Definition and Overview
Status epilepticus (SE) is defined operationally as:
- A single seizure lasting $\geq 5$ minutes, OR
- Two or more seizures without return to baseline consciousness between episodes
This 5-minute threshold has largely replaced the older 30-minute definition in both clinical and paediatric ICU practice, because seizures that persist beyond 5 minutes are unlikely to self-terminate and are increasingly refractory to treatment. Neuronal injury risk rises with duration, establishing urgency for immediate escalation.
Refractory SE (RSE): failure to terminate despite adequate doses of two appropriate anticonvulsant agents (typically a benzodiazepine plus a second-line agent).
Super-refractory SE (SRSE): SE persisting or recurring beyond 24 hours of anaesthetic coma.
Non-convulsive SE (NCSE): electrographic SE without overt motor activity; clinically recognised by unexplained altered consciousness, subtle eye deviation, or subtle facial/limb twitching. Requires EEG for diagnosis. In critically ill children, NCSE may follow convulsive SE as the motor activity subsides while electrographic seizures continue.
Pathophysiology
The underlying mechanism involves an imbalance between excitatory (glutamate, NMDA-receptor mediated) and inhibitory ($\text{GABA}_\text{A}$-receptor mediated) neurotransmission. With prolonged seizure activity:
- Surface $\text{GABA}_\text{A}$ receptors are internalised, reducing benzodiazepine efficacy over time
- NMDA receptor upregulation amplifies excitotoxic calcium influx
- Progressive neuronal metabolic exhaustion, failure of ionic gradients, cerebral oedema, and neuronal death follow
This receptor trafficking explains why early benzodiazepine administration is far more effective than late administration, and why second- and third-line agents targeting different receptor populations are required as SE extends.
Common aetiologies in children:
| Category | Examples |
|---|---|
| Febrile / infectious | Febrile SE, meningitis, encephalitis |
| Structural | Cortical dysplasia, TBI, hypoxic-ischaemic injury, stroke |
| Metabolic | Hypoglycaemia, hyponatraemia, hypocalcaemia, hypomagnasaemia |
| Epilepsy-related | Breakthrough seizures, subtherapeutic AED levels |
| Toxic / withdrawal | Drug ingestion, alcohol (adolescent), benzo withdrawal |
| Immune-mediated | Anti-NMDAR encephalitis, FIRES (febrile infection-related epilepsy syndrome) |
| Genetic / metabolic | GLUT1 deficiency, pyridoxine-dependent epilepsy, mitochondrial disease |
Clinical Features and Diagnosis
Convulsive SE
- Sustained generalised tonic-clonic or focal motor activity
- Evolves to subtle SE: low-amplitude distal twitching, eye deviation, pupillary cycling, while consciousness remains impaired
Non-convulsive SE
- Unexplained coma, encephalopathy, or fluctuating consciousness in a PICU patient
- Subtle facial automatisms, nystagmoid movements, or rhythmic blinking
- EEG is required for diagnosis; continuous EEG monitoring is the standard in the PICU for any patient with unexplained consciousness impairment after seizure management
Age-specific Considerations
- Neonates: seizures are often subtle (lip smacking, cycling, apnoea); EEG dissociation from clinical movements is common; require early EEG
- Infants: spasms and myoclonic events may be missed; developmental context critical
- Older children: focal onset with secondary generalisation is the most common pattern
Investigations
Perform simultaneously with treatment; investigations should not delay anticonvulsant administration.
| Investigation | Purpose |
|---|---|
| Point-of-care glucose (immediate) | Exclude hypoglycaemia; treat if $< 3\,\text{mmol/L}$ |
| Electrolytes (Na, K, Ca, Mg, Ph) | Correct metabolic triggers |
| Venous blood gas | Acid-base; lactate as seizure marker |
| FBC, CRP, blood culture | Infectious aetiology |
| Ammonia | Urea cycle defects in neonates/young children |
| AED drug levels | Subtherapeutic phenytoin, levetiracetam, etc. |
| Urine toxicology | Ingestion in adolescents |
| LP (after imaging if ICP concern) | Meningitis, encephalitis |
| MRI brain (after stabilisation) | Structural, inflammatory, FIRES, ADEM |
| EEG (continuous) | NCSE, post-treatment monitoring, depth of burst suppression in RSE |
| Autoimmune encephalitis panel | Anti-NMDAR and others if no infectious cause found |
| Metabolic screen | Amino acids, organic acids, plasma lactate/pyruvate ratio in neonates/infants |
Hypoglycaemia correction: $10\%$ dextrose $2\,\text{mL/kg}$ IV bolus (neonates) or $2\,\text{mL/kg}$ of $10\%$ dextrose (infants/children); avoid hypertonic glucose in neonates without careful monitoring.
