Hypoxic-Ischaemic Encephalopathy — Causes, Clinical Manifestations, Diagnosis and Management

Definition. Diffuse brain injury caused by a global reduction in oxygen delivery (hypoxia) and/or cerebral blood flow (ischaemia), most often after cardiac arrest. The injury is biphasic: primary ischaemic injury during the arrest, followed by secondary reperfusion injury after return of spontaneous circulation — and it is the secondary phase that is modifiable.

Causes. Cardiac arrest is the commonest. Others: respiratory arrest and severe hypoxaemia (COPD exacerbation, drowning, choking, strangulation, hanging), profound or prolonged shock and haemorrhage, carbon monoxide and cyanide poisoning, severe anaemia, status asthmaticus, anaesthetic and airway mishaps, and prolonged status epilepticus.

Pathophysiology and selective vulnerability. Energy failure → glutamate excitotoxicity → calcium influx → free-radical generation, mitochondrial dysfunction and apoptosis. Certain neurons are selectively vulnerable: the hippocampal CA1 sector, cerebellar Purkinje cells, cortical layers 3, 5 and 6, and the basal ganglia. Prolonged hypotension additionally causes watershed (border-zone) infarction.

Clinical spectrum. Outcomes range from full recovery through persistent coma, vegetative state (unresponsive wakefulness syndrome), minimally conscious state, and brain death. Milder injury leaves an amnestic (Korsakoff-like) syndrome from hippocampal damage, cortical blindness with denial (Anton’s syndrome), the watershed “man-in-a-barrel” pattern of proximal arm weakness with preserved distal function, and post-hypoxic parkinsonism or dystonia.

Post-hypoxic myoclonus. Two distinct forms. Acute myoclonic status within 24 hours of arrest is a poor prognostic sign but is no longer regarded as uniformly fatal and must not alone justify withdrawal of treatment. Lance– Adams syndrome is a delayed action myoclonus appearing days to weeks later in a patient who has regained consciousness; it responds to clonazepam, valproate, levetiracetam or piracetam.

Delayed post-hypoxic leukoencephalopathy. An apparent recovery followed by relapse after 2–4 weeks, with cognitive decline, parkinsonism and akinetic mutism, and diffuse white matter change on MRI — classically after carbon monoxide poisoning, but also after opioid overdose and prolonged hypoxia.

Clinical assessment. Serial neurological examination is central: GCS or FOUR score, pupillary and corneal reflexes, oculocephalic and oculovestibular responses, motor response to a standardised painful stimulus, breathing pattern, and the presence of myoclonus. Confounders must be excluded before any conclusion is drawn — residual sedatives (propofol, opioids, neuromuscular blockers), hypothermia, metabolic and electrolyte derangement, unrecognised seizures, and organ failure.

Investigations. EEG — malignant patterns are burst-suppression, a suppressed background and status epilepticus, whereas a continuous reactive background is favourable. Somatosensory evoked potentials — bilaterally absent N20 responses indicate a very poor prognosis. Serum neuron-specific enolase (NSE) and neurofilament light chain. CT brain — loss of grey–white differentiation, effaced sulci and the “pseudo-subarachnoid haemorrhage” sign. MRI with DWI at 2–7 days is the most sensitive imaging test.

Management — prevent secondary injury. Treat the underlying cause (coronary angiography and PCI where indicated). Maintain MAP ≥65–80 mmHg; avoid both hypoxaemia and hyperoxaemia; maintain normocapnia; keep normoglycaemia while strictly avoiding hypoglycaemia; prevent fever aggressively; treat seizures (levetiracetam or valproate) while avoiding deep prolonged sedation that will later confound prognostication; correct electrolytes; and provide standard critical-care supportive measures.

Prognostication and geriatric/ethical issues. Prognostication must be multimodal and delayed to at least 72 hours after normothermia and after sedation has cleared; no single test may be used alone. Markers of poor outcome: absent pupillary and corneal reflexes at ≥72 hours, bilaterally absent N20 SSEPs, a malignant EEG, myoclonic status, very high NSE, and diffuse injury on CT or MRI. In older adults, discuss goals of care, advance directives and surrogate decision-making early. Because withdrawal of life-sustaining therapy is the commonest mode of death, premature pessimism creates a self-fulfilling prophecy and must be avoided.

ERC/ESICM 2025 Post-Resuscitation Care Guidelines (adopting the 2024 ILCOR recommendations). The goal is now active fever prevention with a target temperature at or below 37.5 °C, rather than routine therapeutic hypothermia at 33 °C — following the TTM2 and HYPERION trials. Temperature control should be maintained for 36–72 hours using devices with feedback-controlled temperature monitoring, and routine prehospital cooling with cold intravenous fluid is not recommended. Neuroprognostication should be multimodal and delayed, with a repeat brain CT at 72–96 hours if the first scan showed no hypoxic-ischaemic change, and MRI ideally at 2–7 days.

AHA Post-Cardiac Arrest Care Guideline (Circulation, 2025). The neuroprognostication section has been expanded to include predictors of favourable outcome, not only of poor outcome, and serum neurofilament light chain (NfL) has been added alongside NSE as a biomarker — when used in combination with other prognostic tests, high NSE or NfL within 72 hours supports a prediction of unfavourable neurological outcome. Temperature control should be maintained for at least 36 hours in patients who remain unresponsive to verbal commands after ROSC, and CT plus echocardiography are reasonable after ROSC to establish the cause of arrest and detect resuscitation complications.