NIHR DC Discover

NIHR Signal Lorazepam confirmed as first-line treatment for stopping prolonged seizures in children

Published on 17 April 2018

doi: 10.3310/signal-00586

Intravenous lorazepam is as effective as intravenous diazepam for stopping children’s tonic-clonic seizures in hospital. Lorazepam also results in fewer breathing problems than diazepam. Giving antiepileptic drugs intravenously generally stops seizures more quickly than giving the drugs buccally (in the cheek), intranasally (in the nose) or rectally. However, this effect can be cancelled out if administering the drug into the veins takes too long.

Two of the 18 included trials were carried out in the UK, but they were all carried out in large children’s hospitals or departments similar to the UK.

The new evidence confirms advice in the existing NICE guideline and also describes the current options regarding the routes and preparations used when it is difficult to secure intravenous access quickly.

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Why was this study needed?

About one in 240 children (aged 16 years and under) have a diagnosis of epilepsy in the UK. Tonic-clonic seizures are the type of epileptic seizure that are most easily recognisable. They have two phases: loss of consciousness with the muscles stiffening; followed by jerking of the limbs. Most tonic-clonic seizures last for less than five minutes. If they last longer, it is likely that they won’t stop spontaneously. If they don’t stop, they can lead to serious complications or death. Around 1,000 people die each year from epilepsy in the UK. There is a range of anti-epileptic drugs available to stop the seizures.

This Cochrane review was last updated in 2008. Since then, a number of new randomised controlled trials have been published. This update aimed to evaluate this new evidence, looking if there were any changes to the estimates of effectiveness and safety of the drugs.

What did this study do?

The review included 18 randomised controlled trials involving 2,199 children who attended hospital A&E departments with a tonic-clonic seizure.

The children were aged between one month and 16 years. Some of them were experiencing their first seizure, and some had an established diagnosis of epilepsy. Any and all causes of the seizures were included.

The trials compared a wide range of antiepileptic drugs used as first-line treatment, with a variety of doses and routes of administration. The drugs included benzodiazepines, phenytoin and paraldehyde.

The trials differed in their designs, and the populations of the children included. The risk of bias in trials varied depending on the drug comparison. Fourteen of these trials were published since the 2008 version of the review. These new studies did not add any high-quality evidence that would change clinical practice. For example, the four trials comparing buccal midazolam with rectal diazepam were graded as low to very low evidence, and because of the uncertainty, the authors considered that the new evidence did not support the use of buccal midazolam when intravenous access was difficult.

What did it find?

  • Intravenous lorazepam appears to be as effective as intravenous diazepam in stopping acute tonic-clonic seizures, (risk ratio [RR] 1.04, 95% confidence interval [CI] 0.94 to 1.16; three trials, 414 children).
  • Compared to other routes, intravenous-administration led to seizures stopping more quickly after a drug was given, but this was off-set by the length of time taken to insert the needle into a vein.
  • Few side effects were observed and reported in the trials. Respiratory depression was the most common and was observed in between 0 and 18% of children in trials that reported it. Lorazepam was associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93; three studies, 439 children).

What does current guidance say on this issue?

NICE’s 2012 guideline on the diagnosis and management of the epilepsies includes a section on the treatment for children, young people and adults with ongoing tonic-clonic seizures in hospital. It recommends intravenous lorazepam as first-line treatment, or intravenous diazepam if unavailable.

Buccal midazolam is recommended if administering drugs intravenously isn’t possible straight away. The recommended doses for children are 0.1mg/kg for intravenous lorazepam and 0.5mg/kg for buccal midazolam.

What are the implications?

This update of the Cochrane review confirms current UK guidance and practice. Though the level of evidence was not high for all the comparisons, this is likely to be as good as it gets given how difficult randomised controlled trials are to carry out in this area and the number of drugs and routes available for study.

Citation and Funding

McTague A, Martland T, Appleton R. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2018;1:CD001905.

Cochrane UK and the Epilepsy Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

CKS. Epilepsy. London: National Institute for Health and Care Excellence; 2017.

NHS Choices. Epilepsy. London: Department of Health; updated 2017.

NICE. Epilepsies: diagnosis and management. CG137. London: National Institute for Health and Care Excellence; 2012.

Why was this study needed?

About one in 240 children (aged 16 years and under) have a diagnosis of epilepsy in the UK. Tonic-clonic seizures are the type of epileptic seizure that are most easily recognisable. They have two phases: loss of consciousness with the muscles stiffening; followed by jerking of the limbs. Most tonic-clonic seizures last for less than five minutes. If they last longer, it is likely that they won’t stop spontaneously. If they don’t stop, they can lead to serious complications or death. Around 1,000 people die each year from epilepsy in the UK. There is a range of anti-epileptic drugs available to stop the seizures.

