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Seizure May 2022Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the... (Review)
Review
BACKGROUND
Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the potential adverse effects caused by exposure to antiseizure medications (ASMs).
OBJECTIVE
The objectives of this review were: to evaluate concentrations of ASMs in breastmilk of lactating WWE, qualitatively synthesize evidence that can be used to estimate theoretical doses as estimated daily intake (EDI) and relative infant dose (RID) of ASMs, and to evaluate potential risks to infants as a result of exposure to ASMs from breastmilk.
METHODS
This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020223645. The databases: MEDLINE/PubMed, EMBASE, CINAHL/EBSCO, COCHRANE, SpringerLink, ScienceDirect, Summon, WHO International Clinical Trials Registry Platform, and SCOPUS were systematically searched. A qualitative synthesis was adopted in this study.
RESULTS
A total of 15 records were included in this systematic review. The included studies reported levels of 8 ASMs in the breastmilk of WWE. The highest RIDs of carbamazepine, lamotrigine, primidone, phenobarbital, gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%, 36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively. Breastfeeding might be limited or even discontinued when signs of excessive sedation/drowsiness and/or poor weight gain are evident on infants exposed to primidone and phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital.
CONCLUSIONS
Concentrations of ASMs can be detected in breastmilk of WWE and plasma/serum of infants exposed via breastmilk. Healthcare providers and WWE might use the findings of this study to make informed decisions on the safety of breastfeeding while taking ASMs.
Topics: Anticonvulsants; Breast Feeding; Epilepsy; Ethosuximide; Female; Humans; Infant; Lactation; Milk, Human; Phenobarbital; Primidone
PubMed: 35427849
DOI: 10.1016/j.seizure.2022.03.017 -
Health Technology Assessment... Mar 2022Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded...
BACKGROUND
Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded as an emergency condition that requires prompt treatment to avoid hospitalisation and to reduce morbidity and mortality. Rapid pre-hospital first-line treatment of convulsive status epilepticus is currently benzodiazepines, administered either by trained caregivers in the community (e.g. buccal midazolam, rectal diazepam) or by trained health professionals via intramuscular or intravenous routes (e.g. midazolam, lorazepam). There is a lack of clarity about the optimal treatment for convulsive status epilepticus in the pre-hospital setting.
OBJECTIVES
To assess the current evidence on the clinical effectiveness and cost-effectiveness of treatments for adults with convulsive status epilepticus in the pre-hospital setting.
DATA SOURCES
We searched major electronic databases, including MEDLINE, EMBASE, PsycInfo, CINAHL, CENTRAL, NHS Economic Evaluation Database, Health Technology Assessment Database, Research Papers in Economics, and the ISPOR Scientific Presentations Database, with no restrictions on publication date or language of publication. Final searches were carried out on 21 July 2020.
REVIEW METHODS
Systematic review of randomised controlled trials assessing adults with convulsive status epilepticus who received treatment before or on arrival at the emergency department. Eligible treatments were any antiepileptic drugs offered as first-line treatments, regardless of their route of administration. Primary outcomes were seizure cessation, seizure recurrence and adverse events. Two reviewers independently screened all citations identified by the search strategy, retrieved full-text articles, extracted data and assessed the risk of bias of the included trials. Results were described narratively.
RESULTS
Four trials (1345 randomised participants, of whom 1234 were adults) assessed the intravenous or intramuscular use of benzodiazepines or other antiepileptic drugs for the pre-hospital treatment of convulsive status epilepticus in adults. Three trials at a low risk of bias showed that benzodiazepines were effective in stopping seizures. In particular, intramuscular midazolam was non-inferior to intravenous lorazepam. The addition of levetiracetam to clonazepam did not show clear advantages over clonazepam alone. One trial at a high risk of bias showed that phenobarbital plus optional phenytoin was more effective in terminating seizures than diazepam plus phenytoin. The median time to seizure cessation from drug administration varied from 1.6 minutes to 15 minutes. The proportion of people with recurrence of seizures ranged from 10.4% to 19.1% in two trials reporting this outcome. Across trials, the rates of respiratory depression among participants receiving active treatments were generally low (from 6.4% to 10.6%). The mortality rate ranged from 2% to 7.6% in active treatment groups and from 6.2% to 15.5% in control groups. Only one study based on retrospective observational data met the criteria for economic evaluation; therefore, it was not possible to draw any robust conclusions on cost-effectiveness.
