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Indian Pediatr 2016;53: 1069-1073 |
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Effect of Withholding
Phenobarbitone Maintenance in Neonatal Seizures:
A Randomized Controlled Trial
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Pranjali Saxena, Abhishek Singh, Amit Upadhyay,
Priyanka Gupta , *Sangeeta
Sharma and
#Sreenivas
Vishnubatla
From Department of Paediatrics, LLRM Medical College,
Meerut, Uttar Pradesh, *Institute of Human Behaviour and Allied
Sciences, New Delhi; and #All India Institute of Medical Sciences, New
Delhi; India.
Correspondence to: Dr Amit Upadhyay, Associate
Professor and Head, Department of Paediatrics, LLRM Medical College,
Meerut, Uttar Pradesh, India.
Email: [email protected]
Received: April 02, 2016;
Initial review: May 19, 2016;
Accepted: October 10, 2016.
Trial Registration: CTRI 2012/08/00395
Published online: July 10, 2016. PII:S097475591600025
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Objective: To compare the effect of withholding maintenance
phenobarbitone on breakthrough seizures.
Design: A double blind randomized controlled
trial.
Setting: Level II neonatal intensive care unit
(NICU) of a teaching hospital in Northern India.
Participants: 152 term and near term neonates (34
weeks of gestation age) with admission weight
³2 kg
with clinically apparent seizures who received intravenous (IV) loading
dose of 20 mg/kg of phenobarbitone.
Interventions: After 12 hours of seizure free
period of the initial loading dose of phenobarbitone, one group received
IV maintenance therapy and other ‘no maintenance’ (saline as placebo).
Main outcome measure: Breakthrough seizures from
randomization till discharge.
Results: Baseline variables were comparable in
the two groups. Breakthrough seizures occurred in 30 (40%) subjects in
placebo group and 24 (31.2%) in phenobarbitone group with RR (95% CI) of
1.28 (0.83-1.97) (P=0.19). Seizure re-currence, re-hospitali-sation,
mortality and abnormal neurological assessment until 3 months were
comparable in the two groups (P>0.05). Babies in either group
with breakthrough seizures were more likely to be neurologically
abnormal at 1 month than babies who did not have breakthrough seizures,
but this difference decreased by 3 months.
Conclusion: In term and near-term neonates, those
who respond to loading dose of phenobarbitone after a single seizure
episode, withholding of phenobarbitone maintenance may not significantly
increase the risk of breakthrough seizures.
Key words: Neonatal convulsions, Management, Seizure
recurrence.
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Phenobarbitone prophylaxis has been used for weeks to months even after
control of neonatal seizures, to minimize the risk of recurrence[1,2].
However, there is accumulating evidence that its long-term use may be
associated with neuronal apoptosis leading to impairment of behavior,
intelligence, cognition, learning and memory [3,4]. It has also been
demonstrated that early phenobarbitone discontinuation after the neonate
is clinically stable does not lead to increase in breakthrough seizures,
even though the signs of neurological damage are still there [5,6].
Moreover, there is data to suggest that phenobarbitone administration
after seizure control does not improve neurological outcome [7]. Though
WHO has recently recommended stoppage of phenobarbitone if seizure free
for >72 hours of loading dose [8], timing of phenobarbitone
discontinuation after seizure control is a matter of debate and needs to
be researched more. We planned this trial to determine if withholding
use of phenobarbitone maintenance after initial loading dose, would
result in increase in breakthrough seizures or affect early neonatal
mortality and morbidity.
Methods
The present study was a double blind, randomized
control trial conducted at a level II neonatal intensive care unit
(NICU) of a teaching hospital in northern India from September 2012 to
September 2013. The study was approved by institutional ethics committee
and was registered with Clinical Trial Registry of India.
Study population included were term or near-term
neonates of ³34
weeks of gestation up to 4 weeks postnatal age and weighing
³2
kg. All types of clinical seizures were included in the study. The
diagnosis of seizure was based on clinical observation only. Neonates
with recurrence of seizures within 12 hrs of the loading dose of
phenobarbitone, major congenital malformations, suspected storage
disease (ruled out by metabolic screen), intrauterine infection (ruled
out by serological screen) and suspected chromosomal abnormalities
(based on facial dysmorphism and other phenotypic abnormalities) were
excluded from the study.