This Cochrane review was last updated in 2008. Since then, a number of new randomised controlled trials have been published. This update aimed to evaluate this new evidence, looking if there were any changes to the estimates of effectiveness and safety of the drugs.

What did this study do?

The review included 18 randomised controlled trials involving 2,199 children who attended hospital A&E departments with a tonic-clonic seizure.

The children were aged between one month and 16 years. Some of them were experiencing their first seizure, and some had an established diagnosis of epilepsy. Any and all causes of the seizures were included.

The trials compared a wide range of antiepileptic drugs used as first-line treatment, with a variety of doses and routes of administration. The drugs included benzodiazepines, phenytoin and paraldehyde.

The trials differed in their designs, and the populations of the children included. The risk of bias in trials varied depending on the drug comparison. Fourteen of these trials were published since the 2008 version of the review. These new studies did not add any high-quality evidence that would change clinical practice. For example, the four trials comparing buccal midazolam with rectal diazepam were graded as low to very low evidence, and because of the uncertainty, the authors considered that the new evidence did not support the use of buccal midazolam when intravenous access was difficult.

What did it find?

  • Intravenous lorazepam appears to be as effective as intravenous diazepam in stopping acute tonic-clonic seizures, (risk ratio [RR] 1.04, 95% confidence interval [CI] 0.94 to 1.16; three trials, 414 children).
  • Compared to other routes, intravenous-administration led to seizures stopping more quickly after a drug was given, but this was off-set by the length of time taken to insert the needle into a vein.
  • Few side effects were observed and reported in the trials. Respiratory depression was the most common and was observed in between 0 and 18% of children in trials that reported it. Lorazepam was associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93; three studies, 439 children).

What does current guidance say on this issue?

NICE’s 2012 guideline on the diagnosis and management of the epilepsies includes a section on the treatment for children, young people and adults with ongoing tonic-clonic seizures in hospital. It recommends intravenous lorazepam as first-line treatment, or intravenous diazepam if unavailable.

Buccal midazolam is recommended if administering drugs intravenously isn’t possible straight away. The recommended doses for children are 0.1mg/kg for intravenous lorazepam and 0.5mg/kg for buccal midazolam.

What are the implications?

This update of the Cochrane review confirms current UK guidance and practice. Though the level of evidence was not high for all the comparisons, this is likely to be as good as it gets given how difficult randomised controlled trials are to carry out in this area and the number of drugs and routes available for study.

Citation and Funding

McTague A, Martland T, Appleton R. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2018;1:CD001905.

Cochrane UK and the Epilepsy Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

CKS. Epilepsy. London: National Institute for Health and Care Excellence; 2017.

NHS Choices. Epilepsy. London: Department of Health; updated 2017.

NICE. Epilepsies: diagnosis and management. CG137. London: National Institute for Health and Care Excellence; 2012.

Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children

Published on 11 January 2018

McTague, A.,Martland, T.,Appleton, R.