LIMITATIONS
The limited number of identified trials and their differences in terms of treatment comparisons and outcomes hindered any meaningful pooling of data. None of the included trials was conducted in the UK and none assessed the use of buccal midazolam or rectal diazepam. The review of economic evaluations was hampered by lack of suitable data.
CONCLUSIONS
Both intravenous lorazepam and intravenous diazepam administered by paramedics are more effective than a placebo in the treatments of adults with convulsive status epilepticus, and intramuscular midazolam is non-inferior to intravenous lorazepam. Large well-designed clinical trials are needed to establish which benzodiazepines are more effective and preferable in the pre-hospital setting.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42020201953.
FUNDING
This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in ; Vol. 26, No. 20. See the NIHR Journals Library website for further project information.
Topics: Adult; Anticonvulsants; Emergency Service, Hospital; Hospitals; Humans; Retrospective Studies; Status Epilepticus
PubMed: 35333156
DOI: 10.3310/RSVK2062 -
Frontiers in Neurology 2021Neonatal seizures are a common neurological emergency in newborns. Phenobarbital (PB) is the first-line antiepileptic drug (AED). However, PB has some side effects,...
Neonatal seizures are a common neurological emergency in newborns. Phenobarbital (PB) is the first-line antiepileptic drug (AED). However, PB has some side effects, such as hypotension and respiratory depression, and it can accelerate neuronal apoptosis in the immature brain. Levetiracetam (LEV), a new antiepileptic drug, has been used as a second-line drug for the treatment of neonatal seizures. Compared with PB, LEV has many advantages, including a low incidence of side effects and better neurodevelopmental outcomes. However, there are only a few systematic reviews of LEV for the treatment of neonatal seizures. To evaluate the efficacy and safety of LEV for neonatal seizures and to compare the efficacy, side effects, and neurological outcomes between LEV and PB in the treatment of neonatal seizures. The keywords LEV, PB, and neonatal seizure were searched in the MEDLINE, Cochrane Library, Web of Science, EMBASE, clinicaltrials.gov, and China National Knowledge Internet (CNKI) databases with a last update in July 2021 to collect high-quality studies. We collected studies studying the efficacy or safety of LEV and PB in the treatment of neonatal seizures applying strict inclusion and exclusion criteria. The data were extracted and outcome measures, including efficacy, side effect rate, neurological score, and mortality rate, were analyzed with RevMan 5.3 software. Ten articles were finally included in the meta-analysis. The meta-analysis showed that there was no difference in efficacy between LEV and PB in the treatment of neonatal seizures. Compared with PB, the incidence of side effects of LEV was lower. The incidence of hypotension and respiratory depression in the LEV group was significantly lower than that in the PB group. In terms of long-term neurodevelopmental outcomes, there was no significant difference in the Bayley Scales of Infant Development (BSID) scores between LEV and PB. PB is still the first-line AED recommended by the WHO for the treatment of neonatal seizures. The new AEDs LEV may not have better efficacy than PB. At the same time, LEV is associated with better neurodevelopment outcomes and a lower risk of adverse effects. In addition, continuous EEG monitoring should be used to diagnose neonatal seizures to evaluate the severity of the seizures, remission, and drug efficacy. PROSPERO, identifier: CRD42021279029.
PubMed: 34867732
DOI: 10.3389/fneur.2021.747745 -
Current Alzheimer Research 2021Patients with dementia have an increased risk of developing epilepsy, especially in patients with vascular dementia and Alzheimer's disease. In selecting the optimal...
BACKGROUND
Patients with dementia have an increased risk of developing epilepsy, especially in patients with vascular dementia and Alzheimer's disease. In selecting the optimal anti- epileptic drug (AED), the possible side effects such as drowsiness and worsening of cognitive function should be taken into consideration, together with co-morbidities and type of epilepsy.
OBJECTIVE
The current systematic review investigates the efficacy, tolerability, and changes in cognitive function after administration of AED in patients with dementia and epilepsy.
