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The New England Journal of Medicine Nov 2019The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.
METHODS
In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.
RESULTS
A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.
CONCLUSIONS
In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).
Topics: Adolescent; Adult; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Double-Blind Method; Drug Resistance; Female; Humans; Hypotension; Infusions, Intravenous; Injections, Intramuscular; Levetiracetam; Male; Middle Aged; Phenytoin; Status Epilepticus; Valproic Acid; Young Adult
PubMed: 31774955
DOI: 10.1056/NEJMoa1905795 -
Drug Design, Development and Therapy 2018Phenytoin is a non-sedative barbiturate derivate and has been recently rediscovered as a neuroprotective and retinoprotective compound in patients affected by optic... (Review)
Review
Phenytoin is a non-sedative barbiturate derivate and has been recently rediscovered as a neuroprotective and retinoprotective compound in patients affected by optic neuritis secondary to multiple sclerosis. However, currently there are still no neuroprotective compounds registered and available in the clinic. We reviewed the literature supporting the retinoprotective properties of phenytoin and analyzed the various approaches and definitions from the first research periods onwards. The retinoprotective role of phenytoin was already known in the 1970s, but only recently has this effect been rediscovered, confirming that it could indeed provide structural protection of the retinal cells.
Topics: Antineoplastic Agents; Drug Discovery; Enzyme Inhibitors; Humans; Multiple Sclerosis; Neuroprotective Agents; Optic Neuritis; Phenytoin; Retina
PubMed: 30410309
DOI: 10.2147/DDDT.S169621 -
BMJ Case Reports Jan 2019A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on...
A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on admission. Routine work-up revealed toxic levels of phenytoin. No cause of hypothermia could be identified but as his phenytoin levels normalised, his body temperature also improved. There are three other reported cases of phenytoin- induced hypothermia in the literature. Could this be a rare cause of hypothermia?
Topics: Aftercare; Ataxia; Cytochrome P-450 CYP1A2 Inducers; Diagnosis, Differential; Humans; Hypothermia; Lethargy; Male; Middle Aged; Phenytoin; Treatment Outcome
PubMed: 30674493
DOI: 10.1136/bcr-2018-227443 -
Health Technology Assessment... Nov 2020Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence.
OBJECTIVE
To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management.
DESIGN
A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent.
SETTING
Participants were recruited from 30 paediatric emergency departments in the UK.
PARTICIPANTS
Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment.
INTERVENTIONS
Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg).
MAIN OUTCOME MEASURES
Primary outcome - time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes - further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions.
RESULTS
Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20-not assessable) minutes in the levetiracetam group and 45 (interquartile range 24-not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions.
LIMITATIONS
First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of 'cessation of all signs of continuous, rhythmic clonic activity' as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups.
CONCLUSIONS
Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials.
FUTURE WORK
Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus.
TRIAL REGISTRATION
Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13.
FUNDING
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.
Topics: Administration, Intravenous; Adolescent; Anticonvulsants; Child; Child, Preschool; Equivalence Trials as Topic; Female; Humans; Infant; Levetiracetam; Male; Phenytoin; Status Epilepticus; United Kingdom
PubMed: 33190679
DOI: 10.3310/hta24580 -
Bioanalysis Feb 2022The purpose of the study was to find methods suitable for measuring the free concentrations of testosterone and phenytoin. Sample solutions of the compounds in buffer...
The purpose of the study was to find methods suitable for measuring the free concentrations of testosterone and phenytoin. Sample solutions of the compounds in buffer and human albumin were processed using liquid-liquid extraction, microextraction and ultrafiltration and analyzed by LC-MS/MS. Liquid-liquid extraction with dibutyl phthalate provided complete extraction from buffer solutions and partial extraction from albumin samples. Spintip C18 devices provided exhaustive extraction from buffer and albumin samples. Spintip C8 devices offered complete extraction from buffer and approximately 50% recovery from albumin samples. Centrifree ultrafiltration devices showed high recovery of free concentrations from all the samples, while Amicon and Nanosep devices provided partial recovery. Spintip C8 and Centrifree devices proved useful for measuring free concentrations.