Cochrane Database Syst Rev Volume 1 , 2018

BACKGROUND: Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and require urgent and appropriate anticonvulsant treatment. International consensus is that an anticonvulsant drug should be administered for any tonic-clonic convulsion that has been continuing for at least five minutes. Benzodiazepines (diazepam, lorazepam, midazolam) are traditionally regarded as first-line drugs and phenobarbital, phenytoin and paraldehyde as second-line drugs. This is an update of a Cochrane Review first published in 2002 and updated in 2008. OBJECTIVES: To evaluate the effectiveness and safety of anticonvulsant drugs used to treat any acute tonic-clonic convulsion of any duration, including established convulsive (tonic-clonic) status epilepticus in children who present to a hospital or emergency medical department. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (23 May 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 23 May 2017), MEDLINE (Ovid, 1946 to 23 May 2017), ClinicalTrials.gov (23 May 2017), and the WHO International Clinical Trials Registry Platform (ICTRP, 23 May 2017). SELECTION CRITERIA: Randomised and quasi-randomised trials comparing any anticonvulsant drugs used for the treatment of an acute tonic-clonic convulsion including convulsive status epilepticus in children. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted data. We contacted study authors for additional information. MAIN RESULTS: The review includes 18 randomised trials involving 2199 participants, and a range of drug treatment options, doses and routes of administration (rectal, buccal, nasal, intramuscular and intravenous). The studies vary by design, setting and population, both in terms of their ages and also in their clinical situation. We have made many comparisons of drugs and of routes of administration of drugs in this review; our key findings are as follows:(1) This review provides only low- to very low-quality evidence comparing buccal midazolam with rectal diazepam for the treatment of acute tonic-clonic convulsions (risk ratio (RR) for seizure cessation 1.25, 95% confidence interval (CI) 1.13 to 1.38; 4 trials; 690 children). However, there is uncertainty about the effect and therefore insufficient evidence to support its use. There were no included studies which compare intranasal and buccal midazolam.(2) Buccal and intranasal anticonvulsants were shown to lead to similar rates of seizure cessation as intravenous anticonvulsants, e.g. intranasal lorazepam appears to be as effective as intravenous lorazepam (RR 0.96, 95% CI 0.82 to 1.13; 1 trial; 141 children; high-quality evidence) and intranasal midazolam was equivalent to intravenous diazepam (RR 0.98, 95% CI 0.91 to 1.06; 2 trials; 122 children; moderate-quality evidence).(3) Intramuscular midazolam also showed a similar rate of seizure cessation to intravenous diazepam (RR 0.97, 95% CI 0.87 to 1.09; 2 trials; 105 children; low-quality evidence).(4) For intravenous routes of administration, lorazepam appears to be as effective as diazepam in stopping acute tonic clonic convulsions: RR 1.04, 95% CI 0.94 to 1.16; 3 trials; 414 children; low-quality evidence. Furthermore, we found no statistically significant or clinically important differences between intravenous midazolam and diazepam (RR for seizure cessation 1.08, 95% CI 0.97 to 1.21; 1 trial; 80 children; moderate-quality evidence) or intravenous midazolam and lorazepam (RR for seizure cessation 0.98, 95% CI 0.91 to 1.04; 1 trial; 80 children; moderate-quality evidence). In general, intravenously-administered anticonvulsants led to more rapid seizure cessation but this was usually compromised by the time taken to establish intravenous access.(5) There is limited evidence from a single trial to suggest that intranasal lorazepam may be more effective than intramuscular paraldehyde in stopping acute tonic-clonic convulsions (RR 1.22, 95% CI 0.99 to 1.52; 160 children; moderate-quality evidence).(6) Adverse side effects were observed and reported very infrequently in the included studies. Respiratory depression was the most common and most clinically relevant side effect and, where reported, the frequency of this adverse event was observed in 0% to up to 18% of children. None of the studies individually demonstrated any difference in the rates of respiratory depression between the different anticonvulsants or their different routes of administration; but when pooled, three studies (439 children) provided moderate-quality evidence that lorazepam was significantly associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93).Much of the evidence provided in this review is of mostly moderate to high quality. However, the quality of the evidence provided for some important outcomes is low to very low, particularly for comparisons of non-intravenous routes of drug administration. Low- to very low-quality evidence was provided where limited data and imprecise results were available for analysis, methodological inadequacies were present in some studies which may have introduced bias into the results, study settings were not applicable to wider clinical practice, and where inconsistency was present in some pooled analyses. AUTHORS' CONCLUSIONS: We have not identified any new high-quality evidence on the efficacy or safety of an anticonvulsant in stopping an acute tonic-clonic convulsion that would inform clinical practice. There appears to be a very low risk of adverse events, specifically respiratory depression. Intravenous lorazepam and diazepam appear to be associated with similar rates of seizure cessation and respiratory depression. Although intravenous lorazepam and intravenous diazepam lead to more rapid seizure cessation, the time taken to obtain intravenous access may undermine this effect. In the absence of intravenous access, buccal midazolam or rectal diazepam are therefore acceptable first-line anticonvulsants for the treatment of an acute tonic-clonic convulsion that has lasted at least five minutes. There is no evidence provided by this review to support the use of intranasal midazolam or lorazepam as alternatives to buccal midazolam or rectal diazepam.

Expert commentary

This review examines the evidence base for treatment of acute prolonged convulsive seizures in children and interestingly fails to identify any new high-quality evidence. It does, however, highlight the effectiveness of intravenous benzodiazepines, but that in the absence of intravenous access, there is a role for buccal or rectal administration.

What is highlighted is despite a number of studies, they are heterogeneous in design, and consequently, much of the data reported for the less frequently used non-intravenous options is of low quality. There is no evidence to suggest we should be making any change to existing guidelines.

Professor Helen Cross, Prince of Wales’s Chair of Childhood Epilepsy at UCL-Institute of Child Health, Great Ormond Street Hospital for Children, London and Young Epilepsy, Lingfield

Expert commentary

This review provides some welcome clarification, but there remains uncertainty around optimum emergency treatment for tonic-clonic seizures when there is lack of intravenous access.

Careful thought needs to be given in designing further trials of any of the three commonly used emergency benzodiazepine drugs delivered by any of the four current non-intravenous route options. There are more than 50 possible two-drug/route and more than two hundred possible three-drug/route combinations; carrying out trials of all these is impractical.  

The evidence supports lorazepam as the preferred intravenous drug; shouldn’t we prioritise trials on whether it should be the preferred non-intravenous one?

Richard Chin, Director, Muir Maxwell Epilepsy Centre, Senior Research Fellow in Paediatric Neurosciences, Honorary Consultant Paediatric Neurologist, The University of Edinburgh and Royal Hospital for Sick Children Edinburgh