A Comparison of Parenteral Phenobarbital vs. Parenteral Phenytoin as Second-Line Management for Pediatric Convulsive Status Epilepticus in a Resource-Limited Setting

Abstract

Introduction: Pediatric convulsive status epilepticus (CSE) which is refractory to first-line benzodiazepines is a significant clinical challenge, especially within resource-limited countries. Parenteral phenobarbital is widely used in Africa as second-line agent for pediatric CSE, however evidence to support its use is limited. Purpose: This study aimed to compare the use of parenteral phenobarbital against parenteral phenytoin as a second-line agent in the management of pediatric CSE. Methodology: An open-labeled single-center randomized parallel clinical trial was undertaken which included all children (between ages of 1 month and 15 years) who presented with CSE. Children were allocated to receive either parenteral phenobarbital or parenteral phenytoin if they did not respond to first-line benzodiazepines. An intention-to-treat analysis was performed with the investigators blinded to the treatment arms. The primary outcome measure was the success of terminating CSE. Secondary outcomes included the need for admission to the pediatric intensive care unit (PICU) and breakthrough seizures during the admission. In addition, local epidemiological data was collected on the burden of pediatric CSE. Results: Between 2015 and 2018, 193 episodes of CSE from 111 children were enrolled in the study of which 144 met the study requirements. Forty-two percent had a prior history of epilepsy mostly from structural brain pathology (53%). The most common presentation was generalized CSE (65%) caused by acute injuries or infections of the central nervous system (59%), with 19% of children having febrile status epilepticus. Thirty-five percent of children required second-line management. More patients who received parenteral phenobarbital were at a significantly reduced risk of failing second-line treatment compared to those who received parenteral phenytoin (RR = 0.3, p = 0.0003). Phenobarbital also terminated refractory CSE faster (p < 0.0001). Furthermore, patients who received parenteral phenobarbital were less likely to need admission to the PICU. There was no difference between the two groups in the number of breakthrough seizures that occurred during admission. Conclusion: Overall this study supports anecdotal evidence that phenobarbital is a safe and effective second-line treatment for the management of pediatric CSE. These results advocate for parenteral phenobarbital to remain available to health care providers managing pediatric CSE in resource-limited settings. Attachments: CONSORT 2010 checklist Trial registration: NCT03650270 Full trial protocol available: https://ichgcp.net/clinical-trials-registry/NCT03650270?recrs=e&type=Intr&cond=Status+Epilepticus&age=0&rank=1.

Keywords: Africa; convulsive status epilepticus; management; pediatrics; phenobarbital.

Figures

Figure 1

Treatment of convulsive status epilepticus (CSE): parenteral phenobarbital protocol. ECG, electrocardiogram; IMI, intramuscular injection; IN, intranasal; IV, intravenous injection; PR, per rectum; PICU, pediatric intensive care unit; SaO2, oxygen saturation; SL, sublingual.

Figure 2

Treatment of convulsive status epilepticus (CSE): parenteral phenytoin protocol. DW, dextrose water; ECG, electrocardiogram; IMI, intramuscular injection; IN, intranasal; IV, intravenous injection; PR, per rectum; PICU, pediatric intensive care unit; SaO2, oxygen saturation; SL, sublingual.

Figure 3

Flow chart of protocol allocation. Number of episodes of pediatric convulsive status epilepticus (n) studied and allocation to the different second-line treatment protocols. All patients allocated a pathway were included in the intention-to-treat analysis. BZP, benzodiazepines (including diazepam, lorazepam and midazolam); CSE, convulsive status epilepticus; PHB, phenobarbital; PHY, phenytoin.

Figure 4

Second-line treatment with parenteral phenobarbital terminates pediatric convulsive status epilepticus more successfully and faster than parenteral phenytoin. (A) Bar graph showing differences in responses to different levels of intervention between the total cohort (blue) as well as for the phenobarbital (PHB, purple) and phenytoin (PHY, orange) treatment groups. Dark shading indicates percentage of patients that responded to level whilst lighter shading shows those patients who failed that level. (B) Cumulative percentage plot showing the proportion of patients who responded (i.e., CSE terminated) to either parenteral phenobarbital (purple) vs. parenteral phenytoin (orange) at specific time points (in minutes) after the second-line agent was introduced. Gray dashed lines indicate when the protocol recommends progression to a third-line agent. Y axis represents the cumulative percentage of patients whose CSE had terminated whilst X axis represents time in minutes.