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Background
Convulsive status epilepticus (CSE) (box 1) is the most common childhood medical neurological emergency, with an incidence of approximately 20 per 100 000 per year in the developed world.1 2
Definition of status epilepticus
Status epilepticus is a condition resulting either from failure of the mechanism responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures (after time point t1 at 5 min).
It is a condition, which can have long-term consequences (after time point t2 after 30 min) including neuronal death, neuronal injury and alteration of neuronal networks, depending on the type and duration of seizures.
CSE can be fatal, but mortality is lower in children than in adults—at about 2%–7%.3
Adverse neurological consequences following CSE consist of subsequent epilepsy, motor deficits, and learning and behavioural difficulties. The main determinant of outcome is the underlying aetiology (box 2). There is low risk of morbidity and mortality in children with unprovoked/prolonged febrile CSE. This risk increases significantly in cases with structural or genetic causes.
Common causes of status epilepticus
Known (ie, symptomatic)
Structural: Intracranial tumour, cerebrovascular
disease, head injury, cortical dysplasia
Infectious: CNS infection (meningitis, encephalitis), tuberculosis, cerebral malaria
Metabolic: Metabolic disturbance (electrolyte imbalance, glucose imbalance, organ failure, etc), metabolic disorders, anoxic injury, mitochondrial disorders
Toxicity or drug-related: Low or high level of antiseizure medication, withdrawal of antiseizure medication, other drug/alcohol overdose, neurotoxins and poisons
Inflammatory: Autoimmune disorders, neurocutaneous disorders
Genetic: Dravet syndrome, ring chromosome 20, Angelman syndrome, fragile X syndrome, Rett syndrome, trisomy 21
Unknown (ie, cryptogenic)
Information about the current guideline
The Advanced Life Support Group (ALSG) who run the Advanced Paediatric Life Support (APLS) programme provides internationally renowned guidance on the emergency management of common childhood emergencies. The APLS programme is also endorsed by the Royal College of Paediatrics and Child Health. Together, a professional working group consisting of members of the ALSG, British Paediatric Neurology Association, Paediatric Intensive Care Unit, Royal College of Emergency Medicine, epilepsy nurses, ambulance representatives, pharmacists and a parent representative worked collaboratively to review and update the emergency management for generalised CSE in children aged 1 month old to 18 years old (see figure 1).
Management of non-CSE and super refractory status epilepticus are beyond the scope of this guideline. In certain circumstances, a child may have an individual emergency care plan which supersedes this guideline.
Previous guideline
The first APLS manual was published in 1997 and last updated in 2016.4 Since then there have been significant changes in practice observed around the world on how to manage the convulsing child based on more recent research. This review aims to summarise key updates which will feature in the upcoming APLS seventh edition.
What can I continue to do as before?
Principles of treatment
Should the convulsion continue beyond t1 (5 min) there is a greater chance of it lasting longer than 30 min.1
Beyond this time point, it is unknown when exactly brain injury may occur and the longer the duration of the convulsion the harder it is to terminate. Together with effective resuscitation, early recognition and treatment of ongoing convulsion may affect outcome.
The aims of acute treatment are summarised in box 3.
Aims for acute treatment
Support airway, breathing, circulation (ABC)
Identify and treat life-threatening causes
Termination of the convulsion
Prevent reoccurrence of the convulsion
Reduce risk of associated mortality and morbidity
Avoid admission to intensive care
Primary assessment and resuscitation
It is important to obtain a brief history of events, current medication and allergies. A focused physical examination will help identify the underlying cause. Simultaneously, acute resuscitation must be undertaken.
The approach to resuscitation remains the same as for any seriously unwell child. Treatment of the convulsion should be assessed and treated only after the Airway, Breathing, Circulation, Disability (ABCD) have been assessed and managed.4
What do I need to know?
Emergency treatment of a convulsion
The updated medical algorithm will continue to be provided in four steps, however with different time intervals. The new time intervals reflect current pharmacological understanding that allows enough time for treatment effect.
There is an emphasis that while completing a step, the team should continually reassess ABCD and get ready for the next step to avoid any delays in treatment.
