Pediatric Status Epilepticus Clinical Trial
Official title:
Childhood Convulsive Status Epilepticus - In Search Of Optimal Drug Management In A Resource Limited Setting
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.
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.
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