Intravenous phenobarbital has not been available at our institution since 2019. This study aimed to determine the effectiveness of oral phenobarbital loading at a dose of 15 to 20 mg/kg to achieve therapeutic serum levels and clinical seizure control in pediatric patients with acute repetitive seizures.
This is a retrospective single-center review of the medical records of pediatric patients admitted for acute repetitive seizures (from January 2019 to June 2022) at the Philippine Children’s Medical Center who were given an oral phenobarbital loading dose of 15 to 20 mg/kg with serum level measurements taken within 48 hours after oral loading.
Eleven patients were given a single oral phenobarbital loading dose of 15 to 20 mg/kg, while 14 were given two doses of 10 mg/kg 12 hours apart. All 25 patients achieved therapeutic serum levels within 48 hours post-loading. Higher serum levels were seen at 48 hours (median, 19.8 μg/mL at 24 hours vs. 24.4 μg/mL at 48 hours). This difference was statistically significant at 5% (
Oral loading of phenobarbital at a dose of 15 to 20 mg/kg given as a single dose or in two divided doses is an effective and safe alternative to achieve therapeutic serum levels and adequate clinical seizure control at 24 hours post-loading. This may be a promising and useful intervention at centers without available intravenous phenobarbital.
One of the oldest antiseizure medications (ASMs), phenobarbital is a gamma-aminobutyric acid (GABA) inhibitor that decreases neuronal excitability by increasing the frequency of chloride channel openings. It has almost complete (95%) oral bioavailability, low total clearance, and a long half-life of 72 to 144 hours [
In our setting, oral phenobarbital has been used as a second- or third-line long-acting ASM for seizure control in patients with repetitive seizures at a total dose of 15 to 20 mg/kg, given as a single dose or in staggered doses to be completed in 24 to 48 hours [
A retrospective review was conducted of the medical records of pediatric inpatients admitted from January 2019 to June 2022 for acute repetitive seizures at the Philippine Children’s Medical Center. Acute repetitive seizures previously known as cluster seizures are defined most commonly as seizures occuring more than three times in 24 hours with interictal period of 8 hours or less, or seizures occuring more than two times in 6 to less than 48 hours [
Only convenience sampling was possible—The initial sample size computation was a minimum of 20 patients per arm satisfying the inclusion criteria, to determine, at 80% power, the effect of oral phenobarbital loading on serum phenobarbital levels, assuming that each subject had three measurements taken and intersubject variability was 50%. However, the number of samples obtained was not achieved from the total charts reviewed, and a total sample size of only 25 was obtained in this study. A total of 142 inpatient medical records with phenobarbital assays from the study period were reviewed. Of these, only 63 patients were given oral phenobarbital loading for acute repetitive seizures. Thirty-eight patients were excluded for various reasons (
Summary statistics were reported as median (interquartile range [IQR]) for quantitative variables with skewed distribution and as percentage (count) for qualitative measures. The minimum and maximum values of continuous data were also reported. The Shapiro-Wilk test was used to determine whether continuous variables deviated from a Gaussian (normal) distribution. The chi-square test of independence was used to determine the significance of associations between two qualitative variables. The Mann Whitney U test was used to compare the serum phenobarbital levels between two groups. Statistical significance was based on a
Ethical approval was obtained from the Philippine Children's Medical center Institutional Review Board (IR-EC #: PRCMC IR-EC 2021-041). This study adhered to the ethical consideration and principles set out in the Data Privacy Act of 2021 and the National Ethical Guidelines for Health and Health-Related research of 2017. Written informed consent from the patients was waived due to the retrospective nature of the study and patients' information and results gathered were strictly kept confidential by removing any identifiers such as names, addresses, and contact numbers before further usage and analysis. The investigator, co-investigator, and supervising investigators have completed the Good Clinical Practice training on the responsible conduct of research with human subjects.
Eleven patients (45.5% male) were given a single dose of oral phenobarbital loading, while 14 patients (50% male) were given two divided doses (
Serum phenobarbital levels were determined once within 24 to 48 hours after oral loading (
Five patients had an assay determined on the 48th hour post-loading with median serum phenobarbital levels of 27.4 μg/mL (IQR, 17.2 to 48.9), range from 13.4 to 51.0 μg/mL. Four of these received two doses (4 of 14, 28.6%) and one had a single dose (1 of 11, 9.1%). The median serum level in the four patients with two doses was 24.4 μg/mL (IQR, 17.45 to 37.15), range from 13.4 to 46.9 μg/mL.