Antiseizure medication doses are based on recommended dosing as per the British National Formulary for children and/or the most current available evidence.5
Key updates
Steps 1 and 2
Shorter 5-min interval between benzodiazepine doses.
Prehospital treatment should count in the number of doses given. A maximum of two doses should be given.
Step 3
Second-line drug is levetiracetam.
Step 4
If the team is ready, they should proceed to rapid sequence induction (RSI) with either ketamine, thiopental or propofol.
If the team is not ready either phenytoin or phenobarbital can be given and if immediately after completing this the child is still convulsing the team should proceed to RSI.
What should I start doing?
First-line treatment
Step 1
Benzodiazepines (BDZ) remain the first-line antiseizure medication of choice. The fact that BDZ can be given quickly and have a rapid onset of action supports their use as first line. There are also time-dependent GABA receptor changes that result in pharmacoresistance to BDZ, further supporting its early use. Studies have shown that the time from BDZ administration to seizure termination is between 2 min and 10 min.6 7
Respiratory depression is the most common and most clinically relevant side effect. The frequency of this adverse event is observed in up to 18% of children.5 6
The choice of BDZ will vary depending on local practices and availability.
In the UK, the BDZ readily available are buccal midazolam, rectal diazepam and intravenous lorazepam. Buccal midazolam is the least invasive option, can be administered quickly and more socially acceptable. From a practical perspective, the BDZ that can be given the quickest should be considered the BDZ of choice.
Given that most convulsions occur prehospital, a trained carer or paramedic is empowered to administer first-line treatment to avoid delay in initiating treatment.
Step 2
It is common practice to administer a second dose of BDZ if the convulsion has not stopped after 5 min from the first dose. However, the evidence to support this practice is limited.2 6
The risk of respiratory depression increases if more than two doses of BDZ are administered.2 6 For this reason, the second dose of BDZ should be given in the presence of a trained health professional.
The main rationale for this step is that establishing intravenous/intraosseous access may invariably take time and thus a second dose of BDZ is commonly considered better than no treatment.6
Any prehospital doses should be counted and no more than two doses of BDZ administered.
The team should continuously monitor and support the child’s airway and breathing.
Summary of first-line BDZ available in UK are provided in table 1.
Second-line treatment
Step 3
Levetiracetam, phenytoin, fosphenytoin, phenobarbital and sodium valproate are all considered to be equally effective second-line treatment for managing a convulsion that has not responded to initial BDZ.8–10
Intravenous levetiracetam is now considered the second-line antiseizure medication of choice in the UK.
One of several advantages of giving levetiracetam is that it can be given to any convulsing child without any contraindications and few side effects. The reason the recommended loading dose of levetiracetam is 40 mg/kg is to provide a margin of safety to those already on levetiracetam maintenance. It is easy to prepare, can be given over 5 min and does not require any specific monitoring.
Step 4
At this stage of management there is no clear evidence that outlines what the next best step is. The treatment options are limited to either trying a further second-line antiseizure medication or to proceed with rapid sequence induction (RSI) with anaesthesia. The professional working group came to the consensus that a second-line antiseizure medication is a suitable interim step should the team not be ready to do an immediate RSI after step 3.
This decision is largely based on evidence from the ConSEPT Trial.9 In the trial, 64% of patients who were given phenytoin and then levetiracetam had their seizures stop and 52% who had levetiracetam then phenytoin had their seizures stop without the need for RSI. This implies giving a further antiseizure medication can reduce the need for RSI and admission to intensive care, which is not without its own risks. Furthermore, recent research has shown that the total duration of the convulsion may not be associated with outcomes.11
This may be deemed enough to justify the new recommendation however there may be potential risks associated with this change. Although the evidence is suggestive that it may be reasonable to consider another antiseizure medication, the long-term implications of delaying RSI in children who would have perhaps had RSI earlier is unknown. For this reason, the group acknowledges there is a need for prospective surveillance of outcomes of children according to whether RSI was delayed or not as this will help guide future recommendations.
There is also potential that a larger proportion of children may have a delayed RSI because of the challenge teams will have in determining when they feel ready to proceed with RSI. Therefore it will be crucial for teams to anticipate and prepare ahead. It is recommended to concurrently activate a team to prepare for RSI after levetiracetam is administered while a further second line anti-seizure medication (phenytoin/phenobarbitone) is being prepared.
