This study will be conducted in emergency department, intensive care unit and medical wards at Yangon Children's Hospital. All children with prolonged seizures who have failed to respond to any two bolus doses of first-line benzodiazepines will be included in the study. Written informed consent will be obtained from one of the parents, guardians, or family members of children after assessing for eligibility. Parents, guardians, or family members of participants can withdrawal from the research study at any time without penalty or loss of benefits.
After selecting cases based on the inclusion criteria and obtaining written informed consent, computerized block randomization will be conducted, using a total of nine blocks to assign participants to either Group A or Group B. Group A patients will be treated with intravenous levetiracetam 40 mg/kg (maximum of 3000 mg) over 15 minutes. Group B patients will be treated with intravenous phenobarbital 20 mg/kg (maximum of 1000 mg) over 20 minutes. Injection levetiracetam will be diluted with 5% dextrose water to a concentration of 50 mg/ml. Injection phenobarbital will be diluted to become 20 ml with 5% dextrose water.
Simultaneously, detailed history and physical examination will be done according to proforma for background sociodemographic characteristics such as age, gender, seizure type and previous history of seizure. Precipitating factors to cause seizure such as fever, vomiting or diarrhoea and history suggestive of underlying aetiologies and comorbidities will also be asked. Conscious level, signs of meningism, signs of increased intracranial pressure, cardiovascular and respiratory examinations and detailed central nervous system examination will be done to find out the causes of seizure, any neurological deficits and drug side effects.
All participants will also be monitored for oxygen saturation, respiratory rate and pattern, pulse rate, pulse volume, and blood pressure to detect treatment-related adverse effects, such as acute anaphylaxis, arrhythmia, ataxia, hepatitis, hypotension, hypoxia, and respiratory depression. Monitoring will be conducted before, during, and 5 minutes after the assigned drug infusion, then hourly for 4 hours, every 2 hours for the following 4 hours, and every 4 hours thereafter.
Routine investigations such as blood for complete picture, C reactive protein, random blood sugar level and serum electrolytes or other required investigations will be tested. All participants will receive other specific treatments or supportive care, such as antibiotics and antipyretics, in accordance with ward treatment guidelines and based on any underlying diseases or comorbid conditions.
Clinical response of seizure cessation will be assessed after five minutes of injection levetiracetam or phenobarbital infusion. The primary outcome of the study will be the clinical cessation of the seizure at five minutes after the completion of the infusion of intravenous levetiracetam or phenobarbital. The secondary outcome of the study will be the recurrence of seizure within 12 hours after the commencement of the study medications, need of other medications for active seizure control within 12 hours after the commencement of the study medications, need for rapid sequence induction (RSI) with thiopentone for on-going seizure management after administration of study medications. These secondary outcomes will be assessed in treatment-responsive groups. Treatment related adverse effects will also be assessed within five minutes of drug infusion in both treatment groups and within 12 hours in treatment-responsive groups. Data analysis will be done to compare the clinical response.
If the patient's seizure has stopped five minutes after completing the infusion of the assigned medication, a maintenance dose of either levetiracetam or phenobarbital, whichever was previously used, will be administered intravenously. For group A, the maintenance dose of injection levetiracetam will be given 24 hours after the initial dose and continued twice daily, and for group B, the maintenance dose of injection phenobarbital will be given every 12 hours. It will be regarded as a response group.
If the patient is still experiencing seizure five minutes after completing the infusion of the assigned medication, the patient will be treated with an alternative second-line ASM of injection levetiracetam or phenobarbital, whichever was not previously used or diazepam infusion or midazolam infusion, following the hospital's standard protocol. It will be regarded as a failure group.
If the patient experiences serious treatment-related adverse effects within five minutes of the levetiracetam or phenobarbital infusion, the drug infusion will be stopped, and the patient will be treated with an alternative second-line ASM for seizure control, along with standard hospital protocol to manage adverse effects. It will also be regarded as a failure group due to treatment-related serious adverse effects.
After completing each block, an interim analysis will be conducted to assess efficacy and futility. To assess efficacy, Pocock's boundary method will be used, applying a consistent, adjusted p-value of approximately 0.02 (rather than the conventional 0.05) for each interim analysis to indicate early efficacy. If the conditional power falls below a pre-set threshold of 20% likelihood of achieving significance, the trial will be stopped for futility.
