GOALS
> Protect airway if threatened, including recovery position, airway adjuncts and intubation if required
> Optimise oxygenation and provide ventilatory support as needed (watch for hypercapnia)
> Get IV (or IO) access
> Treat hypoglycaemia or life threatening electrolyte disturbances (low Na+, low Mg2+, low Ca2+) immediately
> Treat hypertensive crisis if present
> Terminate the seizure ASAP
> Actively treat hyperthermia
> If toxidrome suspected, give appropriate antidote e.g. pyridoxine for isoniazid, lipid emulsion for lipophilic drug overdose
> If > 20 weeks pregnant or up to 8 weeks post-partum, assume eclampsia, give magnesium
Benzodiazepine efficacy decreases over time. Hence time is the most important predictive factor for ease of seizure control
Benzodiazepines act on the GABA-A receptor. However, seizure activity causes these GABA-A receptors to be internalised into the neuronal cytoplasm.
Hence, the longer a seizure continues, the more GABA-A receptors become internalised and hence there will be increasingly less available GABA-A receptors for the benzodiazepines to act upon.
Rapid seizure control is essential to reduce seizure-induced neuronal injury i.e. excitotoxicity.
Evidence of neuronal damage has been found after ~30 minutes of continuous seizures.
Pathophysiology of seizure-induced excitotoxicity:
Excess glutamate during a seizure
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Increase in intracellular Ca
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Electrical signals sent to mitochondria
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Mitochondrial apoptosis
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Neuronal destruction
STABILISE PATIENT
> Protect airway
> Ensure adequate gas exchange, give oxygen for sats > 94%
MONITOR
> Monitor blood pressure, heart rate, oxygen saturations, ECG monitoring
BLOOD GLUCOSE
> Check blood glucose level (Finger prick)
> If <4 mmol/L give 100 mg thiamine then 50 ml of 50% dextrose
ACCESS & BLOODS
> Get IV access
> Bloods for FBC, EUC, CMP, LFT, Coags, relevant drug levels
> Still investigate for underlying cause
> Refer if required
> Give safety advice e.g. not to drive. More advice on this patient advice fact sheet
> Ascertain best disposition, will depend on case
> Still investigate for underlying cause
> Refer if required
> Give safety advice e.g. not to drive. More advice on this patient advice fact sheet
> Ascertain best disposition, will depend on case
BENZODIAZEPINE
One of the following (all work with similar efficacy)
> Midazolam IM or IV (0.1 mg/kg, max 10 mg, once only) IM not inferior to IV lorazepam
> Lorazepam IV (0.1 mg/kg, max 4 mg, slow push once only) onset in 3-5 minutes and last hours; preferred for longer acting effects
> Diazepam IV (0.1 mg/kg, max 10 mg, may repeat once) onset in ~1 minute but lasts only about ~20 min for anticonvulsant activity; not IM as painful
If none of these are available, other benzo options are:
> Diazepam per rectum 0.5 mg/kg max 20 mg
> Midazolam via intranasal or buccal routes
> Still investigate for underlying cause
> Refer if required
> Give advice not to drive
> Ascertain best disposition, will depend on case
SECOND AGENT
One of the following (all work with similar efficacy)
> Levetiracetam IV (60 mg/kg, max 4500 mg)
> Sodium Valproate IV (40 mg/kg, max 3000 mg) rate: give over 10 minutes
> Phenytoin slow IV (20 mg/kg, max 1500 mg) rate: 50 mg/min, 25 mg/min if elderly or cardiovascular comorbidity
> Still investigate for underlying cause
> Refer if required
> Give safety advice e.g. not to drive. More advice on this patient advice fact sheet
> Ascertain best disposition, will depend on case
GENERAL ANAESTHESIA
You could try another 2nd tier option but the seizure is now more likely to be stopped with general anaesthesia
This means Rapid Sequence Induction (RSI) and Intubation
RSI
There is not high level evidence to inform best practice for induction drugs
One approach:
Propofol 1.5 mg/kg AND
Ketamine 1 mg/kg
Rocuronium 1.5 mg/kg
With bolus dose pressors available e.g. metaraminol
POST INDUCTION
Midazolam infusion 0.05 mg/kg/h AND
Propofol infusion 2-5 mg/kg/h
EEG
Essential to exclude ongoing non-convulsive seizures
STILL FITTING?