METHODS
We searched six databases, including MEDLINE and CENTRAL, checked reference lists, contacted experts, and searched Google Scholar to identify studies reporting randomized trials. Studies identified were independently screened, data extracted, and quality appraised by two researchers. A narrative synthesis was used to report findings.
RESULTS
We included one study with 95 patients with Alzheimer's disease randomized to either levetiracetam, lamotrigine, or phenobarbital. No significant differences were found for efficacy, but patients receiving levetiracetam showed an improvement in mini-mental state examination scores and had fewer adverse events.
CONCLUSION
High-quality evidence in the form of randomized controlled trials to guide clinicians in choosing an AED in patients with dementia and concomitant epilepsy remains scarce. However, levetiracetam has previously been shown to possibly improve cognition in patients with both mild cognitive impairment and Alzheimer's disease, is better tolerated in the elderly population, and has no clinically relevant interaction with either cholinesterase inhibitors or NMDA receptor antagonists.
Topics: Aged; Alzheimer Disease; Anticonvulsants; Epilepsy; Humans; Lamotrigine; Levetiracetam; Randomized Controlled Trials as Topic
PubMed: 34825872
DOI: 10.2174/1567205018666211126121529 -
Epilepsia Feb 2022Thyroid hormones play an essential role in central nervous system development, normal physiological brain function, and repair mechanisms. On one hand, thyroid hormone... (Review)
Review
Thyroid hormones play an essential role in central nervous system development, normal physiological brain function, and repair mechanisms. On one hand, thyroid hormone alterations influence cortical excitability, and on the other hand antiseizure medications (ASMs) are associated with alterations in thyroid hormone metabolism. Although this interaction has long been described, and epilepsy is a common and chronic neurological disease, studies describing the interplay are often small and retrospective. We performed a systematic review of the current literature on epilepsy, ASMs, and thyroid hormone metabolism according to PRISMA guidelines. Forty-seven studies were included. Most studies were retrospective cross-sectional studies (n = 25) and investigated thyroid function alterations in patients on older ASMs such as phenobarbital, phenytoin, carbamazepine, and valproate. Overall, almost one third of patients with epilepsy had thyroid hormone alterations, especially patients on valproate (25%) and carbamazepine (10%-25%). Studies with patients receiving polytherapy are scarce, but reported a higher risk for hypothyroidism in patients with older age (p = .004), female sex (p = .014), longer duration of epilepsy (p = .001), intractable epilepsy (p = .009), and polytherapy. Studies on newer ASMs are also limited, and further studies on an interplay with thyroid hormone homeostasis are essential to improve the care for epilepsy patients. ASMs are associated with alterations in thyroid hormone metabolism. Thyroid function monitoring is indicated in patients on ASMs, especially those with refractory epilepsy and those on polytherapy. We provide a practical guidance for thyroid function monitoring for the clinician taking care of patients on ASMs.
Topics: Anticonvulsants; Benzodiazepines; Carbamazepine; Cross-Sectional Studies; Epilepsy; Female; Homeostasis; Humans; Retrospective Studies; Thyroid Hormones; Valproic Acid
PubMed: 34750814
DOI: 10.1111/epi.17117 -
Clinical Toxicology (Philadelphia, Pa.) Dec 2021The use of activated charcoal in poisoning remains both a pillar of modern toxicology and a source of debate. Following the publication of the joint position statements...
INTRODUCTION
The use of activated charcoal in poisoning remains both a pillar of modern toxicology and a source of debate. Following the publication of the joint position statements on the use of single-dose and multiple-dose activated charcoal by the American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists, the routine use of activated charcoal declined. Over subsequent years, many new pharmaceuticals became available in modified or alternative-release formulations and additional data on gastric emptying time in poisoning was published, challenging previous assumptions about absorption kinetics. The American Academy of Clinical Toxicology, the European Association of Poison Centres and Clinical Toxicologists and the Asia Pacific Association of Medical Toxicology founded the Clinical Toxicology Recommendations Collaborative to create a framework for evidence-based recommendations for the management of poisoned patients. The activated charcoal workgroup of the Clinical Toxicology Recommendations Collaborative was tasked with reviewing systematically the evidence pertaining to the use of activated charcoal in poisoning in order to update the previous recommendations.
