Hypoxic-ischaemic encephalopathy

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Interrupted placental or neonatal gas exchange reduces cerebral oxygen delivery. Primary energy failure disrupts ion pumps and causes depolarisation, excitotoxicity, calcium entry and cell swelling.

Partial recovery can be followed hours later by secondary energy failure involving oxidative stress, mitochondrial dysfunction, inflammation and seizures. The latent interval creates the time-limited opportunity for cooling.

HIE severity is described clinically as mild, moderate or severe using consciousness, activity, posture, tone, primitive reflexes, autonomic function and seizures. Findings evolve, so serial examinations matter.

Therapeutic hypothermia reduces cerebral metabolism and secondary injury. Evidence supports selected term and near-term infants with moderate or severe HIE when treatment starts within 6 hours and follows a controlled protocol.

The usual whole-body target is 33–34°C, commonly 33.5°C, maintained for 72 hours. Rectal or core temperature is monitored continuously and rewarming is slow, often no faster than 0.5°C/hour.

Passive cooling without feedback can overshoot, especially during transport. The referring and receiving teams should agree when to switch off external heat, how to monitor core temperature and what lower safety boundary triggers correction.

Seizures increase metabolic demand and are frequently electrographic without visible movements. Antiseizure therapy can abolish clinical signs while electrical seizures continue, making EEG monitoring central.

Hypoxic-ischaemic injury also affects myocardium, pulmonary vascular resistance, kidney, liver, gut and coagulation. Fluid, inotrope, antibiotic and drug-clearance decisions therefore require repeated organ assessment.

Mild encephalopathy does not meet routine cooling evidence in many pathways but is not synonymous with no risk. These infants need careful serial examination and locally defined neurological follow-up.

Family communication should begin early, acknowledge uncertainty, explain cooling and monitoring, and revisit prognosis as objective information accumulates.

Key points

Neonatal encephalopathy is abnormal neurological function; HIE is the subset attributable to impaired oxygen delivery and perfusion around birth after alternative causes are considered.
Assess biological evidence of perinatal compromise and neurological evidence of moderate or severe encephalopathy; neither an isolated low pH nor a difficult birth alone proves HIE.
Stabilise effective ventilation, oxygenation and circulation while avoiding hyperoxia, hypocarbia, hyperthermia, hypoglycaemia, marked hyperglycaemia and hypotension.
First-line disease-modifying treatment for eligible moderate or severe HIE is controlled therapeutic hypothermia started as soon as possible and within 6 hours.
UK standard pathways usually apply to babies at least 36 weeks, using whole-body cooling to about 33.5°C for 72 hours followed by slow controlled rewarming.
Use a regional eligibility protocol incorporating acute event, cord or early gas, 10-minute Apgar or continued ventilation, neurological examination and aEEG or EEG; exact entry criteria vary.
Do not delay referral while waiting for aEEG when clinical and biological criteria strongly suggest eligibility; start controlled thermal management with the cooling centre.
Continuous multichannel EEG is the reference standard for seizure detection. aEEG provides useful bedside trending but can miss brief, focal or low-amplitude seizures.
Treat electrographic seizures that are prolonged or frequent. Phenobarbital remains common first-line neonatal antiseizure therapy, adjusted for organ dysfunction and specialist protocol.
Monitor renal, hepatic, cardiac, coagulation, glucose and electrolyte function because HIE is a multiorgan disease and cooling changes pharmacokinetics.
Brain MRI with diffusion and spectroscopy after the acute phase supports injury definition and prognosis; timing follows the neonatal neurology pathway.
Prognosis must integrate serial examination, EEG background and seizures, MRI, organ course and development; avoid a definitive prediction from one early measure.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Acute sentinel event

Placental abruption, uterine rupture, cord prolapse, fetomaternal haemorrhage and profound bradycardia can abruptly interrupt oxygen delivery.

Prolonged intrapartum compromise

Sustained impaired placental exchange or difficult transition may produce combined hypoxaemia, hypercarbia, acidosis and low perfusion.

Postnatal cardiorespiratory failure

Failure to establish ventilation, severe pulmonary disease or shock can extend or create hypoxic-ischaemic injury after birth.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Primary energy failure
Oxygen and substrate deprivation deplete ATP, disrupt ion gradients and cause cellular swelling and excitotoxic injury.
2
Latent phase
Partial metabolic recovery over several hours creates the window in which controlled cooling can modify secondary injury.
3
Secondary energy failure
Mitochondrial dysfunction, oxidative stress, inflammation and seizures drive delayed neuronal cell death and evolving neonatal encephalopathy after the latent phase.
4
Multiorgan hypoperfusion
The same event injures myocardium, kidney, liver, gut, lung vasculature and coagulation, altering physiology and drug clearance.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Perinatal timeline

Reconstruct the perinatal timeline: fetal heart-rate abnormality, sentinel event, meconium, cord complication, placental abruption, shoulder dystocia, uterine rupture and resuscitation details.

Biological compromise

Record cord arterial and venous gases where available, an early neonatal gas, Apgar components and whether ventilation or compressions continued at 10 minutes.

Neurological examination

Perform and repeat a structured neurological examination covering consciousness, spontaneous activity, posture, tone, suck, Moro, pupils, heart rate, respiration and seizures.

Seizure phenotype

Distinguish seizures from jitteriness: seizures may show stereotyped eye, oral, tonic, clonic or autonomic events and do not reliably stop with gentle restraint.

Multiorgan injury

Assess perfusion, blood pressure, urine, liver size, bleeding, respiratory need, glucose and lactate to identify systemic injury and mimics.

Atypical course

Consider infection, stroke, intracranial haemorrhage, metabolic disease, electrolyte disturbance, maternal drugs and congenital brain disease when course or history is atypical.

Red flags requiring action

Apgar score 5 or lower at 10 minutes, ventilation still needed at 10 minutes, severe early acidosis or a documented acute perinatal event triggers urgent encephalopathy assessment.
Reduced alertness, abnormal tone, weak or absent suck or Moro reflex, abnormal pupils, apnoea or seizures indicates moderate or severe encephalopathy.
Subtle repetitive eye deviation, cycling, chewing, tonic posturing or autonomic change may be neonatal seizures and needs EEG correlation.
Hypotension, oliguria, bleeding, transaminitis, persistent lactate or myocardial dysfunction marks multiorgan hypoxic-ischaemic injury and modifies drug and fluid treatment.
Temperature above 37.5°C after hypoxic-ischaemic injury is harmful; uncontrolled cooling below the target also causes arrhythmia, coagulopathy and instability.
A baby below 36 weeks should not enter routine term cooling criteria automatically; current BAPM advice requires specialist individual decision because evidence of benefit is lacking and harm is possible.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: cord or early blood gas and serial lactateFirst stepFirst line
Why
Document biological evidence of impaired gas exchange and track perfusion recovery.
Interpretation and limitations
Severe acidosis supports eligibility when combined with clinical encephalopathy, but neither pH nor lactate alone confirms cause, severity or prognosis.
02
Reference standard: continuous multichannel EEGReference standard
Why
Detect, quantify and guide treatment of neonatal seizures and assess background recovery.
Interpretation and limitations
aEEG is useful immediately but may miss focal or short seizures. Suppressed background, high seizure burden and poor evolution increase concern but require multimodal interpretation.
03
Serial structured neurological examination
Why
Grade encephalopathy, establish cooling eligibility and follow evolution.
Interpretation and limitations
Sedation, antiseizure medicines, paralysis, hypothermia and systemic illness alter findings; document timing and treatment context.
04
Organ-injury profile
Why
Guide fluids, cardiovascular support and dose adjustment.
Interpretation and limitations
Check glucose, electrolytes including calcium and magnesium, renal and liver function, FBC, coagulation, troponin where used, gas and lactate; trend rather than interpret once.
05
Echocardiography and cranial ultrasound
Why
Assess myocardial function, pulmonary hypertension, volume status and major haemorrhage or structural pathology.
Interpretation and limitations
Ultrasound supports acute decisions but a normal cranial scan does not exclude hypoxic-ischaemic brain injury.
06
Prognostic imaging: brain MRI with diffusion and spectroscopy
Why
Define pattern and extent of injury after stabilisation.
Interpretation and limitations
Timing and sequences follow the regional neonatal-neurology protocol; combine imaging with EEG, serial examination and clinical course rather than predicting from MRI alone.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Infection

Sepsis, meningitis and neonatal HSV can cause depression and seizures and may coexist with significant documented perinatal compromise.

Stroke or haemorrhage

Focal seizures, persistent neurological asymmetry or an atypical clinical course directs urgent cranial imaging and coagulation assessment.

Metabolic or electrolyte disease

Hypoglycaemia, calcium or sodium disturbance, urea-cycle disease and mitochondrial disorders can closely mimic neonatal encephalopathy and seizures.

Medicine or congenital brain effect

Maternal sedatives, analgesics, malformation and genetic epileptic encephalopathy require consideration when the history does not fit HIE.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First 6 hoursIdentify and coolFirst stepPerinatal compromise is followed by abnormal neurological function.

1Stabilise physiology, avoid hyperthermia and gather cord gas, early gas, Apgar and resuscitation data.
2Grade encephalopathy and start aEEG/EEG; contact the regional cooling centre immediately.
3If eligible, begin controlled cooling as soon as possible within 6 hours and organise intensive-care transfer.

