DOI: 10.1097/01.SA.0000370474.73466.67
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Issn Print: 0039-6206
Publication Date: 2010/06/01
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Denis V. Azzopardi,* Brenda Strohm,† A. David Edwards,* Leigh Dyet,* Henry L. Halliday,‡ Edmund Juszczak,† Olga Kapellou,* Malcolm Levene,§ Neil Marlow,∥ Emma Porter,* Marianne Thoresen,¶ Andrew Whitelaw,# and Peter Brocklehurst,† for the TOBY (Total Body Hypothermia for Neonatal Encephalopathy Trial) Study Group
(N Engl J Med, 361:1349-1358, 2009)
*Division of Clinical Sciences and Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Imperial College, London; †National Perinatal Epidemiology Unit, University of Oxford, Oxford; ‡Department of Perinatal Medicine, Royal Maternity Hospital and Department of Child Health, Queen's University, Belfast; §University of Leeds and Leeds General Infirmary, Leeds; ∥Academic Division of Child Health, Queen's Medical Centre, Nottingham; and ¶Department of Clinical Science, University of Bristol, St Michael's Hospital, and #Southmead Hospital, Bristol, United Kingdom.
Perinatal asphyxial encephalopathy carries high rates of morbidity and mortality and, if the infant survives, a huge burden for the patient, family, and society. Hypothermia is one possible method to reduce the adverse neurodevelopmental outcomes in newborns with asphyxial encephalopathy. This multicenter, randomized, controlled trial assessed the technique compared with standard intensive care alone. All centers followed uniform protocols for ventilatory and circulatory care, management of seizures, sedation, and fluid requirements. Eligible infants with asphyxial encephalopathy were less than 6 hours old with a gestational age of 36 weeks or greater. The infants receiving intensive care alone were placed under radiant heaters or in incubators to maintain the rectal temperature at 37.0°C ± 0.2°C. Those in the cooled group were treated in incubators with the power turned off. Hypothermia was provided with a cooling blanket, with the infant's target rectal temperature from 33°C to 34°C. At 72 hours after randomization, when the period of cooling was finished, the rectal temperature was monitored for 4 hours or longer to prevent rebound hyperthermia. Cranial ultrasonography was performed each day for the first 4 days, and magnetic resonance imaging was done within 5 to 14 days after birth. The primary outcome was death or severe disability at age 18 months; secondary outcomes included 12 prespecified neurological outcomes and 14 other adverse outcomes.
Of 325 infants enrolled from 42 hospitals, 163 were in the cooling group and 162 in the intensive-care-alone group. Mean rectal temperatures 6 to 72 hours after randomization were 33.5°C ± 0.5°C and 36.9°C ± 0.6°C in the cooled and standard-care groups, respectively. In the cooled group, 42 infants died and 32 survived with severe neurodevelopmental disabilities; in the noncooled group, 44 infants died and 42 had severe disabilities. The incidence of adverse events was similar in the 2 groups, with hypotension, thrombocytopenia, prolonged coagulation time, and intracranial hemorrhage seen often in both groups. The rate of survival without a neurological abnormality was 44% in the cooled infants compared with 28% in the noncooled group, a statistically significant difference. Among the survivors, cooling led to decreased risks of cerebral palsy and abnormal Gross Motor Function Classification System scores. Rates of multiple neurodevelopment abnormalities were 21 of 112 and 33 of 110 in the cooled and standard-care groups, respectively. The investigators concluded that although moderate hypothermia did not reduce the combined rate of death or severe disability, improved neurological outcomes were apparent in survivors of perinatal asphyxial encephalopathy.
