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3 方法丨ACVIM关于犬猫癫痫持续状态和丛集性抽搐发作管理的共识声明

萌宠菠菠乐园
2024-08-25 03:35

原文作者：Marios Charalambous | Karen Muñana丨Simon R. Platt | Holger A. Volk

原文网址：https://onlinelibrary.wiley.com/doi/10.1111/jvim.16928

野生翻译：杨子依 @苏苏苏苏乔

野生校对：高健 @宠物神经科医生高健

翻译全文观看网址：

https://3taizi.notion.site/ACVIM-Consensus-Statement-on-the-management-of-status-epilepticus-and-cluster-seizures-in-dogs-and-c-4a76ddef67074795aa04f29ccf3b50a0

3 METHODOLOGY 方法

This Consensus Statement is intended to produce guidelines for the management of emergency seizure disorders in dogs and cats. A Consensus Panel, consisting of 5 members, including 1 chairperson (MC) and 4 panelists (KM, NP, SP, HV), was formed with the aim to (i) perform a thorough assessment and systematic review of the literature, (ii) identify any gaps and share knowledge and clinical expertise, and (iii) introduce recommendations regarding the management of SE and CS in dogs and cats. The recommendations of the panel were based on current relevant evidence and clinical experience. Experimental laboratory animal and basic research studies, as well as guidelines used in human medicine, also were reviewed to support the panel's statements, especially when veterinary clinical studies and experience were lacking.

本共识声明旨在为犬猫急性抽搐发作性疾病的管理提供指导。成立了一个由5名成员组成的共识小组，其中包括1名主席(MC)和4名小组成员(KM、NP、SP、HV)，目的是(i)对文献进行彻底的评估和系统的回顾；(ii)找出任何差距，分享知识和临床专业技术，以及(iii)介绍如何处理犬猫的癫痫持续状态和丛集性抽搐发作。专家小组的建议是基于当前的相关证据和临床经验。还审查了实验动物和基础研究，以及用于人类医学的指南，以支持小组的声明，特别是在缺乏兽医临床研究和经验的情况下。

After the establishment of the Consensus Panel, the chairperson drafted the methodology which was approved by the panelists. After approval, all members (chairperson and panelists) proceeded separately through the steps of searching, screening, and assessing the evidence before drafting their recommendations. A modified Delphi process was used. Each panel member individually performed assessments of the evidence and drafted recommendations. The results from each panel member's assessments and recommendations were gathered and anonymized by an independent ACVIM staff member and then were subjected to multiple rounds of review, through meetings that the panel convened. Remaining differences were resolved before a consensus was reached.

在共识小组成立后，主席起草了经小组成员认可的方法。批准后，所有成员(主席和小组成员)在起草建议之前分别进行搜索、筛选和评估证据。过程采用改良德尔菲法（modified Delphi process）。每个小组成员分别对证据进行评估并起草建议。每个小组成员的评估和建议的结果由一名独立的ACVIM工作人员收集和匿名，然后通过小组召集的会议进行多轮审查。剩下的分歧在达成共识之前得到解决。

Overall, the procedure included (i) a literature search, (ii) a screening of each study, (iii) an assessment of the quality of evidence and treatment outcomes in each study, and (iv) drafting of recommendations.

总的来说，该流程包括(i)文献检索，(ii)对每项研究进行筛选，(iii)评估每项研究的证据质量和治疗结果，以及(iv)起草建议。

3.1 Literature search 文献检索

Three scientific databases (MEDLINE/PubMed, Google Scholar and CAB Abstracts) were used. Final electronic searches were carried out during November 2022 by each member separately, with no date or language restrictions. The search terms used are provided in Supplementary file 1. Searching for articles from the reference lists of publications and the proceedings of major veterinary neurology conference meetings (ie, the annual forum of the American College of Veterinary Internal Medicine [ACVIM] and the symposium of the European Society and College of Veterinary Neurology [ESVN/ECVN]) was also performed. All items returned by the search were gathered and entered into the screening process.