OBJECTIVES
The main objective was: Does oral activated charcoal given to adults or children prevent toxicity or improve clinical outcome and survival of poisoned patients compared to those who do not receive charcoal? Secondary objectives were to evaluate pharmacokinetic outcomes, the role of cathartics, and adverse events to charcoal administration. This systematic review summarizes the available evidence on the efficacy of activated charcoal.
METHODS
A medical librarian created a systematic search strategy for Medline (Ovid), subsequently translated for Embase ( Ovid), CINAHL ( EBSCO), BIOSIS Previews ( Ovid), Web of Science, Scopus, and the Cochrane Library/DARE. All databases were searched from inception to December 31, 2019. There were no language limitations. One author screened all citations identified in the search based on predefined inclusion/exclusion criteria. Excluded citations were confirmed by an additional author and remaining articles were obtained in full text and evaluated by at least two authors for inclusion. All authors cross-referenced full-text articles to identify articles missed in the searches. Data from included articles were extracted by the authors on a standardized spreadsheet and two authors used the GRADE methodology to independently assess the quality and risk of bias of each included study.
RESULTS
From 22,950 titles originally identified, the final data set consisted of 296 human studies, 118 animal studies, and 145 studies. Also included were 71 human and two animal studies that reported adverse events. The quality was judged to have a Low or Very Low GRADE in 469 (83%) of the studies. Ninety studies were judged to be of Moderate or High GRADE. The higher GRADE studies reported on the following drugs: paracetamol (acetaminophen), phenobarbital, carbamazepine, cardiac glycosides (digoxin and oleander), ethanol, iron, salicylates, theophylline, tricyclic antidepressants, and valproate. Data on newer pharmaceuticals not reviewed in the previous American Academy of Clinical Toxicology/European Association of Poison Centres and Clinical Toxicologists statements such as quetiapine, olanzapine, citalopram, and Factor Xa inhibitors were included. No studies on the optimal dosing for either single-dose or multiple-dose activated charcoal were found. In the reviewed clinical data, the time of administration of the first dose of charcoal was beyond one hour in 97% ( = 1006 individuals), beyond two hours in 36% ( = 491 individuals), and beyond 12 h in 4% ( = 43 individuals) whereas the timing of the first dose in controlled studies was within one hour of ingestion in 48% ( = 2359 individuals) and beyond two hours in 36% ( = 484) of individuals.
CONCLUSIONS
This systematic review found heterogenous data. The higher GRADE data was focused on a few select poisonings, while studies that addressed patients with unknown and or mixed ingestions were hampered by low rates of clinically meaningful toxicity or death. Despite these limitations, they reported a benefit of activated charcoal beyond one hour in many clinical scenarios.
Topics: Acetaminophen; Animals; Carbamazepine; Charcoal; Decontamination; Drug Overdose; Humans
PubMed: 34424785
DOI: 10.1080/15563650.2021.1961144 -
The Cochrane Database of Systematic... Jul 2021Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems.
OBJECTIVES
To assess the effectiveness and safety of using an opioid for treatment of NAS due to withdrawal from opioids in newborn infants.
SEARCH METHODS
We ran an updated search on 17 September 2020 in CENTRAL via Cochrane Register of Studies Web and MEDLINE via Ovid. We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for eligible trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs), quasi- and cluster-RCTs which enrolled infants born to mothers with opioid dependence and who were experiencing NAS requiring treatment with an opioid.
DATA COLLECTION AND ANALYSIS
Three review authors independently assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of evidence.
