Relevant BNF sections: 4.8.2, 15.1.1
Generalised convulsive status epilepticus (GCSE) is a medical emergency. The mortality in patients with GCSE admitted to an intensive care unit is about 5-10%.1 If figures for the USA can be applied to the UK, about 30,000 episodes of status epilepticus occur here each year.2 In this article we discuss the management of GCSE, concentrating on ways of stopping an episode.
Statistics from Altmetric.com
Relevant BNF sections: 4.8.2, 15.1.1
Status epilepticus can be defined either as two or more seizures occurring consecutively without an intervening period of full recovery of consciousness, or as recurrent epileptic seizures lasting for more than 30 minutes. In patients with GCSE, presentation varies from repeated tonic clonic seizures to subtle convulsive movements and coma.3 In addition to GCSE there are forms of status epilepticus in which convulsions do not occur. These include absence or complex partial status epilepticus, which presents as a confusional state, or simple partial status epilepticus, which presents as repeated seizures (usually focal motor seizures) without significant disturbance of consciousness. Non-convulsive status epilepticus is not discussed further in this article.
GCSE can result from virtually any cerebral pathology or systemic disturbance and can occur in patients with any type of epilepsy. About 60% of all episodes occur in patients without any history of epilepsy.4,5 In a young child the most likely precipitating causes are fever or acute infection of the central nervous system, in an adolescent or young adult head injury, and in an older person cerebrovascular disease. In a patient with a history of epilepsy, GCSE is more likely if there is some frontal lobe abnormality. In these patients, precipitating factors include intercurrent illness, fever, alcohol abuse, abruptly stopping antiepileptic treatment or poor adherence to therapy.
Death, permanent neurological deficit and the subsequent development of chronic epilepsy after an episode of GCSE are principally determined by the aetiology; for instance, they are more likely in a patient with severe pre-existing brain disease.4 A second major determinant of outcome is the duration of an attack.6 The longer the attack lasts the greater the chance of neuronal cell death7 and the greater the chance that the attack will resist treatment.3 The presence of systemic complications also worsens outcome. Rhabdomyolysis, acute tubular necrosis, disseminated intravascular coagulation with multi-organ failure,1 hypoxia, hypoglycaemia, lactic acidosis and hyperthermia8 all increase the risk of irreversible brain damage and death.
Diagnosis of GCSE
The diagnosis of GCSE can be difficult. Witnesses should be asked about the duration of the attack and about any treatment already given. It helps to discover from relatives or close companions whether there is any history of seizures, alcohol or drug abuse, metabolic or vascular disease, head trauma or neurological symptoms. If the patient is known to have epilepsy, an attempt should be made to discover whether the fits or treatment have recently changed. This brief history will help determine treatment and the need for investigations.
Misdiagnosis can lead to inappropriate treatment which itself may carry risks. In any patient referred to a specialist neurological intensive care unit with GCSE refractory to medical treatment, pseudostatus should be considered.9,10 Clinical features that should arouse suspicion of pseudostatus include resistance to passive eye opening, persistence of a positive conjunctival reflex, downgoing plantar reflexes and the occurrence of repeated, apparently generalised seizures without cyanosis.
The aim of management is to stop seizures, prevent complications and control or reverse any underlying cause. The approaches taken will depend on when and where the patient is seen. Treatment is more likely to be successful if it is provided in a hospital equipped with the necessary staff and resources. It is practical to stage treatment according to the duration of the attack and the resistance to interventions.3,11
The patient should be removed from any potential danger (e.g. glass, fire). The airway should be secured and oxygen administered. It may not be possible to introduce the airway until the patient is sedated; no attempt should be made to intubate when the jaw is clenched.
