Childhood Convulsive Status Epilepticus Management In A Resource Limited Setting
Condition: Pediatric Status Epilepticus
MeSH terms: Status Epilepticus
Study type: Interventional
Phase: Phase 3

Summary: 
      Convulsive status epilepticus (CSE) is a potentially devastating condition which can result
      in significant morbidity and mortality. Studies addressing status epilepticus in children are
      rare and there is a paucity of large randomised controlled trials in children looking at
      forms of drug treatment for SE. There is consistency worldwide in guidelines for first line
      treatment of CSE with benzodiazepines, with slight variations in type and route of
      administration of agents. Second line therapy usually entails phenobarbital or phenytoin
      parenterally. Both repeated phenobarbital loading doses and midazolam infusions have been
      shown to be effective and safe in the management of established convulsive SE, but there are
      no prospective randomized controlled trials comparing the two in children.

      Our study has been undertaken to review 2 existing, and routinely used, interventions for
      children presenting to our center with acute convulsive seizures. In order to permit
      comparable data to be collected we are randomly allocating these standard interventions
      prospectively. This is in order to compare the efficacy and safety of two treatment protocols
      (phenobarbital vs phenytoin and midazolam) both of which as stated are already part of
      existing standard protocols internationally and in South Africa. Parenteral phenobarbital is
      a safe, affordable and easy to use drug in the management of status epilepticus especially
      for poorly resourced communities where undertaking infusions may be unsafe, time consuming or
      unavailable.

      We hypothesize that repeated phenobarbital loading is as effective and safe, or more so, than
      phenytoin followed by midazolam infusion in the management of established and refractory
      childhood convulsive SE. If proven, then the former would be a viable option for all health
      care workers with access to intravenous routes (including Day hospitals) where infusions are
      unsafe, time consuming or unavailable.
    

Detailed description: 
      This prospective study was conducted at the Red Cross War Memorial Children's Hospital
      (RCWMCH) and recruitment ran from between March 2015 to March 2018. All patients presenting
      with convulsive status epilepticus (CSE) who presented to the medical emergency unit at
      RCWMCH and needed therapeutic intervention were entered into the study by the attending
      medical staff. Study data was collected using REDCap hosted by the University of Cape Town's
      eResearch Centre and the study was approved by the UCT Human Research Ethics Council (UCT
      HREC 297/2005).

      Definitions The definition of CSE was defined as any convulsive seizure that lasted longer
      than five minutes or multiple discrete seizures between which there is no extended period of
      recovery between events (Trinka et al., 2015). The onset of CSE was defined as the time
      provided by the caregiver who accompanied the child. The time to admission and to treatment
      were recorded by the staff in the unit. If children were admitted multiple times, each
      admission was captured independently, but only data from the first admission was included in
      this report . The full diagnosis of CSE was described using the multiaxial classification
      system. However, as it was not possible to perform EEG on all patients, this axes was
      excluded. Febrile status epilepticus was defined .

      Treatment protocols Upon entry into the study, children were randomly allocated to one of two
      protocols . Both these protocols are well-established treatment protocols used in the
      sub-Saharan African setting for the management of SE . Randomization of protocols was
      performed using a free online platform (Research Randomizer ©). Both protocols began with
      children receiving first-line benzodiazepines (either midazolam, lorazepam or diazepam) which
      were either administered intravenously (IV), per rectally, intranasally or sublingually. If
      the children did not respond to single dose of benzodiazepines, they were given a second dose
      5-10 minutes after the first dose. Pre-hospital administration of benzodiazepines by
      emergency services were counted if administered intravenously. However, all other routes of
      administration were not counted due to the lack of consistency in their administration.

      If CSE continued after two doses of benzodiazepines, children were then randomized to
      second-line agents according to the protocol allocated to them. The one protocol, termed
      'Phenobarbital' (PHB), instructed the clinician to give giving an IV bolus of phenobarbital
      (20mg/kg ). If CSE did not terminate after 5 - 10 minutes, a second dose was given at half
      the dosage (10mg/kg) and a third dose (10mg/kg) was given if CSE persisted 5-10 minutes after
      that.

      In the second protocol, termed 'Phenytoin / Midazolam infusion' (PHY/MDZ), children were
      given a dose (20mg/kg) of IV phenytoin mixed with 50mL of normal saline solution and
      administered over 30 minutes . If the patient was still in CSE 5-10 minutes after the
      phenytoin was given, they were then started on a midazolam infusion. This included a loading
      dose of IV midazolam (0.2mg/kg) followed by an infusion set at 3mg/kg into 50mL 5% dextrose
      water given at a rate of 1-4 mL/hour (equivalent to 1-4 mcg/kg/min ).

      If a patient child did not respond to the PHB or the PHY/MDZ protocols, they were referred to
      the pediatric intensive care unit (PICU). Other reasons for admission to the PICU included
      respiratory depression following administration of the second-line agent, need for inotropic
      support, etiology-related concerns requiring intensive monitoring (e.g. severe electrolyte
      imbalances) and or prolonged state of a depressed level of consciousness.

      Demographic data inclusive of age, sex, etiologies, pre-existing medications, previous
      medical conditions and co-morbidities were recorded.

      Outcome measures In comparing the two treatment protocols, we will only focused on the
      short-term outcomes of the children in each treatment protocol. These include how the agents
      affected the children's physiology, admission to PICU, whether subsequent breakthrough
      seizures occurred and days admitted to hospital. In measuring the effects on the children's
      physiology, their we will calculate heart rate, respiratory rate and mean arterial pressure
      from during CSE to immediately post-ictal period. This will be done by subtracting the first
      measurement as the child presented to the unit from the first measurement taken immediately
      after the child had stopped convulsing.

      Data analysis During the analysis, the investigator performing the analysis was blinded to
      which protocol the patients children were allocated to. Group allocations will only be
      unblinded after statistical analysis is completed and verified by an external party. Data
      will analysed using SPSS Statistics (IBM Corp. Released 2016, Version 24.0. Armonk, NY: IBM
      Corp). Statistical measurements will be performed using both SPSS Statistics and GraphPad
      Prism version 6.0 (GraphPad Software, USA). For continuous data normality will be established
      using the Shapiro-Wilk test and thereafter parametric (i.e. paired or unpaired student's
      t-tests) or nonparametric tests (i.e. Mann-Whitney U test or Wilcoxon signed-rank test) will
      be performed. Normally distributed data will be reported as mean standard deviation. Data
      that is not normally distributed will be reported as median with the interquartile range
      (IQR). Categorical data will be summarized in contingency tables with differences between
      groups being identified using the Fisher-exact or chi-squared (X2) tests and associations
      calculated using odds ratios (OR). Significance will be defined as a p < 0.05.
    

Intervention name(s): Phenobarbital
Intervention type(s): Drug
Intervention description(s): Three repeated doses of pareneteral phenobarbital was compared to a single parenteral infusion of phenytoin followed by an infusion of parenteral midazolam
Other intervention name(s): Phenytoin; Midazolam
Intervention MeSH terms: Phenytoin; Midazolam; Phenobarbital
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: random allocation to 2 study protocols
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment