Time to Treatment in Pediatric Patients with Repeated Episodes of Status Epilepticus

Time to Treatment in Pediatric Patients with Repeated Episodes of Status Epilepticus | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Time to Treatment in Pediatric Patients with Repeated Episodes of Status Epilepticus Jennifer V. Gettings, Iván Sánchez Fernández, Anne Anderson, J. Nicholas Brenton, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4160328/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 May, 2025 Read the published version in BMC Neurology → Version 1 posted 10 You are reading this latest preprint version Abstract Objective To compare pediatric patients who presented with repeated status epilepticus episodes to patients with a single episode of status epilepticus and identify distinguishing clinical factors. Methods Retrospective analysis of a multicenter, prospective observational cohort of pediatric patients with status epilepticus and refractory status epilepticus between 2011 and 2019. Results Out of 504 status epilepticus episodes in 420 patients, 50 patients (10.3%) had repeated episodes of status epilepticus. The only predictor of repeated status epilepticus was a prior diagnosis of epilepsy. There was no difference in time to treatment with the first benzodiazepine in patients presenting with their first status epilepticus episode compared to their second status epilepticus episode [median 10 (interquartile range 5–30) vs 14 (4.5–52.5) minutes; (p = 0.24)] or in time to treatment with the first non- benzodiazepine anti-seizure medication (ASM) [61 (37–125) vs 71 (34.5-117.5) minutes; p = 0.61]. In patients with repeated status epilepticus episodes with onset outside the hospital, the percentage of patients treated by caregivers did not improve between the first and second status epilepticus episode (61% vs 60%, p = 0.56). However, the time to first benzodiazepine was shorter in patients treated by caregivers compared to those who were not [5 (0–25) vs 55 (41–120) minutes; p < 0.001]. Conclusions Time to treatment with benzodiazepine and non-benzodiazepine ASM in patients with repeated episodes of status epilepticus does not improve for a second episode of status epilepticus, suggesting additional opportunities for intervention and teaching. Status epilepticus refractory status epilepticus benzodiazepines anti-seizure medications treatment delay. Figures Figure 1 Figure 2 Figure 3 Figure 4 BACKGROUND In children, status epilepticus (SE) is a frequent life-threatening emergency with an incidence of 17–23 per 100,000 child population.[ 1 ] The mortality rate of pediatric SE is 3–9%.[ 1 – 3 ] Survivors are at risk for developmental disorders, epilepsy, and recurrent episodes of SE.[ 4 , 5 ] Regarding the latter, each episode of SE in children has an approximate cost of $ 9,295- $ 22,8000 per hospital admission[ 6 , 7 ], thus, repeated episodes of SE have a high clinical and economic burden on patients, their families, and society. Several guidelines for the treatment of SE propose administering a benzodiazepine (BZD) within 5–20 minutes of seizure onset [ 8 – 10 ] followed by a non-BZD anti-seizure medication (ASM) within 20–40 minutes if the seizure continues.[ 8 , 9 ] When SE continues despite treatment, it is termed refractory status epilepticus (RSE).[ 11 , 12 ] Several studies have shown that delayed treatment leads to longer convulsive seizure duration,[ 13 – 16 ] the need for continuous infusions and higher mortality.[ 17 ] Unfortunately, in practice, the treatment of SE is often delayed.[ 15 ] Therefore, neurologists commonly prescribe BZDs or other medications to patients with epilepsy to be used to treat SE. There are no studies evaluating whether time to treatment improves for repeated episodes of SE. There is also no information about treatment latency by caregivers for repeated episodes in the out-of-hospital setting. We hypothesized that patients with a history of SE may have a shorter time to treatment during subsequent episodes of SE. To address this knowledge gap, we studied the time to first BZD and the time to first non-BZD ASM in patients with repeated episodes of SE. METHODS Study design The study was performed as a retrospective cross-sectional study based on the prospective data collected by the pediatric Status Epilepticus Research Group (pSERG), a consortium of 21 tertiary pediatric hospitals in the United States and Canada.[ 12 ] Nine of these centers had data on patients that presented with multiple SE episodes between June 2011 and February 2019. Data was collected using a standardized data acquisition tool and entered into an electronic database. At the time of each SE episode, in-hospital data was obtained from the hospital records and inpatient medical teams, and pre-hospital data (including the time to treatment) was obtained from patients’ families and Emergency Medical Services (EMS) records. The research protocol was approved by the institutional review boards of all participating institutions, including Boston Children’s Hospital (IRB P-00001207), and written informed consent was obtained from all participants, parents, or guardians. Patients We included pediatric patients (aged 1 month to 21 years) who were admitted with refractory or non-refractory SE with focal or generalized convulsive epileptic seizures at onset. Refractory SE was defined as SE continuing after at least one dose of BZD and at least one dose of a non-BZD ASM, or when a continuous infusion was required for seizure control. Non-refractory SE was defined as SE that stopped after at least one BZD and a non-BZD ASM. We excluded patients with non-convulsive SE at onset, non-convulsive SE with motor manifestations limited to infrequent myoclonic jerks, or psychogenic non-epileptic events. We also excluded patients with an unknown time to first BZD, repeated SE episodes that occurred during the same day, and patients with one SE episode during the study period but who had a history of prior SE episodes (and thus the one SE episode registered during the study was not their first presentation with SE) (Fig. 1 ). First, we analyzed two groups of patients: patients experiencing their first and only refractory and/or non-refractory SE during the study period (group I) versus patients with two or more episodes of refractory and/or non-refractory SE during the study period (group II). Secondly, for group II patients, we compared the first SE episode (group IIa) with the second SE episode in the same patient (group IIb). Variables We had two research questions. First, we wanted to know whether patients who presented with repeated SE episodes had different characteristics than patients who just had one SE episode. Therefore, between these groups, we compared epidemiological and clinical variables including sex, age, race, ethnicity, SE etiology, prior diagnosis of epilepsy, prior history of SE (before June 2011), in-hospital or pre-hospital onset, treatment with continuous infusion, and SE duration] between group I and group II. These variables were defined at the time of the first SE episode during the study period. Our second and main question was whether treatment of SE is faster in patients with subsequent episodes of SE. For this analysis, we defined our primary outcome as the time to the first BZD for group IIa compared to group IIb. Our secondary outcome was time to non-BZD ASM between groups IIa and IIb. We also compared the time to treatment to the American Epilepsy Society (AES) guideline recommendations, which recommend treatment with the first BZD within 20 minutes and the first non-BZD ASM within 40 minutes.[ 10 ] Lastly, we evaluated whether group II patients received treatment from family members/caregivers at home when they had repeated episodes and compared the time to the first BZD given by caregivers to time to first BZD when it was not administered by medical personnel. Statistical analysis : We used descriptive statistics to summarize the demographic and clinical characteristics. We expressed continuous variables (such as time to treatment) as the median (interquartile range [IQR]: 25th percentile to 75th percentile). We compared the time to treatment during the first and second SE episodes with a paired Wilcoxon sign-rank test. We analyzed the time to treatment compared to the guideline recommendations for time to treatment with an unpaired Wilcoxon rank sum test. The non-parametric tests were performed due to non-normality of the time variables. The time to administration of medication was calculated from seizure onset as reported by family/caregivers and physicians. We compared categorical variables and continuous variables in group I and group II using Fisher’s exact test and the Wilcoxon rank-sum (Mann-Whitney) test, respectively. We used logistic regression for the multivariable analysis that compared subgroups and evaluated predictors of presenting with repeated SE using odds ratio (OR) and the 95% confidence interval (95% CI). A statistical significance level of 0.05 was set for all hypothesis tests. We performed all statistical analyses with STATA 14.2 (Stata Corp., College Station, TX). RESULTS Patients with repeated SE episodes : There are 420 patients in the pSERG database (February 2011 to June 2019) with a total of 504 SE episodes. From this group, 370 (89%) patients had only one SE episode during the study period and no prior history of SE (group I) and 50 patients (12%) had 134 repeated SE episodes (group II). The follow-up period was a median (range) of 7 years and 4 months (2 years and 4 months − 8 years and 7 months). The 50 patients with repeated SE had a median (IQR) age at the first event captured in the study of 4.21 (1.5–9.3) years. Twenty-nine (58%) were males. Among the 134 SE episodes, the median number of SE episodes per patient was 2 (range 2–17) per patient. Out of these, 51/134 (38%) had an in-hospital SE onset, and 83 (62%) had a pre-hospital SE onset. One SE group (group I) vs. repeated SE group (group II) : The demographic and clinical characteristics of both groups are summarized in Table 1 . We compared both groups and the main difference was a prior diagnosis of epilepsy [74% in the repeated SE group (group II) vs 37% in one SE group (group I), p < 0.001. There was no statistical difference in sex, age, race, ethnicity, SE etiology, in-hospital vs. pre-hospital onset, treatment with continuous infusion, or SE duration (Table 1 ). On multivariable analysis, a prior diagnosis of epilepsy was associated with greater odds of repeated episodes of SE (OR 5.3 (95%CI: 2.66–10.7, p < 0.001) (Table 2 ). Table 1 Demographic and clinical characteristics in patients with repeated status epilepticus (SE) episodes (group II) and one SE episode (group I). Characteristics Group II (repeated episodes of SE) Group I (one episode of SE) P value Patients 50 (12%) 370 (88%) Sex Females 21 (42%) 164 (44%) 0.88 Males 29 (58%) 206 (56%) Age (years) (median (IQR)) 4.2 (1.5–9.3) 3.83 (1.38–9.4) 0.87 Race White 31 (62%) 233 (63%) 0.88 Non-white Black or African American 6 (12%) 81 (22%) American Indian 0 (0%) 3 (0.8%) Arabic 4 (8%) 7 (2%) Asian 4 (8%) 9 (2%) Native Hawaiian or Pacific Islander 1 (2%) 1 (0.3%) Unknown 2 (4%) 18 (5%) Not reported 2 (4%) 18 (5%) Ethnicity Not Hispanic or Latino 36 (72%) 276 (72%) 0.91 Hispanic or Latino 9 (18%) 61 (16%) Unknown 1 (2%) 10 (3%) Not reported 4 (8%) 23 (6%) SE etiology Structural 13 (26%) 102 (28%) 0.22 Genetic 12 (14%) 49 (13%) Other 7 (14%) 66 (18%) Metabolic 0 (0%) 17 (5%) Unknown 18 (36%) 133 (36%) Prior epilepsy diagnosis Yes 37 (74%) 138 (37%) < 0.001 No 13 (26%) 230 (62%) SE