What proportion of neonatal hypoxic ischemic encephalopathy (HIE) cases can hypothermia prevent from having long-term adverse effects?

Therapeutic Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: Prevention of Long-term Adverse Effects

Therapeutic hypothermia prevents long-term adverse effects in approximately 15-24% of neonates with moderate-to-severe hypoxic ischemic encephalopathy (HIE), with a number needed to treat of 5-7 infants to prevent one case of death or neurodevelopmental disability. 1

Efficacy of Therapeutic Hypothermia

Prevention of Death or Disability

• Therapeutic hypothermia reduces the risk of death or major neurodevelopmental disability by approximately 22-33% in infants with moderate-to-severe HIE 1
• For every 5-7 infants treated with therapeutic hypothermia, one fewer infant will die or have significant neurodevelopmental disability 1, 2
• The absolute risk reduction for death or neurodevelopmental impairment at 18-24 months is approximately 151 fewer cases per 1000 infants treated 1

Specific Neurological Outcomes

• Cerebral palsy risk is reduced by approximately 48% with therapeutic hypothermia (RR 0.52; 95% CI 0.37-0.72) 1
• Risk of blindness is reduced by approximately 52% (RR 0.48; 95% CI 0.22-1.03) 1
• Risk of deafness is reduced by approximately 58% (RR 0.42; 95% CI 0.21-0.82) 1
• The number needed to treat to prevent one case of cerebral palsy is approximately 12 infants 1

Effectiveness by HIE Severity

• In moderate HIE, therapeutic hypothermia reduces the risk of death or major neurodevelopmental disability by approximately 33% (RR 0.67; 95% CI 0.56-0.81) 1
• In severe HIE, the reduction is approximately 17% (RR 0.83; 95% CI 0.74-0.92) 1
• The benefit appears more pronounced in moderate cases compared to severe cases 1, 2

Implementation Considerations

Timing and Protocol

• Therapeutic hypothermia must be initiated within 6 hours of birth to be effective 1
• Treatment should maintain strict temperature control at 33-34°C for 72 hours 1
• Rewarming should occur over at least 4 hours 1
• Both total body cooling and selective head cooling are effective methods 2

Setting and Resources

• Cooling should only be conducted in neonatal care facilities with capabilities for multidisciplinary care 1
• Required resources include: intravenous therapy, respiratory support, pulse oximetry, antibiotics, anticonvulsants, and pathology testing 1
• Effectiveness varies by setting - better outcomes are seen in high-income countries compared to lower-middle-income countries 3

Limitations and Caveats

• Therapeutic hypothermia is only partially effective - a substantial proportion of infants will still have adverse outcomes despite treatment 4, 5
• Quality of evidence varies, with some studies showing risk of bias 1, 3
• There is a potential risk of persistent pulmonary hypertension with therapeutic hypothermia, though evidence is inconsistent 1
• Implementation without proper protocols and monitoring may lead to harm, including risk of extreme hypothermia 1
• Low-quality trials may overestimate the potential benefit of therapeutic hypothermia 3

Future Directions

• Combination treatments to augment hypothermic neuroprotection show promise, including melatonin, erythropoietin, and noble gases such as xenon 4, 5
• Further research is needed on optimal rewarming rates after hypothermia 1, 4
• Strategies to reduce delays before starting treatment are likely to improve outcomes 4
• Additional adequately powered randomized controlled trials are needed, particularly in resource-limited settings 1