MAIN RESULTS
We included 16 trials (1110 infants) with NAS secondary to maternal opioid use in pregnancy. Seven studies at low risk of bias were included in sensitivity analysis. Opioid versus no treatment / usual care: a single trial (80 infants) of morphine and supportive care versus supportive care alone reported no difference in treatment failure (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.41 to 4.07; very low certainty evidence). No infant had a seizure. The trial did not report mortality, neurodevelopmental disability and adverse events. Morphine increased days hospitalisation (mean difference (MD) 15.00, 95% CI 8.86 to 21.14; very low certainty evidence) and treatment (MD 12.50, 95% CI 7.52 to 17.48; very low certainty evidence), but decreased days to regain birthweight (MD -2.80, 95% CI -5.33 to -0.27) and duration (minutes) of supportive care each day (MD -197.20, 95% CI -274.15 to -120.25). Morphine versus methadone: there was no difference in treatment failure (RR 1.59, 95% CI 0.95 to 2.67; 2 studies, 147 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study reported no difference in days hospitalisation (MD 1.40, 95% CI -3.08 to 5.88; 116 infants; low certainty evidence), whereas data from two studies found an increase in days treatment (MD 2.71, 95% CI 0.22 to 5.21; 147 infants; low certainty) for infants treated with morphine. A single study reported no difference in breastfeeding, adverse events, or out of home placement. Morphine versus sublingual buprenorphine: there was no difference in treatment failure (RR 0.79, 95% CI 0.36 to 1.74; 3 studies, 113 infants; very low certainty evidence). Neonatal or infant mortality and neurodevelopmental disability were not reported. There was moderate certainty evidence of an increase in days hospitalisation (MD 11.45, 95% CI 5.89 to 17.01; 3 studies, 113 infants), and days treatment (MD 12.79, 95% CI 7.57 to 18.00; 3 studies, 112 infants) for infants treated with morphine. A single adverse event (seizure) was reported in infants exposed to buprenorphine. Morphine versus diluted tincture of opium (DTO): a single study (33 infants) reported no difference in days hospitalisation, days treatment or weight gain (low certainty evidence). Opioid versus clonidine: a single study (31 infants) reported no infant with treatment failure in either group. This study did not report seizures, neonatal or infant mortality and neurodevelopmental disability. There was low certainty evidence for no difference in days hospitalisation or days treatment. This study did not report adverse events. Opioid versus diazepam: there was a reduction in treatment failure from use of an opioid (RR 0.43, 95% CI 0.23 to 0.80; 2 studies, 86 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study of 34 infants comparing methadone versus diazepam reported no difference in days hospitalisation or days treatment (very low certainty evidence). Adverse events were not reported. Opioid versus phenobarbital: there was a reduction in treatment failure from use of an opioid (RR 0.51, 95% CI 0.35 to 0.74; 6 studies, 458 infants; moderate certainty evidence). Subgroup analysis found a reduction in treatment failure in trials titrating morphine to ≧ 0.5 mg/kg/day (RR 0.21, 95% CI 0.10 to 0.45; 3 studies, 230 infants), whereas a single study using morphine < 0.5 mg/kg/day reported no difference compared to use of phenobarbital (subgroup difference P = 0.05). Neonatal or infant mortality and neurodevelopmental disability were not reported. A single study (111 infants) of paregoric versus phenobarbital reported seven infants with seizures in the phenobarbital group, whereas no seizures were reported in two studies (170 infants) comparing morphine to phenobarbital. There was no difference in days hospitalisation or days treatment. A single study (96 infants) reported no adverse events in either group. Opioid versus chlorpromazine: there was a reduction in treatment failure from use of morphine versus chlorpromazine (RR 0.08, 95% CI 0.01 to 0.62; 1 study, 90 infants; moderate certainty evidence). No seizures were reported in either group. There was low certainty evidence for no difference in days treatment. This trial reported no adverse events in either group. None of the included studies reported time to control of NAS. Data for duration and severity of NAS were limited, and we were unable to use these data in quantitative synthesis.
AUTHORS' CONCLUSIONS
Compared to supportive care alone, the addition of an opioid may increase duration of hospitalisation and treatment, but may reduce days to regain birthweight and the duration of supportive care each day. Use of an opioid may reduce treatment failure compared to phenobarbital, diazepam or chlorpromazine. Use of an opioid may have little or no effect on duration of hospitalisation or treatment compared to use of phenobarbital, diazepam or chlorpromazine. The type of opioid used may have little or no effect on the treatment failure rate. Use of buprenorphine probably reduces duration of hospitalisation and treatment compared to morphine, but there are no data for time to control NAS with buprenorphine, and insufficient evidence to determine safety. There is insufficient evidence to determine the effectiveness and safety of clonidine.