onset In-hospital 19 (38%) 100 (27%) 0.13 Pre-hospital 31 (62%) 269 (73%) Continuous infusion treatment Yes 14 (28%) 142 (38%) 0.16 No 36 (72%) 228 (62%) SE duration (minutes) (median (IQR)) 112.5 (69–300) 136 (63–480) 0.5 IQR interquartile range, 25th percentile to 75th percentile. Table 2 Multivariable logistic regression comparing demographic and clinical characteristics of patients with one status epilepticus (SE) episode (group I) to patients with repeated SE episodes (group II). Characteristics Odds Ratio (95% Confidence Interval) Standard Error Z statistics P-value Sex 1.37 (0.730–2.59) 0.445 0.99 0.324 Age (years) 0.973 (0.913–1.04) 0.0319 \(-\) 0.83 0.405 Race 0.877 (0.455–1.69) 0.293 0.39 0.694 SE etiology (structural vs. non-structural) 0.792 (0.391-1.60) 0.285 \(-\) 0.65 0.689 Prior epilepsy diagnosis 2.72 (1.29–5.73) 1.03 2.63 0.009 Prior SE (before study period) 2.41 (1.19–4.89) 0.870 2.44 0.015 SE onset (in-hospital vs. pre-hospital) 1.40 (0.727–2.66) 0.459 1.00 0.319 Continuous infusion treatment 0.698 (0.328–1.487) 0.269 0.93 0.351 SE duration (minutes) 1.00 (1.00–1.00) 0.0000312 0.34 0.738 Time to treatment Fifty patients had repeated SE episodes during the study period (group II). Table 3 summarizes the time to treatment in this group, comparing the first SE episode during the study period (group IIa) and the second SE episode (group IIb). In the 50 patients with repeated episodes, the median (IQR) time to treatment with first BZD was 10 (5–30) minutes in the first SE episode and 14.5 (4.5–52.5) minutes in the second SE episode. There was no difference between the time to treatment during the first and second SE episode (Fig. 2 ). The median (IQR) time to the first non-BZD ASM was 61 (37–125) minutes and 71 (34.5-117.5) minutes, in the first and second SE episode, respectively; again, there was no difference (Fig. 3 ). When considering all repeated SE episodes, 50/134 episodes (37%) were treated with the first BZD after the 10 minute AES guideline recommendation (p < 0.001) and 84/134 (63%) were treated with the first non-BZD ASM after the 20 minute AES guideline recommendation (p < 0.001). Table 3 Time to treatment with first benzodiazepine (BZD) and first non-BZD anti-seizure medication (ASM) in patients in the first (group IIa) and second (group IIb) status epilepticus (SE) episode during the study period. Time to treatment (N = 50) Setting Group IIa (first SE episode) Group IIb (second SE episode) P value Time to first BZD [median (IQR)] Time to treatment 10 (5–30) 14.5 (4.5–52.5) p = 0.24 Pre-hospital 15 (5–55) 26 (5–75) p = 0.8 In-hospital 9 (4–20) 9.5 (4–30) p = 0.15 Time to first non-BZD ASM [median (IQR)] Time to treatment 61 (37–125) 71 (34.5-117.5) p = 0.61 Pre-hospital 98 (61–249) 98 (71–291) p = 0.88 In-hospital 38 (20–58) 25.5 (16–53) p = 0.28 N : number, IQR : interquartile range, 25th percentile to 75th percentile. Continuous data are reported as median (IQR) and in minutes. Pre-hospital time to treatment Out of all 134 repeated SE episodes, 83 (62%) had onset in the pre-hospital setting. Of these, 58/83 (70%) episodes were treated by family and 8/83 (10%) by EMS before reaching the hospital, 5/83 (6%) were treated in an outside hospital and 12/83 (14%) were first treated at one of the pSERG hospitals after referral. In the pre-hospital setting, 19/31 (61%) were treated by their families in the first SE episode and 18/31 (58%) in the second SE episode. The number of patients treated by family members did not increase in the second episode (p = 0.56). When families administered a rescue medication [N = 58 (70%)], the median (IQR) time to first BZD was 5 (0–25) minutes compared to 55 (41–120) minutes when the family did not administer a rescue medication [N = 25 (30%)] (p < 0.001) (Fig. 4 ). Overall, the median (IQR) time to the first BZD in the pre-hospital setting was no different when comparing the first SE group [15 (5–55) minutes] compared to the second SE group [26 (5–75)] (p = 0.8). The median (IQR) time to the first non-BZD also did not differ between the first SE and second SE groups that had a pre-hospital SE onset [98 (61–249) minutes vs 98 (71–291) minutes, (p = 0.88)]. In-hospital time to treatment Out of all 134 repeated SE episodes, 51 (38%) had onset in the in-hospital setting. The median (IQR) time to the first BZD in the in-hospital setting was 9 (4–20) minutes, which is within guideline recommendations for the treatment of SE. The time to the first BZD did not differ between the first and second SE during the study period in patients who had an in-hospital SE onset [9 (4–20) minutes vs 9.5 (4–30) minutes, respectively (p = 0.15)]. The median (IQR) time to the first non-BZD did not differ between the first and second SE episode when the onset was in-hospital [38 (20–58) minutes vs 25.5 (16–53) minutes, (p = 0.28)], which was also within guideline recommendations for the treatment of SE. DISCUSSION In this retrospective study, we compared patients who had a single first episode of SE to patients who had repeated episodes of SE. The only explanatory variable that we identified as being associated with experiencing repeated episodes of SE was a prior diagnosis of epilepsy. We failed to identify any other differences in our retrospective groupings. Regarding comparison of ASM management between first and second episode of SE in patients who had repeated episodes of SE during the study period, there was no difference between the time to treatment with the first BZD and the first non-BZD ASM in the first SE episode during the study period compared to their second SE episode. The percentage of families who treated SE at home with rescue ASMs did not increase when comparing the second and first SE episodes. However, when families did use ASM treatment at home, the time to the first BZD was shorter when compared to administration by other medical services. Time to treatment and outcome Outcomes in SE are associated with the etiology of seizures, SE duration, and patient age.[ 5 , 20 ] The duration of SE is a factor that may be modified with timely ASM treatment.[ 17 ] There is a narrow window for early treatment to shorten SE duration, as the efficacy of BZD decreases with prolonged seizures.[ 21 – 23 ] A previous pSERG study concluded that patients who received the first BZD after 10 minutes had longer SE, greater need for continuous infusions, and higher mortality.[ 17 ] Timely ASM administration occurs rarely, as exemplified by a review of 2,212 patients with SE that showed that patients were treated on average 42.4 minutes after SE onset.[ 21 ] In that study, 51.8% of patients received initial ASM treatment by EMS while only 12.8% were initially treated by their families.[ 21 ] In the current report, 70% of the repeated SE episodes with onset in the pre-hospital setting received treatment from family members, and 10% from EMS. The time to treatment that we recorded were faster than descriptions in the literature; however, half of the patients in this study still experienced delayed first BZD treatment, and 86% received a delayed first non-BZD ASM treatment based on current guidelines.[ 10 ] Time to first BZD Several studies have analyzed time to the first BZD. A prior pSERG study of 189 refractory SE patients noted that the time to first BZD in pre-hospital settings was longer for patients with a prior epilepsy diagnosis (29 minutes vs 20 minutes), but shorter in patients with prior SE (5 vs 30 minutes).[ 24 ] A study of 179 children with febrile SE reported a median time to first BZD of 30 minutes, either by EMS or in the emergency department, and a mean time to BZD treatment in pre-hospital setting of 22.3 minutes.[ 25 ] A study of 109 adults reported the mean time of 70 minutes to the first pre-hospital BZD and a mean time of 131 minutes to initiation of ASM in hospital settings.[ 26 ] In addition, the median time to first ASM treatment was reported as 35–45 minutes in other studies, including adult patients.(27–29) In our study, the median (IQR) time to the first BZD in the first SE group was 10 (5–30) minutes, and the median time to treatment in the second SE episode was 14.5 (4.5–52.5) minutes. The median time is comparable to guideline recommendations;(10) however, there was no improvement in the timing of the treatment of the repeated episodes. The median in-hospital time to treatment was under 10 minutes as recommended in current guidelines. The time to the first non-BZD ASM also did not improve in the second SE episode. The role of the caregiver in the treatment of SE To improve the time to initial treatment, caregivers are a crucial factor. In the pre-hospital setting, they may be the only ones who can administer rescue ASMs within 10 minutes of seizure onset. However, in the current study, the percentage of families who treated the patients at home did not increase from the first to second SE episode. This highlights an opportunity to improve pre-hospital care, for example, through additional education. When families administered the rescue medication, the median (IQR) time to first BZD was significantly shorter [5 (0–25) minutes if treated by family vs not 55 (41–120) minutes; p < 0.001)]. A survey of 100 families of patients with epilepsy found that 87% of families have rescue ASMs at home.[ 18 ] In this study, patients were more likely to have rescue medication available if the patients had SE in the past, or if patients had seizures lasting longer than 30 seconds.[ 18 ] Only 61% of families that took the survey received training on how to use the ASMs and only 45% had seizure action plans, suggesting an additional opportunity for education and intervention.[ 18 ] Families and caregivers with seizure action plans had a better knowledge of the rescue medication and schools were more involved in these cases.[ 18 , 30 ] In-hospital time to treatment The impact of timely interventions has been demonstrated by quality improvement studies. One study used educational and logistic quality improvement measurements, to shorten their treatment times and reduce the proportion of patients requiring intensive care transfer for treatment of SE.[ 31 ] After the intervention, 79% of patients received a first BZD before 10 minutes, compared to their historical baseline of 39% and the proportion of patients who were transferred to intensive care due to SE decreased from 39–9%.[ 31 ] A different study of 78 children implemented a standardized hospital treatment protocol and decreased the time to non-BZD ASM from 52 to 21 minutes.[ 32 ] Quality improvement initiatives such as these reduce the time to treatment in the hospital. However, in our study, we failed to identify a difference in the time to treatment between the first and second SE episodes during the study period. In patients who present with multiple SE episodes, there may be an opportunity to create personalized seizure action plans for the in-hospital setting as well. For example, if a patient is known to respond well to a specific medication, this could become part of their seizure action plan in subsequent SE episodes. Statistical predictors of repeated SE In a study of 95 children with SE, 17% had at least a second SE episode and an abnormal neurologic status was identified as a risk factor for repeated SE.(19) Other previous studies have reported chronic etiology, female gender, and lack of treatment response to first ASM during SE to be predictors of repeated SE.[ 35 , 36 ] If we can identify patients at risk of repeated hospital admission, we can implement preventative measures to reduce complications and hospital readmissions. A retrospective study evaluated 139,800 adults with seizure-related admissions, of which 15,094 (10.8%) patients were re-admitted within 30 days.