02CoolingControlled neuroprotectionTherapeutic hypothermia has started for an eligible newborn.

1Maintain core temperature at the protocol target, commonly 33.5°C, for 72 hours using servo control.
2Continuously monitor ECG, blood pressure, oxygenation and EEG and correct glucose, electrolyte, coagulation and organ abnormalities.
3Use analgesia and antiseizure treatment judiciously, recognising slowed clearance during cooling.

03RewarmingPrevent rebound injuryThe 72-hour cooling course is complete or a specialist stop indication arises.

1Rewarm slowly under the protocol, commonly no faster than 0.5°C/hour.
2Watch for hypotension, seizures, electrolyte shift and rebound hyperthermia.
3Continue EEG through rewarming when indicated and reassess the neurological examination after sedating medicines clear.

04After acute careDefine injury and support developmentThe baby is physiologically stable after cooling or encephalopathy care.

1Arrange protocol-timed MRI and formal hearing assessment and integrate findings in a family meeting.
2Establish neonatal neurology, therapy and developmental surveillance before discharge.
3Provide seizure, feeding and tone safety-netting and support parental mental health and bereavement needs when relevant.

Key medicines and prescribing safety1 treatment · regimens, roles and cautions

First-line antiseizure medicine for frequent or prolonged electrographic seizures associated with HIE; treatment decisions use EEG burden and clinical context.

Phenobarbital intravenous

Common first-line neonatal seizure loading is 20 mg/kg IV with cardiorespiratory monitoring; if electrographic seizures continue, specialists may give additional 10 mg/kg loads to a usual cumulative maximum of 40 mg/kg under the neonatal formulary. Maintenance is individualised.

Can cause respiratory depression, hypotension and sedation that obscures examination. Cooling and hepatic or renal injury delay clearance; use levels and specialist dose intervals, and support ventilation when required.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Motor and cognitive disability

Cerebral palsy, learning, language, behavioural and visual difficulties may emerge later and reflect the neonatal brain injury pattern and severity.

Epilepsy and feeding disorder

Persistent seizures, dysphagia, aspiration and growth difficulty may require prolonged neurological, respiratory, nutritional and multidisciplinary developmental support.

Hearing impairment

Auditory pathway injury may occur even when a bedside behavioural response seems present, requiring formal diagnostic audiological assessment and follow-up.

Organ failure and death

Severe HIE can cause refractory shock, pulmonary hypertension, renal failure, coagulopathy, hepatic injury and death despite timely neuroprotection.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Monitor core temperature continuously with an independent safety check; document target, actual temperature and cooling-device changes.
Use continuous ECG, oxygen saturation, respiratory monitoring and invasive blood pressure where indicated; avoid excessive oxygen and hypocarbia.
Continue aEEG or multichannel EEG through cooling and rewarming according to seizure burden and local protocol.
Check glucose frequently and trend sodium, potassium, calcium, magnesium, renal function, liver function, FBC and coagulation.
Measure urine output and fluid balance closely; acute kidney injury and SIADH-like water handling alter drug and fluid prescriptions.
Review antiseizure and sedative doses daily because hypothermia, liver injury and renal injury slow clearance.
After discharge monitor growth, feeding, hearing, vision, tone, movement, epilepsy and development through an explicit high-risk pathway.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Six hours is a therapeutic boundary

Assessment, referral and transfer must run in parallel; serial paperwork should not consume the latent neuroprotective window.

Normal movements do not exclude seizures

Many seizures are electrographic only, while visible abnormal movements can lack an EEG correlate; continuous EEG resolves the distinction.

Avoid fever

Hyperthermia after hypoxic-ischaemic injury worsens secondary damage, including in babies who do not qualify for cooling.

Cooling changes prescribing

Reduced hepatic and renal clearance can accumulate phenobarbital, opioids and other medicines; use levels and repeated organ assessment.

Prognosis is serial

Early acidosis starts the assessment; EEG recovery, examination after rewarming, MRI and subsequent development refine the outlook.

11Common pitfallsFrequent interpretation and management errors.

01
Do not equate every low cord pH with HIE or require acidosis when the clinical sentinel event and encephalopathy are compelling.
02
Do not miss the 6-hour cooling window while awaiting transfer, MRI or a perfect diagnostic label.
03
Do not allow uncontrolled passive cooling or rely on skin temperature rather than core temperature.
04
Do not apply routine term cooling automatically below 36 weeks without current specialist BAPM guidance.
05
Do not assume visible seizure cessation means electrographic seizure control.
06
Do not correct carbon dioxide, sodium or glucose abruptly without understanding cerebral and systemic consequences.
07
Do not use a single early examination or MRI statement as a definitive individual prognosis.
08
Do not discharge without hearing, neurological and developmental follow-up and a family-centred plan.