BEDSIDE ACTION BOX — First 6 Hours (the therapeutic window)
- Identify at-risk infants immediately: sentinel event, need for resuscitation, cord pH <7.0 or base deficit ≥16, and abnormal neurology.
- Assess for moderate–severe encephalopathy and, where available, aEEG — the decision to cool is time-critical.
- Phone the regional cooling centre and start passive cooling now (turn off heaters) — do not wait for consent or transfer. Insert a rectal probe and monitor temperature continuously.
- Avoid overheating at all costs; passive target 33.5–34.5°C and never overshoot (never use ice).
- Support glucose, blood pressure, gases (avoid hypocapnia and hyperoxia), and treat seizures; save cord gases and placenta.
1. Overview & Definition
Overview
Hypoxic-ischaemic encephalopathy (HIE) is brain dysfunction following a perinatal hypoxic-ischaemic insult. Injury evolves over hours to days — an initial insult is followed by a latent phase and then secondary energy failure — which is why the encephalopathy characteristically worsens and then improves, and why a therapeutic window exists. Therapeutic hypothermia (cooling) started within 6 hours reduces death and major neurodisability in term/near-term infants with moderate-to-severe HIE and is the only proven neuroprotective treatment.
Why This Topic Matters
The benefit of cooling is time-dependent — every hour counts, and the window closes at 6 hours. The commonest failures are under-recognising evolving encephalopathy, delaying passive cooling while waiting for consent or transfer, and inadvertent hyperthermia (which worsens injury). A rapid, protocolised pathway with early referral is essential.
Definition
HIE is a clinical syndrome of disturbed neurological function in the early days of life in an infant ≥35 weeks, with difficulty initiating/maintaining respiration, depressed tone and reflexes, altered consciousness, and often seizures, attributable to a peripartum hypoxic-ischaemic event once other causes are excluded.
2. Who This Guideline Applies To
Scope
- Infants ≥36 weeks' gestation with evolving moderate-to-severe HIE meeting cooling criteria, aged ≤6 hours.
- Infants 35+0–35+6 weeks meeting criteria — discuss individually with the cooling centre (evidence is limited and complication risk higher).
- Generally not cooled routinely: infants <35 weeks (limited benefit, increased complications — specialist decision only) and infants with mild HIE (cooling benefit unproven; observe closely and reassess).
- Cross-references: delivery-room resuscitation (1.1), seizures (9.3), IVH (9.2), hypoglycaemia (4.4), and hypotension.
3. Key Definitions
Core Terminology
The concepts underpinning the diagnosis and neuroprotective treatment of HIE.
| Term | Definition | Practical note |
|---|
| HIE | Encephalopathy after a perinatal hypoxic-ischaemic insult. | Evolving — reassess repeatedly in the first 6 hours. |
| Therapeutic hypothermia | Controlled cooling to a target core temperature for 72 hours, then slow rewarming. | Active cooling target 33.5°C; start within 6 hours. |
| Secondary energy failure | Delayed phase of neuronal injury hours after the insult. | The rationale and target of the cooling window. |
| aEEG | Amplitude-integrated EEG — bedside cerebral function monitor. | Supports selection and detects seizures; do not delay cooling if unavailable. |
| Sarnat stage | Clinical grading of encephalopathy (mild/moderate/severe). | Moderate–severe qualifies for cooling. |
4. Cooling Eligibility Criteria
Cool only if every row is met — default criteria (Baylor Ed. 33, Table 12-3)
Do the first modified Sarnat examination at about 1 hour of life, ideally by two NICU providers. Encephalopathy evolves: re-examine an infant with mild signs every hour until the 6-hour window closes. Once candidacy is settled, serial Sarnat scoring stops, but a daily neurological examination continues through cooling.