Topics: Buprenorphine; Chlorpromazine; Clonidine; Diazepam; Humans; Hypnotics and Sedatives; Infant, Newborn; Methadone; Morphine; Narcotics; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Opium; Phenobarbital; Randomized Controlled Trials as Topic
PubMed: 34231914
DOI: 10.1002/14651858.CD002059.pub4 -
The Cochrane Database of Systematic... Jun 2021Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. This is an updated version of a Cochrane Review previously published in 2017.
OBJECTIVES
To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there is a sound biological rationale for its use.
SEARCH METHODS
For the latest update we searched the following databases on 3 February 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 31 January 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We imposed no language restrictions and contacted researchers to identify continuing or unpublished studies.
SELECTION CRITERIA
Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptics, antipyretics or recognised Central Nervous System active agents with each other, placebo, or no treatment.
DATA COLLECTION AND ANALYSIS
For the original review, two review authors independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding, and exclusions. For the 2016 update, a third review author checked all original inclusions, data analyses, and updated the search. For the 2020 update, one review author updated the search and performed the data analysis following a peer-review process with the original review authors. We assessed seizure recurrence at 6, 12, 18, 24, 36, 48 months, and where data were available at age 5 to 6 years along with recorded adverse effects. We evaluated the presence of publication bias using funnel plots.
MAIN RESULTS
We included 42 articles describing 32 randomised trials, with 4431 randomised participants used in the analysis of this review. We analysed 15 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbital, phenytoin, valproate, pyridoxine, ibuprofen, or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, paracetamol, or placebo; nor for continuous phenobarbital versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam. There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment at six months (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.48 to 0.85; 6 studies, 1151 participants; moderate-certainty evidence), 12 months (RR 0.69, 95% CI 0.56 to 0.84; 8 studies, 1416 participants; moderate-certainty evidence), 18 months (RR 0.37, 95% CI 0.23 to 0.60; 1 study, 289 participants; low-certainty evidence), 24 months (RR 0.73, 95% CI 0.56 to 0.95; 4 studies, 739 participants; high-certainty evidence), 36 months (RR 0.58, 95% CI 0.40 to 0.85; 1 study, 139 participants; low-certainty evidence), 48 months (RR 0.36, 95% CI 0.15 to 0.89; 1 study, 110 participants; moderate-certainty evidence), with no benefit at 60 to 72 months (RR 0.08, 95% CI 0.00 to 1.31; 1 study, 60 participants; very low-certainty evidence). Phenobarbital versus placebo or no treatment reduced seizures at six months (RR 0.59, 95% CI 0.42 to 0.83; 6 studies, 833 participants; moderate-certainty evidence), 12 months (RR 0.54, 95% CI 0.42 to 0.70; 7 studies, 807 participants; low-certainty evidence), and 24 months (RR 0.69, 95% CI 0.53 to 0.89; 3 studies, 533 participants; moderate-certainty evidence), but not at 18 months (RR 0.77, 95% CI 0.56 to 1.05; 2 studies, 264 participants) or 60 to 72 months follow-up (RR 1.50, 95% CI 0.61 to 3.69; 1 study, 60 participants; very low-certainty evidence). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64; 1 study, 60 participants; low-certainty evidence), an effect found against an extremely high (83.3%) recurrence rate in the controls, a result that needs replication. When compared to intermittent diazepam, intermittent oral melatonin did not significantly reduce seizures at six months (RR 0.45, 95% CI 0.18 to 1.15; 1 study, 60 participants; very-low certainty evidence). When compared to placebo, intermittent oral levetiracetam significantly reduced recurrent seizures at 12 months (RR 0.27, 95% CI 0.15 to 0.52; 1 study, 115 participants; very low-certainty evidence). The recording of adverse effects was variable. Two studies reported lower comprehension scores in phenobarbital-treated children. Adverse effects were recorded in up to 30% of children in the phenobarbital-treated groups and 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbital versus placebo (seven studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months. There were too few studies to identify publication bias for the other comparisons. The methodological quality of most of the included studies was low or very low. Methods of randomisation and allocation concealment often did not meet current standards, and 'treatment versus no treatment' was more commonly seen than 'treatment versus placebo', leading to obvious risks of bias. AUTHORS' CONCLUSIONS: We found reduced recurrence rates for intermittent diazepam and continuous phenobarbital, with adverse effects in up to 30% of children. The apparent benefit for clobazam treatment in one trial needs to be replicated. Levetiracetam also shows benefit with a good safety profile; however, further study is required. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management, and, most importantly, the benign nature of the phenomenon.
