Evaluation and systematic review of guidance documents for status epilepticus

.1% (ranging from 0% to 83.3%). Notably, the 2016 guideline published by the American Epilepsy Society in Epilepsy (AES) received the highest overall scores. Across these guidance documents, there was consistency in the definition and diagnosis of SE. However, significant variability was observed in therapeutic recommendations, particularly in terms of the timing for adding or changing medications. The methodological approaches used in most SE guidance documents require improvement, and the disparities in recommendations highlight existing gaps in evidence. Enhanced methodological rigor results in increased standardization of the guideline, consequently augmenting its reference value. Given the urgency of SE as an emergency condition, it is imperative that these documents also address relevant management strategies before admission.


Introduction
Status epilepticus (SE), regarded as the most severe manifestation of a seizure, has been classified within the International League Against Epilepsy (ILAE) framework since 1970 [1] and reaffirmed in 2015 [2].On average, SE leads to fatality in approximately 20 % of cases, although some studies have reported mortality rates as high as 57 % in adults [3].The outcomes of SE are subject to various influencing factors, including the type of epilepsy, the nature of SE (such as generalized convulsive status epilepticus or non-convulsive status epilepticus), underlying causes or etiologies, SE duration, and the patient's age [4].Clinicians have soundly advocated for initiating treatment at an earlier stage, recognizing that the prognosis of SE deteriorates with prolonged duration [5,6].
Hence, it is evident that, beyond underlying etiology and patient age, the clinical type, treatment modalities, and timing of intervention represent pivotal factors influencing SE mortality.Our primary objective was to systematically assess the quality of these documents and juxtapose the essential treatment recommendations contained therein.Our focus remained on evaluating the coherence of the prevailing treatment guidelines.

Methods
We followed the study protocol in accordance with the Preferred Reporting Items for Systematic Reviews for Protocols (PRISMA 2020) (File 1) guidelines and have registered our study on PROSPERO with the registration number: CRD42023404683 (File 2) [7,8].The PRISMA checklist, as per the guidelines, is included as Table 1 in this manuscript.

Inclusion/exclusion criteria for study selection
Clinical practice guidelines (CPGs) are developed through a rigorous process that systematically reviews and evaluates the available scientific literature.Expert consensus statements represent a collective agreement or general alignment of opinions among a group of recognized experts in a specific field or subject area.We included all international and national/regional clinical practice guidelines and expert consensus statements addressing the diagnosis, treatment, and management of SE [9].Our inclusion criteria were as follows: (1) the documents were clinical practice guidelines or expert consensus statements; (2) they specifically provided recommendations for SE treatment; (3) they were published by professional societies, associations, or communities for national or international use; and (4) they were published in English or Chinese.We excluded (1) original surveys, research protocols, reviews of existing guideline documents or consensus, conference abstracts, or posters; (2) draft unpublished documents; and (3) previous documents superseded by updated versions from the same organization.

Search strategies
The search strategy was collaboratively developed in consultation with a librarian and involved the use of various search terms combinations, including "epilepsy," "status epilepticus," "guideline documents," "statements," "consensus," and "recommendations."Our comprehensive search spanned multiple databases, including Web of Science, PubMed, EMBASE, and eight guideline databases, such as the National Guideline Clearinghouse (NGC) [10], the Guidelines International Network (GIN) [11], the National Institute for Health and Care Excellence (NICE) [12] website, the National Health Service (NHS) Evidence website [13], the Scottish Intercollegiate Guidelines Network (SIGN) website [14], the Guidelines and Audit Implementation Network (GAIN) [15], the Turning Research Into Practice Database (TRIP) [16], and Epistemonikos [17].
Additionally, we conducted searches in two Chinese academic databases, the China Biomedical Literature Database [18] and Wanfang database [19], as well as two English academic databases, PubMed and EMBASE, spanning from the inception of these databases up to July 24, 2022 (Table 1- 4).
We organized and managed the search results using EndNote 20 Reference Manager (Thomson Reuters, New York, USA).To ensure comprehensiveness, on September 23, 2022, we conducted additional searches on Google [20] and Google Scholar [21] and filtered the top 200 records for further evaluation, inoder to identify potentially eligible guideline documents and consensus statements that might not have been indexed in the databases mentioned earlier.