| Criterion | Requirement |
|---|
| Gestation and age | ≥36 weeks, and under 6 hours old at assessment. |
| A — blood gas available | Cord or first postnatal gas (within 1 hour) with pH ≤7.0 or base deficit ≥16 mEq/L. |
| B — no gas, pH 7.01–7.15, or base deficit 10–15.9 | An acute perinatal event (abruption, cord prolapse, severe fetal heart rate abnormality) plus an Apgar ≤5 at 10 minutes or ventilation (including CPAP) started at birth and continued for ≥10 minutes. Either A or B suffices. |
| Moderate–severe encephalopathy | Seizures, or a score of 2 or more in at least 3 of the 6 modified Sarnat categories (level of consciousness, spontaneous activity, posture, tone, primitive reflexes, autonomic function). |
| Exclusions | Known chromosomal anomaly, major congenital anomalies, or severe growth restriction below 1800 g birth weight. |
Other sources (West Midlands, TOBY-based): Criterion A is Apgar ≤5 or ongoing resuscitation at 10 minutes, or pH <7.0 / base deficit ≥16 mmol/L within 60 minutes; Criterion B is altered consciousness plus hypotonia, abnormal reflexes, weak or absent suck, or seizures; Criterion C, where available, is at least 30 minutes of abnormal aEEG (moderately abnormal or suppressed background, or seizures). Cool if A and B are met, even without aEEG.
5. Encephalopathy Grading (Sarnat)
Mild vs Moderate vs Severe
Grade and document repeatedly through the pathway; moderate or severe encephalopathy is the threshold for cooling.
| Domain | Mild | Moderate | Severe |
|---|
| Consciousness | Hyperalert | Lethargic | Stupor/coma |
| Tone | Normal | Hypotonic | Flaccid |
| Suck / Moro | Normal | Weak / incomplete | Absent / absent |
| Pupils | Normal, reactive | Constricted, reactive | Fixed/dilated, unreactive |
| Heart rate | Normal (>100) | Bradycardia | Variable/irregular |
| Respiration | Normal | Periodic/irregular | Apnoeic, needs ventilation |
| Seizures | None | Common (focal/multifocal) | Uncommon or frequent; ± decerebration |
6. Management Algorithm
1
Identify risk (delivery room / first hour)
Sentinel event, resuscitation need, cord pH <7.0 / BD ≥16, abnormal neurology. Save cord gases and placenta. Note the time of birth (the window is from birth).
2
Assess encephalopathy & criteria
Check gestation, age and the gas/perinatal criterion; modified Sarnat examination at about 1 hour; obtain aEEG if available. Re-examine mild cases hourly until 6 hours.
3
Meets cooling criteria (section 4)?
Phone the cooling centre and start passive cooling immediately. Turn off the radiant heater/incubator heating; nurse naked (nappy only); insert a rectal probe to ~6 cm; continuous temperature monitoring.
4
Stabilise for cooling/transfer
Passive target core 33.5–34.5°C (add heat below 33.5°C); most infants need intubation for transfer; secure access; document baseline neurology before sedation/anticonvulsants; send the HIE blood panel.
5
Active cooling (cooling centre)
Servo-controlled whole-body cooling to 33.5°C for 72 hours with continuous multimodal monitoring; treat seizures; supportive care (below).
6
Rewarm slowly & investigate
Rewarm no faster than ~0.5°C/hour; watch for rebound seizures and hypotension. Obtain MRI with spectroscopy on day 5–6 (other protocols day 5–6) and arrange neurodevelopmental follow-up.
7
⚠ Do-not-miss
Avoid hyperthermia (worsens injury), hypocapnia, hyperoxia, and hypoglycaemia. Consider mimics (sepsis/meningitis, metabolic disease, stroke, structural lesions). Do not delay cooling for consent or aEEG.
7. Cooling Protocol
Passive Cooling (referring unit, immediately)
- Begin as soon as the decision is made — before consent and before transfer; document the time passive cooling started and the temperature.
- Switch off the overhead heater and any active heating; nurse in an open cot (or open incubator portholes), naked except a nappy.
- Insert a rectal probe to ~6 cm; monitor temperature continuously and document at least every 15 minutes.
- Target core 33.5–34.5°C; add heat below 33.5°C (next box). If a servo-controlled cooling mattress is available, use it; use fans/cold-water gloves only with continuous monitoring. Never use ice.