Topics: Anticonvulsants; Antipyretics; Child; Child, Preschool; Confidence Intervals; Humans; Infant; Placebos; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Seizures, Febrile
PubMed: 34131913
DOI: 10.1002/14651858.CD003031.pub4 -
Developmental Medicine and Child... Nov 2021To assess the effectiveness and safety of levetiracetam when used as first-line treatment of neonatal seizures. (Meta-Analysis)
Meta-Analysis
AIM
To assess the effectiveness and safety of levetiracetam when used as first-line treatment of neonatal seizures.
METHOD
Four electronic databases, Medline, Embase, Web of Science, and ClinicalTrials.gov were systematically searched from inception until 20th November 2020. Randomized controlled trials (RCTs) and observational studies that included neonates born preterm and term were eligible for inclusion. The primary outcome measure was levetiracetam effectiveness, defined as seizure cessation within 24 hours of starting treatment. Secondary outcomes included short-term adverse events, mortality before discharge, and long-term neurodevelopmental outcomes.
RESULTS
Fourteen studies assessing 1188 neonates were included: four RCTs, three observational trials with phenobarbital as the control arm, and seven observational studies of levetiracetam with no control arm. Pooled efficacy of levetiracetam from observational studies was 45% (95% confidence interval [CI] 34-57%) (GRADE - very low). Meta-analysis of RCTs evaluating levetiracetam versus phenobarbital showed that both were equally effective (risk ratio [95% CI] 0.6 [0.30-1.20]) (GRADE - very low). Levetiracetam resulted in a lower risk of short-term adverse events compared to phenobarbital (risk ratio [95% CI] 0.24 [0.06-0.92]) (GRADE - moderate).
INTERPRETATION
Very low certainty of evidence suggests levetiracetam might not be more effective than phenobarbital. Moderate certainty of evidence indicates levetiracetam is associated with a lower risk of adverse events. Future trials on neonatal antiseizure medication therapy should include continuous electroencephalogram (EEG) monitoring as standard of care and enrol a homogenous population with similar seizure aetiology. What this paper adds Levetiracetam is effective in 45% of neonatal seizures. Levetiracetam might not be more effective than phenobarbital. Levetiracetam is likely to be safer than phenobarbital. Evidence available is limited and of very low certainty.
Topics: Anticonvulsants; Humans; Infant, Newborn; Levetiracetam; Seizures
PubMed: 34124790
DOI: 10.1111/dmcn.14943 -
The Cochrane Database of Systematic... May 2021Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems.
OBJECTIVES
To assess the effectiveness and safety of using a sedative versus control (placebo, usual treatment or non-pharmacological treatment) for NAS due to withdrawal from opioids and determine which type of sedative is most effective and safe for NAS due to withdrawal from opioids.
SEARCH METHODS
We ran an updated search on 17 September 2020 in CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.
SELECTION CRITERIA
We included trials enrolling infants with NAS born to mothers with an opioid dependence with more than 80% follow-up and using randomised, quasi-randomised and cluster-randomised allocation to sedative or control.
DATA COLLECTION AND ANALYSIS
Three review authors assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of the evidence.
