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The New England Journal of Medicine Sep 1998Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized,... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND AND METHODS
Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled.
RESULTS
Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days.
CONCLUSIONS
As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.
Topics: Aged; Anticonvulsants; Diazepam; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Lorazepam; Male; Middle Aged; Phenobarbital; Phenytoin; Status Epilepticus; Treatment Outcome
PubMed: 9738086
DOI: 10.1056/NEJM199809173391202 -
Epilepsia Sep 2023The Salzburg criteria for nonconvulsive status epilepticus (NCSE) and the American Clinical Neurophysiology Society (ACNS) Standardized Critical Care EEG Terminology...
OBJECTIVE
The Salzburg criteria for nonconvulsive status epilepticus (NCSE) and the American Clinical Neurophysiology Society (ACNS) Standardized Critical Care EEG Terminology 2021 include a diagnostic trial with intravenous (IV) antiseizure medications (ASMs) to assess electroencephalographic (EEG) and clinical response as a diagnostic criterion for definite NCSE and possible NCSE. However, how to perform this diagnostic test and assessing the EEG and clinical responses have not been operationally defined.
METHODS
We performed a Delphi process involving six experts to standardize the diagnostic administration of IV ASM and propose operational criteria for EEG and clinical response.
RESULTS
Either benzodiazepines (BZDs) or non-BZD ASMs can be used as first choice for a diagnostic IV ASM trial. However, non-BZDs should be considered in patients who already have impaired alertness or are at risk of respiratory depression. Levetiracetam, valproate, lacosamide, brivaracetam, or (if the only feasible drug) fosphenytoin or phenobarbital were deemed appropriate for a diagnostic IV trial. The starting dose should be approximately two thirds to three quarters of the full loading dose recommended for treatment of status epilepticus, with an additional smaller dose if needed. ASMs should be administered during EEG recording under supervision. A monitoring time of at least 15 min is recommended. If there is no response, a second trial with another non-BDZ or BDZs may be considered. A positive EEG response is defined as the resolution of the ictal-interictal continuum pattern for at least three times the longest previously observed spontaneous interval of resolution (if any), but minimum of one continuous minute. For a clinical response, physicians should use a standardized examination before and after IV ASM administration. We suggest a definite time-locked improvement in a focal deficit or at least one-step improvement on a new dedicated one-domain 10-level NCSE response scale.
SIGNIFICANCE
The proposed standardized approach of a diagnostic IV ASM trial further refines the ACNS and Salzburg diagnostic criteria for NCSE.
Topics: Humans; Administration, Intravenous; Benzodiazepines; Electroencephalography; Phenobarbital; Status Epilepticus; Clinical Trials as Topic
PubMed: 37350392
DOI: 10.1111/epi.17694 -
Epilepsy & Behavior : E&B Apr 2023Phenobarbital (PB) is one of the oldest Antiseizure Medicines (ASMs), which is in clinical use since 1912. Its value in the treatment of Status epilepticus is currently... (Review)
Review
Phenobarbital (PB) is one of the oldest Antiseizure Medicines (ASMs), which is in clinical use since 1912. Its value in the treatment of Status epilepticus is currently discussed controversially. Phenobarbital has fallen out of favor in many countries across Europe because of reports of hypotension, arrhythmias, and hypopnea. Phenobarbital has a strong antiseizure effect with remarkably little sedation. It exerts its clinical effects, through the increase of GABE-ergic inhibition and decrease of glutamatergic excitation by inhibition of AMPA receptors. Despite good preclinical evidence, there are remarkably few randomized controlled studies on humans in SE, which suggest, that it is at least as good as lorazepam in first-line treatment in early SE, and significantly better than valproic acid in benzodiazepine-resistant SE. Data from randomized trials and large non-randomized prospective and retrospective studies suggest, that Phenobarbital is well tolerated even if used in very high dose protocols. Thus, despite its decline in its popularity at least in Europe and North America, it should be considered a highly cost-effective treatment for early and established SE, not only in resource-limited settings. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.
Topics: Humans; Anticonvulsants; Retrospective Studies; Prospective Studies; Status Epilepticus; Phenobarbital
PubMed: 36807987
DOI: 10.1016/j.yebeh.2023.109104 -
Canadian Medical Association Journal Jul 1964Although sneezing is a particularly common symptom, there are surprisingly few references to this subject in the medical literature. Many of these references are...