Management: Escalation Protocol
The following stepwise approach is aligned with ANZCOR paediatric guidelines and major Australian/New Zealand tertiary PICU practice. Time stamps are critical: document seizure onset time and each intervention.
Step 1: Immediate (0-5 minutes)
- Protect airway, position lateral, apply supplemental oxygen
- Establish IV or IO access while seizure is occurring
- Check point-of-care glucose immediately; correct hypoglycaemia
- Do not leave child unattended; call for nursing and senior assistance
- If no IV/IO within 2 minutes: intranasal (IN) midazolam $0.2\,\text{mg/kg}$ (max $10\,\text{mg}$) or buccal midazolam $0.3\,\text{mg/kg}$ (max $10\,\text{mg}$) or rectal diazepam $0.5\,\text{mg/kg}$ (max $10\,\text{mg}$)
Step 2: First-line Benzodiazepine (5 minutes, access obtained)
IV/IO lorazepam $0.1\,\text{mg/kg}$ (max $4\,\text{mg}$) IV over 1-2 minutes
- Lorazepam is preferred over diazepam IV because of its longer duration of anticonvulsant action
- May repeat once after 5 minutes if seizure continues: second dose lorazepam $0.1\,\text{mg/kg}$ IV (max $4\,\text{mg}$)
- Diazepam IV $0.3\,\text{mg/kg}$ (max $10\,\text{mg}$) is an acceptable alternative if lorazepam unavailable
- Have airway equipment and bag-mask ventilation immediately available before benzodiazepine administration
Step 3: Second-line Agent (15-20 minutes, benzodiazepine failed)
Choose one of the following; give IV/IO:
| Drug | Dose | Infusion rate | Notes |
|---|---|---|---|
| Levetiracetam | $40-60\,\text{mg/kg}$ (max $3000\,\text{mg}$) | Over 15 min | Preferred in many ANZ centres; minimal haemodynamic effect |
| Sodium valproate | $25-40\,\text{mg/kg}$ (max $3000\,\text{mg}$) | Over 15 min | Avoid in suspected mitochondrial disease, urea-cycle defects, liver disease |
| Phenytoin (fosphenytoin preferred) | $20\,\text{mg/kg}$ phenytoin equivalents (PE) | $\leq 1\,\text{mg/kg/min}$ PE (max $50\,\text{mg/min}$) | Requires cardiac monitoring; avoid in known structural heart disease; ECG monitoring mandatory |
| Phenobarbitone | $20\,\text{mg/kg}$ | Over 20-30 min | First-line in neonates; higher sedation and respiratory depression risk |
Neonatal-specific note: Phenobarbitone $20\,\text{mg/kg}$ IV is first-line second-line agent in neonates because of its superior efficacy in neonatal seizures; additional increments of $5-10\,\text{mg/kg}$ can be given to a total of $40\,\text{mg/kg}$. Pyridoxine $100\,\text{mg}$ IV should be administered empirically if pyridoxine-dependent epilepsy is possible.
Step 4: Refractory SE (30-60 minutes, two agents failed)
At this point the child almost certainly requires:
- Intubation and mechanical ventilation (RSA with fentanyl $1-2\,\text{microgram/kg}$ + ketamine $1-2\,\text{mg/kg}$ or midazolam; note propofol infusion for induction is acceptable for RSI in older children but avoid propofol infusion for ongoing seizure suppression in children $< 16$ years due to PRIS risk)
- Continuous EEG monitoring to target burst suppression if required
- Second second-line agent (e.g. if levetiracetam given, add valproate or phenobarbitone)
Midazolam infusion: Loading dose $0.15\,\text{mg/kg}$ IV then infusion $0.05-0.4\,\text{mg/kg/h}$, titrating to seizure cessation on EEG
Step 5: Super-Refractory SE (anaesthetic coma)
Reserve for SE persisting $> 24$ hours or recurrence on waking from anaesthesia:
| Agent | Initial dose | Infusion | Special considerations |
|---|---|---|---|
| Midazolam (if not already running) | $0.15\,\text{mg/kg}$ bolus | $0.05-0.4\,\text{mg/kg/h}$ | Accumulates in adipose/renal impairment |
| Thiopentone | $3-5\,\text{mg/kg}$ IV bolus | $1-5\,\text{mg/kg/h}$ | Profound haemodynamic depression; vasopressor support usually required; requires arterial line |
| Ketamine | $1.5\,\text{mg/kg}$ bolus | $0.3-7.5\,\text{mg/kg/h}$ | NMDA antagonist; emerging role in SRSE; haemodynamic stability advantage |
| Propofol | $1\,\text{mg/kg}$ bolus | $1-4\,\text{mg/kg/h}$ | AVOID in children as a continuous infusion: propofol infusion syndrome (PRIS) risk, especially $> 4\,\text{mg/kg/h}$ or $> 48$ hours; only use if absolutely no alternative and with triglyceride and lactate monitoring |
Target: EEG burst suppression with 2-6 second interburst intervals, confirmed on continuous EEG.
