What is the treatment protocol for therapeutic hypothermia in neonates with Hypoxic-Ischemic Encephalopathy (HIE)?

Therapeutic Hypothermia Protocol for Neonatal 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

Patient Selection Criteria

All three of the following criteria must be met: 1

• Gestational age ≥36-37 weeks 1
• 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) 1
• Moderate-to-severe encephalopathy on clinical examination (altered consciousness, abnormal tone, abnormal reflexes, or seizures) 1
• Age <6 hours from birth 2, 1

Efficacy by HIE Severity

• Moderate HIE: 33% reduction in death or major neurodevelopmental disability (RR 0.67; 95% CI 0.56-0.81) 1, 3
• Severe HIE: 17% reduction in death or major neurodevelopmental disability (RR 0.83; 95% CI 0.74-0.92) 1, 3

Core Temperature Protocol

The protocol requires strict adherence to specific temperature targets and timing: 2, 1

Cooling Phase (72 hours)

• Target core temperature: 33-34°C 2, 1, 4
• Initiate within 6 hours of birth - efficacy decreases significantly after this window 2, 1, 4
• Duration: 72 hours of continuous cooling 2, 1, 4
• Temperature monitoring: Continuous core temperature monitoring (rectal or esophageal probe) 2

Rewarming Phase (minimum 4 hours)

• Rewarming rate: approximately 0.5°C per hour 1, 4
• Duration: at least 4 hours 2, 1, 4
• Critical pitfall: Rapid rewarming causes complications and must be avoided 1, 4

Cooling Methods

Both whole-body cooling and selective head cooling are effective: 5

• Whole-body cooling: Using cooling blankets or servo-controlled devices (RR 0.75; 95% CI 0.66-0.85) 5
• Selective head cooling: Using cooling caps with mild systemic hypothermia (RR 0.77; 95% CI 0.65-0.93) 5
• Cool gel packs: Effective in resource-limited settings when properly monitored 6
• Passive cooling with ice packs: May be used in low-resource settings but requires close monitoring to prevent extreme hypothermia 2

Required Facility Capabilities

Cooling should ONLY be conducted in facilities with ALL of the following capabilities: 2, 1, 4

• Multidisciplinary neonatal intensive care team 2, 1
• Intravenous therapy and fluid management 2, 1, 4
• Respiratory support and mechanical ventilation 2, 1, 4
• Continuous pulse oximetry 2, 1, 4
• Antibiotics and anticonvulsant medications 2, 1, 4
• Transfusion services 1
• Radiology including ultrasound and MRI 1
• Pathology testing 2, 1, 4

Supportive Care During Cooling

Respiratory Management

• Maintain adequate oxygenation to prevent hypoxemia, which worsens neurological outcomes 4
• Target PaCO₂: 4.5-5.0 kPa 1, 4
• Avoid hyperventilation except short-term when there is evidence of raised intracranial pressure 4

Cardiovascular Management

• Maintain systolic blood pressure >110 mmHg to preserve cerebral blood flow and prevent secondary cerebral insults 1, 4
• Avoid hypovolemia and hypotension as they adversely affect neurological outcomes 4

Fluid and Metabolic Management

• Use 0.9% saline as the crystalloid of choice to prevent increases in brain water 4
• Provide intravenous glucose infusion to maintain normoglycemia 1
• Monitor and correct electrolyte disturbances 1

Seizure Management

• Monitor with continuous or serial EEG 7
• Treat clinical and electrographic seizures with anticonvulsants 2, 1, 4
• Common anticonvulsants: Phenobarbital as first-line, with alternatives including phenytoin, levetiracetam, or midazolam 7

Positioning

• Position with 20-30° head-up tilt to optimize cerebral perfusion while minimizing intracranial pressure 4

Transport Considerations

For outborn infants requiring transfer: 8

• Initiate passive cooling at the birth center before transport 8
• Continue cooling during transportation with temperature monitoring 8
• Calculate pre- and post-transport TRIPS scores to evaluate transport impact 8
• Ensure receiving facility has required capabilities before initiating transfer 2, 1

Specific Neurological Benefits

Therapeutic hypothermia provides substantial reductions in major disabilities: 1, 3

• Cerebral palsy: 48% reduction (RR 0.52; 95% CI 0.37-0.72) - NNT = 12 1, 3
• Blindness: 52% reduction (RR 0.48; 95% CI 0.22-1.03) 1, 3
• Deafness: 58% reduction (RR 0.42; 95% CI 0.21-0.82) 1, 3
• Absolute risk reduction: 151 fewer cases of death or neurodevelopmental impairment per 1000 infants treated at 18-24 months 1, 3

Neuroimaging and Prognostication

• Perform MRI within 10 days of life to assess brain injury patterns 7, 8
• Avoid early prognostication to prevent self-fulfilling prophecy bias 4
• Most crucial evaluation: After rewarming is complete 4
• Use multidimensional assessment: Clinical examination, EEG, biomarkers (NSE), and neuroimaging 4

Critical Pitfalls to Avoid

The American Heart Association identifies these critical errors: 1, 4

• Never initiate cooling beyond 6 hours of life - efficacy decreases significantly after this window 1, 4
• Never perform rapid rewarming - must occur over at least 4 hours 1, 4
• Never cool without proper monitoring capabilities - risk of extreme hypothermia and complications 2, 1
• Never cool in facilities lacking multidisciplinary support - increases risk of adverse outcomes 2, 1
• Never rely on passive cooling alone without temperature monitoring - risk of uncontrolled hypothermia 2

Implementation in Resource-Limited Settings

The World Health Organization recommends therapeutic hypothermia ONLY when suitable supportive care is available (weak recommendation, low-certainty evidence): 1

• Simple cooling methods (passive cooling, ice packs) can effectively lower body temperature 2
• Close nursing monitoring is essential to prevent extreme hypothermia 2
• Evidence quality is very low in resource-limited settings (2 RCTs, 338 infants showed benefit OR 0.43; 95% CI 0.26-0.7 for death or disability) 2
• Mortality benefit unclear in low-resource settings (4 RCTs, 416 infants showed OR 0.72; 95% CI 0.44-1.16) 2

Adjuvant Therapies Under Investigation

Currently being evaluated but not yet standard of care: 9

• Erythropoietin and analogues: Currently in large RCTs 9
• Melatonin, xenon, argon, stem cells: Promising but require further research 9
• These should not replace standard therapeutic hypothermia 9