Although sneezing is a particularly common symptom, there are surprisingly few references to this subject in the medical literature. Many of these references are shrouded in superstition and unscientific theory. Preparation of this report was stimulated by an interesting example of severe uncontrollable non-allergic paroxysmal sneezing which was carefully investigated with regard to both physical and psychological factors. A further example of paroxysms of sneezing occurring in a patient with temporal lobe seizures is also discussed with particular reference to the control of the sneezing episodes in association with anticonvulsant medication and control of the epileptic attacks. In addition, the neurophysiological mechanisms of sneezing are reviewed and the specific neurological references to the subject are discussed in relation to physiological and clinical data. At times the symptom of sneezing would appear to reflect some unknown disorder which may have central and possibly cortical affiliations.
Topics: Anticonvulsants; Child; Child Psychiatry; Epilepsy; Epilepsy, Temporal Lobe; Humans; Hydantoins; Methamphetamine; Phenobarbital; Primidone; Sneezing; Temporal Lobe
PubMed: 14180524
DOI: No ID Found -
Epilepsia Dec 2012This article reviews the current position of phenobarbital using articles published since 2000 and speculates on its likely future contribution to epilepsy care. Over... (Review)
Review
This article reviews the current position of phenobarbital using articles published since 2000 and speculates on its likely future contribution to epilepsy care. Over the last decade there have been no major double-blind randomized placebo-controlled or comparative trials with phenobarbital. Previous studies have suggested that phenobarbital is as effective in monotherapy as phenytoin and carbamazepine. Several observational studies undertaken in developing countries over the last decade have confirmed its efficacy and safety for the common epilepsies. This was particularly so in the substantial demonstration project undertaken in rural China under the auspices of the World Health Organization in partnership with the International League Against Epilepsy and International Bureau for Epilepsy. Phenobarbital is still widely used for neonatal and childhood seizures and for drug-resistant convulsive and nonconvulsive status epilepticus. Recent data have confirmed in a prospective cohort of women taking phenobarbital as monotherapy that the drug can be associated with a range of congenital defects in exposed infants. Much effort has gone into exploring the apparent contradiction of higher withdrawal rates due to cognitive and behavioral side effects in studies undertaken in developed countries but not in those sited in the developing world. A raft of data over the last 10 years, including a systematic review, showed no important differences between the tolerability of phenobarbital compared to that with other antiepileptic drugs. Finally, cognitive test scores and mood ratings in 136 people with epilepsy receiving phenobarbital for a year were similar to those in 137 age-, sex-, and education-matched controls in a number of Chinese villages. Indeed, there were some cognitive gains in the patients possibly due to improved seizure control. Phenobarbital is still the most cost-effective pharmacologic treatment for epilepsy. All these data predict a healthy future for phenobarbital, particularly in helping to close the treatment gap in low- and middle-income countries during its second century of clinical use.
Topics: Anticonvulsants; China; Epilepsy; Forecasting; Humans; Phenobarbital; Randomized Controlled Trials as Topic
PubMed: 23205961
DOI: 10.1111/epi.12027 -
Annals of Neurology Dec 2022Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective...
OBJECTIVE
Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia.
METHODS
Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology.
RESULTS
Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus.
INTERPRETATION
Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.
Topics: Animals; Humans; Infant, Newborn; Anticonvulsants; Asphyxia Neonatorum; Epilepsy; Phenobarbital; Seizures; Sheep; Animals, Newborn; Pregnanolone; Disease Models, Animal
PubMed: 36054160
DOI: 10.1002/ana.26493 -
Epilepsia Open Dec 2021Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate...
OBJECTIVE
Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist.
METHODS
We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset.
RESULTS
The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity.
SIGNIFICANCE
Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.
Topics: Animals; Anticonvulsants; Brain; Drug Therapy, Combination; Ketamine; Midazolam; Phenobarbital; Rats; Soman
PubMed: 34657398
DOI: 10.1002/epi4.12552 -
Journal of the American Veterinary... Mar 2000To determine clinical findings, cytologic and histologic characteristics of salivary glands, and response to treatment with phenobarbital in dogs with clinical signs...
OBJECTIVE
To determine clinical findings, cytologic and histologic characteristics of salivary glands, and response to treatment with phenobarbital in dogs with clinical signs typical of sialadenosis.
DESIGN
Prospective study.
ANIMALS
13 dogs with enlarged salivary glands.
PROCEDURE
Data were collected from dogs with clinical signs attributable to enlarged salivary glands. Salivary gland biopsy and cytologic specimens were examined. Dogs were treated with phenobarbital and monitored for response to treatment.
RESULTS
Clinical signs commonly associated with sialadenosis included retching and gulping. Substantial cellular changes were not detected by histologic or cytologic examination of enlarged salivary glands. Response to treatment with phenobarbital was rapid, although most dogs required continuous treatment to prevent recurrence of clinical signs.