MAIN RESULTS
We included 10 trials (581 infants) with NAS secondary to maternal opioid use in pregnancy. There were multiple comparisons of different sedatives and regimens. There were limited data available for use in sensitivity analysis of studies at low risk of bias. Phenobarbital versus supportive care: one study reported there may be little or no difference in treatment failure with phenobarbital and supportive care versus supportive care alone (risk ratio (RR) 2.73, 95% confidence interval (CI) 0.94 to 7.94; 62 participants; very low-certainty evidence). No infant had a clinical seizure. The study did not report mortality, neurodevelopmental disability and adverse events. There may be an increase in days' hospitalisation and treatment from use of phenobarbital (hospitalisation: mean difference (MD) 20.80, 95% CI 13.64 to 27.96; treatment: MD 17.90, 95% CI 11.98 to 23.82; both 62 participants; very low-certainty evidence). Phenobarbital versus diazepam: there may be a reduction in treatment failure with phenobarbital versus diazepam (RR 0.39, 95% CI 0.24 to 0.62; 139 participants; 2 studies; low-certainty evidence). The studies did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be little or no difference in days' hospitalisation and treatment (hospitalisation: MD 3.89, 95% CI -1.20 to 8.98; 32 participants; treatment: MD 4.30, 95% CI -0.73 to 9.33; 31 participants; both low-certainty evidence). Phenobarbital versus chlorpromazine: there may be a reduction in treatment failure with phenobarbital versus chlorpromazine (RR 0.55, 95% CI 0.33 to 0.92; 138 participants; 2 studies; very low-certainty evidence), and no infant had a seizure. The studies did not report mortality and neurodevelopmental disability. One study reported there may be little or no difference in days' hospitalisation (MD 7.00, 95% CI -3.51 to 17.51; 87 participants; low-certainty evidence) and 0/100 infants had an adverse event. Phenobarbital and opioid versus opioid alone: one study reported no infants with treatment failure and no clinical seizures in either group (low-certainty evidence). The study did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be a reduction in days' hospitalisation for infants treated with phenobarbital and opioid (MD -43.50, 95% CI -59.18 to -27.82; 20 participants; low-certainty evidence). Clonidine and opioid versus opioid alone: one study reported there may be little or no difference in treatment failure with clonidine and dilute tincture of opium (DTO) versus DTO alone (RR 0.09, 95% CI 0.01 to 1.59; 80 participants; very low-certainty evidence). All five infants with treatment failure were in the DTO group. There may be little or no difference in seizures (RR 0.14, 95% CI 0.01 to 2.68; 80 participants; very low-certainty evidence). All three infants with seizures were in the DTO group. There may be little or no difference in mortality after discharge (RR 7.00, 95% CI 0.37 to 131.28; 80 participants; very low-certainty evidence). All three deaths were in the clonidine and DTO group. The study did not report neurodevelopmental disability. There may be little or no difference in days' treatment (MD -4.00, 95% CI -8.33 to 0.33; 80 participants; very low-certainty evidence). One adverse event occurred in the clonidine and DTO group. There may be little or no difference in rebound NAS after stopping treatment, although all seven cases were in the clonidine and DTO group. Clonidine and opioid versus phenobarbital and opioid: there may be little or no difference in treatment failure (RR 2.27, 95% CI 0.98 to 5.25; 2 studies, 93 participants; very low-certainty evidence). One study reported one infant in the clonidine and morphine group had a seizure, and there were no infant mortalities. The studies did not report neurodevelopmental disability. There may be an increase in days' hospitalisation and days' treatment with clonidine and opioid versus phenobarbital and opioid(hospitalisation: MD 7.13, 95% CI 6.38 to 7.88; treatment: MD 7.57, 95% CI 3.97 to 11.17; both 2 studies, 91 participants; low-certainty evidence). There may be little or no difference in adverse events (RR 1.55, 95% CI 0.44 to 5.40; 2 studies, 93 participants; very low-certainty evidence). However, there was oversedation only in the phenobarbital and morphine group; and hypotension, rebound hypertension and rebound NAS only in the clonidine and morphine group.
AUTHORS' CONCLUSIONS
There is very low-certainty evidence that phenobarbital increases duration of hospitalisation and treatment, but reduces days to regain birthweight and duration of supportive care each day compared to supportive care alone. There is low-certainty evidence that phenobarbital reduces treatment failure compared to diazepam and very low-certainty evidence that phenobarbital reduces treatment failure compared to chlorpromazine. There is low-certainty evidence of an increase in days' hospitalisation and days' treatment with clonidine and opioid compared to phenobarbital and opioid. There are insufficient data to determine the safety and incidence of adverse events for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine.
Topics: Bias; Chlorpromazine; Clonidine; Diazepam; Humans; Hypnotics and Sedatives; Infant, Newborn; Narcotics; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Phenobarbital; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34002380
DOI: 10.1002/14651858.CD002053.pub4