Phenytoin is licensed in the UK for paediatric use. Common side effects of phenytoin are that it can cause arrhythmia, hypotension and more rarely respiratory arrest.5 Continuous cardiac monitoring is therefore recommended during its administration. If the child is already on maintenance phenytoin then phenobarbital could be considered.
Phenobarbital is licensed for use in the UK and is a reasonable alternative to phenytoin. Phenobarbital is associated with a greater incidence of side effects. Continuous cardiac monitoring is also recommended.
Table 2 provides a summary of the currently recommended second-line antiseizure medication.
There is little to no evidence which suggests one anaesthetic drug is superior to another when managing an ongoing convulsion at this stage. The drug of choice for RSI is largely influenced by the underlying aetiology, pharmacological evidence and the experience of the anaesthetic team. The advantages of ketamine are that it can be given in a haemodynamically unstable child who is not catecholamine deplete unlike thiopentone and propofol which may cause hypotension. In addition, there is rationale for using ketamine (with NMDA receptor antagonist action) in BDZ resistant CSE.
Critical appraisal by RA
The management of any medical emergency should include a clear and unambiguous guideline and algorithm to maximise its clinical usefulness and patient benefit. This updated CSE guideline has four updates. The first is that if the child has received two (or more) doses of BDZ prior to attendance in A&E then no further BDZ will be given. This practice is similar to many European countries but in the USA additional doses of BDZ are permitted. The second is a shorter time interval (5 min, rather than 10 min) between steps 1 and 2 and between steps 2 and 3. Although this is not supported by any evidence, it is consistent with the ‘5 min’ principle which states that an anti-seizure medication should be given if a seizure has not stopped spontaneously after 5 min. This is appropriate to try and terminate CSE as soon as possible. The third update reflects important new evidence on the second-line treatment when CSE has persisted after two doses of a BDZ (or the child’s personal rescue treatment). Although levetiracetam was shown to be no more effective or better tolerated than phenytoin in three large randomised controlled trials8–10 that involved over 750 children, its ease of preparation and administration and safety profile in not causing cardiac arrhythmias or severe hypotension, justifies its position as the preferred second-line anticonvulsant. Its rapid rate of infusion also means that another second-line anticonvulsant (phenytoin or phenobarbital) can be given if RSI and ventilatory support are not immediately available: this is the fourth update. The evidence justifying two sequential second-line drugs is far less robust and based on a single randomised controlled trial in which not all randomised children received two drugs. The use of two second-line drugs will inevitably prolong CSE prior to RSI and intubation. This mandates the importance of strictly adhering to the timelines in the algorithm and obsessional ABCD monitoring of the child throughout CSE. In summary, this updated CSE guideline reflects new evidence and should be commended.
Conclusion
CSE is a medical emergency associated with significant morbidity and mortality. Management of CSE is time critical. It is important that any recommendations on the emergency management of CSE in children and young people is regularly reviewed and reflects the emerging new evidence and medications available.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Footnotes
Contributors The authors had multiple virtual meetings to create consensus for guideline. MB drafted the algorithm and article, other authors reviewed and edited. RA provided an independent critical appraisal of the guideline.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests AM: GW Pharma - Personal payment, Honorarium; UCB - Honorarium; LivaNova - support to attend meeting; BPNA - Trustee and Professional Support Officer; Epilepsy Scotland - Co-opted Board Member; Ring 20 - Medical Advisory Board Member. NM: Veriton Supply training materials to NM's organisation including demonstration kits of midazolam oromucosal solution for use in training simulations. RFMC: GW Pharma – personal payment, Honorarium, support to attend meeting, local principal investigator in clinical trials; UCB- Honorarium; Eisai – Honorarium, personal payment, support to attend meetings; Zogenix - Honorarium, personal payment, support to attend meetings; Shares in Rize Medical Cannabis & Life Sciences. RA: Chairman of the Independent Data Safety Monitoring Committee for an NIHR HTA-funded study on mental health in children with epilepsy (the ‘MICE’ Study). 2019 – ongoing. Voluntary role.
Provenance and peer review Not commissioned; externally peer reviewed.