CONCLUSIONS AND CLINICAL RELEVANCE
Sialadenosis is a condition of unknown cause that may have been underdiagnosed in dogs. Criteria for diagnosis include typical clinical signs, enlarged salivary glands, and lack of substantial microscopic lesions. Response to treatment with phenobarbital is rapid.
Topics: Animals; Dog Diseases; Dogs; GABA Modulators; Phenobarbital; Salivary Glands; Sialadenitis
PubMed: 22570898
DOI: 10.2460/javma.2000.216.872 -
Journal of Clinical Pharmacology Mar 2021The objective of this study was to describe the pharmacokinetics (PK) of intravenous phenobarbital in neonates and infants on extracorporeal membrane oxygenation (ECMO)...
The objective of this study was to describe the pharmacokinetics (PK) of intravenous phenobarbital in neonates and infants on extracorporeal membrane oxygenation (ECMO) and to provide dosing recommendations in this population. We performed a retrospective single-center PK study of phenobarbital in neonates and infants on ECMO between January 1, 2014, and December 31, 2018. We developed a population PK model using nonlinear mixed-effects modeling, performed simulations using the final PK parameters, and determined optimal dosing based on attainment of peak and trough concentrations between 20 and 40 mg/L. We included 35 subjects with a median (range) age and weight of 14 days (1-154 days) and 3.4 kg (1.6-8.1 kg), respectively. A total of 194 samples were included in the analysis. Five children (14%) contributing 30 samples (16%) were supported by continuous venovenous hemodiafiltration (CVVHDF). A 1-compartment model best described the data. Typical clearance and volume of distribution for a 3.4-kg infant were 0.038 L/h and 3.83 L, respectively. Clearance increased with age and CVVHDF. Although on ECMO, phenobarbital clearance in children on CVVHDF was 6-fold higher than clearance in children without CVVHDF. In typical subjects, a loading dose of 30 mg/kg/dose followed by maintenance doses of 6-7 mg/kg/day administered as divided doses every 12 hours reached goal concentrations. Age did not impact dosing recommendations. However, higher doses were needed in children on CVVHDF. We strongly recommend therapeutic drug monitoring in children on renal replacement therapy (excluding slow continuous ultrafiltration) while on ECMO.
Topics: Administration, Intravenous; Age Factors; Anticonvulsants; Computer Simulation; Continuous Renal Replacement Therapy; Dose-Response Relationship, Drug; Extracorporeal Membrane Oxygenation; Female; Humans; Infant; Infant, Newborn; Male; Models, Biological; Nonlinear Dynamics; Phenobarbital; Retrospective Studies; Tissue Distribution
PubMed: 32960986
DOI: 10.1002/jcph.1743 -
Canadian Medical Association Journal Jun 1963The main clinical types of epilepsy and their treatment are described. The treatment of choice in petit mal epilepsy is trimethadione (Trimedone) 0.3 g., three to six...
The main clinical types of epilepsy and their treatment are described. The treatment of choice in petit mal epilepsy is trimethadione (Trimedone) 0.3 g., three to six times a day, or acetazolamide (Diamox) 125-250 mg., three to four times a day. Phenobarbital is usually given as well to prevent grand mal seizures. Diphenylhydantoin sodium (Dilantin Sodium), 100 mg., and/or phenobarbital, 30-100 mg., three to four times a day, is recommended in patients with focal and grand mal epilepsy. Psychomotor automatisms are a form of focal seizure. Primidone (Mysoline), in doses of 125-250 mg. two to three times a day, is a very useful anticonvulsant in patients with myoclonic features, psychomotor automatisms and grand mal seizures. Primidone should be started in small doses. Drug reactions, especially cerebellar ataxia in the case of diphenylhydantoin and blood dyscrasias in the case of some drugs, should be recognized. Excessive drowsiness can be avoided by proper dosage and proper timing of drug administration. Patients should be seen regularly at least two to three times a year. The objective of treatment is to achieve optimum control of seizures by using the appropriate drug in adequate dosage. Social adaptation is good in the majority of patients, who should be encouraged to carry on their life independently, usually free to marry and have children. Attention to special occupational hazards has to be considered. Education of employers and employees is often necessary. Special work arrangements are occasionally indicated for selected patients. Patients should be seizure-free for two to three years before permission is given to drive an automobile.
Topics: Acetazolamide; Anticonvulsants; Automatism; Child; Epilepsy; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Humans; Phenobarbital; Phenytoin; Primidone; Seizures
PubMed: 13969008
DOI: No ID Found