Default referring-unit passive cooling protocol (Baylor Ed. 33, Ch 18.6)
- Steps: turn off the radiant warmer (and the transport incubator heater if decided in the delivery room); pass a lubricated rectal probe about 5–6 cm (axillary if unavailable). Target 33.5–34.5 °C — set the skin servo to 34.0 °C or turn heater output to zero, and check rectal temperature every 15 minutes (or continuously). Axillary readings are unreliable for core temperature, and skin temperature should never drive decisions.
- Avoiding overcooling: below 33.5 °C, turn heater output to 10–25% (about 10% until 34 °C); below 33 °C, add a warmed blanket over the trunk with about 25% output until 33 °C, then remove it; turn heating off again at 34 °C.
- Access and labs: peripheral IV on arrival (avoid scalp), then a double-lumen UVC and single-lumen UAC. Cord gas; postnatal gas with lactate within 1 h; CBC, blood culture, CMP, ionized calcium, bedside glucose; send the placenta for pathology.
- Fluids and drugs: NPO, total fluids about 40 mL/kg/day including drugs and flushes, with a GIR of at least about 4 mg/kg/min. Ampicillin plus an aminoglycoside. Prevent shivering with morphine 0.1 mg/kg, or load 0.1 mg/kg and infuse 0.01 mg/kg/h. Clinical seizures → phenobarbital 20 mg/kg IV and discuss with neurology.
- Documentation until transfer: hourly neurological and Sarnat examinations by the physician; temperature and vital signs every 15 minutes; the time passive cooling started and the time target temperature was reached. Keep the family informed.
- Mild HIE at a referring hospital: if signs persist at 2–3 hours without improvement, or biochemistry worsens, call the cooling centre to decide where to observe — factoring in distance and transport availability, so the 6-hour window is not lost.
Active Cooling (cooling centre)
- Servo-controlled whole-body cooling to a target core temperature of 33.5°C, maintained for 72 hours.
- Continuous rectal temperature, cardiorespiratory, blood pressure, aEEG/EEG, and metabolic monitoring throughout.
- Rewarm slowly at the end of 72 hours — no faster than approximately 0.5°C per hour — and monitor closely for rebound seizures and haemodynamic instability.
Mild HIE — why Baylor does not cool
Mild HIE does carry a real risk: of 341 infants with mild HIE across observational studies and trials, 25% had abnormal neurodevelopmental outcomes. But the trial data do not show cooling helps. In the randomized subset — 45 cooled, 46 not — abnormal outcome was 29% versus 37%, odds ratio 0.67 (95% CI 0.28–1.61): a trend in the right direction that is nowhere near significant. Baylor therefore does not recommend routine therapeutic hypothermia for mild HIE (very low certainty evidence, strong recommendation), citing not only the absent benefit but the cost — more separation from parents, more invasive procedures and delayed oral feeding.
Probe placement and the rewarming sequence
- Oesophageal probe depth: measure nose tip → earlobe → xiphoid, then subtract 2 cm. Confirm with a two-view radiograph, the tip in the lower oesophagus above the stomach. Baylor cools to 33.5 °C oesophageal core temperature for 72 hours on a servo-controlled blanket with the incubator or warmer heat source off throughout.
- Rewarming: raise the servo set point by 0.5 °C every hour until it reaches 36.5 °C, held for 1 hour. Then switch the radiant warmer on with its servo set point 0.4 °C above the infant's skin temperature. Once skin temperature reaches 36.5–37 °C, return to standard thermal care. Monitor oesophageal and skin temperature continuously throughout.
- During passive cooling before transfer, check the temperature every 15 minutes — overcooling is the risk. Active servo-controlled cooling with continuous rectal monitoring should be used in transport where available.
Managing the cooled infant, system by system
- Respiratory: most need ventilation for poor effort, but usually at low settings — there is rarely intrinsic lung disease. Avoid hypocarbia and hyperoxia, both of which worsen brain injury, and watch for pulmonary hypertension. Keep the ventilator humidifier and heater running during cooling.
