Determinants of Outcomes After Head Cooling for Neonatal Encephalopathy

OBJECTIVE. The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy. METHODS. A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 ± 0.5°C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial). RESULTS. Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as ≥25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (≥38°C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy. CONCLUSIONS. Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.

[1]  D. Murphy,et al.  Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies , 1995, The Lancet.

[2]  J. Bucerius,et al.  Postischemic hyperthermia exacerbates neurologic injury after deep hypothermic circulatory arrest. , 1998, The Journal of thoracic and cardiovascular surgery.

[3]  Andrew Whitelaw,et al.  Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial , 2005, The Lancet.

[4]  N. Finer,et al.  Long-term follow-up of term neonates with perinatal asphyxia. , 1993, Clinics in perinatology.

[5]  T R Gunn,et al.  Selective Head Cooling in Newborn Infants After Perinatal Asphyxia: A Safety Study , 1998, Pediatrics.

[6]  A. Martín-Ancel,et al.  Interleukin-6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations. , 1997, Pediatrics.

[7]  A. Gunn,et al.  Selective head cooling with mild systemic hypothermia to improve neurodevelopmental outcome following neonatal encephalopathy: The CoolCap Study , 2004 .

[8]  H. Hagberg,et al.  Hypoxic Preconditioning Confers Long-Term Reduction of Brain Injury and Improvement of Neurological Ability in Immature Rats , 2005, Pediatric Research.

[9]  A. Gunn,et al.  Is temperature important in delivery room resuscitation? , 2001, Seminars in neonatology : SN.

[10]  R. Ordidge,et al.  Depth of delayed cooling alters neuroprotection pattern after hypoxia‐ischemia , 2005, Annals of Neurology.

[11]  J. Perlman,et al.  Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers? , 1996, Pediatrics.

[12]  A. Herbst,et al.  Low 5‐Minute Apgar Score: A Population‐Based Register Study of 1 Million Term Births , 2001, Obstetrics and gynecology.

[13]  D. Ferriero,et al.  Human Perinatal Asphyxia: Correlation of Neonatal Cytokines with MRI and Outcome , 2001, Developmental Neuroscience.

[14]  Carol L Wagner,et al.  Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. , 2005, Pediatric neurology.

[15]  J. Kurinczuk,et al.  Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study , 1998 .

[16]  J Kattwinkel,et al.  International Guidelines for Neonatal Resuscitation: An excerpt from the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Contributors and Reviewers for the Neonatal Resuscitation Guidelines. , 2000, Pediatrics.

[17]  K. Jordan.  Status epilepticus. A perspective from the neuroscience intensive care unit. , 1994, Neurosurgery clinics of North America.

[18]  A. Shah,et al.  Nitric Oxide Mediates Cerebral Ischemic Tolerance in a Neonatal Rat Model of Hypoxic Preconditioning , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[19]  N. Finer,et al.  School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. , 1989, The Journal of pediatrics.

[20]  A. Gunn,et al.  Treatment of Term Infants With Head Cooling and Mild Systemic Hypothermia (35.0°C and 34.5°C) After Perinatal Asphyxia , 2003 .

[21]  S. Dutta,et al.  Selective head cooling after neonatal encephalopathy , 2005, The Lancet.

[22]  Helen Porter,et al.  Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective , 2003, Annals of neurology.

[23]  S. Donn,et al.  Should amplitude-integrated electroencephalography be used to identify infants suitable for hypothermic neuroprotection? , 2008, Journal of Perinatology.

[24]  Jon E. Tyson,et al.  Predicting Outcomes of Neonates Diagnosed With Hypoxemic-Ischemic Encephalopathy , 2006, Pediatrics.

[25]  R. Vannucci,et al.  Delayed Cerebral Atrophy following Moderate Hypoxia-Ischemia in the Immature Rat , 2001, Developmental Neuroscience.

[26]  Shripada Rao,et al.  A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy – are we there yet? , 2007, BMC pediatrics.