Additional drugs to consider:
> Lacosamide 10 mg/kg max 500 mg IV over 10 minutes; if still fitting can give an additional 5 mg/kg max 250 mg over 5 minutes
> Phenytoin 20 mg /kg IV max 2000 mg. 50 mg/min (25 mg /min if elderly / hypotensive); if still fitting can give an additional 5 mg/kg IV
> Still investigate for underlying cause
> Refer if required
> Give safety advice e.g. not to drive. More advice on this patient advice fact sheet
> Ascertain best disposition, will depend on case
THIOPENTONE COMA
> 2-7 mg/kg over 50mg/min, with additional boluses 1-2 mg/kg as required
> Titrate to cessation of seizures on EEG
KETAMINE
> 1-2 mg/kg, max 4.5 mg/kg
> Infusion 1-10 mg/kg/h
> With benzodiazepine e.g. midazolam
> Continue supportive care in ICU
> Continue to investigate cause of seizures
> Reduce / cease general anaesthetic medications first
> Regular if not continuous EEG monitoring
LIGNOCAINE
> Has proconvulsant effects at higher doses and anticonvulsant effects at lower doses
VERAPAMIL
> Not actually an anti-epileptic, but appears to have a synergistic effect and can increase serum concentrations of other anti-epileptic drugs by affecting calcium channels
HYPOTHERMIA
> Cooling to ~32-35 degrees
> Complications: hypotension, electrolyte derangement, acidosis, DIC, VTE, infection, bowel ischaemia, arrhythmia on rewarming
KETOGENIC DIET
> 4:1 diet with initial complete avoidance of glucose
> Small evidence base
> Easy to administer via NG tube
SURGICAL RESECTION
> Obviously useful when related to the underlying aetiology i.e. space occupying lesion
> Can also be useful if there is a clear electrographic focus or lesion.
> The most common surgical procedure for focal medically refractory epilepsy is temporal lobectomy.
INHALATIONAL ANESTHETICS
> e.g. isoflurane, desflurane
> Hypotension and risk of hippocampal atrophy
> Difficult to wean due to frequent relapse on medication withdrawal
NEUROSTIMULATION
> e.g. vagal nerve stimulation, electroconvulsive therapy, trigeminal nerve stimulation, deep brain stimulation
> Unknown mechanism – thought to modulate neural networks and depends on location of stimulation
> Sparse and low quality evidence to support, mainly case series and case reports which suggest that neuromodulation techniques can abort SE
NEUROSTEROIDS
> e.g. allopregnanolone, THDOC
> Interact with GABA-A receptors and can directly activate these receptors at high concentrations.
> Favourable outcomes in animal studies and initial human studies show good efficacy
MAGNESIUM OR PYRIDOXINE
> Although usually used for specific causes, they are relatively safe and easy to administer, and are sometimes used in super refractory SE
> Continue supportive care in ICU
> Continue to investigate cause of seizures
> Reduce / cease general anaesthetic medications first
> Regular if not continuous EEG monitoring
OTHER EMERGENCY MANAGEMENT
The priority is stopping the seizure, but there some other important things not to forget…
It’s helpful to have the differential diagnosis for the cause of the seizures in mind at all times.
Drugs
> Withdrawal
from alcohol commonest
from benzodiazepines, barbiturates, baclofen, or gabapentin.
> Non-adherence with anti-epileptic therapy, changes in regimen, drug-drug interactions
> Medications that lower seizure threshold e.g.
Psychiatric medications (antipsychotics; antidepressants, especially bupropion or tricyclics; lithium)
Antimicrobials (e.g. beta-lactams, quinolones, metronidazole, acyclovir, gancyclovir, isoniazid)
Local anaesthetics (e.g. lidocaine)
Antihistamines
Ancient analgesics (tramadol, meperidine, propoxyphene)
Chemotherapeutics & immunomodulators (e.g. cisplatin, methotrexate, tacrolimus, cyclosporine)
Theophylline
> Toxicologic
Overdose with sympathomimetic, salicylate, tricyclic, anticholinergic, lithium, synthetic cannabinoids, more
Metabolic
> Hyponatraemia/hypernatraemia
> Hypoglycaemia/hyperglycaemia (hyperglycaemia may tend to cause focal seizures)
> Hypophosphataemia
> Hypoxemia, respiratory alkalosis
> Uraemia, dialysis disequilibrium
> Hyperammonaemia (of any cause), hepatic encephalopathy
> Hyperthermia
Malignancy
> Primary brain tumor (e.g. glioblastoma multiforme)
> Metastatic cerebral disease
Infectious / inflammatory
> Meningitis, encephalitis (viral, paraneoplastic, anti-NMDA receptor encephalitis)
> Brain abscess
> Lupus, vasculitis
> Sepsis with systemic inflammation (may reduce seizure threshold)
Vascular
> Previous stroke which caused scarring / residual epileptogenic focus.
> Acute stroke (ischemic > haemorrhagic).
> Hypertension-related:
Hypertensive encephalopathy /Posterior Reversible Encephalopathy Syndrome (PRES)
Eclampsia
Traumatic brain injury
> Any TBI can cause seizures
> More common in:
Severe TBI
Penetrating TBI
Open depressed skull fracture
History of alcohol abuse with TBI
EDH, ICH and SDH
A judgment call.
> You will often be able to manage without intubating.
> If there are persisting seizures and you are reaching tier 3 therapies using general anaesthesia (propofol & midazolam), then intubation will be necessary.
Note: If the patient is not to be intubated (e.g. they have previously indicated they would not want to be), then escalation beyond tier 2 ASM’s may be done with medications that don’t compromise respiratory function e.g. after initial benzodiazepines and levetiracetam consider another tier 2 ASM e.g. phenytoin, then lacosamide and or ketamine.
The “Neurolytic” Intubation
Intubating to stop a refractory seizure
A ketamine & propofol approach can be used. Here’s Josh Farkas’ way:
Keep physiology normal
> Anti seizure medications may cause hypotension
> An arterial line is usually required
> Vasopressors often required
> Blood pressure targets may depend on the underlying cause of the seizure e.g. if seizures are from an ICH, that will dictate BP targets
> Default could be MAP > 65 mmHg, NISBP > 100 mmHg
Signs and symptoms associated with seizures
Signs and symptoms of raised ICP: N/V, headache, papilloedema, dilated pupil, Cushing’s reflex, non reactive pupil(s)
Rapid neurological examination
Signs of head trauma
Fluid status
Signs of a toxidrome
> BGL – never forget glucose
> Bloods: FBC, EUC, CMP, LFT, BSL, drug levels, ß-hCG
> Blood culture
> Blood gas
> Urine MCS and urinalysis, urine toxicology
> CT brain after seizures controlled; consider contrast after non-con. Look for:
– Intracranial haemorrhage
– ischaemia
– Space-occupying lesion
> Lumbar puncture for CSF cell count and differential, protein, glucose, culture, viral PCR
– Take extra CSF to add tests later if needed
OUR CASE
Sharon is given IV midazolam and loaded with IV levetiracetam.
After, the generalised tonic-clonic seizure activity stops but Sharon remains unresponsive with a fixed lateral gaze.
A decision is made to intubate and commence infusions of midazolam and propofol, and she is admitted to ICU for further management.