The distribution of these patients and comparison between the two regimens did not show any statistical difference (
The overall median serum phenobarbital level was 21.5 mg/mL (IQR, 15.14 to 27.37), range from 13.4 to 51.0 mg/mL. The median serum levels within 24 hours and 24 to 48 hours were 19.8 mg/mL (IQR, 15.02 to 26.45) and 27.4 mg/mL (IQR, 21.46 to 46.86). A comparison between these two groups showed marginal results (
Clinical to seizure control between the two groups was not significantly different (
Acute repetitive seizures are neurologic emergencies that may progress to status epilepticus if left untreated. Intravenous phenobarbital is a well-established second-line ASM used for acute repetitive seizures when the recommended benzodiazepines fail to control seizures [
Acceptable serum therapeutic levels may vary across laboratories, but are considered effective at 10 to 40 μg/mL [
Phenobarbital is effective in focal seizures, the most common seizure type seen in this study [
The acute adverse effects of phenobarbital include rashes, hypersensitivity reactions, somnolence, drowsiness, and acute liver dysfunction [
This study was limited due to its retrospective nature and small sample size. Because of the short interval for study inclusion and the non-routine phenobarbital serum monitoring, the study participants were limited. A review of patients’ medical records would also be unable to fully document all the adverse events that may occur in these patients. A prospective and broader-spectrum study is thus recommended.
This study showed that oral loading of phenobarbital at a dose of 15 to 20 mg/kg/day given as a single dose or in two divided doses is an effective and safe method for achieving serum therapeutic effects within 24 hours after oral loading. This serum level was maintained and increased with maintenance doses. Children were able to tolerate this method with minimal and transient adverse reactions. This practice may thus be a helpful alternative at centers without access to intravenous phenobarbital or other newer ASMs.
No potential conflict of interest relevant to this article was reported.
Conceptualization: JGDF, MMGV, and CMCU. Data curation: JGDF. Formal analysis: JGDF. Methodology: JGDF. Project administration: JGDF. Visualization: JGDF. Writing-original draft: JGDF. Writing-review & editing: JGDF, MMGV, and CMCU.
Distribution of data samples included in the study. Within the study period, 142 patients had medical records documenting a phenobarbital assay. Only 63 patients had acute repetitive seizures and oral loading of phenobarbital. Thirty-eight patients did not meet the inclusion criteria and were excluded for the following reasons: 13 patients had no phenobarbital serum level measurements taken after the loading dose, 18 underwent oral loading but were already on phenobarbital maintenance with minimum therapeutic serum levels; four were given phenobarbital oral loading at 5 mg/kg/dose for 4 doses over 48 hours; two were given an oral phenobarbital loading dose to control clinical status epilepticus, and one had nonconvulsive status epilepticus.
Serum phenobarbital levels attained within 24 to 48 hours post-loading. The X-axis corresponds to the time in hours when the measurement was made, while the Y-axis corresponds to the serum levels of each patient. Patients who received a single dose of phenobarbital oral loading are shown in purple, while those who received two divided doses are colored green. The therapeutic range is marked by the orange area. Serum values ranged from 13.5 to 38.5 μg/mL at 24 hours and from 13.4 to 51 μg/mL at 48 hours.
