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Three Part Question

In [children acutely convulsing in a low-resource setting] does [a 5-minute interval between doses of benzodiazepines] versus a 10-minute interval [increase seizure termination success (primary outcome) and increase rates of benzodiazepine-related respiratory depression (secondary outcome)]?

Clinical Scenario

You are the medical officer intern on-call for paediatrics in a small district general hospital in rural Kenya. You are called to see a young girl with meningitis who is actively convulsing. Her blood sugar is normal. She has already had one dose of IV diazepam 5 minutes ago. The nursing staff ask about giving her a second dose dose as per the Kenyan paediatric protocol book, but you are worried about the risk of hypoventilation in a hospital without high dependency or intensive care facilities. What do you do?

Search Strategy

A literature search was performed using the Cochrane library and Pubmed.
The initial terms used were: Benzodiazepine* AND paed*. This yielded 168 results from Pubmed, and 40 from Cochrane, none of which were relevant. We therefore considered the following search terms: Benzodiazepine AND “time interval” AND seiz*; this provided 47 results from Pubmed and 6 results from Cochrane, again none of which were relevant. We made a further attempt with: Benzodiazepine AND interval AND seiz*; this resulted in 107 results from Pubmed and 102 from Cochrane, and none of these were relevant either.
These were carried out on 29th November 2014, with Pubmed (1946 to current date) limits of “English language” only.

Benzodiazepines have been used for the acute treatment of seizures for many years in one form or another. Similarly, respiratory depression as a side effect has been well known for more than 2 decades.1,2

The differences in the timing of a second dose of benzodiazepine would, at first glance, seem to be important in the development of side effects from relative toxicity. It is therefore surprising, that this has not been recorded in clinical trials.

The subject of timing of the second dose of benzodiazepine came to light during work in a district general hospital in rural Kenya, where national paediatric guidelines are usually followed, during the treatment of a young girl with meningitis. The patient, following a second dose of IV diazepam, subsequently developed respiratory depression requiring a brief period of manual ventilatory support.
Diazepam, in intravenous and rectal preparations, is the most readily available benzodiazepine preparation in the majority of Kenya.

The Kenyan Paediatric Assosciation (KPA) guidelines state that, in a child more than 1month of age, following an initial dose of diazepam (0.3mg/kg IV or 0.5mg/kg PR), a period of 5 minutes should be observed before a second dose of diazepam is given (same dose as first)3 .
This is shorter than national UK guidelines, led by the Advanced Life Support Group (ALSG) and National Institute of Clinical Excellence (NICE) which indicates a period of 10 minutes should be observed.4

Benzodiazepines work by activation of the GABAA receptor in the presence of GABA, and increase the frequency of chloride channel opening.7
They are known to cross the blood-brain barrier rapidly,5 and diazepam plasma concentrations are reported to have reached a therapeutic range of 200ng/ml within 5 minutes in 88% of children with malaria and prolonged seizures in a study in Kenya.6 The plasma concentrations appear to reduce rapidly, to below therapeutic range within 20minutes even after a second dose6. While therapeutic levels are generally reached within 5 minutes, peak levels are achieved from 6 to 10 minutes following the dose.9

The Kenyan study above mentioned no cases of respiratory depression after 2 doses of diazepam (case number of 5). This is at odds with older studies as referenced above, along with a study based in Liverpool, England, in 1999 which showed an incidence of respiratory depression of around 8% among children treatment with one single dose of rectal diazepam,8 at a dose lower (0.4mg/kg) than that recommended in the KPA guidelines.

While Diazepam is preferred due to availability issues in Kenya and other low-resources settings, it should be noted that lorazepam has a better profile in terms of termination of seizure after a single dose10,11 and in the reduced incidence of respiratory depression.11 Indeed, another study from Kenya highlighted the possibility of use of lorazepam intramuscularly, particularly for low-resource settings, with better seizure termination and respiratory depression rates compared with IV diazepam12.

Search Outcome

Although it appears significant volumes of research has been conducted into the use of benzodiazepines in the acute treatment of seizures, the question of a 5 minute, versus a 10 minute interval between doses, has yet been formally approached, based on our literature searches.
In light of the evidence regarding the risk of respiratory depression from diazepam particularly, and the better seizure termination rates from lorazepam, we propose two things.
Firstly, the KPA should consider the possibility of implementation of lorazepam as acute first line treatment for paediatric seizures within their national guidelines.
Secondly, urgent randomized controlled trials are needed, in Kenya or elsewhere, regarding the ideal time for a second benzodiazepine dose or other anticonvulsant treatment for the management of ongoing seizures.

Comment(s)

References 1. Leppik IE, Derivan AT, Homan RW, Walker J, Ramsey RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. Journal of the American Medical Association 1983;
249:p1452–4. 2. Appleton R, Sweeney A, Choonara I, Robson J, Molyneux E. Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus. Developmental Medicine and Child Neurology 1995;37:p683–8. 3. Republic of Kenya Ministry of Health. Basic Paediatric Protocols. November 2013 edition, p21. 4. NICE Guideline 137 – Guideline for treating convulsive status epilepticus in children – published in 2011, accessed via NICE website on 30th November 2014 at: http://www.nice.org.uk/guidance/cg137/chapter/appendix-f-protocols-for-treating-convulsive-status-epilepticus-in-adults-and-children-adults 5. Rey E, Tréluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy for acute seizures: Focus on delivery routes. Clin Pharmacokinet. 1999;36(6):409-24. 6. Ogutu BR, Newton CRJC, Crawley J, et al. Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions. Br J Clin Pharmacol. 2002; 53(1): 49–57. 7. Graeme J. Sills, Martin J. Brodie. Update on the mechanisms of action of antiepileptic drugs. Journal of Epileptic disorders 2001;3(4):165-72. 8. Norris E, Marzouk O, Nunn A, McIntyre J, Choonara I. Respiratory depression in children receiving diazepam for acute seizures: a prospective study. Dev Med Child Neurol. 1999;41(5):340-3. 9. Dulac O, Aicardi J, Rey E, et al. Blood levels of diazepam after a single rectal administration in infants and children. J Pediatr 1978;93:1040–1 10. Sánchez Fernández I, Abend NS, Agadi S. Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure. 2014;23(2):87-97. 11. Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2008;(3):CD001905. 12. Muchohi SN, Obiero K, Newton CRJC, Ogutu BR, Edwards G, Kokwaro GO. Pharmacokinetics and clinical efficacy of lorazepam in children with severe malaria and convulsions. Br J Clin Pharmacol. 2008;65(1):12–21.

Clinical Bottom Line

There is no trial-based evidence available for the use of a 5 minute versus a 10 minute interval between benzodiazepine doses. Studies are needed to address this and subsequently reduce the incidence of respiratory depression, particularly in geographical areas where access to paediatric high dependency or intensive care facilities is not feasible.