Efficacy of Combined Ketamine and Midazolam for Treatment of Generalized Convulsive Status Epilepticus in Children .
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 144
- 试验地点
- 1
- 主要终点
- Cessation of seizures at 5 minutes
研究概览
简要总结
Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children. Benzodiazepines are the recommended first line antiseizure medication (ASMs), but they fail to control seizures in a third of cases. Combination of benzodiazepines with another ASM that has a different mechanism of action may be a promising option for faster control of GCSE. In this study, the investigators aim to evaluate the efficacy and safety of ketamine plus midazolam versus midazolam alone as first-line therapy of pediatric GCSE.
详细描述
Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children, which is associated with significant morbidity and mortality. This condition is defined as > 5 minutes of continuous or recurrent generalized tonic-clonic seizure activity without regaining consciousness. GCSE requires immediate evaluation and management in order to control ongoing seizures.
According to most guidelines, benzodiazepines are the recommended first line antiseizure medication (ASMs). Second-line ASMs for benzodiazepines-refractory GCSE include multiple options, such as fosphenytoin/phenytoin, valproic acid, or levetiracetam. Last, refractory GCSE requires treatment with third-line ASMs, such as another second-line ASMs or infusion with thiopental, midazolam, pentobarbital, propofol, or ketamine.
However, about 35% of cases with GCSE are not controlled by benzodiazepines, and up to 40% of benzodiazepines-refractory GCSE don't respond to second-line ASMs. As GCSE persists for a longer time, it becomes more difficult to control with worse prognosis. Indeed, the effectiveness of benzodiazepines to control seizures decreases by 50% when given after 10-15 minutes of continuous seizures. Therefore, new ASMs or combinations are required for earlier control of seizures, which will contribute to better outcome. Combination of benzodiazepines with another ASM that has a different mechanism of action may be a promising option for faster control of GCSE. One of the potential drugs for such combination is ketamine.
Several adult and pediatric studies have shown effectiveness of ketamine in refractory and super-refractory GCSE. Unlike benzodiazepines that act through inhibitory Gamma-aminobutyric acid (GABA), ketamine is a non-competitive antagonist for N- methyl- d- aspartate (NMDA) receptors, which mediates excitatory glutamate action. Continuous seizure activity is associated with internalization of GABA receptors and upregulation of NMDA receptors.
A number of animal studies have demonstrated synergistic action of combined ketamine and benzodiazepines for status epilepticus. While combined ketamine and benzodiazepines have been used in pediatric sedation/analgesia, there are limited studies on such combination for children with GCSE.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Enrolled children will be equally randomized into study and control group using computer generated numbers, which will be sealed into sequentially numbered opaque envelopes by a person not belonging to the research team. For each enrolled participant, the envelope in order will be opened, and the assigned study drug will be used. A pharmacist will fill the active and placebo preparations in similar containers with sealed code for identification. Participants' families, treating clinicians, and investigators will be unaware of group assignment and drug/placebo therapy.
入排标准
- 年龄范围
- 6 Months 至 16 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age from 6 month to 16 years.
- •Generalized convulsive status epilepticus, defined as > 5 minutes of clinically observed continuous or recurrent generalized, tonic-clonic seizure activity without regaining of consciousness.
排除标准
- •Failure to obtain informed consent.
- •Previous treatment with any antiseizure medication for the presenting seizure episode.
- •Hypertension
- •Alcohol intake
- •Conditions associated with increased intracranial pressure (e.g., central nervous system mass lesions, hydrocephalus)
- •Known allergy or contraindications to any of the study drugs.
- •End-stage kidney disease.
- •End stage liver disease
- •Arrhythmia, severe heart disease, or pulmonary hypertension.
- •Hyperthyroidism
- •Pheochromocytoma
- •Hypoglycemia or hyperglycemia.
- •Inborn errors of metabolism.
- •Known or suspected psychiatric disorder.
- •Failure to obtain intravenous access in the first 5 minutes of stabilization phase.
- •Cessation of seizures during the stabilization phase (0 - 5 minutes).
- •Traumatic brain injury.
研究组 & 干预措施
Study group (Ket-Mid)
Children receiving ketamine + midazolam
干预措施: Ketamine (Drug)
Study group (Ket-Mid)
Children receiving ketamine + midazolam
干预措施: Midazolam (Drug)
Control group (Pla-Mid)
Children receiving placebo + midazolam
干预措施: Midazolam (Drug)
Control group (Pla-Mid)
Children receiving placebo + midazolam
干预措施: Placebo (Drug)
结局指标
主要结局
Cessation of seizures at 5 minutes
时间窗: 5 minutes
Cessation of clinical seizures at 5 minutes study timepoint
次要结局
- Mortality(24 hours)
- Skin rash(24 hours)
- Cessation of seizures at 35 minutes(35 minutes)
- Cessation of seizures at 55 minutes(55 minutes)
- Need for repeating midazolam(15 minutes)
- Cessation of seizures at 15 minutes(15 minutes)
- Seizure recurrence(24 hours)
- Hypotension(24 hours)
- Intubation(24 hours)
- Hypertension(24 hours)
- Arrhythmia(24 hours)
- Emergence phenomenon(24 hours)
研究者
Esraa Abdelsamee Ahmed
Principal Investigator
Sohag University