After 24-48 hours of burst suppression, gradually wean infusion while monitoring EEG for recurrence.
Special Considerations
FIRES (Febrile Infection-Related Epilepsy Syndrome)
- Previously healthy school-age child; febrile prodrome followed by explosive refractory SE
- EEG: continuous or sub-continuous focal or multifocal seizure activity
- MRI often normal early; may show thalamic or multifocal signal change later
- Immunotherapy (IVIG, methylprednisolone, plasma exchange, anakinra) used empirically alongside anaesthetic agents
- Ketogenic diet has evidence in FIRES; early dietitian and metabolic physician involvement
- High mortality and severe neurocognitive morbidity in survivors
Anti-NMDAR Encephalitis
- Prodromal psychiatric features followed by seizures, movement disorder, autonomic instability
- CSF: pleocytosis; serum and CSF anti-NMDAR antibodies
- First-line: IVIG $2\,\text{g/kg}$ total (divided over 2-5 days) + high-dose methylprednisolone; second-line: rituximab or cyclophosphamide
- Seizures may partially respond to anaesthetic agents; immunotherapy is the definitive treatment
Neonatal Seizures
- Often electroclinical dissociation: EEG seizure without clinical correlate after phenobarbitone loading
- Confirm seizure cessation with EEG, not just clinical observation
- Levetiracetam increasingly used as second agent in neonates (evidence base still evolving)
- Exclude and treat: hypoglycaemia, hypocalcaemia, hypomagnesaemia, hyponatraemia, pyridoxine dependency, biotinidase deficiency
Benzodiazepine Selection Summary
| Drug | Route | Dose (child) | Comments |
|---|---|---|---|
| Lorazepam | IV/IO | $0.1\,\text{mg/kg}$ (max $4\,\text{mg}$) | Preferred IV first-line; longer duration than diazepam |
| Midazolam | IN/buccal | $0.2\,\text{mg/kg}$ IN, $0.3\,\text{mg/kg}$ buccal (max $10\,\text{mg}$) | Pre-hospital / no IV access |
| Diazepam | IV, rectal | IV $0.3\,\text{mg/kg}$; rectal $0.5\,\text{mg/kg}$ (max $10\,\text{mg}$) | Shorter CNS duration; rectal route for pre-hospital |
| Clonazepam | IV | $0.01-0.02\,\text{mg/kg}$ (max $1\,\text{mg}$) | Used in some centres; available in ANZ |
Monitoring in the PICU
- Continuous EEG for any child with RSE, NCSE concern, or after neuromuscular blockade; amplitude-integrated EEG (aEEG) for neonates
- Arterial line for continuous BP, gas sampling during thiopentone infusion or any haemodynamically unstable child
- End-tidal CO$_2$ and pulse oximetry: respiratory depression risk with every agent
- Drug levels of anticonvulsants at steady state and if clinical response is inadequate
- Glucose monitoring $q2$h during IV dextrose and in any metabolic or neonatal cause
Complications
| Complication | Comment |
|---|---|
| Respiratory depression / aspiration | Benzodiazepines and phenobarbitone; anticipate need for airway management at each step |
| Hypotension | Thiopentone and high-dose midazolam; vasopressor support often needed |
| PRIS (propofol infusion syndrome) | Metabolic acidosis, rhabdomyolysis, cardiac failure; avoid prolonged propofol infusions in children |
| Cerebral oedema | Consequence of prolonged SE; hyperpyrexia and hypoxia worsen outcome |
| NCSE after convulsive SE | Occurs when motor activity stops but electrographic seizures continue; only detectable by EEG |
| Hyperpyrexia | Muscle activity generates heat; active cooling, paralysis reduces metabolic demand |
| Electrolyte derangement | Hyponatraemia from inappropriate ADH; hypoglycaemia from metabolic demand |
PICU-Specific Practical Points for the Viva
- Airway first: at any step where further sedating anticonvulsants are given, prepare for intubation; do not administer second-line agents without airway backup immediately available
- IO access is equivalent to IV: place IO without delay in a seizing child when IV access is not rapidly obtained
- Treat the cause in parallel: hypoglycaemia, hyponatraemia, hypocalcaemia, and meningitis are treated simultaneously with anticonvulsant escalation, not after
- Propofol infusion is contraindicated for ongoing seizure suppression in children: use midazolam or thiopentone infusion; if propofol is used for RSI, switch to an alternative within minutes
- Document everything by time: seizure onset, each drug given with dose, response, and when EEG monitoring commenced
- The ketogenic diet has a legitimate role in medically refractory epilepsy including RSE in the PICU; involve neurology and nutrition teams early in FIRES