[ 33 ] They found that the most common reason for re-admission was epilepsy or convulsion (17%), followed by the presence of inpatient adverse effects of medical drugs or medical care complications (10.1%).[ 33 ] In our study, having a prior diagnosis of epilepsy was associated with up to a 5-fold greater odds of repeated SE and thus a hospital re-admission. There were no other explanatory variables. Therefore, based on these observations, patients with epilepsy may benefit from preventive measures, including seizure detection devices[ 34 ], seizure action plans, and provision of and training for use of rescue medications.[ 18 , 30 ] Challenges Our observations need to be interpreted cautiously in the setting of data acquisition. In this multicenter retrospective cross-sectional study based on the prospective data, we focused on patients with refractory and non-refractory SE episodes who required at least two ASMs. Recall bias was minimized due to prospective data collection and confirmation of crucial variables with the family, patients, and clinicians at the bed side. Patients who had repeated SE episodes that stopped with one rescue medication were not included. Thus, these data are representative of patients with more severe presentations. Families who administered prompt rescue medications at home may have prevented repeated SE episodes. Patients had multiple SE episodes, but the sample size was not sufficiently large for a longitudinal analysis with mixed effects models, and only a few patients had more than two episodes, so we focused on comparing the first and second SE episodes. Also, we could not adjust for the time interval between episodes. It is unclear if the time between SE episodes could affect the response time of the caregivers or medical team. SE is rare and thus, data from multiple centers are needed to evaluate potential interventions and effects.[ 12 ] While we compared structural versus non-structural etiologies and did not find a difference, we cannot rule out that more granular etiologic categories such as progressive neurologic disorders may present with more frequent repeated status epilepticus episodes. Ultimately, an even larger sample size and longer follow-up periods may be required to study repeated SE over time. Difficulties tracking patients across different hospitals and sites longitudinally continue to pose analytic challenges, but to our knowledge, this is the first study that evaluates the timing of treatment in repeated SE episodes. The current study was conducted over a long dataset enrollment period (2011 to 2019) and the data was prospectively collected in each of its 21 different sites. Timing data was also corroborated with families and caregivers. Accounting for multiple SE episodes per patient and studying time to treatment as multidimensional problems are important steps toward studying and developing meaningful interventions in the pre-hospital and in-hospital settings. CONCLUSIONS Patients with repeated SE do not necessarily receive ASM treatment faster during a subsequent SE episode. Furthermore, families and caregivers often do not administer rescue ASMs during these subsequent SE episodes. However, when families and caregivers do provide rescue medication, the time to treatment is faster than waiting for EMS intervention. Patients with known diagnosis of epilepsy are at risk for recurrent SE. Future studies are needed to investigate the efficacy of quality improvement measures and education to improve the time to treatment of SE. Abbreviations Anti-seizure medication (ASM), American Epilepsy Society (AES), benzodiazepine (BZD), confidence interval (CI), electroencephalogram (EEG), emergency medical services (EMS), interquartile range (IQR), odds ratio (OR), Pediatric Status Epilepticus Research Group (pSERG), status epilepticus (SE). Declarations Ethics approval and consent to participate The research protocol was approved by the institutional review boards of all participating institutions, including Boston Children’s Hospital (IRB P-00001207), and written informed consent was obtained from all participants, parents, or guardians. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests Dr. J. Nicholas Brenton receives research support from the NIH. He has served as a consultant for Cycle Pharmaceuticals and the Institute for Advanced Clinical Trials (I-ACT) for Children on a Novartis-sponsored project. Dr. Mark Wainwright is a member of the Clinical Advisory Board for Sage Therapeutics. Dr. Tobias Loddenkemper receives research support from NIH, Epitel, and MIKU. He received past research support from Upsher Smith, Proximagen, and UCB. Dr. Tobias Loddenkemper is part of patent applications to detect and predict clinical outcomes, and to detect, manage, diagnose, and treat neurological conditions, epilepsy, and seizures. Some of Dr. Tobias Loddenkemper’s trainees received salary support from international foundations/societies and academic centers while working in his laboratory. Dr. Marina Gaínza-Lein was previously funded by the Epilepsy Research Fund. Funding This study and consortium were funded in the past by the Epilepsy Foundation of America (EF-213583, Targeted Initiative for Health Outcomes) and by American Epilepsy Society/Epilepsy Foundation of America Infrastructure Awards and the Pediatric Epilepsy Research Foundation. Author’s contributions MGL and TL conceptualized the design of the study. MGL made substantial contributions to this study in terms of data acquisition. JG, MGL, and TL contributed substantially to the analysis and interpretation of data and drafted the article. BZ made a substantial contribution to the analysis and interpretation of data. All authors critically and substantially revised the article. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank Theodore Sheehan for his contribution to data entry. References Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet. 2006;368(9531):222–9. Chin RF, Neville BG, Scott RC. A systematic review of the epidemiology of status epilepticus. Eur J Neurol. 2004;11(12):800–10. Neligan A, Noyce AJ, Gosavi TD, Shorvon SD, Köhler S, Walker MC. Change in Mortality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time: A Systematic Review and Meta-analysis. JAMA Neurol. 2019;76(8):897–905. Martinos MM, Yoong M, Patil S, Chong WK, Mardari R, Chin RF, et al. Early developmental outcomes in children following convulsive status epilepticus: a longitudinal study. Epilepsia. 2013;54(6):1012–9. Raspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol. 2006;5(9):769–79. Sánchez Fernández I, Amengual-Gual M, Barcia Aguilar C, Loddenkemper T. Estimating the cost of status epilepticus admissions in the United States of America using ICD-10 codes. Seizure. 2019;71:295–303. Williams CN, Piantino J, McEvoy C, Fino N, Eriksson CO. The burden of pediatric neurocritical care in the United States. Pediatr Neurol. 2018;89:31–8. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3–23. Wilkes R, Tasker RC. Pediatric intensive care treatment of uncontrolled status epilepticus. Crit Care Clin. 2013;29(2):239–57. Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48–61. Kravljanac R, Djuric M, Jankovic B, Pekmezovic T. Etiology, clinical course and response to the treatment of status epilepticus in children: A 16-year single-center experience based on 602 episodes of status epilepticus. Eur J Paediatr Neurol. 2015;19(5):584–90. Sánchez Fernández I, Abend NS, Agadi S, An S, Arya R, Carpenter JL, et al. Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure. 2014;23(2):87–97. Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Currents. 2016;16(1):48–61. Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol. 2002;59(2):205–10. Sanchez Fernandez I, Abend NS, Agadi S, An S, Arya R, Brenton JN, et al. Time from convulsive status epilepticus onset to anticonvulsant administration in children. Neurology. 2015;84(23):2304–11. Eriksson K, Kalviainen R. Pharmacologic management of convulsive status epilepticus in childhood. Expert Rev Neurother. 2005;5(6):777–83. Gainza-Lein M, Sanchez Fernandez I, Jackson M, Abend NS, Arya R, Brenton JN, et al. Association of Time to Treatment With Short-term Outcomes for Pediatric Patients With Refractory Convulsive Status Epilepticus. JAMA Neurol. 2018;75(4):410–8. Gainza-Lein M, Benjamin R, Stredny C, McGurl M, Kapur K, Loddenkemper T. Rescue Medications in Epilepsy Patients: A Family Perspective. Seizure. 2017;52:188–94. Shinnar S, Maytal J, Krasnoff L, Moshe SL. Recurrent status epilepticus in children. Ann Neurol. 1992;31(6):598–604. Sahin M, Menache CC, Holmes GL, Riviello JJ. Outcome of severe refractory status epilepticus in children. Epilepsia. 2001;42(11):1461–7. Gainza-Lein M, Fernandez IS, Ulate-Campos A, Loddenkemper T, Ostendorf AP. Timing in the treatment of status epilepticus: From basics to the clinic. Seizure. 2018. Goodkin HP, Liu X, Holmes GL. Diazepam terminates brief but not prolonged seizures in young, naive rats. Epilepsia. 2003;44(8):1109–12. Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res. 1998;814(1–2):179–85. Sánchez Fernández I, Jackson MC, Abend NS, Arya R, Brenton JN, Carpenter JL, et al. Refractory status epilepticus in children with and without prior epilepsy or status epilepticus. Neurology. 2017;88(4):386–94. Seinfeld S, Shinnar S, Sun S, Hesdorffer DC, Deng X, Shinnar RC, et al. Emergency management of febrile status epilepticus: results of the FEBSTAT study. Epilepsia. 2014;55(3):388–95. Hillman J, Lehtimaki K, Peltola J, Liimatainen S. Clinical significance of treatment delay in status epilepticus. Int J Emerg Med. 2013;6(1):6. Aranda A, Foucart G, Ducasse JL, Grolleau S, McGonigal A, Valton L. Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice. Epilepsia. 2010;51(10):2159–67. Kamppi L, Mustonen H, Soinila S. Analysis of the delay components in the treatment of status epilepticus. Neurocrit Care. 2013;19(1):10–8. Alvarez V, Lee JW, Drislane FW, Westover MB, Novy J, Dworetzky BA, et al. Practice variability and efficacy of clonazepam, lorazepam, and midazolam in status epilepticus: A multicenter comparison. Epilepsia. 2015;56(8):1275–85. Stredny CM, Abend NS, Loddenkemper T. Towards acute pediatric status epilepticus intervention teams: Do we need Seizure Codes? Seizure. 2018;58:133–40. Ostendorf AP, Merison K, Wheeler TA, Patel AD. Decreasing Seizure Treatment Time Through Quality Improvement Reduces Critical Care Utilization. Pediatr Neurol. 2018;85:58–66. Cassel-Choudhury G, Beal J, Longani N, Leone B, Rivera R, Katyal C. Protocol-Driven Management of Convulsive Status Epilepticus at a Tertiary Children's Hospital: A Quality Improvement Initiative. Pediatr Crit Care Med. 2019;20(1):47–53. Blank LJ, Crispo JAG, Thibault DP, Davis KA, Litt B, Willis AW. Readmission after seizure discharge in a nationally representative sample. Neurology. 2018;92(5):e429–42. Ulate-Campos A, Coughlin F, Gainza-Lein M, Fernandez IS, Pearl PL, Loddenkemper T. Automated seizure detection systems and their effectiveness for each type of seizure. Seizure. 2016;40:88–101. Hesdorffer DC, Logroscino G, Cascino GD, Hauser WA. Recurrence of afebrile status epilepticus in a population-based study in Rochester, Minnesota. Neurology. 2007;69(1):73–8. Tsetsou S, Novy J, Rossetti AO. Recurrence of status epilepticus: prognostic role and outcome predictors. Epilepsia. 