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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 -
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 -
BMJ Case Reports Nov 2022
Topics: Humans; Phenytoin; Anticonvulsants; Parathyroid Hormone
PubMed: 36368739
DOI: 10.1136/bcr-2022-253250 -
The American Journal of Emergency... Oct 2014Phenytoin has a narrow therapeutic window, and when managing cases of toxicity, clinicians are very wary of this fact. Typically, if patient presents with symptoms...
Phenytoin has a narrow therapeutic window, and when managing cases of toxicity, clinicians are very wary of this fact. Typically, if patient presents with symptoms suggestive of phenytoin toxicity, total serum phenytoin is promptly ordered. That could be falsely low especially in elderly or critically ill patients, which may lead to a low albumin level resulting in this discrepancy. The free phenytoin can be best estimated using the Sheiner-Tozer equation. Herein, we describe a case of an elderly male patient who presented with drowsiness, gait changes, and elevated liver enzymes and a normal total serum phenytoin level of 18 ng/dL (normal, 10-20 ng/dL).After taking his albumin level into account, his free phenytoin level was calculated to be 27 ng/dL, and the phenytoin was discontinued leading to resolution of his symptoms as well as a return of his liver function panel values to baseline.
Topics: Aged; Anticonvulsants; Chemical and Drug Induced Liver Injury; Gait Disorders, Neurologic; Humans; Hypoalbuminemia; Male; Phenytoin; Sleep Stages
PubMed: 24768668
DOI: 10.1016/j.ajem.2014.03.036 -
Neurocritical Care Jun 2024There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury... (Meta-Analysis)
Meta-Analysis
Guidelines for Seizure Prophylaxis in Adults Hospitalized with Moderate-Severe Traumatic Brain Injury: A Clinical Practice Guideline for Health Care Professionals from the Neurocritical Care Society.
BACKGROUND
There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury (TBI).
METHODS
We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with moderate-severe TBI (acute radiographic findings and requiring hospitalization). The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM versus no ASM be used in patients with moderate-severe TBI and no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT/fPHT) be preferentially used? (3) If an ASM is used, should a long versus short (> 7 vs. ≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure, late seizure, adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations.
RESULTS
The initial literature search yielded 1998 articles, of which 33 formed the basis of the recommendations: PICO 1: We did not detect any significant positive or negative effect of ASM compared to no ASM on the outcomes of early seizure, late seizure, adverse events, or mortality. PICO 2: We did not detect any significant positive or negative effect of PHT/fPHT compared to LEV for early seizures or mortality, though point estimates suggest fewer late seizures and fewer adverse events with LEV. PICO 3: There were no significant differences in early or late seizures with longer versus shorter ASM use, though cognitive outcomes and adverse events appear worse with protracted use.
CONCLUSIONS
Based on GRADE criteria, we suggest that ASM or no ASM may be used in patients hospitalized with moderate-severe TBI (weak recommendation, low quality of evidence). If used, we suggest LEV over PHT/fPHT (weak recommendation, very low quality of evidence) for a short duration (≤ 7 days, weak recommendation, low quality of evidence).
Topics: Humans; Brain Injuries, Traumatic; Anticonvulsants; Seizures; Levetiracetam; Critical Care; Adult; Phenytoin; Hospitalization; Practice Guidelines as Topic
PubMed: 38316735
DOI: 10.1007/s12028-023-01907-x -
Journal of Neurology May 2016Phenytoin is an established drug in the treatment of acute repetitive seizures and status epilepticus. One of its main advantages over benzodiazepines is the less... (Review)
Review
Phenytoin is an established drug in the treatment of acute repetitive seizures and status epilepticus. One of its main advantages over benzodiazepines is the less sedative effect. However, the possibility of cardiovascular adverse effects with the intravenous use of phenytoin cause a reluctance to its usage, and this has lead to a search for safer anticonvulsant drugs. In this study, we aimed to review the studies which evaluated the safety of phenytoin with respect to cardiovascular adverse effects. The original clinical trials and case reports listed in PUBMED in English language between the years of 1946-2014 were evaluated. As the key words, "phenytoin, diphenylhydantoin, epilepsy, seizure, cardiac toxicity, asystole, arrhythmia, respiratory arrest, hypotension, death" were used. Thirty-two clinical trials and ten case reports were identified. In the case reports, a rapid infusion rate (>50 mg/min) of phenytoin appeared as the major cause of increased mortality. In contrast, no serious cardiovascular adverse effects leading to death were met in the clinical trials which applied the recommended infusion rate and dosages. An infusion rate of 50 mg/min was reported to be safe for young patients. For old patients and patients with a cardiovascular co-morbidity, a slower infusion rate was recommended with a careful follow-up of heart rhythm and blood pressure. No cardiovascular adverse effect was reported in oral phenytoin overdoses except one case with a very high serum phenytoin level and hypoalbuminemia. Phenytoin is an effective and well tolerated drug in the treatment of epilepsy. Intravenous phenytoin is safe when given at recommended infusion rates and doses.