使用了三个科学数据库(MEDLINE/PubMed，Google Scholar 和 CAB Abstracts)。最终的电子搜索将于2022年11月由各成员分别进行，没有日期和语言限制。所使用的搜索词在补充文件1中提供。从主要兽医神经病学会议（如美国兽医内科学会年度论坛[ACVIM]和欧洲兽医神经病学学会研讨会[ESVN/ECVN]）的出版物参考书目和论文集中检索文章。搜索返回的所有项目都被收集起来并进入筛选过程。

The inclusion criteria during the search were:

Peer-reviewed studies of dogs and cats with no limitations on year or language of publication.Any type of clinical or pharmacokinetic study.Studies evaluating or describing the efficacy (clinical studies), safety (clinical and pharmacokinetic studies), or pharmacokinetic properties (pharmacokinetic studies) of antiseizure medications (ASMs) and other treatment modalities.Studies conducted with the aim of evaluating the use of ASMs for emergency seizures only. Studies that evaluated the use of ASMs in chronic epileptic disorders (eg, idiopathic or structural epilepsy) but that did not refer to SE or CS were excluded. Regarding CS, only studies focusing on the short-term (emergency) treatment phase, rather than long-term (preventive) treatment, were included.

检索时的纳入标准为:

对犬猫的同行评审研究，没有出版年份或语言的限制。任何类型的临床或药代动力学研究。评估或描述抗癫痫药物和其他治疗方式的有效性(临床研究)、安全性(临床和药代动力学研究)或药代动力学特性(药代动力学研究)的研究。为评估抗癫痫药物仅用于急诊抽搐发作而进行的研究。评估抗癫痫药物在慢性癫痫性疾病（如特发性或结构性癫痫）中的应用，但未涉及癫痫持续状态或丛集性抽搐发作的研究被排除在外。关于丛集性抽搐发作，只包括短期（急诊）治疗阶段的研究，而没有包括长期（预防性）治疗。

3.2 Screening 筛查

A 2-stage selection process was used. At stage 1, studies retrieved from the search were included based on the title and abstracts. Only studies describing therapeutic outcomes regarding the management of emergency seizures in companion animals were included. At stage 2, the papers included from stage 1 were selected for full data extraction according to the inclusion criteria and were assessed on the grounds of the quality of evidence and treatment outcomes.

采用两阶段的筛选流程。在第一阶段，根据标题和摘要纳入从检索中检索到的研究。仅包括描述伴侣动物急诊抽搐发作管理的治疗结果的研究。在第二阶段，根据纳入标准选择第一阶段纳入的论文进行完整的数据提取，并根据证据质量和治疗结果进行评估。

3.3 Quality of evidence assessment 证据评估的质量

The quality assessment method included modified criteria from previous systematic reviews and meta-analysis.13-15 The elements of assessment included study design, study group sizes, and methods of evaluating treatment outcomes. A numeric scale was allocated to each element, with higher scores indicating studies with a lower risk of bias.

质量评价方法包括的修改先前系统性的回顾的标准和meta分析。评估要素包括研究设计、研究组规模和评估治疗结果的方法。对每个要素分配一个数字评分量表，分数越高表明研究的偏倚风险越低。

3.3.1 Study design 研究设计

Blinded, randomized comparison group clinical trials (score 6).Open-labeled, randomized comparison group clinical trials (score 5).Open-labeled non-randomized clinical trials (score 4).Retrospective case series (score 3).Case reports (score 2).Expert opinions or personal views (score 1).盲选，随机对照组临床试验(评分6)。开放性随机对照组临床试验(评分5)。开放性非随机临床试验(评分4)。回顾性病例系列(得分3)。病例报告(2分)。专家意见或个人观点(得1分)

3.3.2 Study group sizes 研究组规模

30 subjects in total (score 3).10-30 subjects in total (score 2).<10 subjects in total (score 1).共>30例(3分)。共10-30例(2分)。共<10例(1分)。

3.3.3 Assessment of methods for evaluating study treatment outcomes

评估治疗结果的评估方法

This element referred to the study's evaluation methods for determining an intervention's efficacy (seizure termination). Seizure termination was defined as the cessation of seizure-related convulsive activity (clinical confirmation) or epileptiform discharges based on ictal electroencephalography (EEG confirmation).

EEG confirmation (score 3).Clinical confirmation only (ie, studies reporting details of seizure termination such as cessation of convulsive activity including precise cessation times; score 2).No objective confirmation mentioned (ie, studies reporting successful termination without further details or explanation on the assessment criteria for seizure termination; score 1).

这一要素指的是该研究确定干预措施有效性的评估方法（抽搐发作终止)。抽搐发作终止（Seizure termination）定义为抽搐发作相关惊厥性活动（临床确认）或基于发作中脑电图的癫痫样放电（脑电图确认）的停止。

脑电图确认(3分)。仅临床确认（即，研究报告抽搐发作终止的细节，如停止惊厥性活动，包含准确的停止时间)；2分)。未提及客观确认（即，研究报告成功终止，但没有进一步的细节或解释抽搐发作停止的情况；1分)。

3.3.4 Overall assessment scores 综合评估分数

For each study, the scores from all of the elements were summed up to provide an overall score. Based on this score, the overall quality of evidence for each study was characterized as high, moderate or low.

High overall study quality (scores 9-12).Moderate overall study quality (scores 5-8).Low overall study quality (scores <4).

计算每一项研究中的所有项得分以计算总分。基于这个评分，将每项研究的总体证据质量分为高、中、低三个等级。

整体研究质量高（得分9-12)整体研究质量中等（得分5-8)整体研究质量低（得分<4)

3.4 Treatment outcomes assessment 治疗结果评估

Each study's treatment outcome regarding a specific intervention was analyzed. A modified methodology from previous systematic reviews and meta-analysis was followed.13-15

分析了每项研究的具体干预措施的治疗结果。采用先前系统性综述和meta分析的改良方法。

Specifically, a clinical study was considered in favor of an intervention if >50% of the members of study population in each treatment group were responders (ie, seizure termination). The 95% confidence interval (CI) was calculated using standard statistical methods with the aim to identify the true population of responders. The interpretation of the 95% CI results for each study was as follows:

95% CI of the study's proportion of responders falling within a range of >50%: the intervention was considered as likely effective.95% CI of the study's proportion of responders overlapping within a range between <50% and >50%: the intervention was considered as possibly effective.95% CI of the study's proportion of responders falling within a range of <50%: the intervention was considered as likely ineffective.

具体来说，如果每个治疗组中有50%的研究群体有反应（即抽搐发作终止），则认为该临床研究支持干预。使用标准统计方法计算95%置信区间(CI)，目的是确定有反应者的真实总体。对每项研究的95% CI的结果解读如下:

研究中有反应者比例的95% 置信区间在>50%范围内：认为该干预可能有效。研究中有反应者重叠比例的95% 置信区间在<50%至>50%之间：认为该干预可能有效。研究中有反应者比例的95% 置信区间在<50%范围内：认为该干预可能无效。

For pharmacokinetic studies, parameters, such as plasma or serum maximum concentrations, time to maximum concentration, and bioavailability, were evaluated to determine whether the study reported a favorable pharmacokinetic profile in companion animals that could be extrapolated to emergency seizure management. For instance, a drug was considered to have a favorable pharmacokinetic profile if, when administered by a specific route, it reached the specific minimum plasma or serum concentrations required for an antiseizure effect within a short period of time as defined by the reference values used in each study and needed in emergency settings. Lastly, the safety profile of each intervention also was considered as part of a study's treatment outcomes assessment. The number of animals affected by specific adverse effects for each intervention was recorded.

对于药代动力学研究，评估了血浆或血清最大浓度、达到最大浓度所需时间和生物利用度等参数，以确定该研究是否在伴侣动物中报告了可以推断为急诊抽搐发作的管理有利的药代动力学特征。例如，如果一种药物在通过特定途径给药时，在短时间内达到抗抽搐作用所需的特定最低血浆或血清浓度，则认为具有良好的药代动力学特征，该浓度由每个研究中使用的参考值界定，并且是在急诊情况下所需的。最后，每种干预措施的安全性也视为研究治疗结果评估的一部分。记录每种干预措施中受特定不良反应影响的动物数量。

3.5 Drafting the recommendations 起草建议

The ACVIM recommendations for each individual therapeutic option were based on the combination of 2 elements, (i) current evidence from published studies and (ii) each panel member's expert opinion taking into consideration the overall knowledge in the field. Regarding element (i), for each specific intervention, the panel members independently gathered and summarized the results from the evaluation of the quality of evidence available and the treatment outcomes from all of the studies. The members indicated the number of studies that were in favor of or against the use of each intervention and provided a “level of evidence” scale for each intervention. Specifically, the “level of evidence” scale was based on the overall quality of evidence scores of the studies and included:

I—“High level of evidence for or against the intervention”: when at least 2 clinical studies with an overall high-quality score evaluated the use of the intervention for the management of SE or CS in dogs or cats.II—“Moderate level of evidence for or against the intervention”: when at least 2 clinical studies with an overall moderate quality score or 1 clinical study with an overall high-quality score evaluated the use of the intervention for the management of SE or CS in dogs or cats.III—“Low level of evidence for or against the intervention”: when ≥1 clinical study with an overall low-quality score or 1 clinical study with an overall moderate quality score or when only pharmacokinetic studies exist, without any existing study with an overall high-quality score, evaluated the use of the intervention for the management of SE or CS in dogs or cats.IV—“Conflicting level of evidence”: when a minimum of 2 clinical studies (particularly with overall high-quality scores) evaluated the use of a specific intervention for the management of SE or CS in dogs or cats as a primary treatment outcome; however, conflicting results regarding the intervention's efficacy or safety or both were shown.V—“Absence of evidence”: when there were neither clinical nor pharmacokinetic studies evaluating the use of the intervention for the management of SE or CS in dogs or cats.