Study selection and data extraction
Two independent reviewers, namely Yue Cao and Anjiao Peng, conducted the initial screening of titles and abstracts for all the documents identified in our search.Subsequently, we thoroughly reviewed the full texts of the selected documents.Any disagreements that arose during this process were resolved through discussions with neurologists.We diligently documented the reasons for excluding specific documents during the full-text review.
The task of data extraction was performed independently by Yue Cao and Anjiao Peng.The extracted data from each included document encompassed fundamental details, including the first author, year of publication, title, issuing organization, country, and funding agency.Furthermore, we meticulously gathered data pertaining to the diagnosis and definition of SE, along with recommendations for the treatment and management of various SE types.This encompassed general support and monitoring measures, the stages of therapy phases, and medication strategies for CSE, GCSE, RSE (refractory status epileptics), super-RSE (super refractory status epileptics), and NCSE, as outlined in the included documents.

Appraisal of guidance documents
Four reviewers, namely Pei Wang, Mingyue Chen, Hua Li, and Xi Zhu, were responsible for assessing the quality of the included documents using the Appraisal of Guideline Documents for Research & Evaluation II (AGREE II) instrument (File 3).AGREE II is a validated and standardized tool designed for the evaluation of guideline document quality.It comprises 23 items distributed across six domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence.Each item underwent scoring on a 7-point scale, where 1 denoted 'strongly disagree,' and 7 represented 'strongly agree.'To calculate the scores, we used the following formula: (Obtained Score -Minimum Possible Score) / (Maximum Possible Score -Minimum Possible Score).The minimum possible score was determined as the number of questions multiplied by the number of appraisers, while the maximum possible score was calculated as the number of questions multiplied by the number of appraisers and further multiplied by 7 [22].
Before commencing the assessment, all reviewers underwent an online training tutorial to ensure a standardized approach.The scoring instructions adhered to the AGREE II user manual, with objective scoring criteria established for each item.Pilot scoring guides were employed to provide further clarity on the scoring criteria.In cases where scores for specific items differed by more than 1 point, consensus meetings were convened to facilitate discussions and achieve alignment among the reviewers.Following these consensus meetings, reviewers had the option to revise their scores or maintain their original assessments [23].

Patient and public involvement
Patients and the public were not involved in the conceptualization or implementation of this research.

Search results
We initially identified a total of 5,811 publications through searches across academic, guideline, Google, and Google Scholar databases.Following the meticulous application of our inclusion and exclusion criteria, a total of 25 documents  were deemed eligible and included in the final assessment and recommendation synthesis (Fig. 1).Exclusions were made during the full-text review, and the specific reasons for these exclusions can be found in the supplementary table (Table 5).

Characteristics of included guideline documents and consensuses
Table 6 presents a summary of the characteristics of the included guideline documents, consisting of 14 clinical practice guideline documents and 11 expert consensus documents.These documents were issued by twenty-four academic organizations representing nine countries or regions academic societies, spanning the years from 1993 to 2022.Specifically, six were issued by neurology organizations, one by pediatric organizations, one by nursing organizations, and sixteen by multinational development groups, encompassing critical care medicine groups and pharmacologists.
Regarding the focus on disease type, 10 guideline documents were dedicated to a single type of SE, including four for CSE, four for GCSE (including one for tonic-clonic SE), one for NCSE, and one for custodial management.Additionally, 15 guideline documents addressed two or more types of SE.CPSE and SSE received brief mentions in only three guideline documents.
As for target audiences, 17 documents identified healthcare professionals as the primary audience, while two documents recognized patients as one of the target audiences, and one included the broader category of a healthy population.
Among the included guidelines, 16 conducted systematic literature reviews as part of their development process, with seven reporting Levels of Evidence (LOEs) and six reporting Strength of Recommendations (SORs).Four studies explicitly addressed the timing of guideline updates.Furthermore, ten documents provided information on their funding sources, with one receiving funding from the pharmaceutical industry, while others were supported by foundations of academic institutions or units (Table 6).