- Cardiovascular: expect asymptomatic sinus bradycardia at 80–100 bpm — that is the therapy working, not a complication. Monitor blood pressure closely, treat hypotension with vasoactives, and consider echocardiography for function and right-sided pressures.
- Fluids: start at 40–60 mL/kg/day and adjust to urine output and renal function. Avoid fluid boluses and avoid bicarbonate — the lactic acidosis will correct with time. NPO throughout, on parenteral nutrition. Follow calcium, potassium, magnesium, creatinine, urine output and glucose closely.
- Infection: treat infection as a serious possible cause of the encephalopathy — blood culture on admission and ampicillin with an aminoglycoside.
- Neurology: continuous EEG for clinical and electrographic seizures, treated with neurology. Morphine for pain, shivering and irritability — load 0.1 mg/kg then infuse at 0.01 mg/kg/h, titrated. Brain MRI with spectroscopy on day 5–6, without contrast. Cranial ultrasound can show haemorrhage and resistive indices as a marker of cerebral oedema.
- Skin: reposition every 2 hours while cooled.
- Access and labs: UAC for continuous pressure, UVC for fluids and nutrition. On admission: CBC with differential, blood gas, DIC panel, chemistry, ionized calcium, liver function tests, blood culture and a point-of-care glucose.
- Prognosis: an improved or normal EEG and neurological examination by 7 days are good signs. In the NICHD trial, death or moderate-to-severe disability at 18–22 months was 44% with cooling against 62% without, with mortality 24% versus 37%, moderate-to-severe cerebral palsy 19% versus 30%, blindness 7% versus 14% and hearing impairment 4% versus 6%. At 6–7 years death or severe disability was 41% versus 60%. Sobering counterpoint: of the children already disabled at 18 months, 88% in the cooled group and 95% of controls remained so at 6–7 years — cooling changes who becomes disabled, not the course once disability is established.
Evidence & Source Notes
- Cooling to 33.5°C for 72 h within 6 h of birth for moderate–severe HIE at ≥36 weeks reduces death/disability (TOBY, NICHD, CoolCap; Cochrane).
- Other sources: the West Midlands protocol targets 33–34°C during stabilisation/passive cooling (default here 33.5–34.5°C); the active maintenance target is 33.5°C in both.
- ⚠ Uncertain / individualised: cooling for mild HIE, cooling at 35 weeks, "late" cooling (6–24 h), and cooling in low-resource settings — flagged for expert review; do not extend indications without specialist agreement.
8. Supportive Care During Cooling
Physiological Targets
Keep physiology in a narrow, brain-protective range; note that targets during active cooling may differ slightly from your local proforma.
| System | Target | Notes |
|---|
| Temperature | Core 33.5°C (active) / 33.5–34.5°C (passive) | Avoid overshoot and hyperthermia; continuous rectal monitoring. |
| Oxygenation | Avoid hypoxaemia and hyperoxia (e.g., SpO₂ >94%, PaO₂ ~10–12 kPa) | Correct blood gases for temperature per your analyser policy. |
| CO₂ | PaCO₂ ~6–8 kPa; avoid hypocapnia | Hyperventilation is contraindicated (reduces cerebral blood flow). |
| Blood pressure | Mean arterial pressure ≥45 mmHg | Use inotropes for poor cardiac output; avoid unnecessary volume. |
| Heart rate | ~80–100 bpm expected during cooling | A rising rate may signal pain/seizures/hypovolaemia. |
| Glucose | Normoglycaemia | Avoid hypo- and hyperglycaemia (both worsen outcome). |
| Fluids | Start ~40 mL/kg/day, restrict | Watch for AKI and SIADH; avoid severe hyponatraemia. |
| Sedation | Morphine infusion (e.g., ~20 microgram/kg/hr) | Cooling is uncomfortable; titrate to comfort; watch accumulation with hepatic/renal impairment. |
Baseline Investigations
Blood culture, FBC, blood gas, lactate, electrolytes, urea/creatinine, calcium, magnesium, glucose, coagulation (PT/APTT), and liver function; save cord gases and placenta for histology. Add MRI (day 5–6) and EEG/aEEG for prognostication and seizure detection.