2015;56(3):473–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 May, 2025 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 10 Dec, 2024 Reviews received at journal 08 Dec, 2024 Reviewers agreed at journal 27 Nov, 2024 Reviews received at journal 18 Nov, 2024 Reviewers agreed at journal 05 Nov, 2024 Reviewers invited by journal 27 Mar, 2024 Editor invited by journal 27 Mar, 2024 Editor assigned by journal 26 Mar, 2024 Submission checks completed at journal 26 Mar, 2024 First submitted to journal 24 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4160328","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":285007489,"identity":"20a5efe4-a884-4e9c-8198-26dc0e383732","order_by":0,"name":"Jennifer V. Gettings","email":"","orcid":"","institution":"Boston Children’s Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"V.","lastName":"Gettings","suffix":""},{"id":285007490,"identity":"bd3770eb-a6d6-4879-83f6-733d81a4bf81","order_by":1,"name":"Iván Sánchez Fernández","email":"","orcid":"","institution":"Boston Children’s Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Iván","middleName":"Sánchez","lastName":"Fernández","suffix":""},{"id":285007491,"identity":"c8bb2404-022e-4ede-ba2a-d4f8b98c0c11","order_by":2,"name":"Anne Anderson","email":"","orcid":"","institution":"Texas Children’s Hospital, Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"","lastName":"Anderson","suffix":""},{"id":285007492,"identity":"aacb3722-53fb-4fa7-93b2-cdf4799c85e9","order_by":3,"name":"J. Nicholas Brenton","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"J.","middleName":"Nicholas","lastName":"Brenton","suffix":""},{"id":285007493,"identity":"f097f412-fe4b-428b-864a-56c775650d22","order_by":4,"name":"Afra Can","email":"","orcid":"","institution":"University of Rochester Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Afra","middleName":"","lastName":"Can","suffix":""},{"id":285007494,"identity":"ebe1128d-3ba4-46dd-b0e9-de07e453d138","order_by":5,"name":"Justice Clark","email":"","orcid":"","institution":"Boston Children’s Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Justice","middleName":"","lastName":"Clark","suffix":""},{"id":285007495,"identity":"9f375e52-9ab8-4dca-bda9-723415b6aae1","order_by":6,"name":"Raquel Farias Moeller","email":"","orcid":"","institution":"Children’s Hospital of Wisconsin, Medical College of Wisconsin","correspondingAuthor":false,"prefix":"","firstName":"Raquel","middleName":"Farias","lastName":"Moeller","suffix":""},{"id":285007496,"identity":"a29c4ea8-84f8-4899-9db1-209bb95354e7","order_by":7,"name":"Howard P. Goodkin","email":"","orcid":"","institution":"University of Virginia","correspondingAuthor":false,"prefix":"","firstName":"Howard","middleName":"P.","lastName":"Goodkin","suffix":""},{"id":285007497,"identity":"0103ddec-c73d-4b6a-b940-2e9c053ee202","order_by":8,"name":"Yi-Chen Lai","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yi-Chen","middleName":"","lastName":"Lai","suffix":""},{"id":285007498,"identity":"ef71b4a3-ea0c-44ba-9b6d-2e06df961e0d","order_by":9,"name":"Mohamad A. Mikati","email":"","orcid":"","institution":"Duke University Medical Center, Duke University","correspondingAuthor":false,"prefix":"","firstName":"Mohamad","middleName":"A.","lastName":"Mikati","suffix":""},{"id":285007499,"identity":"785581e2-f4d9-4d29-ad8b-301b647a8c3b","order_by":10,"name":"Lindsey A. Morgan","email":"","orcid":"","institution":"University of Washington","correspondingAuthor":false,"prefix":"","firstName":"Lindsey","middleName":"A.","lastName":"Morgan","suffix":""},{"id":285007500,"identity":"a87fed48-fc56-4934-a283-931ae4bb057b","order_by":11,"name":"Edward Novotny","email":"","orcid":"","institution":"University of Washington","correspondingAuthor":false,"prefix":"","firstName":"Edward","middleName":"","lastName":"Novotny","suffix":""},{"id":285007501,"identity":"6fe36757-be59-4abb-9d47-e740441f9b0f","order_by":12,"name":"Adam P. Ostendorf","email":"","orcid":"","institution":"Nationwide Children's Hospital, The Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"P.","lastName":"Ostendorf","suffix":""},{"id":285007502,"identity":"d4d8ea3b-2319-4664-a016-a9842cbbf6f3","order_by":13,"name":"Juan Piantino","email":"","orcid":"","institution":"Doernbecher Children’s Hospital, Oregon Health \u0026 Science University","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Piantino","suffix":""},{"id":285007503,"identity":"6e6e37a0-7d66-4a15-a902-586b9c60ecbb","order_by":14,"name":"James J. Riviello","email":"","orcid":"","institution":"Texas Children’s Hospital, Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"J.","lastName":"Riviello","suffix":""},{"id":285007504,"identity":"3b651357-5b00-4201-acd9-d2be73e74dfe","order_by":15,"name":"Kumar Sannagowdara","email":"","orcid":"","institution":"Advocate Aurora Health Care","correspondingAuthor":false,"prefix":"","firstName":"Kumar","middleName":"","lastName":"Sannagowdara","suffix":""},{"id":285007505,"identity":"e35fab14-0cd0-4f00-8018-d226cbe55948","order_by":16,"name":"Robert C. Tasker","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"C.","lastName":"Tasker","suffix":""},{"id":285007506,"identity":"8a39968a-22d5-49ba-83fa-5f0c4e56233d","order_by":17,"name":"Dmitry Tchapyjnikov","email":"","orcid":"","institution":"Logan Health Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Dmitry","middleName":"","lastName":"Tchapyjnikov","suffix":""},{"id":285007507,"identity":"26490b95-1f00-4986-9421-480bf96db99c","order_by":18,"name":"Mark S. Wainwright","email":"","orcid":"","institution":"University of Washington","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"S.","lastName":"Wainwright","suffix":""},{"id":285007508,"identity":"8608b69c-236f-4d8d-8756-489d9f3ef7a0","order_by":19,"name":"Angus Wilfong","email":"","orcid":"","institution":"University of Arizona College of Medicine and Barrow Neurological Institute at Phoenix Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Angus","middleName":"","lastName":"Wilfong","suffix":""},{"id":285007509,"identity":"b7a36e35-fcde-4091-baa7-105355e4775b","order_by":20,"name":"Korwyn Williams","email":"","orcid":"","institution":"University of Arizona College of Medicine and Barrow Neurological Institute at Phoenix Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Korwyn","middleName":"","lastName":"Williams","suffix":""},{"id":285007510,"identity":"642ace7c-c6a7-41bd-aedd-c60457ce8c63","order_by":21,"name":"Bo Zhang","email":"","orcid":"","institution":"Boston Children’s Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Zhang","suffix":""},{"id":285007511,"identity":"458c35fd-e27a-43cd-b937-8857918ccba4","order_by":22,"name":"Tobias Loddenkemper","email":"","orcid":"","institution":"Boston Children’s Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Tobias","middleName":"","lastName":"Loddenkemper","suffix":""},{"id":285007512,"identity":"620550f4-d312-4eb7-8a5c-0609e7208c20","order_by":23,"name":"Marina Gaínza-Lein","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYLCCBCDmY2BsYPgAZLCxE6uFDaiFcQaIwUysTWxAzMwDYhHSotvAfvHDwx118mzszW2PbX5tk+djZmD88DEHtxazAzzFEoln2AzbeA62G+f23TZsY2Zglpy5Da+WBInENh7GNiApndtzmxGohY2ZF7+W5B+JbRL2bfIP26Qte27bE6GF/RjQfAOgLsY2aYYftxMJaznMw2aR2JaQ3MaT2CbZ23A7uY2ZsRm/X463P775s63Otp/9+DOJH39u285vbz744SMeLcC4MEBwGNvAZAMe9SDA/gCJ84eA4lEwCkbBKBiRAAA5V0wqLgoHvgAAAABJRU5ErkJggg==","orcid":"","institution":"Boston Children’s Hospital, Harvard Medical School","correspondingAuthor":true,"prefix":"","firstName":"Marina","middleName":"","lastName":"Gaínza-Lein","suffix":""}],"badges":[],"createdAt":"2024-03-25 03:14:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4160328/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4160328/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12883-025-04200-w","type":"published","date":"2025-05-26T15:57:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53875954,"identity":"c91bad89-092c-4ce7-b36d-1bb0cb5708aa","added_by":"auto","created_at":"2024-04-01 16:37:50","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":454036,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInclusion and exclusion criteria.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4160328/v1/cb9bdc8689886ca48e1aab92.jpeg"},{"id":53875952,"identity":"314cf995-bbce-43fd-97e4-9edbeb3dab39","added_by":"auto","created_at":"2024-04-01 16:37:50","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":133878,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to treatment with first BZD in the first (group IIa) compared to the second (group IIb) status epilepticus (SE) episode.\u003c/strong\u003e The time to treatment [median (IQR)] with the first BZD was not different in patients in the first compared to the second SE episode [10 (5-30) minutes vs 14.5 (4.5-52.5); (p=0.24p)]. Circles represent outliers greater than 3rd quartile plus 1.5 times interquartile range or less than 1st quartile minus 1.5 times interquartile range; asterisks represent extreme outliers greater than 3rd quartile plus 3 times interquartile range or less than 1st quartile minus 3 times interquartile range; an extreme outlier with a value of 1605 minutes which occurred during the second episode is not displayed.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4160328/v1/29b2efd8ba6a913a1863dad4.jpeg"},{"id":53875955,"identity":"a50ab0ca-7141-455c-8fd6-63f059db221b","added_by":"auto","created_at":"2024-04-01 16:37:50","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":153666,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to treatment with first non-benzodiazepine (BZD) in the first (group IIa) compared to the second (group IIb) status epilepticus (SE) episode.\u003c/strong\u003e The time to treatment [median (IQR)]with the first non-BZD anti-seizure medication (ASM) was not different in patients in the first compared to the second SE episode [61 (37-125) minutes vs 71 (34.5-117.5) minutes; p=0.61]. Circles represent outliers greater than 3rd quartile plus 1.5 times interquartile range or less than 1st quartile minus 1.5 times interquartile range; asterisks represent extreme outliers greater than 3rd quartile plus 3 times interquartile range or less than 1st quartile minus 3 times interquartile range; an extreme outlier with a value of 1031 minutes which occurred during the second episode is not displayed.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4160328/v1/09787a38c86be06a74d6c305.jpeg"},{"id":53875956,"identity":"ade7efc9-9918-46c5-93ba-d05513100c86","added_by":"auto","created_at":"2024-04-01 16:37:50","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":144072,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to treatment with first benzodiazepine (BZD) in patients with repeated status epilepticus (SE) episodes (group II) with onset in the pre-hospital setting.\u003c/strong\u003e Time to treatment [median (IQR)] with the first BZD was significantly shorter in patients treated by family members than in patients not treated by family members [5 (0-25) minutes vs 55 (41-120) minutes, (p\u0026lt;0.001)].Circles represent outliers greater than 3rd quartile plus 1.5 times interquartile range or less than 1st quartile minus 1.5 times interquartile range; asterisks represent extreme outliers greater than 3rd quartile plus 3 times interquartile range or less than 1st quartile minus 3 times interquartile range; an extreme outlier with a value of 1605 minutes which occurred during the second episode and was treated by family is not displayed.