What is the role of phenobarbital (phenobarb) in treating acute seizures?

From the Guidelines

Phenobarbital is not the first-line treatment for acute seizures, but it can be used as a second or third-line agent for status epilepticus when benzodiazepines fail, due to its effectiveness in terminating seizures, as seen in the VA Cooperative Study where it was equally efficacious as lorazepam, phenytoin, and phenytoin plus diazepam 1. In emergency settings, benzodiazepines like lorazepam (0.1 mg/kg IV) or diazepam (0.15-0.2 mg/kg IV) are preferred for immediate seizure control. Some key points to consider when using phenobarbital for acute seizures include:

• Administration: 15-20 mg/kg IV at a rate not exceeding 50-100 mg/minute, with a loading dose followed by maintenance dosing of 1-3 mg/kg/day.
• Mechanism of action: Enhancing the inhibitory effects of GABA in the brain, reducing neuronal excitability by prolonging chloride channel opening time.
• Side effects: Significant risks including respiratory depression, hypotension, and sedation, requiring careful monitoring of vital signs, respiratory function, and potentially mechanical ventilation support during administration.
• Efficacy: Effective in terminating seizures, with a success rate of 58.2% in the Veterans Affairs cooperative trial of refractory status epilepticus 1. The long half-life of phenobarbital (72-144 hours in adults) makes it less suitable for acute intervention but valuable for preventing seizure recurrence after initial control is achieved. Overall, while phenobarbital can be an effective treatment for status epilepticus, its use should be carefully considered due to its potential side effects and the availability of other treatment options.

From the FDA Drug Label

A therapeutic anticonvulsant level of phenobarbital in the serum is 10 to 25 µg/mL. To achieve the blood levels considered therapeutic in children, higher per-kilogram dosages are generally necessary for phenobarbital and most other anticonvulsants In children and infants, phenobarbital at loading doses of 15 to 20 mg/kg produces blood levels of about 20 µg/mL shortly after administration. In status epilepticus, it is imperative to achieve therapeutic blood levels of a barbiturate (or other anticonvulsants) as rapidly as possible Phenobarbital has been used in the treatment and prophylaxis of febrile seizures Phenobarbital limits the spread of seizures and raises the seizure threshold in grand mal (generalized tonic-clonic) epilepsy.

The role of phenobarbital (phenobarb) in treating acute seizures is as an anticonvulsant. It is used to achieve therapeutic blood levels as rapidly as possible, especially in status epilepticus. Phenobarbital can help limit the spread of seizures and raise the seizure threshold in grand mal (generalized tonic-clonic) epilepsy. The recommended therapeutic anticonvulsant level of phenobarbital in the serum is 10 to 25 µg/mL 2.

From the Research

Role of Phenobarbital in Treating Acute Seizures

• Phenobarbital is one of the oldest Antiseizure Medicines (ASMs) and has been in clinical use since 1912 3.
• It has a strong antiseizure effect with remarkably little sedation, exerting its clinical effects through the increase of GABA-ergic inhibition and decrease of glutamatergic excitation by inhibition of AMPA receptors 3.
• Despite its decline in popularity, phenobarbital should be considered a highly cost-effective treatment for early and established status epilepticus (SE), not only in resource-limited settings 3.

Efficacy of Phenobarbital in Benzodiazepine-Resistant Status Epilepticus

• Phenobarbital appears to be the most effective agent for seizure cessation within 60 minutes of administration in patients with benzodiazepine-resistant status epilepticus, based on low-quality evidence 4.
• Network meta-analysis demonstrated that phenobarbital had the highest probability of being the best among the studied interventions, followed by high-dose levetiracetam and high-dose valproate 4.
• However, phenobarbital was found to be associated with a higher risk of need for intubation and cardiovascular instability compared to other treatments 4.

Clinical Experience with Phenobarbital in Status Epilepticus

• A retrospective analysis of nonintubated patients with refractory SE treated with parenteral phenobarbital found that moderate-dose parenteral PB was effective in attaining seizure control in a significant proportion of noncomatose refractory SE patients 5.
• None of the patients required ventilatory support, and only one patient required intervention for hypotension 5.
• High-dose phenobarbital therapy was also found to be effective in controlling intractable tonic seizure with apnea in a case of multiple anomalies syndrome, with no significant cardiopulmonary complications 6.

Side Effects of Phenobarbital

• A study in rural Zambia found that patients taking phenobarbital reported a significant number of side effects, including sleepiness, dizziness, memory problems, and depression 7.
• The most common side effects reported were similar to those reported in high-income countries, with a median of 6 symptoms and a mean side effects score of 28/76 7.
• However, the significant burden of phenobarbital-associated side effects in this African cohort is in contrast to data from non-randomized clinical trials in China that reported phenobarbital to be well-tolerated with few side effects 7.