9. Medication Considerations
Drug Table (Verify All Doses Locally)
Confirm every dose against the Neonatal Formulary; drug clearance is altered during hypothermia.
| Agent | Role | Practical dosing note | Cautions / monitoring |
|---|
| Morphine (infusion) | Sedation/comfort during cooling | e.g., ~20 microgram/kg/hr, titrate to HR/comfort. | Accumulation with hepatic/renal impairment; respiratory depression (usually ventilated). |
| Phenobarbital | First-line anticonvulsant for seizures | Loading 20 mg/kg IV; further 10 mg/kg increments per protocol (max often ~40 mg/kg). | Sedation, hypotension, respiratory depression; monitor levels. |
| Levetiracetam / phenytoin (2nd line) | Ongoing seizures | Per local seizure protocol (see 9.3). | Phenytoin: cardiac monitoring; levetiracetam generally well tolerated. |
| Inotropes (dopamine/dobutamine/adrenaline) | Support MAP/cardiac output | Titrate to perfusion and echo. | Blood pressure is a poor surrogate for cardiac output. |
| Dextrose infusion | Maintain normoglycaemia | Higher glucose concentration if needed. | Frequent glucose monitoring. |
Not Recommended
Prophylactic anticonvulsants are not recommended; treat clinical/electrographic seizures. Routine sodium bicarbonate, mannitol, and high-dose steroids are not part of standard HIE care. Adjunct neuroprotective agents (e.g., erythropoietin, melatonin, xenon) remain investigational.
10. Monitoring
Monitoring Table
Multimodal monitoring throughout cooling, rewarming, and the early recovery period.
| Parameter | Frequency | Target | Action if abnormal |
|---|
| Core (rectal) temperature | Continuous; document ≥q15 min in stabilisation | 33.5°C (active); 33.5–34.5°C (passive) | Avoid <33°C and any hyperthermia; adjust device. |
| aEEG/EEG | Continuous where available | Improving background; no seizures | Treat electrographic seizures; aids prognosis. |
| Blood gas / lactate | Regular | PaCO₂ 6–8 kPa, adequate PaO₂, falling lactate | Adjust ventilation; avoid hypocapnia/hyperoxia. |
| Blood pressure / perfusion | Continuous (arterial) | MAP ≥45 mmHg, good perfusion | Inotropes; echo-guided. |
| Glucose, electrolytes, Ca/Mg | Regular | Normal ranges | Correct; watch AKI, SIADH, coagulopathy. |
| Renal output / coagulation / LFTs | Daily+ | Adequate urine; stable coagulation | Multi-organ support; product replacement as needed. |
| MRI brain | Once, day 5–6 | — | Prognostication; guides counselling/follow-up. |
11. Contraindications & Precautions
Safety Cautions
- Never allow hyperthermia — even brief overheating worsens brain injury; and never overshoot below 33°C (never use ice).
- Do not delay cooling for consent, aEEG, or transfer — start passive cooling immediately when criteria are met.
- Avoid hypocapnia (hyperventilation) and hyperoxia — both reduce cerebral perfusion/oxidative safety.
- Avoid hypoglycaemia and hyperglycaemia; maintain MAP ≥45 mmHg.
- Relative cautions for cooling: significant coagulopathy/bleeding, major congenital anomaly incompatible with benefit, and moribund infants — discuss with the cooling centre.
- Rewarm slowly (~0.5°C/h) — rapid rewarming can provoke seizures and hypotension.
- Drug clearance is reduced during hypothermia — watch for morphine and anticonvulsant accumulation.
12. Escalation & Follow-Up
Escalate / Refer
- Contact the regional cooling centre the moment criteria are met; arrange neonatal transport.
- Refractory seizures, refractory hypotension/multi-organ failure, coagulopathy, or diagnostic uncertainty → senior/subspecialty input (neurology, metabolic).
- Consider redirection-of-care discussions with severe, unresponsive encephalopathy per network ethics guidance.
Follow-Up
- MRI (day 5–6) and EEG for prognostication; document findings for counselling.
