

    (2005)
  • M. Douglas-Escobar et al.

    Biomarkers of brain injury in the premature infant

    Front Neurol

    (2012)
  • J. van der Linden et al.

    Is cerebral blood flow/metabolic mismatch during rewarming a risk factor after profound hypothermic procedures in small children?

    Eur J Cardiothorac Surg

    (1989)
  • T. Nakamura et al.

    Do rapid systemic changes of brain temperature have an influence on the brain?

    Acta Neurochir (Wien)

    (2003)
  • C.M. Gebauer et al.

    Hemodynamics among neonates with hypoxic-ischemic encephalopathy during whole-body hypothermia and passive rewarming

    Pediatrics

    (2006)
  • S. Enomoto et al.

    Rapid rewarming causes an increase in the cerebral metabolic rate for oxygen that is temporarily unmatched by cerebral blood flow. A study during cardiopulmonary bypass in rabbits

    Anesthesiology

    (1996)
  • Y. Ueda et al.

    Uncomplicated rapid posthypothermic rewarming alters cerebrovascular responsiveness

    Stroke

    (2004)
  • A. Foster-Barber et al.

    Human perinatal asphyxia: correlation of neonatal cytokines with MRI and outcome

    Dev Neurosci

    (2001)
  • H. Hagberg et al.

    Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats

    Pediatr Res

    (1996)
  • X.H. Liu et al.

    Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage

    J Cereb Blood Flow Metab

    (1999)
  • H.B. Sarnat et al.

    Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study

    Arch Neurol

    (1976)
  • S. Shankaran et al.

    Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy

    Arch Dis Child Jul

    (2012)
  • Cited by (189)

    View all citing articles on Scopus

    L.C. is supported by the National Institutes of Health (K23HD069521) and the Gerber Foundation. The authors declare no conflicts of interest.

    View full text