Participants were randomly assigned (1:1) by computer
generated table to either Plan A or Plan B in blocks of eight. The paper
slips with Plan A or B written on them were kept in a serially numbered
opaque envelopes and sealed. Parents of babies, investigator, trial
staff and statistician were masked to treatment allocation.
Standard definitions and type of seizures were
followed [3]. Each subject was enrolled after obtaining written informed
consent of the parent(s). After ensuring adequacy of airway, breathing
and circulation, intravenous cannula was secured and blood sugar and
serum calcium levels were done. If seizures persisted even after
correction of hypoglycemia and hypocalcemia, baby was loaded with
intravenous phenobarbitone at 20 mg/kg in 1:10 dilution with normal
saline (NS) over a 15-20 min period at a rate of 1mg/kg/min. A responder
was defined as a subject who remained seizure-free for a period of 12
hours after loading dose. All responders were randomized into two
groups, 12 hours after the loading dose into Plan A or Plan B. Identical
injectable solutions were made and labelled ‘Solution A’ or ‘Solution B’
in 20 mL syringes and covered by opaque tape from outside by a person
not involved in any other process of the study and kept everyday morning
in the refrigerator for 24 hours. Phenobarbitone (200 mg/mL) was diluted
1:20 in NS (1mL phenobarbitone + 19 mL NS) to make its concentration 200
mg/20 mL or 10mg/mL. Placebo was 20 mL of normal saline kept in an
identical syringe. Maintenance dose was 2.5 mg/kg (of phenobarbitone)
which was equivalent to 0.25 mL/kg/dose of prepared solution (as well as
placebo). When an eligible case was admitted, the doctor on duty opened
the envelope and gave the solution A or B accordingly, in dose of 0.25
mL/kg every 12 hourly for 5 days. Babies in both groups were monitored
for occurrence of any breakthrough clinical seizures as a primary end
point. The study intervention stopped after five days of seizure-free
period. If a breakthrough seizure occurred, the baby was reloaded with
10 mg/kg of phenobarbitone and put on open-label maintenance of
phenobarbitone till discharge. If the baby was neurologically abnormal
at discharge, maintenance was continued after discharge and baby was
reassessed at 1 month with repeat neurological examination by standard
assessment format by trained attending neonatologist. Blood samples for
analysis of serum phenobarbitone levels were obtained at 12 hours after
the completion of loading dose (before randomization and giving first
maintenance dose). Conventional EEG recording of 30 minute duration were
made during wakefulness and spontaneous sleep before discharge.
Seizure recurrence, mortality, need for inotropic
support, time to reach full oral enteral nutrition, duration of hospital
stay, neurodevelopment status, seizure recurrence and re-hospitalization
up to 3 months of age were secondary end points.
Neurodevelopment assessment was done at discharge, 1
month and 3 months of age by residents trained in Amiel-Tison
Neurological Assessment [9]. For those babies who could not come for
follow up at 1 and 3 months, telephonic discussion with parents or local
treating practitioner was done. They were asked about weight gain,
feeding, persistence of seizures, and over-all perception of parents
about neurological status. The patients in whom phenobarbitone was
continued, treatment was stopped as per the standard unit protocol [10].
Sample size calculation was done based on seizure
control rates in study by Wasim, et al. [11]. Sample size of 76
babies in each group, with a two-group large-sample normal approximation
test of proportions with a one-sided 0.05 significance level had 80%
power to reject the null hypothesis that with and without maintenance
dose are not equivalent (the difference in proportions: proportion of
recurrence in maintenance - proportion in no maintenance, is 20%
(absolute) or farther from zero in the same direction) in favour of the
alternative hypothesis that the proportions in the two groups are
equivalent, assuming that the expected difference in proportions is 0%
and the proportion in the standard group is 56%. All study outcomes were
evaluated on intention-to-treat basis.
