• death
• moderate/severe disability at 18-22 mos of age

• Length of hospital stay [ Time Frame: Until discharge ] [ Designated as safety issue: No ]
• Frequency of multi-organ dysfunction [ Time Frame: Until discharge ] [ Designated as safety issue: Yes ]
• Withdrawal of support [ Time Frame: Until discharge ] [ Designated as safety issue: Yes ]
• Post-neonatal deaths [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
• Multiple disability [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
• Seizure disorders [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
• Rehospitalizations [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]

• length of hospital stay
• frequency of multi-organ dysfunction
• withdrawal of support
• post-neonatal deaths
• multiple disability
• seizure disorders
• rehospitalization

Acute birth asphyxia is a cause of death and neurological injury. At present, there is no proven treatment; however, studies in animals suggest that brain cooling may protect against brain injury. This large multicenter trial will randomize term infants with a history of problems at delivery and signs of depression to total body cooling or standard care. Eligible infants greater than 36 wks gestation identified less than 6 hours after birth will be randomized and treated for 72 hrs to determine if cooling reduces the risk of death or moderate to severe neurologic disability at 18-22 mos.

Perinatal cerebral hypoxia-ischemia injury is an important cause of death and neurodevelopmental disability. Data from animal models suggest that brain cooling immediately after injury is neuroprotective. Experience with total body cooling during surgery, accidental near drownings, and one Phase I trial of term infants suggest that it is effective and safe in children. This large multicenter trial will test whether cerebral cooling initiated within 6 hrs of birth and continued for 72 hrs will reduce the risk of death and moderate to severe neurodevelopmental injury at 18-22 mos. Infants at least 36 weeks gestation with an abnormal blood gas within 1 hr of birth event or a history of an acute perinatal event and a 10-min Apgar score less than 5 or continued need for ventilation will be identified. Those with moderate to severe encephalopathy will be randomized to a 72 hr period of total body cooling (cooling blanket, followed by slow rewarming). The study will be conducted in two phases: Phase I (20 infants) will examine safety of an esophageal temperature of 34-35 C, Phase II (main trial, 200 infants) will evaluate the safety and efficacy of an esophageal temperature of 33-34 C. The primary outcome is death or moderate/severe disability at 18-22 mos of age; secondary outcomes include length of hospital stay, frequency of multi-organ dysfunction; withdrawal of support; post-neonatal deaths; multiple disability; seizure disorders; rehospitalization.

The sample size was based on a 50 percent incidence of death or disability (defined as cerebral palsy, Bayley MDI less than 70, deafness or blindness) following moderate to severe encephalopathy in the control group; a 30 percent reduction in the cooled group; 80 percent power; a two-tailed Type 1 error of 0.05; and 10 percent loss to follow up.

Cardio-respiratory, EEG, renal,metabolic and hematologic status and esophageal and abdominal skin temperature will be monitored during 72 hours of intervention.

Neurodevelopmental outcome will be assessed at 18-22 mos of age by masked certified examiners.

The outcome at 18-22 months has shown that whole body cooling reduces the risk of death or moderate to severe disability in infants with hypoxic ischemic encephalopathy.

Follow up will be assessed at 6-7 years in the surviving cohort of infants.

• Infant, Newborn
• Hypoxia-Ischemia, Brain

• Device: Induced hypothermia
• Device: Control

• Experimental: Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
• Placebo Comparator: Placebo: Normothermic control group (with esophageal temperature at or near 37.0°C) for 96 hours

• Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; 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 Oct 13;353(15):1574-84.
• Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA, Stark AR, Tyson JE, Poole K, Carlo WA, Lemons JA, Oh W, Stoll BJ, Papile LA, Bauer CR, Stevenson DK, Korones SB, McDonald S. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002 Aug;110(2 Pt 1):377-85.
• Ambalavanan N, Carlo WA, Shankaran S, Bann CM, Emrich SL, Higgins RD, Tyson JE, O'Shea TM, Laptook AR, Ehrenkranz RA, Donovan EF, Walsh MC, Goldberg RN, Das A; National Institute of Child Health and Human Development Neonatal Research Network. Predicting outcomes of neonates diagnosed with hypoxemic-ischemic encephalopathy. Pediatrics. 2006 Nov;118(5):2084-93.
• Oh W, Perritt R, Shankaran S, Merritts M, Donovan EF, Ehrenkranz RA, O'Shea TM, Tyson JE, Laptook AR, Das A, Higgins RD. Association between urinary lactate to creatinine ratio and neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy. J Pediatr. 2008 Sep;153(3):375-8. Epub 2008 May 9.
• Mietzsch U, Parikh NA, Williams AL, Shankaran S, Lasky RE. Effects of hypoxic-ischemic encephalopathy and whole-body hypothermia on neonatal auditory function: a pilot study. Am J Perinatol. 2008 Aug;25(7):435-41. Epub 2008 Aug 21.
• Laptook A, Tyson J, Shankaran S, McDonald S, Ehrenkranz R, Fanaroff A, Donovan E, Goldberg R, O'Shea TM, Higgins RD, Poole WK; National Institute of Child Health and Human Development Neonatal Research Network. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. 2008 Sep;122(3):491-9.
• Shankaran S, Pappas A, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE, Walsh M, Goldberg RN, Higgins RD, Das A; NICHD Neonatal Research Network. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2008 Oct;122(4):e791-8.
• Parikh NA, Lasky RE, Garza CN, Bonfante-Mejia E, Shankaran S, Tyson JE. Volumetric and anatomical MRI for hypoxic-ischemic encephalopathy: relationship to hypothermia therapy and neurosensory impairments. J Perinatol. 2009 Feb;29(2):143-9. Epub 2008 Nov 20.
• Lasky RE, Parikh NA, Williams AL, Padhye NS, Shankaran S. Changes in the PQRST intervals and heart rate variability associated with rewarming in two newborns undergoing hypothermia therapy. Neonatology. 2009;96(2):93-5. Epub 2009 Mar 2.
• Shankaran S, Laptook A. Challenge of conducting trials of neuroprotection in the asphyxiated term infant. Semin Perinatol. 2003 Aug;27(4):320-32. Review.
• Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma. 2009 Mar;26(3):437-43. Review.

Inclusion Criteria:

• At least 36 weeks gestation
• Any blood gas (cord, postnatal) done within the first 60 minutes had a pH less than or equal to 7.0
• Any blood gas (cord postnatal) done within the first 60 minutes had a base deficit greater than or equal to 16 mEq/L
• All infants must have seizures or signs of moderate to severe encephalopathy before randomization

Exclusion Criteria:

• Inability to randomize by 6 hours of age
• Presence of known chromosomal anomaly or major congenital anomaly
• Severe intrauterine growth restriction (weight less than 1800g)
• All blood gases done within the first 60 minutes had a pH less than 7.15 and a base deficit less than 10 mEq/L
• Infants in extremis for whom no additional intensive therapy will be offered by attending neonatologist
• Parents refuse consent
• Attending neonatologist refuses consent