Therapeutic Hypothermia in Hypoxic-Ischemic Encephalopathy (HIE)
Therapeutic hypothermia is 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
Indications and Patient Selection
Therapeutic hypothermia should be offered to term or near-term infants (≥37 weeks gestational age) who meet ALL of the following criteria: 2
- Evidence of perinatal asphyxia (Apgar score ≤5 at 10 minutes, need for resuscitation at 10 minutes, or severe acidosis) 2
- Moderate-to-severe encephalopathy on clinical examination (altered consciousness, abnormal tone, abnormal reflexes, or seizures) 2
- Age <6 hours from birth 1, 2, 3
For late preterm infants (33-35 weeks gestational age), therapeutic hypothermia remains controversial. 4 TH may be considered for select infants at 35 weeks' GA, but routine use at 34 weeks or earlier should be limited to research settings given higher complication rates and lack of proven benefit. 4
Specific Neurological Benefits
Therapeutic hypothermia provides substantial reductions in major neurological disabilities:
- Cerebral palsy risk reduced by 48% (RR 0.52; 95% CI 0.37-0.72), with a number needed to treat of 12 infants 1
- Blindness risk reduced by 52% (RR 0.48; 95% CI 0.22-1.03) 1
- Deafness risk reduced by 58% (RR 0.42; 95% CI 0.21-0.82) 1
- Absolute risk reduction of 151 fewer cases of death or neurodevelopmental impairment per 1000 infants treated at 18-24 months 1
Effectiveness by HIE Severity
The magnitude of benefit varies by encephalopathy severity:
- Moderate HIE: 33% reduction in death or major neurodevelopmental disability (RR 0.67; 95% CI 0.56-0.81) 1, 5
- Severe HIE: 17% reduction in death or major neurodevelopmental disability (RR 0.83; 95% CI 0.74-0.92) 1, 5
Both total body cooling and selective head cooling are effective methods, with similar outcomes. 5
Protocol Requirements
Therapeutic hypothermia must follow strict protocols to be safe and effective: 6
Timing
- Initiate within 6 hours of birth - efficacy decreases significantly beyond this window 1, 2, 3
- Earlier initiation is associated with better outcomes 7
Temperature Management
- Target core temperature: 33-34°C 6, 2, 3
- Duration: 72 hours of continuous cooling 6, 2, 3
- Rewarming: minimum 4 hours at approximately 0.5°C per hour 6, 2, 3
- Strict temperature control with continuous monitoring is essential 6
Required Facility Capabilities
Cooling should ONLY be conducted in neonatal care facilities with multidisciplinary capabilities including: 6, 2, 3
- Intravenous therapy 6, 2, 3
- Respiratory support and mechanical ventilation 6, 2, 3
- Continuous pulse oximetry 6, 2, 3
- Antibiotics and anticonvulsant medications 6, 2, 3
- Transfusion services 6
- Radiology including ultrasound 6
- Pathology testing 6, 2, 3
Supportive Care During Cooling
Maintain physiological stability throughout the cooling period: 2, 3
- Adequate ventilation and oxygenation to prevent hypoxemia, which worsens neurological outcomes 3
- Target PaCO₂ of 4.5-5.0 kPa 3
- Systolic blood pressure >110 mmHg to preserve cerebral perfusion 3
- Intravenous glucose infusion to prevent hypoglycemia 2
- Monitor and treat complications including thrombocytopenia, coagulopathy, and need for inotropic support 2, 8
Adverse Events and Monitoring
Common complications during therapeutic hypothermia include: 2, 8
- Thrombocytopenia (54.8% of cases) 8
- Coagulopathy (30.6% of cases) 8
- Shock requiring inotropic support (30.6% of cases) 8
- Skin changes (12.9% of cases) 8
- Persistent pulmonary hypertension (8.1% of cases) 8
Serious adverse events requiring premature cessation of cooling include disseminated intravascular coagulation, gangrene, and arrhythmia. 8
Implementation in Resource-Limited Settings
For low- and middle-income countries, therapeutic hypothermia is recommended ONLY when suitable supportive care is available (weak recommendation, low-certainty evidence). 6
Low-cost devices such as ice packs and phase-changing material (e.g., MiraCradle™) can be safe and effective alternatives when:
- Adequate monitoring is available 8
- Standard protocols are followed 8
- Mean core temperatures of 33.4-33.5°C can be maintained 8
Critical caveat: Adoption of hypothermia without close monitoring, protocols, or comprehensive neonatal intensive care may lead to harm. 6
Critical Pitfalls to Avoid
Do not initiate cooling beyond 6 hours of life - efficacy decreases significantly after this window 2, 3
Do not attempt therapeutic hypothermia without:
- Proper monitoring equipment and trained staff 2
- Capabilities for multidisciplinary care 6, 2, 3
- Established protocols for temperature management 6
Avoid rapid rewarming - rewarming must occur over at least 4 hours to prevent complications 6, 2, 3
Mild HIE Considerations
Infants with mild HIE are NOT routinely cooled in current protocols, as randomized trials have not included this population. 9 However, recent evidence suggests that children with mild HIE may have lower cognitive scores at age 2 years compared to healthy controls, with scores not significantly different from survivors of moderate HIE treated with hypothermia. 9 This remains an area requiring further research. 9
Future Directions and Adjunctive Therapies
Current protocols for therapeutic hypothermia appear near-optimal, with the key to better outcomes being earlier diagnosis and initiation after birth. 7
Small phase II trials suggest that combined treatment with recombinant erythropoietin may further reduce disability risk, but definitive studies are still needed. 7
Further research is essential for: