Safety of selective head cooling with mild systemic hypothermia after neonatal encephalopathy:multicentre randomized trial

Objective Although it had been shown that mild or moderate hypothermia is safe in treatment of neonatal hopoxic-ischemic encephalopathy (HIE) in small scaled pilot clinical study, it is necessary to make multicentre randomized controlled trial to verify its efficacy in neonates with HIE. This multicentre randomized trial was to study the safety of selective head cooling (SHC) with mild systemic hypothermia in neonates with HIE. Methods Infants were qualified for the study if they were ≥36of weeks gestation,≥2 500 g of birth weight,and ≤6 h after birth. Cord blood gas pH ≤7. 0 or base deficit≥16 mmol ·L-1,or Apgar score ≤3 at 1 min, continued≤5 at 5 min. Neurological findings of neonatal encephalopathy included lethargy, stupor, or coma, with one or more of hypotonia, abnormal reflexes, absent or weak suck or clinical seizures. Exclusion criteria included:major congenital abnormalities, head trauma causing major intracranial hemorrhage, infection or severe anemia.Two hundred and forty-six term infants from 16 tertiary referral hospitals with various severity of neonatal encephalopathy were randomly assigned to either head cooling (n=134) or control group (n=112). In 29 babies follow up was not available (17 in cooling and 12 in control respectively). Thus 217 allocated to head cooling (n=117) and control group (n=100) respectively. In head cooling group,the nasopharyngeal temperature was maintained at (34±0. 2)℃ and rectal temperature maintained at 34 -35℃ for 72 h,then rewarmed spontaneously. In control group,normal rectal temperature was maintained. During study period,the babies in both groups were given mornitoring of nasopharyngeal temperature, heart rate, respiration rate, transcutaneous arterial oxygen saturation and blood pressure. Severe adverse events were recorded which included death, major cardiac arrhythmia, major venous thrombosis or hemorrhage and severe hypotension despite full support. Na+,K+,Ca2+,glucose, GPT,GOT,BUN,Cr,pH and BE were measured at 72h after treatment. Results The case-fatality rate was not significantly different in both groups(17.9% in cooling vs 25% in control group,P=0.20). The major cause of death was severe HIE (6. 8% in cooling vs 7% in control group,P = 0. 96) and respiratory failure (6. 8% in cooling vs 6% in control group respectively,P=0. 80) . There was one neonate with ventricular arrhythmia and DIC in control group and two neonates with DIC and severe gastrointestinal hemorrhage respectively in SHC group. The rate of severe adverse events was not signicantly different in both groups (1.7% in cooling vs 2% in control group, P = 1.00). In SHC group,most neonates had lower heart rates during the period of hypothermia,but HR below 80 beats/min was observed in only 4 cases (3.4%) . The systolic and diastolic blood pressures were stable,and no difference were found between SHC and control group. The rate of abnormal renal function, elevated liver enzyme activities, metabolic acidosis, hypoglycemia, hyperglycemia, hypocalcaemia, hyponatraemia, and hyperkalaemia were not significantly different between two groups. The average values of white blood cells, platelets, and the rate of thrombocytopenia were not significantly different between two groups. Conclusion These data suggest that selective head cooling with mild systemic hypothermia in neonates with HIE is safe during 72 h therapy.