Lorazepam vs Diazepam for Pediatric Status Epilepticus A Randomized Clinical Trial

ArticleinJAMA The Journal of the American Medical Association 311(16):1652-60 · April 2014with38 Reads
Impact Factor: 35.29 · DOI: 10.1001/jama.2014.2625 · Source: PubMed
Abstract

Benzodiazepines are considered first-line therapy for pediatric status epilepticus. Some studies suggest that lorazepam may be more effective or safer than diazepam, but lorazepam is not Food and Drug Administration approved for this indication. To test the hypothesis that lorazepam has better efficacy and safety than diazepam for treating pediatric status epilepticus. This double-blind, randomized clinical trial was conducted from March 1, 2008, to March 14, 2012. Patients aged 3 months to younger than 18 years with convulsive status epilepticus presenting to 1 of 11 US academic pediatric emergency departments were eligible. There were 273 patients; 140 randomized to diazepam and 133 to lorazepam. Patients received either 0.2 mg/kg of diazepam or 0.1 mg/kg of lorazepam intravenously, with half this dose repeated at 5 minutes if necessary. If status epilepticus continued at 12 minutes, fosphenytoin was administered. The primary efficacy outcome was cessation of status epilepticus by 10 minutes without recurrence within 30 minutes. The primary safety outcome was the performance of assisted ventilation. Secondary outcomes included rates of seizure recurrence and sedation and times to cessation of status epilepticus and return to baseline mental status. Outcomes were measured 4 hours after study medication administration. Cessation of status epilepticus for 10 minutes without recurrence within 30 minutes occurred in 101 of 140 (72.1%) in the diazepam group and 97 of 133 (72.9%) in the lorazepam group, with an absolute efficacy difference of 0.8% (95% CI, -11.4% to 9.8%). Twenty-six patients in each group required assisted ventilation (16.0% given diazepam and 17.6% given lorazepam; absolute risk difference, 1.6%; 95% CI, -9.9% to 6.8%). There were no statistically significant differences in secondary outcomes except that lorazepam patients were more likely to be sedated (66.9% vs 50%, respectively; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%). Among pediatric patients with convulsive status epilepticus, treatment with lorazepam did not result in improved efficacy or safety compared with diazepam. These findings do not support the preferential use of lorazepam for this condition. clinicaltrials.gov Identifier: NCT00621478.

    • "The current consensus is that treatment should be initiated after 5 min in cases of convulsive SE (Trinka et al. 2015). Based on several randomized trials (Treiman et al. 1998; Alldredge et al. 2001; Silbergleit et al. 2012; Chamberlain et al. 2014), there is consensus that the first-line treatment is a benzodiazepine. Unfortunately, despite the recognition for the need for early treatment of SE, the initial treatment and escalation to second and subsequent line agents is often delayed in both the inhospital and out-of-hospital settings. "
    [Show abstract] [Hide abstract] ABSTRACT: Although the majority of seizures are brief and cause no long-term consequences, a subset is sufficiently prolonged that long-term consequences can result. These very prolonged seizures are termed “status epilepticus” (SE) and are considered a neurological emergency. The clinical presentation of SE can be diverse. SE can occur at any age but most commonlyoccurs in the very young and the very old. There are numerous studies on SE in animals in which the pathophysiology, medication responses, and pathology can be rigorously studied in a controlled fashion. Human data are consistent with the animal data. In particular, febrile status epilepticus (FSE), a form of SE common in young children, is associated with injury to the hippocampus and subsequent temporal lobe epilepsy (TLE) in both animals and humans. © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.
    Preview · Article · Mar 2016 · Cold Spring Harbor Perspectives in Medicine
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    • "Overall, 26 RCTs (two class I [24, 34] and 24 class III [27, 30,) examined efficacy of initial therapy. In 25 of these RCTs, benzodiazepines were one or both of the study medications (two class I studies and 23 class III studies). "
    [Show abstract] [Hide abstract] ABSTRACT: Context: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. Objective: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. Data sources: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. Study selection: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. Data extraction: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. Results: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. Conclusions: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline.
    Full-text · Article · Feb 2016 · Epilepsy Currents
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    • "Overall, 26 RCTs (two class I [24, 34] and 24 class III [27, 30,) examined efficacy of initial therapy. In 25 of these RCTs, benzodiazepines were one or both of the study medications (two class I studies and 23 class III studies). "
    [Show abstract] [Hide abstract] ABSTRACT: Convulsive status epilepticus is an emergency that is associated with high morbidity and mortality. The outcome largely depends on etiology, but prompt and appropriate pharmacological therapy can reduce morbidity and mortality. Etiology varies in children and adults and reflects the distribution of disease in these age groups. Antiepileptic drug administration should be initiated whenever a seizure has lasted 10 minutes. Immediate concerns include supporting respiration, maintaining blood pressure, gaining intravenous access, and identifying and treating the underlying cause. Initial therapeutic and diagnostic measures are conducted simultaneously. The goal of therapy is rapid termination of clinical and electrical seizure activity; the longer a seizure continues, the greater the likelihood of an adverse outcome. Several drug protocols now in use will terminate status epilepticus. Common to all patients is the need for a clear plan, prompt administration of appropriate drugs in adequate doses, and attention to the possibility of apnea, hypoventilation, or other metabolic abnormalities.
    No preview · Article · Aug 1993
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