Sepsis-Associated Encephalopathy

Sepsis associated encephalopathy is diffuse brain dysfunction caused by the systemic response to infection, without direct central nervous system infection, structural lesion or other identifiable cause. It ranges from mild inattention and delirium to coma.

Epidemiology. It occurs in about 30 to 70% of patients with sepsis, and is among the commonest causes of delirium in intensive care. It is associated with higher mortality and long term cognitive impairment.

Risk factors. Older age, pre-existing dementia or cognitive impairment, alcohol use, chronic organ disease (renal, hepatic), severity of sepsis, hypotension, hypoxia, hyperglycaemia and hypoglycaemia, electrolyte disorders, and sedative and anticholinergic drugs.

Pathophysiology. Blood brain barrier disruption, neuroinflammation with microglial activation, endothelial dysfunction, impaired cerebral autoregulation, disordered neurotransmission (cholinergic and GABAergic), mitochondrial dysfunction, ischaemic injury and metabolic derangements. Hepatic and renal failure and amino acid imbalance add to the injury.

Presentation is inattention, disorientation, fluctuating consciousness, agitation or hypoactive delirium, sleep disturbance, tremor, asterixis, multifocal myoclonus, paratonia and sometimes seizures or coma. Focal deficits are uncommon and suggest another diagnosis. Onset often precedes other organ failure.

Red flags.

• Focal deficit, new seizures or signs of meningism.
• Persisting coma after sepsis control.
• Fever and headache, or recent neurosurgery, which suggest CNS infection.

Sepsis associated encephalopathy is a diagnosis of exclusion. Screen with a validated delirium instrument (confusion assessment method for intensive care).

Check glucose, sodium, calcium, magnesium, phosphate, ammonia, urea, creatinine, liver tests, thyroid function, blood gas, vitamin B12 and thiamine (alcohol), drug levels, toxicology and infection markers.

CT or MRI head for focal signs, trauma or no improvement. Lumbar puncture if CNS infection is suspected. EEG (diffuse slowing, triphasic waves, or nonconvulsive seizures) when consciousness is unexplained or fluctuating.

Differential diagnosis. Meningitis, encephalitis, nonconvulsive status epilepticus, stroke, hepatic or uraemic encephalopathy, sedative and opioid effect, alcohol withdrawal, Wernicke encephalopathy, hypoglycaemia, hypercapnia and cerebral fat embolism.

Treat sepsis. Early antibiotics, source control, restoration of perfusion (mean arterial pressure at least 65 mmHg, higher in chronic hypertension), and avoidance of hypoxia and hypoglycaemia.

Correct metabolic causes. Sodium 135 to 145 mmol/L, glucose 7.8 to 10 mmol/L, calcium, magnesium, phosphate, and hepatic and renal dysfunction. Give thiamine 100 to 500 mg IV daily in patients at risk of Wernicke encephalopathy.

Medicine review. Reduce or stop sedatives (avoid benzodiazepines), opioids at high doses, anticholinergics and other deliriogenic drugs. Adjust renally cleared drugs (cefepime and carbapenems cause encephalopathy and seizures in renal impairment).

Sedation and agitation.

• Light sedation with dexmedetomidine 0.2 to 0.7 microgram/kg/h (monitor bradycardia and hypotension) or propofol when sedation is needed.
• Haloperidol 0.5 to 2 mg IV, repeated every 30 to 60 minutes if needed (maximum 10 mg in 24 hours) for severe agitation endangering the patient, with QT monitoring, and avoid in long QT.

Non-drug care. Reorientation, glasses and hearing aids, sleep promotion, family presence, early mobilisation, avoidance of restraints, and daily interruption of sedation.

Seizures. Levetiracetam 60 mg/kg IV (maximum 4500 mg) for confirmed seizures. Prophylaxis is not advised.

Prognosis and follow up. Many recover over days to weeks, but cognitive deficits persist in some. Arrange follow up clinic, cognitive screening and rehabilitation.

Monitoring. Delirium screening every shift, sedation scores, glucose, electrolytes, EEG as indicated and drug review daily.

Referral and escalation. Neurology for seizures, focal signs or prolonged coma, and intensive care. Psychiatry for severe agitation.

Special groups. In older adults, avoid anticholinergics and benzodiazepines. In alcohol use disorder, treat withdrawal with benzodiazepine (lorazepam 1 to 2 mg every 4 to 6 hours as needed) and thiamine.