In Hospital

The following agents may be used in the management of patients with SE:

Benzodiazepines

This group represents the first line of agents for treating SE, preventing the propagation of the seizure rather than affecting the original focus [10].

All have a rapid onset of action due to their lipid solubility and consequent ability to cross the blood-brain barrier.

The agents used most frequently are:

• Diazepam
• Lorazepam
• Midazolam

Both diazepam and lorazepam are lipid-soluble, the former being available as both intravenous and rectal preparations. Rectal diazepam will terminate seizures in 70% of patients; intravenous diazepam will terminate seizures in 60-80% of patients in SE.

Lorazepam is less lipophilic, has a smaller volume of distribution and a longer intracerebral half-life (12 hours) than diazepam. It may therefore provide more prolonged suppression of seizures. Intravenous lorazepam will terminate seizures in 60-90% of patients in SE.

Midazolam is water-soluble making it available for buccal or intranasal use, primarily in the pre-hospital setting.

All benzodiazepines carry the risk of respiratory depression and hypotension.

Hydantoins

Phenytoin is a long-acting drug whose advantage is the prevention of seizure recurrence over an extended period of time.

Its delayed onset (10 to 30 minutes) necessitates use in combination with a rapidly acting agent, typically a benzodiazepine.

Phenytoin is not water-soluble and is formulated with propylene glycol, which has the potential to cause significant side-effects including:

• Local infusion site reactions
• Arrhythmias mandating cardiac monitoring during infusion
• Hypotension

Phenytoin is associated with the ‘purple glove syndrome’ characterised by local oedema, skin discolouration and pain distal to the infusion site. Skin necrosis and limb ischaemia have been reported.

Complications are reduced by keeping infusion rates below 50 mg per minute and by avoiding co-infusion with dextrose-containing fluids which can lead to the formation of precipitates.

Fosphenytoin is the inactive prodrug of phenytoin which is broken down into the active drug by serum phosphatases. It has the advantage that it is water-soluble and hence is associated with fewer of the local side-effects. It may also be infused at a faster rate. However, the time taken for the active metabolite to be formed means that the time taken to achieve therapeutic phenytoin levels is similar for both.

Paraldehyde

Paraldehyde is recommended in many treatment algorithms as a second-line agent to be used after benzodiazepines in the absence of intravenous access.

It is given via the rectal route, mixed with an equal volume of olive oil.

Whilst there is little published evidence to support its use, there is a large body of anecdotal evidence.

Barbiturates

Barbiturates have a similar mode of action to benzodiazepines by modification of the actions of GABA.

These agents are not standard first-line drugs but may be used for patients with refractory SE.

Side-effects include respiratory depression and sedation, particularly if used after benzodiazepines.

Agents used include:

• Phenobarbital
• Thiopental
• Pentobarbital, a short-acting agent with a rapid onset of action that is very effective at terminating seizures.

Other Agents

Intravenous Pabrinex® or thiamine should be given in patients with known, or suspected, alcohol abuse or poor nutritional status.

The evidence base for the use of agents other than first-line drugs is limited, hence numerous other drugs are used for the treatment of refractory SE without any clear standardisation. These include:

• Propofol: an intravenous anaesthetic agent with rapid onset and short duration of action that has been shown to be effective in terminating seizures. Use is limited in children due to a risk of ‘propofol infusion syndrome’ – not seen in adults – and also by hypotension resulting from the high doses required to produce burst suppression on the EEG
• Levetiracetam: a new antiepileptic drug, with a unique pharmacological profile not metabolised in the liver [11]. This has been shown to be a useful adjunct in the treatment of refractory SE in several case series, having the benefit of causing less cardiovascular and respiratory depression than other agents
• Midazolam: whilst often used as a first-line agent, particularly in the pre-hospital setting, midazolam may also be useful for the treatment of refractory SE. It has been shown to be capable of rapidly controlling seizures when given as a continuous infusion.

Note: An acidosis is commonly seen in status epilepticus. This is seen more frequently in the setting of single prolonged seizures rather than in that of recurrent seizures without full recovery in between.

The acidosis has both metabolic and respiratory components, the former resulting from lactic acid production with continued muscle contraction, and the latter resulting from hypoventilation.

The induced acidosis does not correlate with any degree of neuronal injury and is thought to act as an anticonvulsant contributing to the termination of seizures.