Within 60 minutes
A single intravenous bolus of a rapidly acting benzodiazepine should be given within the first few minutes of seeing the patient. A standard choice is diazepam (as diazemuls) given in a dose of 10-20mg in 2-4ml at a rate of 0.5ml/30sec (for children, 200-300µg/kg or 1mg per year of age). This should abolish seizure activity in about 80% of patients.12 A second bolus should be given if seizures last longer than, or recur after, 30-60 minutes. After a bolus injection, unwanted effects such as respiratory depression or hypotension occur in up to 13% of patients and so resuscitation facilities should be available.12 Where such facilities are not available, for example in general practice, 10mg of the drug can be given rectally as a 2-4mg/ml solution (5mg in children 1-3 years and in older patients).13 This can be repeated after 5 minutes if necessary.
Intravenous lorazepam, given in a dose of 4mg in 1ml, diluted 1:1 with physiological saline or water for injection, at a rate of 0.5ml/30sec (for children, 2mg), is an alternative to diazepam. Lorazepam has a longer duration of action than diazepam but a slower onset of action.14,15 Patients can rapidly develop tolerance to lorazepam so it should not be used if chronic or repeated benzodiazepine treatment is required.10
Paraldehyde, given rectally, is an alternative treatment to rectal diazepam in children when intravenous access is difficult. It is also an alternative to an intravenous benzodiazepine where intravenous therapy is not possible, such as in patients in nursing homes. The recommended adult dose is 5-10ml as a 10% enema in physiological saline. For children up to 3 months it is 0.5ml; 3-6 months 1ml; 6-12months 1.5ml; 1-2 years 2ml; 3-5 years 3-4ml; 6-12 years 5-6ml.
Whichever drug is given, blood glucose should be checked at the bedside to exclude hypoglycaemia. If the patient is hypoglycaemic, 50ml of 50% dextrose should be given intravenously. If the patient is thought to chronically abuse alcohol, 250mg of thiamine should be administered by slow intravenous injection (over 10 minutes); parenteral thiamine can cause anaphylaxis and so facilities for treating this should be available.
Heart rate, blood pressure, ECGs, temperature and neurological status should be assessed regularly. An intravenous line should be established and physiological saline infused to keep it patent. It is best to use a large vein to minimise the risk of phlebitis when antiepileptic drugs are given. Blood should be taken for the measurement of blood glucose, urea, electrolytes (including calcium and magnesium), acid-base balance, liver function, full blood count, clotting, and antiepileptic drug and alcohol concentrations. Blood should be cultured if the patient is febrile. A serum sample should be stored so that further tests can be carried out later if required.
Within 90 minutes
If there is a clear history that the patient has recently stopped taking an antiepileptic drug, it is important to restart (and continue) the usual treatment as soon as possible.
The patient should be examined for evidence of head trauma, meningeal irritation, focal neurological deficit, an underlying metabolic condition or drug abuse and treated accordingly. Whether the patient will need more specific investigations such as cerebral imaging and cerebrospinal fluid examination will depend on the initial assessment and response to treatment.
From 30 to 90 minutes
GCSE is considered established when it has continued for 30 minutes despite treatment. At this stage the patient should be transferred to an intensive care unit. Once admitted, there are two first-line approaches - phenytoin in conjunction with a benzodiazepine (diazepam or lorazepam) or phenobarbitone. Chlormethiazole is also sometimes used. If facilities are available, management should also include continuous or frequent monitoring of intra-arterial pressure, central venous pressure, blood gases, pulmonary wedge pressure and, in children, intracranial pressure. Continuous EEG recording can be used to assess the effect of treatment on abnormal electrical activity. Raised intracranial pressure may need to be lowered using intermittent positive pressure ventilation, dexamethasone, mannitol or sometimes surgery, depending on the underlying cause.
Phenytoin suppresses seizure spread without causing cortical or respiratory depression. Some specialists suggest giving phenytoin with diazepam in the early stages of GCSE but this is rarely necessary.1 The recommended loading dose for phenytoin is 15mg/kg (15-20mg/kg in neonates) given intravenously. Further boluses up to a total loading dose of 30mg/kg may be given if seizures persist.3 This treatment should be followed by maintenance doses of about 100mg intravenously every 6-8 hours. Because rapid infusion can cause cardiac dysrhythmias, the infusion rate should not exceed 50mg/min (1-3mg/kg/min in neonates). Phenytoin should not be injected through the same giving set as diazepam because of the possibility of crystallization.