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4160328/v1/2441bf645a149adbb1cd54e5.jpeg"},{"id":83782847,"identity":"8f7908f8-a8ec-4e15-a222-b5e2a0fcbfab","added_by":"auto","created_at":"2025-06-02 16:07:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2245304,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4160328/v1/b115c625-ecc5-4216-a4f6-b846fa8debf4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Time to Treatment in Pediatric Patients with Repeated Episodes of Status Epilepticus","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eIn children, status epilepticus (SE) is a frequent life-threatening emergency with an incidence of 17\u0026ndash;23 per 100,000 child population.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The mortality rate of pediatric SE is 3\u0026ndash;9%.[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Survivors are at risk for developmental disorders, epilepsy, and recurrent episodes of SE.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Regarding the latter, each episode of SE in children has an approximate cost of \u003cspan\u003e$\u003c/span\u003e9,295-\u003cspan\u003e$\u003c/span\u003e22,8000 per hospital admission[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], thus, repeated episodes of SE have a high clinical and economic burden on patients, their families, and society.\u003c/p\u003e \u003cp\u003eSeveral guidelines for the treatment of SE propose administering a benzodiazepine (BZD) within 5\u0026ndash;20 minutes of seizure onset [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] followed by a non-BZD anti-seizure medication (ASM) within 20\u0026ndash;40 minutes if the seizure continues.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] When SE continues despite treatment, it is termed refractory status epilepticus (RSE).[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Several studies have shown that delayed treatment leads to longer convulsive seizure duration,[\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] the need for continuous infusions and higher mortality.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Unfortunately, in practice, the treatment of SE is often delayed.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Therefore, neurologists commonly prescribe BZDs or other medications to patients with epilepsy to be used to treat SE. There are no studies evaluating whether time to treatment improves for repeated episodes of SE. There is also no information about treatment latency by caregivers for repeated episodes in the out-of-hospital setting. We hypothesized that patients with a history of SE may have a shorter time to treatment during subsequent episodes of SE. To address this knowledge gap, we studied the time to first BZD and the time to first non-BZD ASM in patients with repeated episodes of SE.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e \u003cstrong\u003eStudy design\u003c/strong\u003e \u003cp\u003eThe study was performed as a retrospective cross-sectional study based on the prospective data collected by the pediatric Status Epilepticus Research Group (pSERG), a consortium of 21 tertiary pediatric hospitals in the United States and Canada.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Nine of these centers had data on patients that presented with multiple SE episodes between June 2011 and February 2019. Data was collected using a standardized data acquisition tool and entered into an electronic database. At the time of each SE episode, in-hospital data was obtained from the hospital records and inpatient medical teams, and pre-hospital data (including the time to treatment) was obtained from patients\u0026rsquo; families and Emergency Medical Services (EMS) records. The research protocol was approved by the institutional review boards of all participating institutions, including Boston Children\u0026rsquo;s Hospital (IRB P-00001207), and written informed consent was obtained from all participants, parents, or guardians.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePatients\u003c/strong\u003e \u003cp\u003eWe included pediatric patients (aged 1 month to 21 years) who were admitted with refractory or non-refractory SE with focal or generalized convulsive epileptic seizures at onset. Refractory SE was defined as SE continuing after at least one dose of BZD and at least one dose of a non-BZD ASM, or when a continuous infusion was required for seizure control. Non-refractory SE was defined as SE that stopped after at least one BZD and a non-BZD ASM. We excluded patients with non-convulsive SE at onset, non-convulsive SE with motor manifestations limited to infrequent myoclonic jerks, or psychogenic non-epileptic events. We also excluded patients with an unknown time to first BZD, repeated SE episodes that occurred during the same day, and patients with one SE episode during the study period but who had a history of prior SE episodes (and thus the one SE episode registered during the study was not their first presentation with SE) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFirst, we analyzed two groups of patients: patients experiencing their first and only refractory and/or non-refractory SE during the study period (group I) versus patients with two or more episodes of refractory and/or non-refractory SE during the study period (group II). Secondly, for group II patients, we compared the first SE episode (group IIa) with the second SE episode in the same patient (group IIb).\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eVariables\u003c/strong\u003e \u003cp\u003eWe had two research questions. First, we wanted to know whether patients who presented with repeated SE episodes had different characteristics than patients who just had one SE episode. Therefore, between these groups, we compared epidemiological and clinical variables including sex, age, race, ethnicity, SE etiology, prior diagnosis of epilepsy, prior history of SE (before June 2011), in-hospital or pre-hospital onset, treatment with continuous infusion, and SE duration] between group I and group II. These variables were defined at the time of the first SE episode during the study period.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eOur second and main question was whether treatment of SE is faster in patients with subsequent episodes of SE. For this analysis, we defined our primary outcome as the time to the first BZD for group IIa compared to group IIb. Our secondary outcome was time to non-BZD ASM between groups IIa and IIb. We also compared the time to treatment to the American Epilepsy Society (AES) guideline recommendations, which recommend treatment with the first BZD within 20 minutes and the first non-BZD ASM within 40 minutes.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Lastly, we evaluated whether group II patients received treatment from family members/caregivers at home when they had repeated episodes and compared the time to the first BZD given by caregivers to time to first BZD when it was not administered by medical personnel.\u003c/p\u003e \u003cp\u003e\u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eStatistical analysis\u003c/span\u003e: We used descriptive statistics to summarize the demographic and clinical characteristics. We expressed continuous variables (such as time to treatment) as the median (interquartile range [IQR]: 25th percentile to 75th percentile). We compared the time to treatment during the first and second SE episodes with a paired Wilcoxon sign-rank test. We analyzed the time to treatment compared to the guideline recommendations for time to treatment with an unpaired Wilcoxon rank sum test. The non-parametric tests were performed due to non-normality of the time variables. The time to administration of medication was calculated from seizure onset as reported by family/caregivers and physicians. We compared categorical variables and continuous variables in group I and group II using Fisher\u0026rsquo;s exact test and the Wilcoxon rank-sum (Mann-Whitney) test, respectively. We used logistic regression for the multivariable analysis that compared subgroups and evaluated predictors of presenting with repeated SE using odds ratio (OR) and the 95% confidence interval (95% CI). A statistical significance level of 0.05 was set for all hypothesis tests. We performed all statistical analyses with STATA 14.2 (Stata Corp., College Station, TX).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ePatients with\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003erepeated SE episodes\u003c/span\u003e: There are 420 patients in the pSERG database (February 2011 to June 2019) with a total of 504 SE episodes. From this group, 370 (89%) patients had only one SE episode during the study period and no prior history of SE (group I) and 50 patients (12%) had 134 repeated SE episodes (group II). The follow-up period was a median (range) of 7 years and 4 months (2 years and 4 months \u0026minus;\u0026thinsp;8 years and 7 months). The 50 patients with repeated SE had a median (IQR) age at the first event captured in the study of 4.21 (1.5\u0026ndash;9.3) years. Twenty-nine (58%) were males. Among the 134 SE episodes, the median number of SE episodes per patient was 2 (range 2\u0026ndash;17) per patient. Out of these, 51/134 (38%) had an in-hospital SE onset, and 83 (62%) had a pre-hospital SE onset.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eOne SE group (group I) vs. repeated SE group (group II)\u003c/span\u003e: The demographic and clinical characteristics of both groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We compared both groups and the main difference was a prior diagnosis of epilepsy [74% in the repeated SE group (group II) vs 37% in one SE group (group I), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001. There was no statistical difference in sex, age, race, ethnicity, SE etiology, in-hospital vs. pre-hospital onset, treatment with continuous infusion, or SE duration (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). On multivariable analysis, a prior diagnosis of epilepsy was associated with greater odds of repeated episodes of SE (OR 5.3 (95%CI: 2.66\u0026ndash;10.7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eDemographic and clinical characteristics in patients with repeated\u003c/b\u003e status epilepticus \u003cb\u003e(SE) episodes (group II) and one SE episode (group I).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup II (repeated episodes of SE)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup I (one episode of SE)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatients\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e370 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemales\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e164 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMales\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e206 (56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e (median (IQR))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2 (1.5\u0026ndash;9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.83 (1.38\u0026ndash;9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRace\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e233 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-white\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlack or African American\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmerican Indian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eArabic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNative Hawaiian or Pacific Islander\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot Hispanic or Latino\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e276 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHispanic or Latino\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSE etiology\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStructural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGenetic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMetabolic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior epilepsy diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e138 (37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e230 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSE onset\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIn-hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e269 (73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eContinuous infusion treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e142 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e228 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSE duration (minutes)\u003c/b\u003e (median (IQR))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112.5 (69\u0026ndash;300)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e136 (63\u0026ndash;480)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eIQR\u003c/strong\u003e \u003cp\u003einterquartile range, 25th percentile to 75th percentile.