Appraisal of guideline documents and consensus statements
The AGREE II tool assessed guideline documents and consensus statements across six domains, encompassing aspects from development to implementation.The inclusion of appropriate stakeholder involvement (domain 2) served to mitigate individual biases, ensuring a balanced and well-rounded perspective.Clinicians placed primary emphasis on the rigor of development (domain 3), a factor critical not only for their own confidence but also for ensuring the validity of the overall development approach.
The clarity of presentation (domain 4) was instrumental in conveying precise and readily accessible information to clinicians within the development group.Robust performance in the applicability domain (domain 5) and editorial independence domain (domain 6) further bolstered the validity and independence of the documentation.
Fig. 2 displays the standardized AGREE II domain scores for each guideline, with detailed values provided in supplementary table 7. Mean scores for each item of the AGREE II are presented in supplementary table 8, while detailed scores can be found in table 9.It can be seen intuitively from the histogram that all guide documents perform well in scope and purpose (Domain 1) and clarity of presentation (Domain 4), with most scores exceeding the median line.In terms of stakeholder (Domain 2) and applicability (Domain 5), the performance of each guide document is relatively average, but the average score of the former is significantly higher than that of the latter.In the rigor of development (Domain 3) and editorial independence (Domain 6), the scores varied Interestingly, guidelines did not consistently outperform consensus statements in terms of quality assessment.Moreover, there was no discernible evidence of an upward trend in quality ratings over time (Fig. 2).
The assessment also revealed that the guideline documents achieved their highest scores in the domains of scope and purpose (domain 1, median 70.5 %, range 20.8 to 90.3 %) and clarity of presentation (domain 4, median 71.8 %, range 15.3 to 91.7 %).The remaining domains ranked in the following order: stakeholder involvement (domain 2, median 48.1 %, range 12.5 to 80.6 %), rigor of development (domain 3, median 40.6 %, range 8.3 to 75 %), and applicability (domain 5, median 34.9 %, range 16.7 to 54.2 %).The lowest scores were observed in the domain of editorial independence (domain 6, median 32.1 %, range 0 to 83.3 %), with nearly half of the guidelines scoring below 25 %.
Regarding specific domain scores, 'the potential resource implications of applying the recommendations have been considered' received the lowest scores (item 20, mean score 1.74, range 1-5), followed by 'a procedure for updating the guideline' (item 14, mean score 2, range 1-5.5), and 'The guideline describes facilitators and barriers to its application' (item 18, mean score 2.41, range 1-6.5).

Synthesis of recommendations
Among the 25 included guidelines, 18 provided clarity regarding the applicable population.Specifically, 3 guidelines were suitable for both adults and children, 7 were intended exclusively for adults, and 7 were tailored for children alone.
Furthermore, the included guidelines covered four major areas: general support and monitoring of SE, treatment of CSE/GCSE, treatment of RSE, treatment of super-RSE, and treatment of NCSE.

General managment and monitoring of SE
Twenty of the included guidelines addressed the topic of general support and monitoring of SE.All 20 guidelines emphasized the importance of respiratory monitoring and protection.Monitoring and maintaining the circulatory system were addressed in 15 of these guidelines.Blood tests were discussed in 16 guidelines, with 11 of them highlighting the necessity of toxicology testing, and 15 guidelines emphasizing the significance of monitoring blood concentrations.Additionally, eight guidelines underscored the importance of monitoring cerebral function.Brain computed tomography scans for ruling out SE caused by trauma or occupational lesions were recommended in five guidelines.Furthermore, two guideline documents covered cerebrospinal fluid examinations, and an additional two addressed neurological examinations.

Stages of therapy phases
Among the 22 guidance documents, various therapy phases were mentioned, with only one not specifying the precise timing of treatment.In the context of convulsive SE, there are typically five treatment stages: initial patient management, first phase, second phase, third phase, and fourth therapy phases.However, only three guideline documents comprehensively covered all five phases, while just five documents made reference to the fourth line therapy phase (Table 10).
Notably, there were significant variations in the initiation point and duration of the proposed second and third stages (see Image 1).Different studies have suggested that the second line therapy phase spanned from 5 to 30 min to 30 to 90 min, and the third line therapy phases ranged from 40 min to over 90 min.