ACVIM对每种治疗方案的建议基于两个要素的结合，(i)来自已发表研究的当前证据和(ii)考虑到该领域的整体知识每个专家组成员的专家意见。关于要素(i)，对于每个特定的干预措施，专家组成员独立收集并总结了现有证据质量的评估结果和所有研究的治疗结果。成员们指出了支持或反对使用每种干预措施的研究数量，并为每种干预措施提供了“证据水平”评分量表。具体而言，“证据水平”评分量表基于研究的总体证据质量得分，包括:

I - “支持或反对干预的高水平证据“：当至少有2项临床研究以总体高质量评分评估干预措施对犬猫癫痫持续状态或丛集性抽搐发作的管理效果时。II - “支持或反对干预措施的中等水平证据“：当至少有2项总体质量评分为中等的临床研究或1项总体质量评分为高质量的临床研究评估干预措施对犬猫癫痫持续状态或丛集性抽搐发作的管理效果时。III - “支持或反对干预的低水平证据“：当≥1项总体质量评分为低质量的临床研究或1项总体质量评分为中等质量的临床研究，或只有药代动力学研究存在，没有任何现有的总体质量评分的研究时，评估干预对犬猫癫痫持续状态或丛集性抽搐发作管理的使用。IV - “证据水平矛盾”：当至少有2项临床研究(特别是总体高质量评分)评估将特定干预措施用于犬猫癫痫持续状态或丛集性抽搐发作管理作为主要治疗结果；但关于干预的有效性或安全性或两者都显示出相互矛盾的结果。V - “缺乏证据“：对于犬猫癫痫持续状态或丛集性抽搐发作的管理措施既没有临床研究也没有药代动力学研究。

Regarding the assessment of element (ii), this was based not only on the assessment of evidence derived from element (i) but also on the panel's own critical assessment (personal experience and knowledge, information from the use of intervention in primary and specialty clinical practice, and literature reviews or textbooks). As previously described, when there was limited or no evidence from veterinary clinical or pharmacokinetic studies regarding the use of a specific intervention in emergency seizure disorders, experimental and fundamental research or studies of humans were recruited to support the panel's recommendations.

The ACVIM recommendation scale used by the authors for this consensus statement included:

A— High recommendation: intervention is most likely an effective and safe treatment.B—Moderate recommendation: intervention is possibly an effective and safe treatment.C—Low recommendation: intervention is possibly an inadequately effective and safe treatment.D—Intervention is not supported for use: ineffective or unsafe treatment or both.E—Recommendation withheld: intervention might be a potentially effective and safe treatment, but there is currently limited to absent evidence, clinical experience or both regarding its applicability, feasibility, and efficacy.

关于要素(ii)的评估，这不仅基于对要素(i)得出的证据的评估，还基于专家组自己的批判性评价（个人经验和知识，来自基础和专业临床实践中，文献综述或教科书所使用干预措施的信息）。如前所述，当兽医临床或药代动力学研究中关于在急诊抽搐发作疾病中使用特定干预措施的证据有限或没有证据时，就会招募实验和基础研究或人类研究来支持小组的建议。

作者在此共识声明中使用的ACVIM推荐评分量表包括：

推荐度A - 高度推荐：干预可能是最有效和安全的治疗方法。推荐度B - 中度建议：干预可能是一种有效和安全的治疗方法。推荐度C - 低推荐：干预措施可能不够有效和安全。推荐度D - 不支持使用的干预措施：无效或不安全的治疗，或两者兼而有之。推荐度E - 推荐保留：干预可能是一种潜在有效和安全的治疗方法，但目前仅限于缺乏证据，临床经验或缺乏其应用，可行性和有效性。

Finally, in addition to creating the recommendations regarding the use of each intervention in SE and CS of dogs and cats, the Consensus Panel also introduced specific clinical concepts in the treatment of emergency seizure disorders supported by current scientific evidence, knowledge, and clinical experience.

最后，除了提出关于在犬猫的癫痫持续状态和丛集性抽搐发作中使用每种干预措施的建议外，共识小组还介绍了在当前科学证据、知识和临床经验的支持下治疗急诊抽搐发作疾病的具体临床理念。