[27]  Zhiyi Zuo,et al.  Prenatal hypoxia-induced adaptation and neuroprotection that is inducible nitric oxide synthase-dependent , 2005, Neurobiology of Disease.

[28]  P. Davis,et al.  Cooling for newborns with hypoxic ischaemic encephalopathy. , 2013, The Cochrane database of systematic reviews.

[29]  A. David Edwards,et al.  Assessment of Neonatal Encephalopathy by Amplitude-integrated Electroencephalography , 1999, Pediatrics.

[30]  A. Gunn.  Cerebral hypothermia for prevention of brain injury following perinatal asphyxia , 2000, Current opinion in pediatrics.

[31]  N. Bayley.  Bayley Scales of Infant Development , 1999 .

[32]  S. Bello.  Selective head cooling after neonatal encephalopathy , 2005, The Lancet.

[33]  O. Iwata,et al.  Bench to bedside strategies for optimizing neuroprotection following perinatal hypoxia-ischaemia in high and low resource settings. , 2007, Early human development.

[34]  Steven P. Miller,et al.  Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy. , 2004, American journal of obstetrics and gynecology.

[35]  S. Renowden,et al.  Mild Hypothermia and the Distribution of Cerebral Lesions in Neonates With Hypoxic-Ischemic Encephalopathy , 2005, Pediatrics.

[36]  P. Steen,et al.  Posthypoxic Hypothermia in Newborn Piglets , 1997, Pediatric Research.

[37]  O. Iwata,et al.  Superficial brain is cooler in small piglets: Neonatal hypothermia implications , 2006, Annals of neurology.

[38]  T. O'Shea,et al.  Prenatal events and the risk of cerebral palsy in very low birth weight infants. , 1998, American journal of epidemiology.

[39]  T. Ikeda,et al.  Effects of hypothermia and hyperthermia on attentional and spatial learning deficits following neonatal hypoxia-ischemic insult in rats , 2004, Behavioural Brain Research.

[40]  M. Sherman,et al.  Interventions for perinatal hypoxic-ischemic encephalopathy. , 1998, Pediatrics.

[41]  R. Guillet,et al.  Electrographic seizures in neonates correlate with poor neurodevelopmental outcome , 2000, Neurology.

[42]  A. Gunn,et al.  Effect of radiant heat on head temperature gradient in term infants. , 1996, Archives of disease in childhood. Fetal and neonatal edition.

[43]  R. Palisano,et al.  Development and reliability of a system to classify gross motor function in children with cerebral palsy , 1997, Developmental medicine and child neurology.

[44]  H. Sarnat,et al.  Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. , 1976, Archives of neurology.

[45]  William Oh,et al.  Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. , 2005, The New England journal of medicine.

[46]  T R Gunn,et al.  Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. , 2001, Pediatrics.

[47]  R. Busto,et al.  Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischemia , 1997, Neurology.

[48]  P. Shah,et al.  Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. , 2007, Archives of pediatrics & adolescent medicine.

[49]  W. Poole,et al.  Elevated Temperature After Hypoxic-Ischemic Encephalopathy: Risk Factor for Adverse Outcomes , 2008, Pediatrics.

[50]  P. Gluckman,et al.  Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rat: evidence for apoptosis during selective neuronal loss. , 1995, Brain research. Molecular brain research.

[51]  C. Robertson.  Fetal and Neonatal Brain Injury: Long-term follow-up of term infants with perinatal asphyxia , 2003 .

[52]  A. Aguzzi,et al.  Resuscitative Hypothermia Protects the Neonatal Rat Brain from Hypoxic‐Ischemic Injury , 2000, Brain pathology.

[53]  A D Edwards,et al.  Therapeutic hypothermia following perinatal asphyxia , 2006, Archives of Disease in Childhood - Fetal and Neonatal Edition.

[54]  M. Diringer,et al.  Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system , 2004, Critical care medicine.

[55]  P. Van Reempts,et al.  International guidelines for neonatal resuscitation: an excerpt from the guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: international consensus on science , 2000 .