Demographic and clinical profile of patients with oral loading of phenobarbitala
Characteristic | Oral loading of phenobarbital received |
|
---|---|---|
1 dose (15–20 mg/kg/dose) (n=11) | 2 doses (10 mg/kg/dose) (n=14) | |
Demographic | ||
Sex | ||
Male | 5 (45.5) | 7 (50.0) |
Female | 6 (54.5) | 7 (50.0) |
Age in years | ||
<1 | 5 (45.5) | 4 (28.6) |
1–5 | 2 (18.2) | 6 (42.9) |
6–10 | 2 (18.2) | 3 (21.4) |
11–18 | 2 (18.2) | 1 (7.1) |
Clinical profile | ||
Seizure/epilepsy etiology | ||
Structural | 6 (54.5) | 10 (71.42) |
Infectious/post-infectious | 1 (18.2) | 3 (14.3) |
Epilepsy syndrome | 1 (9.1) | 1 (7.1) |
Metabolic | 2 (18.2) | - |
Unknown | 1 (9.1) | - |
Characteristics of seizures | ||
Focal motor | 10 (90.9) | 13 (92.9) |
Focal nonmotor | - | 1 (7.1) |
Generalized, motor | 1 (9.1) | - |
Others (myoclonus, spasms) | 1 (9.1) | 2 (14.2) |
Presence of comorbidities at time of admission/seizures | ||
None | 3 (27.3) | 5 (35.7) |
Cerebral palsy | 1 (9.1) | 2 (14.3) |
Pneumonia | 3 (27.3) | 7 (50.0) |
Other infections (ventriculitis, URTI) | 1 (36.4) | 5 (35.7) |
Missed doses of phenobarbital | 1 (9.1) | 2 (14.3) |
Missed doses of other ASM | - | 1 (7.1) |
Metabolic derangements | 1 (9.1) | - |
On phenobarbital maintenance medication | ||
Yes | 3 (27.3) | 2 (14.3) |
No | 8 (72.7) | 12 (85.7) |
Other maintenance ASMs | ||
Levetiracetam | 5 (45.5) | 3 (21.4) |
Valproic acid | - | 1 (7.1) |
Phenytoin | 3 (27.3) | 2 (14.3) |
Others | 4 (36.4) | 1 (7.1) |
Other ASMs administered before phenobarbital | ||
None | 1 (9.1) | 6 (42.9) |
Diazepam/midazolam | 7 (63.6) | 7 (50.0) |
Levetiracetam (intravenous) | 5 (45.5) | 5 (35.7) |
Valproic acid (intravenous) | 3 (27.3) | - |
Phenytoin (intravenous) | 2 (18.2) | - |
Oxcarbazepine (oral) | 1 (9.1) | - |
Values are presented as number (%) among 25 patients given oral phenobarbital loading: 11 patients given a single dose of 15 to 20 mg/kg, and 14 patients given two doses of 10 mg/kg 12 hours apart.
URTI, upper respiratory tract infection; ASM, anti-seizure medication.
aSome patients presented with multiple seizure types, comorbities and maintenance medications.
Comparison of median phenobarbital serum levels achieved at 24 and 24 hours after oral loading
Time when phenobarbital assay taken | No. of patients | Median serum phenobarbital levels achieved per oral loading regimen (μg/mL) |
|
---|---|---|---|
1 Dose (15–20 mg/kg/dose) (n=11) | 2 Doses (10 mg/kg/dose) (n=14) | ||
24th-hour | 20 | 25.98 (19.11–31.78) | 15.24 (19.11–31.78) |
48th-hour | 5 | 51 | 24.4 (17.45–37.15) |
Values are presented as median (interquartile range). The comparison of serum levels between the two oral loading regimens was significant at 5% (
Distribution and comparison of patients who achieved serum therapeutic levels after oral loading of phenobarbital
Time when the phenobarbital assay was taken | No. of patients | Oral loading dose given |
|
---|---|---|---|
1 dose (15–20 mg/kg/dose) (n=11) | 2 doses (10 mg/kg/dose) (n=14) | ||
24 hours | 20 | 10 (90.9) | 10 (71.4) |
48 hours | 5 | 1 (9.1) | 4 (28.6) |
Values are presented as number (%) among 11 patients given a single dose of oral phenobarbital and 14 patients with two divided doses. The one-sided test of independence did not yield significant results (
Comparison of seizure control in patients given an oral loading dose of phenobarbital
Seizure recurrence | No. of patients | Oral loading dose given |
|
---|---|---|---|
1 dose (15–20 mg/kg/dose) | 2 doses (10 mg/kg/dose) | ||
Patients without seizure recurrence | 19 | 8 (72.7) | 11 (78.6) |
Patients with seizure recurrence | 6 | 3 (27.3) | 3 (21.4) |
Values are presented as number (%) among 11 patients given a single dose of oral phenobarbital and 14 patients with two divided doses. The one-sided test of independence did not yield significant results (
Adverse effects noted after oral phenobarbital loading
Adverse effects reported | No. of patients | Oral loading dose given |
|
---|---|---|---|
1 dose (15–20 mg/kg/dose) | 2 doses (10 mg/kg/dose) | ||
Drowsiness | 18 | 10 (90.9) | 8 (57.1) |
Decreased sensorium | 4 | 1 (9.1) | 3 (21.4) |
Elevated liver enzymes | 3 | 3 (27.3) | - |
Values are presented as number (%) among 11 patients given a single dose of oral phenobarbital and 14 patients with two divided doses. The one-sided test of independence did not yield significant results (