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eMultivariable logistic regression comparing demographic and clinical characteristics of patients with one\u003c/b\u003e status epilepticus \u003cb\u003e(SE) episode (group I) to patients with repeated SE episodes (group II).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds Ratio (95% Confidence Interval)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStandard Error\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ statistics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.37 (0.730\u0026ndash;2.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.324\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.973 (0.913\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0319\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(-\\)\u003c/span\u003e\u003c/span\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.405\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.877 (0.455\u0026ndash;1.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.694\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSE etiology (structural vs. non-structural)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.792 (0.391-1.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(-\\)\u003c/span\u003e\u003c/span\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.689\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior epilepsy diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.72 (1.29\u0026ndash;5.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior SE (before study period)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.41 (1.19\u0026ndash;4.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.870\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSE onset (in-hospital vs. pre-hospital)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.40 (0.727\u0026ndash;2.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.319\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContinuous infusion treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.698 (0.328\u0026ndash;1.487)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.269\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.351\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSE duration (minutes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00 (1.00\u0026ndash;1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0000312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eTime to treatment\u003c/strong\u003e \u003cp\u003eFifty patients had repeated SE episodes during the study period (group II). Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes the time to treatment in this group, comparing the first SE episode during the study period (group IIa) and the second SE episode (group IIb). In the 50 patients with repeated episodes, the median (IQR) time to treatment with first BZD was 10 (5\u0026ndash;30) minutes in the first SE episode and 14.5 (4.5\u0026ndash;52.5) minutes in the second SE episode. There was no difference between the time to treatment during the first and second SE episode (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median (IQR) time to the first non-BZD ASM was 61 (37\u0026ndash;125) minutes and 71 (34.5-117.5) minutes, in the first and second SE episode, respectively; again, there was no difference (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). When considering all repeated SE episodes, 50/134 episodes (37%) were treated with the first BZD after the 10 minute AES guideline recommendation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 84/134 (63%) were treated with the first non-BZD ASM after the 20 minute AES guideline recommendation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTime to treatment with first benzodiazepine (BZD) and first non-BZD anti-seizure medication (ASM) in patients in the first (group IIa) and second (group IIb) status epilepticus (SE) episode during the study period.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTime to treatment (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSetting\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup IIa (first SE episode)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup IIb (second SE episode)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eTime to first BZD [median (IQR)]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTime to treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (5\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.5 (4.5\u0026ndash;52.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePre-hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (5\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 (5\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eIn-hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (4\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.5 (4\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eTime to first non-BZD ASM [median (IQR)]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTime to treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (37\u0026ndash;125)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71 (34.5-117.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePre-hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e98 (61\u0026ndash;249)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98 (71\u0026ndash;291)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eIn-hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (20\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.5 (16\u0026ndash;53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eN\u003c/b\u003e: number, \u003cb\u003eIQR\u003c/b\u003e: interquartile range, 25th percentile to 75th percentile. Continuous data are reported as median (IQR) and in minutes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePre-hospital time to treatment\u003c/strong\u003e \u003cp\u003eOut of all 134 repeated SE episodes, 83 (62%) had onset in the pre-hospital setting. Of these, 58/83 (70%) episodes were treated by family and 8/83 (10%) by EMS before reaching the hospital, 5/83 (6%) were treated in an outside hospital and 12/83 (14%) were first treated at one of the pSERG hospitals after referral. In the pre-hospital setting, 19/31 (61%) were treated by their families in the first SE episode and 18/31 (58%) in the second SE episode. The number of patients treated by family members did not increase in the second episode (p\u0026thinsp;=\u0026thinsp;0.56). When families administered a rescue medication [N\u0026thinsp;=\u0026thinsp;58 (70%)], the median (IQR) time to first BZD was 5 (0\u0026ndash;25) minutes compared to 55 (41\u0026ndash;120) minutes when the family did not administer a rescue medication [N\u0026thinsp;=\u0026thinsp;25 (30%)] (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Overall, the median (IQR) time to the first BZD in the pre-hospital setting was no different when comparing the first SE group [15 (5\u0026ndash;55) minutes] compared to the second SE group [26 (5\u0026ndash;75)] (p\u0026thinsp;=\u0026thinsp;0.8). The median (IQR) time to the first non-BZD also did not differ between the first SE and second SE groups that had a pre-hospital SE onset [98 (61\u0026ndash;249) minutes vs 98 (71\u0026ndash;291) minutes, (p\u0026thinsp;=\u0026thinsp;0.88)].\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eIn-hospital time to treatment\u003c/strong\u003e \u003cp\u003eOut of all 134 repeated SE episodes, 51 (38%) had onset in the in-hospital setting. The median (IQR) time to the first BZD in the in-hospital setting was 9 (4\u0026ndash;20) minutes, which is within guideline recommendations for the treatment of SE. The time to the first BZD did not differ between the first and second SE during the study period in patients who had an in-hospital SE onset [9 (4\u0026ndash;20) minutes vs 9.5 (4\u0026ndash;30) minutes, respectively (p\u0026thinsp;=\u0026thinsp;0.15)]. The median (IQR) time to the first non-BZD did not differ between the first and second SE episode when the onset was in-hospital [38 (20\u0026ndash;58) minutes vs 25.5 (16\u0026ndash;53) minutes, (p\u0026thinsp;=\u0026thinsp;0.28)], which was also within guideline recommendations for the treatment of SE.\u003c/p\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this retrospective study, we compared patients who had a single first episode of SE to patients who had repeated episodes of SE. The only explanatory variable that we identified as being associated with experiencing repeated episodes of SE was a prior diagnosis of epilepsy. We failed to identify any other differences in our retrospective groupings. Regarding comparison of ASM management between first and second episode of SE in patients who had repeated episodes of SE during the study period, there was no difference between the time to treatment with the first BZD and the first non-BZD ASM in the first SE episode during the study period compared to their second SE episode. The percentage of families who treated SE at home with rescue ASMs did not increase when comparing the second and first SE episodes. However, when families did use ASM treatment at home, the time to the first BZD was shorter when compared to administration by other medical services.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eTime to treatment and outcome\u003c/strong\u003e \u003cp\u003eOutcomes in SE are associated with the etiology of seizures, SE duration, and patient age.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] The duration of SE is a factor that may be modified with timely ASM treatment.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] There is a narrow window for early treatment to shorten SE duration, as the efficacy of BZD decreases with prolonged seizures.[\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] A previous pSERG study concluded that patients who received the first BZD after 10 minutes had longer SE, greater need for continuous infusions, and higher mortality.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Timely ASM administration occurs rarely, as exemplified by a review of 2,212 patients with SE that showed that patients were treated on average 42.4 minutes after SE onset.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] In that study, 51.8% of patients received initial ASM treatment by EMS while only 12.8% were initially treated by their families.