Topics: Anticonvulsants; Cardiovascular Diseases; Cardiovascular System; Humans; Phenytoin
PubMed: 26645393
DOI: 10.1007/s00415-015-7967-1 -
Cleveland Clinic Journal of Medicine Sep 2022
Topics: Humans; Phenytoin; Gingival Overgrowth; Anticonvulsants
PubMed: 37907437
DOI: 10.3949/ccjm.89a.21107 -
Central Nervous System Agents in... 2022The derivatives of Phenytoin conjugated with various anilines were synthesized. The synthesized derivatives were evaluated for different physicochemical parameters along...
BACKGROUND
The derivatives of Phenytoin conjugated with various anilines were synthesized. The synthesized derivatives were evaluated for different physicochemical parameters along with log P values using different software programs to discover their ability to cross the blood brain barrier. The pharmacological activities such as antianxiety, skeletal muscle relaxant and anticonvulsant were evaluated by using different models.
OBJECTIVE
The new Phenytoin derivatives were synthesized and evaluated for different properties to predict CNS activity. The drugs synthesized by chloroacetylation and then different aniline were added to it. The compounds were evaluated for their different CNS activity by using different methods.
METHODS
The compounds were synthesized by firstly chloroacetylating the phenytoin and then different substituted anilines were added to it. The compounds were evaluated for antianxiety activity, muscle relaxant activity and anticonvulsant activity by using different models.
RESULTS
The number of derivatives of Phenytoin was synthesized and various physicochemical parameters were optimized which revealed that the compound containing chloro groups such as C2 and C5 exhibited significant potential when compared with the standard drug Diazepam.
CONCLUSION
It was portrayed that the synthesis, computational studies and evaluation of anticonvulsant, antianxiety and skeletal muscle relaxant activity of new Phenytoin derivatives were carried out. The compounds were productively synthesized and portrayed by molecular docking studies. The compounds also exhibit mild to moderate similarity with respect to standard drug. The synthesized drugs have the potential to be optimized further to engender new scaffolds to treat various CNS disorders.
Topics: Aniline Compounds; Anticonvulsants; Humans; Molecular Docking Simulation; Phenytoin; Seizures; Structure-Activity Relationship
PubMed: 35507791
DOI: 10.2174/1871524922666220429122141 -
Die Pharmazie Jul 2023Physiologic changes due to aging, pregnancy, nutritional status, drug interactions, and can affect pharmacokinetics and pharmacodynamics of antiepileptic drugs. In this... (Review)
Review
Physiologic changes due to aging, pregnancy, nutritional status, drug interactions, and can affect pharmacokinetics and pharmacodynamics of antiepileptic drugs. In this review article, the interactions between phenytoin and herbs recorded in the literature were summarized according to the Medline database (via PubMed). Our results revealed that, changes in phenytoin's bioavailability were reported for co-administration of herbs or herbal extracts. An increase in phenytoin blood levels was established with , Mentat, and in and/or studies. In contrast, herbphenytoin interactions led to sub-therapeutic levels of phenytoin in other cases with herbs such as Cannabis, , , , and . In addition, the findings of other pharmcodynamic experiments showed that various herbs, including , , L, and , improved the pharmacological impact of phenytoin. To reduce the patients' health risks, health professionals involved in their treatment are expected to be thoroughly educated about the interactions between phenytoin and medicinal plants.
Topics: Humans; Plants, Medicinal; Phenytoin; Anticonvulsants; Drug Interactions
PubMed: 37537774
DOI: 10.1691/ph.2023.3546 -
Enfermeria Intensiva 2022To identify commonly used intravenous drugs that may produce endothelial damage.
AIMS
To identify commonly used intravenous drugs that may produce endothelial damage.
METHODS
An experimental research study was performed using a sample of 62 intravenous drugs commonly used in emergency care, pH and osmolarity were measured. Subsequently, based on these values, the theoretical capacity to cause irritation or endovascular damage was determined and classified as high, moderate, and low.
RESULTS
Samples from 19 drugs for fluid therapy, 21 antibiotics and 22 drugs for intravenous use were studied. Glucose solutions, sodium bicarbonate 1M and mannitol 10% showed a high capacity to cause venous irritation. Vancomycin, ciprofloxacin, amiodarone, haloperidol, and labetalol solution presented a high capacity for irritation based on their acidic pH. The antibiotics, dexketoprofen, diazepam, digoxin, etomidate, phenytoin, levetiracetam and metamizole also showed high osmotic values in their reconstituted or undiluted presentations. Moreover, osmolarity of diazepam, digoxin and phenytoin remained high despite being diluted in 100 ml of saline.
CONCLUSIONS
Knowing the pH and osmolarity of intravenous drugs allows their capacity to cause endothelial damage to be assessed. The use of comprehensive tables based on the chemical properties of the drugs can be a useful tool to help prevent chemically-induced phlebitis.
Topics: Anti-Bacterial Agents; Diazepam; Digoxin; Humans; Phenytoin; Phlebitis
PubMed: 35941074
DOI: 10.1016/j.enfie.2021.05.003