Phenobarbitone is a potent antiepileptic. The recommended dose by intravenous injection is 15mg/kg at a rate of not more than 100mg/min. In randomised trials, doses of 10-15mg/kg were as effective as either diazepam, or lorazepam, plus phenytoin without a greater incidence of serious unwanted effects.16,17 Phenobarbitone can cause hypotension, sedation and respiratory depression although these unwanted effects usually only occur with high doses of the drug.1
Chlormethiazole is sometimes used but there are few studies reporting its efficacy and if the drug accumulates it has several serious unwanted effects, such as sudden cardiovascular collapse, hypotension, respiratory depression and sedation. 10 Circulatory fluid overload commonly occurs and careful monitoring of electrolyte balance is essential because the infusion contains sodium ions but no other electrolytes. The recommended dose in adults is initially 40-120mg/min up to a maximum total dose of 320-800mg of 0.8% solution, followed by a continuous infusion at the minimum dose required to control seizures, usually 4-8mg/min. In children, the recommended dose is 80µg/kg/ min initially, increased every 2-4 hours if necessary. The infusion should be tapered off from 12 hours after cessation of seizures. Chlormethiazole should only be given in the presence of an anaesthetist and/or in an intensive care unit. If a continuous infusion is being given, the patient's cardiovascular and respiratory functions must be closely monitored.
After 60 to 90 minutes
If GCSE persists despite these measures, it is considered refractory. At this stage, it is important to exclude pseudostatus9 and to check that the drugs and doses have been given according to the protocol.18 If status epilepticus persists, the next step is to give a general anaesthetic and provide ventilation, haemodynamic and organ support and ensure treatment of any underlying condition such as meningitis. Traditionally, intravenous thiopentone has been used as the first-line treatment.10 The newer, non-barbiturate drug propofol is also now being used.10
Thiopentone should be given intravenously. The manufacturer's recommended dose in adults is 75-125mg (3-5ml of a 2.5% solution) given over 10-15 seconds. Further doses can then be given according to response. The recommended dose in children is 2-7mg/kg. Thiopentone has a rapid onset of action of about 10-20 seconds10 but hypotension requiring inotropic support is a common complication. In patients without status epilepticus, consciousness is usually regained after about 7-10 minutes with a single bolus of thiopentone.10 However, the drug has a long elimination half-life and so accumulates if large amounts are infused over a long period, thus producing prolonged coma and delaying recovery.10
The intravenous anaesthetic propofol is being used in intensive care units in the management of refractory GCSE as an alternative to thiopentone; it is not licensed for this indication. Propofol acts quickly and recovery with it is rapid. It can cause bradycardia, prolonged use in children may cause metabolic acidosis19 and there are reports that it can itself cause seizures.20 More information is needed before it can be recommended for routine use in this situation.
Other drug treatments
Several other drugs have been used in the management of GCSE but they remain experimental. Intravenous sodium valproate21 and lignocaine22 have been given but comparative studies are needed. Intravenous midazolam,23,24 etomidate25 and isoflurane26 have also been tried but, again, well-controlled, published data on their safety and effectiveness is limited.
Generalised convulsive status epilepticus is a common and serious medical emergency. The effectiveness of management has a direct influence on outcome and subsequent morbidity. Adherence to a treatment plan, which is best provided in a well-equipped hospital where full resuscitation and diagnostic facilities are available, should increase the chances of recovery. Further randomised trials are required to compare the relative merits of barbiturate and non-barbiturate anaesthetics and midazolam in refractory status epilepticus.
[M = meta-analysis; R = randomised controlled trial; S = sponsored symposium]
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.