Statistical analysis: Analysis of continuous data
with normal distribution was done by unpaired t test and non-normally
distributed data by Mann-Whitney test. Categorical data was compared
using chi square or Fisher exact test, as applicable. Kaplan Meier
survival analysis was done for occurrence of breakthrough seizure. P
value of less than 0.05 was considered significant. Strata 12.1
software was used for statistical analysis.
Results
Out of the total 184 babies with seizures admitted in
our NICU during the study period, 152 babies fulfilled study criteria (Fig.
1). The baseline variables were comparable in the two groups (Table
I).
TABLE I Baseline Data of Neonates in the Two Groups
|
Placebo group |
Phenobar- |
|
(n=75) |
bitone group |
|
|
(n=77) |
#Weight (g) |
2677(448.7) |
2742(342.7) |
#Gestation (w) |
37(1.3) |
38(1.4) |
*Male |
41(54.7) |
50(64.9) |
*Intramural delivery |
28(37.3) |
27(35.0) |
$Age at admission (h) |
4(0-28) |
3(0-16) |
$Onset of convulsion (h) |
12(5-42.5) |
12(4-24) |
*HIE (at admission) |
Stage I |
1(1.3) |
4(5.2) |
Stage II |
49(65.3) |
52(68.8) |
Stage III |
14(18.7) |
9(11.7) |
#Serum PB level(µg/mL) at 12 h, |
24.8(23.4) |
20.2(22.0) |
*Etiology |
Birth asphyxia |
65(86.7) |
69(89.6) |
Meningitis/sepsis |
6(8) |
7(9.1) |
Metabolic |
2(2.7) |
1(1.3) |
Intracranial hemorrhage |
2(2.7) |
0 |
PB: Phenobarbitone; HIE: Hypoxic ischemic encephalopathy;
P>0.05 for all comparisons; * No.(%); #Mean(SD);
$Median (IQR). |
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Fig. 1 Flow diagram of participants.
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Twelve hours after randomization of first loading
dose of phenobarbitone, breakthrough seizures till discharge (primary
outcome) occurred in 30 (40%) subjects in placebo group and 24 (31.16%)
in phenobarbitone group after first loading dose of phenobarbitone (P=0.19)
with RR of 1.28 (95%CI) (0.8, 1.97) (Table II).The age of
onset of breakthrough seizures was comparable in two groups with maximum
likelihood of breakthrough seizure within 72 hours of first episode (Fig.
2). Other secondary outcomes were also comparable in the two groups
(Table II).
TABLE II Seizure Recurrence and Morbidity in the Two Groups
Outcome |
Placebo group |
Phenobarbitone group |
P value |
|
(n=75) |
(n=77) |
|
Breakthrough seizure during NICU stay* |
30 (40.0) |
24 (31.2) |
0.19** |
|
|
|
1.28 (0.8-1.97) |
Need of inotropic support* |
31 (41.33 ) |
31 (40.25) |
0.89 |
Abnormal EEG after seizure control* |
8/55 (14.54) |
7/63 (11.110) |
0.38 |
Time to full enteral nutrition (d) # |
5.6 (3.24) |
6.09 (3.79) |
0.52 |
Duration of hospital stay (d) # |
7.41 (4.32) |
7.23 (4.20) |
0.79 |
Mortality in NICU*Mortality at 3 months |
13/75 (17.33)7/58 (12.06) |
9/77 (11.66)6/53 (9.52) |
0.360.19 |
Re-hospitalization till 3 months* |
10/60 (16.67) |
8/66 (12.12) |
0.51 |
Seizure recurrence till 3 months* |
2/60 (3.33) |
7/66 (10.6) |
0.10 |
Abnormal neurological outcome * |
Discharge (n=152)` |
23/75 (30.66) |
16/77 (20.77) |
0.14 |
1 month (n=126) |
12/60 (20.0) |
9/66 (13.63) |
0.37 |
3 Months (n=108) |
2/51 (3.92) |
2/57 (3.50) |
0.79 |
Values indicate mean ±SD#, n (%)*; ** RR (95% Confidence
interval), (P> 0.05) for all. |
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Fig. 2 Kaplan-Meier curve for seizure
control in the 2 groups.