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] In the current report, 70% of the repeated SE episodes with onset in the pre-hospital setting received treatment from family members, and 10% from EMS. The time to treatment that we recorded were faster than descriptions in the literature; however, half of the patients in this study still experienced delayed first BZD treatment, and 86% received a delayed first non-BZD ASM treatment based on current guidelines.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eTime to first BZD\u003c/strong\u003e \u003cp\u003eSeveral studies have analyzed time to the first BZD. A prior pSERG study of 189 refractory SE patients noted that the time to first BZD in pre-hospital settings was longer for patients with a prior epilepsy diagnosis (29 minutes vs 20 minutes), but shorter in patients with prior SE (5 vs 30 minutes).[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] A study of 179 children with febrile SE reported a median time to first BZD of 30 minutes, either by EMS or in the emergency department, and a mean time to BZD treatment in pre-hospital setting of 22.3 minutes.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] A study of 109 adults reported the mean time of 70 minutes to the first pre-hospital BZD and a mean time of 131 minutes to initiation of ASM in hospital settings.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] In addition, the median time to first ASM treatment was reported as 35\u0026ndash;45 minutes in other studies, including adult patients.(27\u0026ndash;29) In our study, the median (IQR) time to the first BZD in the first SE group was 10 (5\u0026ndash;30) minutes, and the median time to treatment in the second SE episode was 14.5 (4.5\u0026ndash;52.5) minutes. The median time is comparable to guideline recommendations;(10) however, there was no improvement in the timing of the treatment of the repeated episodes. The median in-hospital time to treatment was under 10 minutes as recommended in current guidelines. The time to the first non-BZD ASM also did not improve in the second SE episode.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eThe role of the caregiver in the treatment of SE\u003c/strong\u003e \u003cp\u003eTo improve the time to initial treatment, caregivers are a crucial factor. In the pre-hospital setting, they may be the only ones who can administer rescue ASMs within 10 minutes of seizure onset. However, in the current study, the percentage of families who treated the patients at home did not increase from the first to second SE episode. This highlights an opportunity to improve pre-hospital care, for example, through additional education. When families administered the rescue medication, the median (IQR) time to first BZD was significantly shorter [5 (0\u0026ndash;25) minutes if treated by family vs not 55 (41\u0026ndash;120) minutes; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)]. A survey of 100 families of patients with epilepsy found that 87% of families have rescue ASMs at home.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] In this study, patients were more likely to have rescue medication available if the patients had SE in the past, or if patients had seizures lasting longer than 30 seconds.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] Only 61% of families that took the survey received training on how to use the ASMs and only 45% had seizure action plans, suggesting an additional opportunity for education and intervention.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] Families and caregivers with seizure action plans had a better knowledge of the rescue medication and schools were more involved in these cases.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eIn-hospital time to treatment\u003c/strong\u003e \u003cp\u003eThe impact of timely interventions has been demonstrated by quality improvement studies. One study used educational and logistic quality improvement measurements, to shorten their treatment times and reduce the proportion of patients requiring intensive care transfer for treatment of SE.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] After the intervention, 79% of patients received a first BZD before 10 minutes, compared to their historical baseline of 39% and the proportion of patients who were transferred to intensive care due to SE decreased from 39\u0026ndash;9%.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] A different study of 78 children implemented a standardized hospital treatment protocol and decreased the time to non-BZD ASM from 52 to 21 minutes.[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] Quality improvement initiatives such as these reduce the time to treatment in the hospital. However, in our study, we failed to identify a difference in the time to treatment between the first and second SE episodes during the study period. In patients who present with multiple SE episodes, there may be an opportunity to create personalized seizure action plans for the in-hospital setting as well. For example, if a patient is known to respond well to a specific medication, this could become part of their seizure action plan in subsequent SE episodes.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStatistical predictors of repeated SE\u003c/strong\u003e \u003cp\u003eIn a study of 95 children with SE, 17% had at least a second SE episode and an abnormal neurologic status was identified as a risk factor for repeated SE.(19) Other previous studies have reported chronic etiology, female gender, and lack of treatment response to first ASM during SE to be predictors of repeated SE.[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] If we can identify patients at risk of repeated hospital admission, we can implement preventative measures to reduce complications and hospital readmissions.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eA retrospective study evaluated 139,800 adults with seizure-related admissions, of which 15,094 (10.8%) patients were re-admitted within 30 days.[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] They found that the most common reason for re-admission was epilepsy or convulsion (17%), followed by the presence of inpatient adverse effects of medical drugs or medical care complications (10.1%).[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] In our study, having a prior diagnosis of epilepsy was associated with up to a 5-fold greater odds of repeated SE and thus a hospital re-admission. There were no other explanatory variables. Therefore, based on these observations, patients with epilepsy may benefit from preventive measures, including seizure detection devices[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], seizure action plans, and provision of and training for use of rescue medications.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eChallenges\u003c/strong\u003e \u003cp\u003eOur observations need to be interpreted cautiously in the setting of data acquisition. In this multicenter retrospective cross-sectional study based on the prospective data, we focused on patients with refractory and non-refractory SE episodes who required at least two ASMs. Recall bias was minimized due to prospective data collection and confirmation of crucial variables with the family, patients, and clinicians at the bed side. Patients who had repeated SE episodes that stopped with one rescue medication were not included. Thus, these data are representative of patients with more severe presentations. Families who administered prompt rescue medications at home may have prevented repeated SE episodes. Patients had multiple SE episodes, but the sample size was not sufficiently large for a longitudinal analysis with mixed effects models, and only a few patients had more than two episodes, so we focused on comparing the first and second SE episodes. Also, we could not adjust for the time interval between episodes. It is unclear if the time between SE episodes could affect the response time of the caregivers or medical team. SE is rare and thus, data from multiple centers are needed to evaluate potential interventions and effects.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] While we compared structural versus non-structural etiologies and did not find a difference, we cannot rule out that more granular etiologic categories such as progressive neurologic disorders may present with more frequent repeated status epilepticus episodes. Ultimately, an even larger sample size and longer follow-up periods may be required to study repeated SE over time. Difficulties tracking patients across different hospitals and sites longitudinally continue to pose analytic challenges, but to our knowledge, this is the first study that evaluates the timing of treatment in repeated SE episodes. The current study was conducted over a long dataset enrollment period (2011 to 2019) and the data was prospectively collected in each of its 21 different sites. Timing data was also corroborated with families and caregivers. Accounting for multiple SE episodes per patient and studying time to treatment as multidimensional problems are important steps toward studying and developing meaningful interventions in the pre-hospital and in-hospital settings.\u003c/p\u003e \u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003ePatients with repeated SE do not necessarily receive ASM treatment faster during a subsequent SE episode. Furthermore, families and caregivers often do not administer rescue ASMs during these subsequent SE episodes. However, when families and caregivers do provide rescue medication, the time to treatment is faster than waiting for EMS intervention. Patients with known diagnosis of epilepsy are at risk for recurrent SE. Future studies are needed to investigate the efficacy of quality improvement measures and education to improve the time to treatment of SE.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAnti-seizure medication (ASM), American Epilepsy Society (AES), benzodiazepine (BZD), confidence interval (CI), electroencephalogram (EEG), emergency medical services (EMS), interquartile range (IQR), \u003cem\u003eodds ratio (OR),\u0026nbsp;\u003c/em\u003ePediatric Status Epilepticus Research Group (pSERG), status epilepticus (SE).\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;research protocol was approved by the institutional review boards of all participating institutions, including Boston Children\u0026rsquo;s Hospital (IRB P-00001207), and written informed consent was obtained from all participants, parents, or guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. J. Nicholas Brenton receives research support from the NIH. \u0026nbsp;He has served as a consultant for Cycle Pharmaceuticals and the Institute for Advanced Clinical Trials (I-ACT) for Children on a Novartis-sponsored project. Dr. Mark Wainwright is a member of the Clinical Advisory Board for Sage Therapeutics.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDr. Tobias Loddenkemper receives research support from NIH, Epitel, and MIKU. He received past research support from Upsher Smith, Proximagen, and UCB. Dr. Tobias Loddenkemper is part of patent applications to detect and predict clinical outcomes, and to detect, manage, diagnose, and treat neurological conditions, epilepsy, and seizures. Some of Dr. Tobias Loddenkemper\u0026rsquo;s trainees received salary support from international foundations/societies and academic centers while working in his laboratory. Dr. Marina Ga\u0026iacute;nza-Lein was previously funded by the Epilepsy Research Fund.