Medication strategy of CSE/GCSE
Convulsive Status Epilepticus (CSE) is a medical emergency characterized by prolonged and continuous seizure activity, specifically convulsive seizures.It is a serious condition that requires immediate medical attention.In CSE, the individual experiences prolonged convulsions without regaining consciousness between seizures.Generalized Convulsive Status Epilepticus (GCSE) is a subtype of convulsive status epilepticus where the seizures are generalized tonic-clonic seizures.These seizures affect the entire brain and body, leading to loss of consciousness, muscle rigidity (tonic phase), and rhythmic jerking movements (clonic phase).There are 22 guidelines that mention CSE or GCSE.There is not much difference in the treatment drugs for these two types of conditions, so they are displayed together.Among these, 14 focused on CSE, while 8 provided medication treatment alternatives for GCSE.The initial drug regimen in the treatment process was influenced by the The pharmacological regimens recommended by each guideline exhibited variations and encompassed benzodiazepines, sedatives, and barbiturates.These drugs were prescribed in different combinations across the guidelines, ranging from 5 to 11 different drugs.In the initial patient management phase, the most common suggestions, when venous access was not available, were midazolam buccal or diazepam rectal administration.In the first-line therapy phase, the preferred drug was lorazepam (intravenous, IV), followed by midazolam (intramuscular, IM), levetiracetam (IV), and phenytoin (IV) when venous access was attainable (Image 2A).For the second-line therapy phase, the commonly recommended drugs included valproic acid (IV), levetiracetam (IV), fosphenytoin (IV), phenytoin (IV), and phenobarbital (IV) (Image 2B, 2C).(Table 11-13).

Medication strategy of RSE
Out of the 14 guidelines, intensive care unit (ICU) monitoring was recommended by all, with eight providing specific monitoring guidelines.These recommendations encompassed tracheal intubation/mechanical ventilation, ICU treatment, internal environmental monitoring (including blood tests), and continuous electroencephalography (EEG) monitoring.
Treatment strategies for Refractory Status Epilepticus (RSE) generally fall under the category of the third-line therapy phase, often involving anesthetic drugs.These drugs were recommended in different combinations across the guidelines, ranging from 1 to 7 different drugs (Table 14).Information regarding specific medication doses and their associated side effects was available in five of the guidelines, while three only presented the dose without detailing side effects, and the remaining six documents did not include this information.
In summary, IV isoproterenol (propofol) and midazolam were the most frequently recommended drugs, followed by IV thiopental and pentobarbital (Image 2D).

Medication strategy of super-RSE
Five guidelines specifically addressed the treatment of super-Refractory Status Epilepticus (super-RSE), categorized as the fourthline therapy phase.These guidelines recommended combinations of two to eight different drugs (Table 15) for managing super-RSE.Among the pharmacological treatments, ketamine (IV) emerged as the most frequently indicated medication, followed closely by thiopental (IV).
Beyond pharmacotherapy, alternative treatment approaches for super-RSE were also mentioned.These included the consideration of a ketogenic diet, low-temperature therapy, and immunomodulating therapy.Among these, epilepsy surgery was the most frequently suggested alternative.Additionally, recommendations encompassed electroconvulsive therapy, vagus nerve stimulation, trigeminal nerve stimulation, transcranial magnetic stimulation, and IV administration of magnesium sulfate (MgSO4) (Image 2E).
However, it's noteworthy that detailed protocols for ketogenic diet and immunotherapy were provided in only two of the guidelines.

Medication strategy of NCSE
Four guidelines specifically addressed the treatment of Non-Convulsive Status Epilepticus (NCSE).Among them, only one guideline differentiated treatment approaches between patients in a coma and those not in a coma.These guidelines recommended two main categories of medications for NCSE treatment: anaesthetic and Anti-Seizure Medications (ASMs).Under the anaesthetic, the recommended medications included sodium thiopental, midazolam, chloroamphetamine, and tranquilizers.Within the ASM category, phenobarbital, lorazepam, or diazepam, were suggested for NCSE treatment [49].

Discussion
Despite the increasing number of guidelines released between 1993 and 2022, there was no discernible improvement in overall quality over time.Our evaluation results revealed that more than half of the guideline documents failed to achieve an average score of > 50 %.Furthermore, even the guideline documents with the highest total scores did not surpass the quartile.
It's worth noting that the AGREE II assessment tool employed in our study is internationally validated and meticulously developed.To our knowledge, this study represents the first systematic assessment of the quality of Status Epilepticus (SE) guideline documents and consensus statements.Additionally, it marks the first systematic review of SE guideline documents, consolidating the best recommendations-a notable strength of this study.
To maintain the accuracy of our evaluation and systematic review of the guidelines, we acknowledge several limitations in our study.Firstly, we restricted our inclusion criteria to texts in English or Chinese, potentially resulting in the oversight of essential documents from other regions.To address this limitation, we adapted our search strategy to identify English versions of guidance documents published in these regions, aiming to mitigate this risk.
In our analysis of basic information, we observed that one-third of the guideline documents were composed of relatively simple work groups.However, considering the clinical specificity of Status Epilepticus (SE), it is advisable for guideline development to involve specialists in various fields such as neurology, critical care medicine, pediatrics, pharmacology, and health economics.This multi-disciplinary approach can contribute to more comprehensive and effective guidelines.
Furthermore, the guideline documents displayed variations in the specific types of SE and the populations they covered, leading to inconsistencies in the provided definitions.It's important to note that the clinical scenario for SE is complex.A patient initially presenting with Generalized Convulsive Status Epilepticus (GCSE) at the time of consultation may undergo treatment and transition to Non-Convulsive Status Epilepticus (NCSE), progress to Refractory Status Epilepticus (RSE), or even advance to super-Refractory Status Epilepticus (super-RSE).The absence of a comprehensive classification of SE guidelines means that some critical points in disease progression may not be adequately covered.This could potentially lead to inappropriate clinical decisions, impacting treatment outcomes and potentially resulting in serious consequences.
These guidelines exhibit significant disparities in crucial aspects of patient management, encompassing variations in the timing of drug adjustments during different stages of Status Epilepticus (SE), diverse pharmacological regimens, and variations in the particulars of initial management and monitoring protocols.These discrepancies may stem from differences in etiology, patient age, and sociodemographic factors.Additionally, they can also arise from conflicting recommendations within the guidelines themselves.
It's important to recognize that low-quality evidence can pose a substantial challenge to the development of SE guidance documents, potentially resulting in suboptimal clinical treatment outcomes.
The International League Against Epilepsy (ILAE) tasked a task force with revising concepts, definitions, and classifications of Status Epilepticus (SE) in 2015 [2].However, the recommendations, such as that for "the timing for changing the medication", remains unclear and inconsistent.Presently, clinical practice guidelines and consensus statements on SE play a pivotal role in directing clinical treatment decisions.As an illustration, in the two highest-scoring guideline documents, both AES_2016 and HIS_2015 recommended valproate sodium (VPA) (IV).However, while HIS_2015 suggested VPA as a first-line therapy drug, AES_2016 classified it as a second-line therapy drug.A comparison of the original clinical studies, which served as evidence for these two guidelines, revealed that neither class B evidence nor class III Y. Cao et al.
clinical trials categorized and examined patients based on the time of onset before enrollment.Furthermore, the conclusions drawn from these two clinical realizations were inconsistent [50,51].As a result, there is currently no direct evidence to ascertain the most effective time phase for administering VPA in cases of SE onset.
Furthermore, there is a critical need for a definitive and uniform medication strategy tailored to different types of Status Epilepticus (SE) across various phases.For example, in the same two guidelines, HIS_2015 clearly recommends the use of lacosamide in the first stage of treatment, but does not indicate the original reference; on the other hand, AES_2016 never recommends the use of lacosamide in any stage of treatment.
In addition to pharmaceutical therapy, alternative treatments for super-Refractory Status Epilepticus (super-RSE) have emerged, such as the ketogenic diet and cryotherapy.However, the efficacy of these alternative therapies remains unclear, making it challenging to provide precise recommendations.
Furthermore, due to the specificity of antiepileptic drugs, their availability, and health insurance policies can vary significantly between countries and regions.As such, it is essential to consider additional factors, such as drug accessibility and health economics, when providing recommendations that are contextually relevant and suitable for local implementation.
It's important to emphasize the significance of considering both Evidence-Based Guidelines and Consensus-Based Guidelines concurrently.While it's undeniable that evidence-based Clinical Practice Guidelines (CPGs) adhere to rigorous methodologies, they do have a notable limitation when addressing conditions with limited available evidence, as is often the case with Refractory Status Epilepticus (RSE) and Super-Refractory Status Epilepticus (SRSE).
In real-world clinical practice, the establishment of a consensus, which is practical and readily applicable based on clinical experience and expert input, becomes more suitable and feasible for managing conditions like status epilepticus within localized settings.This approach allows for adaptability to unique circumstances and the utilization of locally available resources, making it a valuable complement to international guidelines [52].
In terms of the initial management and monitoring of various types of Status Epilepticus (SE), it is advisable for guidelines to prioritize the standardization of general management and monitoring protocols.This should include explicit instructions on monitoring departments responsible for ensuring the stability of the respiratory system, circulatory system, and internal environment.Furthermore, guidelines should provide specific implementation criteria, such as those for noninvasive ventilation and intubation.
Hematologic tests should encompass toxicological screening and blood concentration measurements, while continuous EEG (cEEG) monitoring should be recommended for assessing brain function, differentiating between categories of brain dysfunction, and detecting electroencephalographic seizures (ES).Research has shown that patients can derive significant value and effectiveness from cEEG monitoring following SE [53].
It's crucial not to overlook neurological examinations and brain imaging when exploring the underlying etiology of SE.Additionally, guidelines should consider whether monitoring and safeguarding liver, gastrointestinal, and bone marrow function are indeed essential during the initial management phase.
Furthermore, in our research, we identified guidelines beyond clinical guidelines, specifically targeting monitoring, first aid, caregiving, and primary management aspects related to the unique characteristics of epileptic seizures.We propose the integration of these guidelines with clinical guidelines to create a comprehensive series of guidelines.This integrated approach would offer users the convenience of accessing a cohesive set of guidelines without the need for separate searches.

