When should therapeutic hypothermia be initiated for hypoxic‑ischemic encephalopathy?

Optimal Timing for Initiating Therapeutic Hypothermia in HIE

Therapeutic hypothermia must be initiated within 6 hours of birth for term or near-term infants (≥36 weeks gestational age) with moderate-to-severe hypoxic-ischemic encephalopathy, with earlier initiation providing superior neuroprotection. 1, 2, 3

Critical Time Window

• The 6-hour window is an absolute deadline, not a target. Starting cooling as early as possible within this timeframe maximizes benefit, as neuroprotection decreases linearly with each hour of delay. 2, 4
• Preclinical evidence demonstrates that neuroprotection diminishes by approximately 1.8% per hour of delay after moderate hypoxic-ischemic injury, making immediate initiation after diagnosis paramount. 5
• Cooling initiated beyond 6 hours loses efficacy and may cause harm, particularly after severe insults where 12-hour delayed hypothermia actually increased brain injury in experimental models. 5

Patient Selection Criteria (All Must Be Met)

The infant must satisfy ALL three criteria to qualify for treatment: 2, 3

1. Gestational age ≥36 weeks (term or near-term)
2. Evidence of perinatal asphyxia (cord pH ≤7.0, base deficit ≥16 mmol/L, Apgar score ≤5 at 10 minutes, or need for resuscitation at 10 minutes)
3. Moderate-to-severe encephalopathy on clinical examination using modified Sarnat criteria (≥3 of 6 categories scored as moderate or severe)

Implementation Protocol

Core temperature target: 33.5°C ± 0.5°C (range 33-34°C) 1, 2, 6

• Duration: 72 hours of continuous cooling 1, 2, 3
• Rewarming: Must occur over at least 4 hours at approximately 0.5°C per hour to prevent complications 1, 2, 3
• Passive cooling during transport is acceptable and should be initiated immediately while arranging transfer, but core temperature must be continuously monitored to avoid overcooling below 33°C 7

Magnitude of Benefit by Timing and Severity

For moderate HIE: Therapeutic hypothermia reduces death or major neurodevelopmental disability by 33% (RR 0.67), with absolute risk reduction of 151 fewer cases per 1000 infants treated (NNT = 7). 2, 6

For severe HIE: The benefit is more modest at 17% reduction (RR 0.83), and immediate hypothermia provides no neuroprotection after severe insults in animal models, though clinical guidelines still recommend treatment. 6, 5

Specific neurological outcomes: 2, 6

• Cerebral palsy risk reduced by 48% (NNT = 12)
• Blindness risk reduced by 52%
• Deafness risk reduced by 58%

Facility Requirements (Non-Negotiable)

Cooling should ONLY occur in facilities with: 2, 3

• Multidisciplinary neonatal intensive care capabilities
• Mechanical ventilation and respiratory support
• Continuous pulse oximetry and temperature monitoring
• Intravenous therapy and inotropic support
• Anticonvulsant medications readily available
• Transfusion services
• Neuroimaging (MRI with diffusion-weighted imaging)
• Longitudinal neurodevelopmental follow-up programs

Critical Pitfalls to Avoid

• Never delay transfer to a cooling center while attempting to meet all eligibility criteria—if HIE is suspected, initiate passive cooling and immediate transport. 2, 7
• Never initiate cooling beyond 6 hours of life, as efficacy is lost and harm may occur. 2, 5
• Never rewarm rapidly—rewarming faster than 0.5°C per hour risks metabolic instability and complications. 1, 2
• Never administer prophylactic antiepileptic drugs before seizures are confirmed, as electrographic seizures are rare in the first few hours after intrapartum injury. 7
• Never perform cooling without proper temperature monitoring—both overcooling and undercooling reduce efficacy. 8, 7

Supportive Care During Cooling

Maintain physiological stability throughout treatment: 2, 3

• Target PaCO₂: 4.5-5.0 kPa (approximately 34-38 mmHg)
• Systolic blood pressure >110 mmHg (inotropic support often needed)
• Intravenous glucose infusion to avoid hypoglycemia
• Monitor for thrombocytopenia and coagulopathy
• Continuous EEG or amplitude-integrated EEG monitoring for seizure detection

Resource-Limited Settings

The WHO recommends therapeutic hypothermia ONLY when suitable supportive care is available (weak recommendation, low-certainty evidence), as implementation without proper protocols and monitoring may cause harm including extreme hypothermia. 2, 6