Topics: Humans; Liquid Phase Microextraction; Liquid-Liquid Extraction; Phenytoin; Testosterone; Ultrafiltration
PubMed: 35034505
DOI: 10.4155/bio-2021-0249 -
BMJ Clinical Evidence Apr 2011Unrelieved pressure or friction of the skin, particularly over bony prominences, can lead to pressure ulcers in up to one third of people in hospitals or community care,... (Review)
Review
INTRODUCTION
Unrelieved pressure or friction of the skin, particularly over bony prominences, can lead to pressure ulcers in up to one third of people in hospitals or community care, and one fifth of nursing home residents. Pressure ulcers are more likely in people with reduced mobility and poor skin condition, such as older people or those with vascular disease.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in people at risk of developing pressure ulcers? What are the effects of treatments in people with pressure ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 64 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: air-filled vinyl boots, air-fluidised supports, alternating-pressure surfaces (including mattresses), alternative foam mattresses, constant low-pressure supports, debridement, electric profiling beds, electrotherapy, hydrocellular heel supports, low-air-loss beds (including hydrotherapy beds), low-level laser therapy, low-tech constant-low-pressure supports, medical sheepskin overlays, nutritional supplements, orthopaedic wool padding, pressure-relieving overlays on operating tables, pressure-relieving surfaces, repositioning (regular "turning"), seat cushions, standard beds, standard care, standard foam mattresses, standard tables, surgery, therapeutic ultrasound, topical lotions and dressings, topical negative pressure, and topical phenytoin.
Topics: Anticonvulsants; Bandages; Bedding and Linens; Beds; Debridement; Humans; Low-Level Light Therapy; Negative-Pressure Wound Therapy; Patient Positioning; Phenytoin; Pressure Ulcer; Standard of Care; Ultrasonic Therapy
PubMed: 21524319
DOI: No ID Found -
Indian Journal of Pharmacology 2019Phenytoin is an anticonvulsant which is also a Class IB antiarrhythmic. Its common adverse drug reactions (ADRs) include gastrointestinal symptoms, psychiatric...
Phenytoin is an anticonvulsant which is also a Class IB antiarrhythmic. Its common adverse drug reactions (ADRs) include gastrointestinal symptoms, psychiatric disorders, gingival hyperplasia, and rash. Bradycardia and hypotension following intravenous (IV) phenytoin are rare ADRs. We report the case of a 62-year-old female with subarachnoid hemorrhage and right bundle branch block, who developed sinus bradycardia and hypotension on administration of IV phenytoin. This case report serves as a note for caution on patient selection for the administration of phenytoin and highlights the need for specific guidelines on the same.
Topics: Anticonvulsants; Bradycardia; Female; Humans; Hypotension; Middle Aged; Phenytoin
PubMed: 31142948
DOI: 10.4103/ijp.IJP_254_17 -
Journal of Neurology, Neurosurgery, and... Jan 2023Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line... (Randomized Controlled Trial)
Randomized Controlled Trial
Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial.
OBJECTIVE
Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE.
METHODS
We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug.
RESULTS
A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061).
CONCLUSION
The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT.
TRIAL REGISTRATION NUMBER
jRCTs031190160.
Topics: Humans; Adult; Levetiracetam; Phenytoin; Diazepam; Anticonvulsants; Status Epilepticus; Seizures; Treatment Outcome
PubMed: 36207063
DOI: 10.1136/jnnp-2022-329485 -
Cleveland Clinic Journal of Medicine Sep 2022
Topics: Humans; Phenytoin; Gingival Overgrowth; Anticonvulsants
PubMed: 37907437
DOI: 10.3949/ccjm.89a.21107 -
Neurology India 2021
Topics: Anticonvulsants; Epilepsy; Humans; Phenytoin
PubMed: 34507421
DOI: 10.4103/0028-3886.325320