Therapeutic Hypothermia in Hypoxic-Ischemic Encephalopathy (HIE)

Introduction to Therapeutic Hypothermia

The American Academy of Pediatrics recommends therapeutic hypothermia as the standard of care for term and near-term infants (≥36 weeks gestational age) with moderate-to-severe HIE, reducing death or major neurodevelopmental disability by 22-33%, with one fewer infant dying or having significant disability for every 5-7 infants treated 1, 2

Therapeutic hypothermia should be offered to term or near-term infants (≥37 weeks gestational age) who meet ALL of the following criteria: evidence of perinatal asphyxia, moderate-to-severe encephalopathy on clinical examination, and age <6 hours from birth 1, 2, 3

Therapeutic hypothermia provides substantial reductions in major neurological disabilities, including a 48% reduction in cerebral palsy risk (RR 0.52; 95% CI 0.37-0.72), a 52% reduction in blindness risk (RR 0.48; 95% CI 0.22-1.03), and a 58% reduction in deafness risk (RR 0.42; 95% CI 0.21-0.82) 1
Therapeutic hypothermia results in an absolute risk reduction of 151 fewer cases of death or neurodevelopmental impairment per 1000 infants treated at 18-24 months 1

The magnitude of benefit varies by encephalopathy severity, with a 33% reduction in death or major neurodevelopmental disability for moderate HIE (RR 0.67; 95% CI 0.56-0.81) and a 17% reduction for severe HIE (RR 0.83; 95% CI 0.74-0.92) 1

The American Heart Association recommends that therapeutic hypothermia must follow strict protocols to be safe and effective, including initiation within 6 hours of birth, target core temperature of 33-34°C, and duration of 72 hours of continuous cooling 1, 2, 3, 4, 5
Rewarming must occur over at least 4 hours at approximately 0.5°C per hour to prevent complications 4, 5, 2, 3

Cooling should ONLY be conducted in neonatal care facilities with multidisciplinary capabilities, including intravenous therapy, respiratory support and mechanical ventilation, continuous pulse oximetry, antibiotics and anticonvulsant medications, transfusion services, radiology including ultrasound, and pathology testing 4, 5, 2, 3

The American Academy of Pediatrics recommends maintaining physiological stability throughout the cooling period, including adequate ventilation and oxygenation, target PaCO₂ of 4.5-5.0 kPa, systolic blood pressure >110 mmHg, intravenous glucose infusion, and monitoring and treating complications 2, 3

The World Health Organization recommends that therapeutic hypothermia is ONLY recommended when suitable supportive care is available (weak recommendation, low-certainty evidence) 4, 5

The American Heart Association recommends avoiding initiation of cooling beyond 6 hours of life, as efficacy decreases significantly after this window, and avoiding rapid rewarming, as it must occur over at least 4 hours to prevent complications 2, 3, 4, 5

Rewarming after therapeutic hypothermia does not directly cause lactic acidosis, but the metabolic derangements from the underlying hypoxic-ischemic injury persist during rewarming, and rapid rewarming may worsen metabolic instability 6
The optimal rate of rewarming remains a knowledge gap, with current recommendations based on preventing hyperthermia and other complications rather than specific metabolic endpoints 6

Future research is specifically needed on the effect of rewarming rate on metabolic markers such as acidosis, indicating this remains an area of uncertainty 6