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study and consortium were funded in the past by the Epilepsy Foundation of America (EF-213583, Targeted Initiative for Health Outcomes) and by American Epilepsy Society/Epilepsy Foundation of America Infrastructure Awards and the Pediatric Epilepsy Research Foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMGL and TL conceptualized the design of the study. MGL made substantial contributions to this study in terms of data acquisition. JG, MGL, and TL contributed substantially to the analysis and interpretation of data and drafted the article. BZ made a substantial contribution to the analysis and interpretation of data. All authors critically and substantially revised the article. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Theodore Sheehan for his contribution to data entry.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet. 2006;368(9531):222\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChin RF, Neville BG, Scott RC. A systematic review of the epidemiology of status epilepticus. Eur J Neurol. 2004;11(12):800\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeligan A, Noyce AJ, Gosavi TD, Shorvon SD, K\u0026ouml;hler S, Walker MC. Change in Mortality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time: A Systematic Review and Meta-analysis. JAMA Neurol. 2019;76(8):897\u0026ndash;905.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartinos MM, Yoong M, Patil S, Chong WK, Mardari R, Chin RF, et al. Early developmental outcomes in children following convulsive status epilepticus: a longitudinal study. Epilepsia. 2013;54(6):1012\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol. 2006;5(9):769\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS\u0026aacute;nchez Fern\u0026aacute;ndez I, Amengual-Gual M, Barcia Aguilar C, Loddenkemper T. Estimating the cost of status epilepticus admissions in the United States of America using ICD-10 codes. Seizure. 2019;71:295\u0026ndash;303.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams CN, Piantino J, McEvoy C, Fino N, Eriksson CO. The burden of pediatric neurocritical care in the United States. Pediatr Neurol. 2018;89:31\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilkes R, Tasker RC. Pediatric intensive care treatment of uncontrolled status epilepticus. Crit Care Clin. 2013;29(2):239\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKravljanac R, Djuric M, Jankovic B, Pekmezovic T. Etiology, clinical course and response to the treatment of status epilepticus in children: A 16-year single-center experience based on 602 episodes of status epilepticus. Eur J Paediatr Neurol. 2015;19(5):584\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS\u0026aacute;nchez Fern\u0026aacute;ndez I, Abend NS, Agadi S, An S, Arya R, Carpenter JL, et al. Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure. 2014;23(2):87\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Currents. 2016;16(1):48\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol. 2002;59(2):205\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanchez Fernandez I, Abend NS, Agadi S, An S, Arya R, Brenton JN, et al. Time from convulsive status epilepticus onset to anticonvulsant administration in children. Neurology. 2015;84(23):2304\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEriksson K, Kalviainen R. Pharmacologic management of convulsive status epilepticus in childhood. Expert Rev Neurother. 2005;5(6):777\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGainza-Lein M, Sanchez Fernandez I, Jackson M, Abend NS, Arya R, Brenton JN, et al. Association of Time to Treatment With Short-term Outcomes for Pediatric Patients With Refractory Convulsive Status Epilepticus. JAMA Neurol. 2018;75(4):410\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGainza-Lein M, Benjamin R, Stredny C, McGurl M, Kapur K, Loddenkemper T. Rescue Medications in Epilepsy Patients: A Family Perspective. Seizure. 2017;52:188\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShinnar S, Maytal J, Krasnoff L, Moshe SL. Recurrent status epilepticus in children. Ann Neurol. 1992;31(6):598\u0026ndash;604.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSahin M, Menache CC, Holmes GL, Riviello JJ. Outcome of severe refractory status epilepticus in children. Epilepsia. 2001;42(11):1461\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGainza-Lein M, Fernandez IS, Ulate-Campos A, Loddenkemper T, Ostendorf AP. Timing in the treatment of status epilepticus: From basics to the clinic. Seizure. 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoodkin HP, Liu X, Holmes GL. Diazepam terminates brief but not prolonged seizures in young, naive rats. Epilepsia. 2003;44(8):1109\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res. 1998;814(1\u0026ndash;2):179\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS\u0026aacute;nchez Fern\u0026aacute;ndez I, Jackson MC, Abend NS, Arya R, Brenton JN, Carpenter JL, et al. Refractory status epilepticus in children with and without prior epilepsy or status epilepticus. Neurology. 2017;88(4):386\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeinfeld S, Shinnar S, Sun S, Hesdorffer DC, Deng X, Shinnar RC, et al. Emergency management of febrile status epilepticus: results of the FEBSTAT study. Epilepsia. 2014;55(3):388\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHillman J, Lehtimaki K, Peltola J, Liimatainen S. Clinical significance of treatment delay in status epilepticus. Int J Emerg Med. 2013;6(1):6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAranda A, Foucart G, Ducasse JL, Grolleau S, McGonigal A, Valton L. Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice. Epilepsia. 2010;51(10):2159\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamppi L, Mustonen H, Soinila S. Analysis of the delay components in the treatment of status epilepticus. Neurocrit Care. 2013;19(1):10\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlvarez V, Lee JW, Drislane FW, Westover MB, Novy J, Dworetzky BA, et al. Practice variability and efficacy of clonazepam, lorazepam, and midazolam in status epilepticus: A multicenter comparison. Epilepsia. 2015;56(8):1275\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStredny CM, Abend NS, Loddenkemper T. Towards acute pediatric status epilepticus intervention teams: Do we need Seizure Codes? Seizure. 2018;58:133\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstendorf AP, Merison K, Wheeler TA, Patel AD. Decreasing Seizure Treatment Time Through Quality Improvement Reduces Critical Care Utilization. Pediatr Neurol. 2018;85:58\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCassel-Choudhury G, Beal J, Longani N, Leone B, Rivera R, Katyal C. Protocol-Driven Management of Convulsive Status Epilepticus at a Tertiary Children's Hospital: A Quality Improvement Initiative. Pediatr Crit Care Med. 2019;20(1):47\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlank LJ, Crispo JAG, Thibault DP, Davis KA, Litt B, Willis AW. Readmission after seizure discharge in a nationally representative sample. Neurology. 2018;92(5):e429\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUlate-Campos A, Coughlin F, Gainza-Lein M, Fernandez IS, Pearl PL, Loddenkemper T. Automated seizure detection systems and their effectiveness for each type of seizure. Seizure. 2016;40:88\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHesdorffer DC, Logroscino G, Cascino GD, Hauser WA. Recurrence of afebrile status epilepticus in a population-based study in Rochester, Minnesota. Neurology. 2007;69(1):73\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsetsou S, Novy J, Rossetti AO. Recurrence of status epilepticus: prognostic role and outcome predictors. Epilepsia. 2015;56(3):473\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Status epilepticus, refractory status epilepticus, benzodiazepines, anti-seizure medications, treatment delay.","lastPublishedDoi":"10.21203/rs.3.rs-4160328/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4160328/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo compare pediatric patients who presented with repeated status epilepticus episodes to patients with a single episode of status epilepticus and identify distinguishing clinical factors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eRetrospective analysis of a multicenter, prospective observational cohort of pediatric patients with status epilepticus and refractory status epilepticus between 2011 and 2019.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOut of 504 status epilepticus episodes in 420 patients, 50 patients (10.3%) had repeated episodes of status epilepticus. The only predictor of repeated status epilepticus was a prior diagnosis of epilepsy. There was no difference in time to treatment with the first benzodiazepine in patients presenting with their first status epilepticus episode compared to their second status epilepticus episode [median 10 (interquartile range 5\u0026ndash;30) vs 14 (4.5\u0026ndash;52.5) minutes; (p\u0026thinsp;=\u0026thinsp;0.24)] or in time to treatment with the first non- benzodiazepine anti-seizure medication (ASM) [61 (37\u0026ndash;125) vs 71 (34.5-117.5) minutes; p\u0026thinsp;=\u0026thinsp;0.61]. In patients with repeated status epilepticus episodes with onset outside the hospital, the percentage of patients treated by caregivers did not improve between the first and second status epilepticus episode (61% vs 60%, p\u0026thinsp;=\u0026thinsp;0.56). However, the time to first benzodiazepine was shorter in patients treated by caregivers compared to those who were not [5 (0\u0026ndash;25) vs 55 (41\u0026ndash;120) minutes; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001].\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTime to treatment with benzodiazepine and non-benzodiazepine ASM in patients with repeated episodes of status epilepticus does not improve for a second episode of status epilepticus, suggesting additional opportunities for intervention and teaching.\u003c/p\u003e","manuscriptTitle":"Time to Treatment in Pediatric Patients with Repeated Episodes of Status Epilepticus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-01 16:37:45","doi":"10.21203/rs.3.rs-4160328/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-10T13:25:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-08T10:22:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"45568875792179641081867980494857319854","date":"2024-11-27T22:18:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-18T22:39:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"166624488429845382165008525545475632569","date":"2024-11-05T13:17:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-27T23:08:50+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-03-27T17:29:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-26T09:14:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-26T09:14:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2024-03-25T03:00:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68047c5c-f824-436e-a488-91db244c65df","owner":[],"postedDate":"April 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-02T16:00:37+00:00","versionOfRecord":{"articleIdentity":"rs-4160328","link":"https://doi.org/10.1186/s12883-025-04200-w","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2025-05-26 15:57:19","publishedOnDateReadable":"May 26th, 2025"},"versionCreatedAt":"2024-04-01 16:37:45","video":"","vorDoi":"10.1186/s12883-025-04200-w","vorDoiUrl":"https://doi.org/10.1186/s12883-025-04200-w","workflowStages":[]},"version":"v1","identity":"rs-4160328","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4160328","identity":"rs-4160328","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}