Intensive Care Treatment of Uncontrolled Status Epilepticus in Children

Systematic Literature Search of Midazolam and Anesthetic Therapies

Ryan Wilkes, MD; Robert C. Tasker, MBBS, MD


Pediatr Crit Care Med. 2014;15(7):632-639. 

In This Article

Abstract and Introduction


Objective A systematic literature search and review of the best evidence for intensive care treatment of refractory status epilepticus in children using continuous infusion of midazolam or anesthetic agents.

Design MEDLINE and EMBASE search before December 2013 using key words and/or Medical Subject Headings identified English-language citations that were screened for eligibility and used if 1) the study was about high-dose benzodiazepine or anesthetic agent for children; 2) the treatment protocol was described and used for refractory status epilepticus; 3) the outcomes included seizure control; and 4) the series included at least five children.

Main Results Sixteen studies (645 patients) were identified, including midazolam (nine studies), barbiturate (four studies), and other anesthetic approaches (three studies). When midazolam was used as the initial agent for refractory status epilepticus, the rate of clinical seizure control was 76%, which was achieved on average 41 minutes after starting the infusion. When midazolam was used in conjunction with continuous electroencephalography, the time to seizure control was much longer and the mean dose required for seizure control was 10.7 μg/kg/min compared with a lower dose (2.8 μg/kg/min) in the studies not using this form of monitoring, suggesting that continuous electroencephalography provided additional targets for treatment. Barbiturates were usually used after midazolam failed and treatment was started, on average, 66 hours after refractory status epilepticus onset with the goal of electroencephalography burst suppression, which was achieved, on average, 22.6 hours later. Among patients failing midazolam, barbiturate infusion was effective in 65%. Inhaled anesthetics, ketamine, and hypothermia were generally used after prior therapy with midazolam and barbiturates had failed, usually several days after seizure onset.

Conclusions The data on intensive care treatment of pediatric refractory status epilepticus are of poor quality, yet they show a hierarchy in strategies: early midazolam, then barbiturates, and then trial of other anesthetic strategies. In addition, using a solely clinical endpoint for seizure control may be missing significant seizure burden in pediatric refractory status epilepticus.


The initial treatment of status epilepticus (SE) usually consists of one or two doses of a benzodiazepine, which is frequently referred to as "first-tier therapy," followed by some combination of fosphenytoin or phenobarbital, which is frequently referred to as "second-tier therapy." Refractory status epilepticus (RSE) is most commonly defined as continued seizure activity despite administration of two adequately dosed anticonvulsants. RSE accounts for 1.6–4% of all admissions to the PICU and develops in 10–25% of pediatric patients presenting with uncontrolled seizures[1–5]

After failure of first- and second-tier therapies for SE, most treatment protocols recommend high-dose benzodiazepine, pentobarbital infusions, and anesthesia.[6–9] Despite these recommendations, little is known about the relative efficacy between agents and the options available when anesthesia fails and so-called super-RSE is present.[10] Nor is there high-quality evidence from randomized controlled trials (RCTs) for an appropriate therapeutic goal. That is, whether the primary goal is clinical seizure control or whether neuroprotection by an induced state of reduced cerebral metabolic demand should be targeted. The aim of this systematic literature search and review of the best available clinical evidence was to evaluate, summarize, and quantify the use of these two strategies in pediatric RSE and super-RSE.