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Subgroup analysis was done to compare the babies who
developed breakthrough seizures in either of the groups (n=54)
and those who did not develop any breakthrough seizures (n=98).
Time to full feed and duration of hospital stay were significantly more
in babies who developed breakthrough seizures. Babies with breakthrough
seizure were also more likely to have abnormal neurological examination
at discharge and 1 month, but this difference decreased by 3 months of
age (P=0.06) (Web
Table I).
Discussion
This double-blind randomized control trial of 152
babies in a Level II NICU found that the clinical breakthrough seizures
till discharge are not likely to increase on withholding phenobarbitone
maintenance after the loading dose. It was observed that mortality and
abnormal neurodevelopmental outcomes till three months were slightly
higher in those in whom phenobarbitone had been withheld, though it was
not statistically significant.
Hellstrom, et al. [5] reported that despite
short median duration of antiepileptic treatment of about 4.5 days, only
8.3% infants developed seizure recurrence in the first year of life.
Theodore, et al. [12] have reported that little relation exists
between the rate of phenobarbitone withdrawal and seizure control.
Guillet, et al. [4] retrospectively studied the impact of
outpatient phenobarbital prophylaxis on the frequency of seizure
recurrence and long-term neurodevelopmental outcome at 1 to 11 years. He
observed no significant difference in seizure recurrence, irrespective
of maintenance therapy after discharge. It has been shown that asphyxia
may lead to exaggerated expression of the sodium-potassium-chloride
co-transporter (NKCC1) which renders the neonatal brain hyperexcitable
[13,14].The variation in seizure control could also be attributed to
varying levels of free phenobarbitone entering the brain in neonates
with different sickness profiles [15].
With concerns of phenobarbitone-related apoptotic
neurodegeneration and related long term cognitive side effects [16],
there was a felt need for shortening the maintenance therapy. Although
recurrent seizures can potentially enhance the brain damage, there is
insufficient evidence to suggest that prolonged treatment with
phenobarbitone can actually prevent them. So, early recognition of
seizures and targeted therapy of recurrences in high-risk babies may be
the most appropriate option. Outcomes of babies may be improved by
safely avoiding prolonged phenobarbitone therapy in babies who have
already suffered an insult to their developing brain [4].
A limitation of our study was lack of cerebral
function or continuous EEG monitoring. Presence of electrical seizures
in absence of clinical correlates have been reported to be harmful [3].
Though we did not measure the serial serum phenobarbitone levels,
sub-therapeutic levels are less likely to contribute to breakthrough
seizures, as breakthrough incidence was similar in the two groups.
Though cessation of all electrical seizures should be
the therapeutic end point of phenobarbitone or other anti-epileptic
drugs, majority of centres still lack good EEG monitoring. Moreover,
there are concerns over inter-observer variation in continuous EEG or
cerebral functioning monitoring [15]. So control of clinical seizures
may be next best achievable goal, especially in developing countries.
Further trials with larger sample size to detect even smaller
differences in breakthrough seizures and neurological outcome are
desirable. Such studies should also monitor for recurrence of electrical
seizures and serial serum phenobarbitone levels to determine if
declining levels could be contributing to seizure recurrence.
Contributers: PS, PG: collected and
compiled the data for the study, and drafted the manuscript; AU:
conceptualized and designed the study, finalized the manuscript. He will
act as guarantor of paper; AS: helped in allocation concealment,
blinding and pharmacy related issues in the study; SS: did
phenobarbitone level analysis and provided intellectual inputs from
protocol stage and helped in drafting the paper; SV: did the sample size
calculation, statistical analysis and intermittent data check. Critical
review was performed by all.
Funding: Partially funded by ‘Thesis/
Research grant’ of Indian Council for Medical Research (ICMR).
Competing Interest: None stated.
What is Already Known?
• The duration of phenobarbitone prophylaxis
after control of acute neonatal seizures is debatable.
What This Study Adds?
• After clinical control of neonatal seizures
with first loading dose of phenobarbitone, withholding
phenobarbitone maintenance may not lead to seizure recurrence in
term and near-term infants.
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