Conclusions
Guidance documents call for more rigorous and transparent methodologies with prevalent inconsistent recommendations.
Although numerous global organizations are actively addressing SE, with the Pediatric Status Epilepticus Research Group (PSERG) standing out as an example, the methodological rigor warrants improving.PSERG has embarked on the establishment of a prospective Refractory Status Epilepticus (RSE) registry, focusing on standardized RSE outcome assessment, and is committed to delivering ongoing research outcomes.High-quality evidence from well-designed randomized trials and observational studies are essential for improving the evidence ecosystem of SE practice.
The synergy between Evidence-Based Guidelines and Consensus-Based Guidelines is essential.By embracing both types of guidelines, healthcare providers are equipped with a comprehensive toolkit that empowers them to make informed decisions, drawing upon both robust evidence and collective expertise.
In addition, it is incumbent upon society as a whole to place due emphasis on guidelines related to the emergency treatment, transfer, and prehospital management monitoring.These aspects are vital for the overall improvement of healthcare outcomes in the context of SE.
Collaboration across academic societies could be helpful in integrating research resources and forming improved recommendations for SE guidelines.

Fig. 1 .
Fig. 1.Flow diagram for literature search.AGREE, appraisal of guidelines for research and evaluation; CBM, Chinese Biomedical Literature Database; GAIN, Guidelines and Audit Implementation Network; GIN, Guidelines InternationalNetwork; NGC, National Guideline Clearinghouse; NHS, National Health Service; NICE, National Institute for Health and Care Excellence; SIGN, Scottish Intercollegiate Guidelines Network; TRIP, Turning Research into Practice Database.

Fig. 2 .
Fig. 2. Domain scores Green bars represent consensus.Blue bars represent guidlines.Red lines represent midline.Domain 1, scope and purpose.Domain 2, stakeholder.Domain 3, rigour of development.Domain 4, clarity of presentation.Domain 5, applicability.Domain 6, editorial independence.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)