What is the recommended treatment for therapeutic hypothermia in patients with hypoxic-ischemic encephalopathy (HIE)?

Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: NNF CPG Position

Therapeutic hypothermia at 33-34°C for 72 hours is the standard of care for term and near-term infants (≥36 weeks gestational age) with moderate-to-severe HIE, and must be initiated within 6 hours of birth in facilities equipped with multidisciplinary neonatal intensive care capabilities. 1, 2, 3

Patient Selection Criteria

All three of the following criteria must be met to offer therapeutic hypothermia 2:

• Gestational age: Term or near-term infants ≥36-37 weeks 1, 2
• Evidence of perinatal asphyxia: Including metabolic acidosis, Apgar scores, or need for resuscitation 2
• Moderate-to-severe encephalopathy: Confirmed on clinical neurological examination 2
• Age: Less than 6 hours from birth 1, 2, 3

Cooling Protocol Requirements

Strict adherence to protocol parameters is mandatory for safety and efficacy 2:

• Initiation window: Within 6 hours of birth—efficacy decreases significantly beyond this timeframe 1, 2, 3
• Target temperature: Core temperature of 33-34°C 1, 2, 3
• Duration: 72 hours of continuous cooling 1, 2, 3
• Rewarming: Gradual over at least 4 hours at approximately 0.5°C per hour 1, 2, 3

Expected Clinical Benefits

The magnitude of benefit varies by encephalopathy severity 3:

• Moderate HIE: 33% reduction in death or major neurodevelopmental disability (RR 0.67; 95% CI 0.56-0.81) 3
• Severe HIE: 17% reduction in death or major neurodevelopmental disability (RR 0.83; 95% CI 0.74-0.92) 3
• Overall benefit: 22-33% reduction in death or major neurodevelopmental disability 1, 2, 3
• Number needed to treat: 5-7 infants to prevent one case of death or significant disability 1, 2, 3

Specific Neurological Outcomes

• Cerebral palsy: 48% risk reduction (RR 0.52; 95% CI 0.37-0.72); NNT = 12 3
• Blindness: 52% risk reduction (RR 0.48; 95% CI 0.22-1.03) 3
• Deafness: 58% risk reduction (RR 0.42; 95% CI 0.21-0.82) 3
• Absolute risk reduction: 151 fewer cases of death or neurodevelopmental impairment per 1000 infants treated at 18-24 months 2, 3

Facility Requirements

Cooling must ONLY be conducted in facilities with comprehensive neonatal intensive care capabilities 1, 2, 3:

• Intravenous therapy and fluid management 1, 2
• Respiratory support and mechanical ventilation 1, 2
• Continuous pulse oximetry and cardiorespiratory monitoring 1, 2
• Antibiotics and anticonvulsant medications 1, 2
• Transfusion services 2
• Radiology including ultrasound 2
• Pathology testing capabilities 1, 2

Supportive Care During Cooling

Maintain physiological stability throughout the 72-hour cooling period 1:

• Ventilation: Adequate oxygenation to prevent hypoxemia 1
• PaCO₂ target: 4.5-5.0 kPa 1
• Blood pressure: Systolic BP >110 mmHg 1
• Fluid management: 0.9% saline as crystalloid of choice 1
• Glucose: Intravenous glucose infusion with monitoring 1
• Head positioning: 20-30° head-up tilt to optimize cerebral perfusion 1

Monitoring for Adverse Events

While therapeutic hypothermia is generally safe, monitor for 4:

• Cardiac arrhythmias: More common with hypothermia (RR 3.51; 95% CI 1.29-9.54), though typically clinically benign 4
• Coagulation disorders: Increased incidence (RR 1.23; 95% CI 1.03-1.48), but usually not clinically significant 4
• Persistent pulmonary hypertension: Potential risk, though evidence is inconsistent 3

Seizure Management During and After Cooling

• During cooling: Treat clinical seizures with anticonvulsants at sufficiently high doses 1
• EEG monitoring: Perform EEG to detect non-convulsive status epilepticus 1
• Post-discharge benefit: Therapeutic hypothermia is associated with reduced seizures up to 6 months after NICU discharge (16% vs 53% in non-cooled infants) 5

Critical Pitfalls to Avoid

• Late initiation: Do not start cooling beyond 6 hours of life—efficacy is significantly reduced 2
• Rapid rewarming: Rewarming must occur over at least 4 hours to prevent complications 2
• Inadequate facilities: Never attempt cooling without proper multidisciplinary support and monitoring equipment 2, 3
• Extreme hypothermia: Maintain strict temperature control; avoid temperatures below 33°C 3
• Hypotension and hypovolemia: These worsen neurological outcomes and must be aggressively prevented 1
• Early prognostication: Avoid premature withdrawal of care decisions; comprehensive assessment should occur after rewarming 1

Resource-Limited Settings

In resource-limited settings, therapeutic hypothermia is ONLY recommended when suitable supportive care is available (weak recommendation, low-certainty evidence) 2. Without adequate monitoring and support capabilities, the risks may outweigh benefits 2.

Prognostication After Therapeutic Hypothermia

Conduct comprehensive assessment after rewarming 1:

• Timing: Most crucial evaluation occurs after completion of rewarming 1
• Multimodal approach: Clinical examination, EEG, biomarkers (NSE >60 μg/L), and neuroimaging 1
• Poor prognosis indicators: At least two of the following: absent pupillary/corneal reflexes, bilateral absence of N20 SSEP responses, highly malignant EEG, NSE >60 μg/L, status myoclonus, or extensive diffuse anoxic injury on neuroimaging 1
• Avoid confounders: Rule out sedatives, electrolyte disturbances, and residual hypothermia effects before prognostication 1