- Structured neurodevelopmental follow-up (motor, cognitive, hearing, vision, feeding, growth) into early childhood.
- Hearing screen (SNHL risk), feeding/swallow assessment, and early-intervention referral as needed.
Parent Counselling Points
- "Your baby had a period of reduced oxygen/blood flow around birth that can affect the brain. We are lowering the body temperature slightly for three days, which is proven to protect the brain."
- "Cooling needs to start quickly, so we begin here and, if needed, transfer your baby to a specialist cooling centre. We will keep you fully informed."
- "An MRI scan after cooling and ongoing follow-up help us understand your baby's brain and development. Outcomes vary, and we will support you through each step."
13. Key Pearls
High-Value Clinical Pearls
- The clock starts at birth — cooling must begin within 6 hours; start passive cooling immediately, before consent or transfer.
- Encephalopathy evolves — reassess an at-risk but initially normal infant repeatedly through the first 6 hours.
- If aEEG isn't available and A + B are met, cool anyway — don't wait.
- Hyperthermia is the enemy: never overheat, and don't overshoot below 33°C.
- Cool to 33.5°C for 72 hours, then rewarm slowly (~0.5°C/h) watching for rebound seizures.
- Treat seizures (phenobarbital first-line); don't give prophylactic anticonvulsants.
- MRI on day 5–6 gives the best prognostic picture.
14. Common Mistakes to Avoid
Pitfalls & Better Practice
The recurring errors in HIE recognition and cooling.
| Mistake | Why it harms | Better practice |
|---|
| Waiting for consent/transfer before cooling. | Loses irreplaceable therapeutic time. | Start passive cooling immediately; consent can follow. |
| Missing evolving encephalopathy. | Eligible infant not cooled in the window. | Reassess repeatedly in the first 6 hours. |
| Inadvertent hyperthermia (heater left on, over-bundling). | Worsens brain injury. | Turn off heat sources; continuous temperature monitoring. |
| Hyperventilating / chasing high saturations. | Hypocapnia and hyperoxia reduce cerebral protection. | PaCO₂ 6–8 kPa; avoid hyperoxia. |
| Prophylactic anticonvulsants. | No benefit; adds sedation. | Treat clinical/electrographic seizures only. |
| Rapid rewarming. | Rebound seizures, hypotension. | Rewarm ~0.5°C/hour with monitoring. |
15. Board-Style High-Yield Summary
Key Takeaways
- Cool infants ≥36 weeks (35 wk discuss), ≤6 h old, with moderate–severe HIE meeting Criteria A + B (± aEEG C).
- Criterion A: Apgar ≤5 at 10 min, resuscitation at 10 min, pH <7.0, or base deficit ≥16. Criterion B: altered consciousness plus hypotonia/abnormal reflexes/weak suck/seizures.
- Start passive cooling immediately (turn off heat, rectal probe); do not wait for consent/aEEG/transfer.
- Active cooling to 33.5°C for 72 h, then rewarm ~0.5°C/h; avoid hyperthermia and overshoot.
- Supportive targets: PaCO₂ 6–8 kPa (avoid hypocapnia), avoid hyperoxia, MAP ≥45 mmHg, normoglycaemia, fluid restriction ~40 mL/kg/day.
- Treat seizures (phenobarbital first-line); no prophylactic anticonvulsants. MRI day 5–6 for prognosis.
16. References
- 1.Bedside Clinical Guidelines Partnership / West Midlands Neonatal ODN. Hypoxic Ischaemic Encephalopathy including Preparation for Active Cooling. Neonatal Guidelines 2025–28.
- 2.Azzopardi D, et al. (TOBY Study Group). Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361:1349–1358.
- 3.Shankaran S, et al. (NICHD). Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. N Engl J Med. 2005;353:1574–1584.
- 4.Jacobs SE, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013.
- 5.Committee on Fetus and Newborn (AAP). Hypothermia and neonatal encephalopathy. Pediatrics. 2014 (reaffirmed).
- 6.Baylor College of Medicine, Division of Neonatology. Guidelines for Acute Care of the Neonate, Edition 33, 2025–2026.
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