Optimizing pediatric status epilepticus management: The role of early midazolam infusion and adherence to clinical practice guidelines

Anna Rosati^{1

2}, Patrizia Bartolotta³, Carla Marini⁴, Maria Cristina Mondardini⁵, Duccio Maria Cordelli^{6

7}, Anna Fetta^{6

7}, Luca Bergonzini^{6

7}, Manuela L'Erario⁸, Giulia Cannizzaro², Emmanuele Mongelli⁸, Clarissa Tona⁹, Stefano Sartori⁹, Claudia Maria Bonardi¹⁰, Fabrizio Chiusolo¹¹, Federico Vigevano¹², Nicola Specchio^{13

14}, Francesca Darra¹⁵, Jacopo Proietti¹⁵, Paolo Biban¹⁶, Elisabetta Cesaroni⁴, Alessandro Simonini¹⁷, Francesca Izzo¹⁸, Massimo Mastrangelo^{19

20}, Sara Olivotto¹⁹, Silvia Maria Pulitanò²¹, Domenica Immacolata Battaglia^{22

23}, Silvia Buratti²⁴, Emanuele Giacheri²⁵, Caterina Zanus²⁶, Paola Costa²⁶, Roberta Vittorini²⁷, Alessandra Conio²⁸, Angela Amigoni¹⁰, Lucia Fusco¹³; Italian Pediatric Status Epilepticus Group

Affiliations

¹ Child Neuropsychiatry Unit, Santa Chiara Hospital, Trento Health Service (Azienda Provinciale Servizi Sanitari), Trento, Italy.
² Neuroscience and Human Genetics Department, Meyer Children's Hospital, IRCCS, Florence, Italy.
³ Department of Clinical and Evaluative Epidemiology, Trento Health Service (Azienda Provinciale Servizi Sanitari), Trento, Italy.
⁴ Child Neurology and Psychiatric Unit, G. Salesi Pediatric Hospital, Azienda Ospedaliera-Universitaria Delle Marche, Ancona, Italy.
⁵ Pediatric Anesthesia and Intensive Care Unit, IRCCS, Azienda Ospedaliera-Universitaria di Bologna, Bologna, Italy.
⁶ IRCCS Istituto Delle Scienze Neurologiche di Bologna, Neuropsichiatria Dell'età Pediatrica, Bologna, Italy.
⁷ Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
⁸ Pediatric Intensive Care Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
⁹ Pediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.
¹⁰ Pediatric Intensive Care Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.
¹¹ Anesthesia and Critical Care Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹² Pediatric Neurorehabilitation Department, full member of European Reference Network EpiCARE, IRCCS San Raffaele, Rome, Italy.
¹³ Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children's Hospital, Full member of European Reference Network EpiCARE, IRCCS, Rome, Italy.
¹⁴ University Hospitals, Leuven, Belgium.
¹⁵ Child Neuropsychiatric Unit, Department of Engineering for Innovation Medicine, University of Verona, full member of European Reference Network EpiCARE, Verona, Italy.
¹⁶ Department of Neonatal and Pediatric Intensive Care, University of Verona, Verona, Italy.
¹⁷ Pediatric Anesthesia and Intensive Care Unit, G. Salesi Pediatric Hospital, Azienda Ospedaliera-Universitaria Delle Marche, Ancona, Italy.
¹⁸ Anesthesia and Critical Care Medicine, Buzzi Children's Hospital, via Ludovico Castelvetro, Milan, Italy.
¹⁹ Child Neurology Unit, Buzzi Children's Hospital, Milan, Italy.
²⁰ Department of Cardiothoracic and Vascular Anesthesia and Intensive Care Unit, IRCCS, Policlinico San Donato, Milan, Italy.
²¹ Pediatric Intensive Care Unit, Pediatric Trauma Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.
²² Child Neurology and Psychiatric Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.
²³ Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
²⁴ Neonatal and Pediatric Intensive Care Unit, Emergency Department, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²⁵ Intermediate Care Unit, Emergency Department, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²⁶ Institute for Maternal and Child Health, IRCCS, Trieste, Italy.
²⁷ Department of Pediatrics, Regina Margherita Children's Hospital, Turin, Italy.
²⁸ Pediatric Intensive Care Unit, Anesthesia, Resuscitation, and Emergency Department, University of Turin, Turin, Italy.

PMID: 40377450
DOI: 10.1111/epi.18455

Optimizing pediatric status epilepticus management: The role of early midazolam infusion and adherence to clinical practice guidelines

Anna Rosati et al. Epilepsia. 2025.

. 2025 May 16.

doi: 10.1111/epi.18455. Online ahead of print.

Authors

Affiliations

¹ Child Neuropsychiatry Unit, Santa Chiara Hospital, Trento Health Service (Azienda Provinciale Servizi Sanitari), Trento, Italy.
² Neuroscience and Human Genetics Department, Meyer Children's Hospital, IRCCS, Florence, Italy.
³ Department of Clinical and Evaluative Epidemiology, Trento Health Service (Azienda Provinciale Servizi Sanitari), Trento, Italy.
⁴ Child Neurology and Psychiatric Unit, G. Salesi Pediatric Hospital, Azienda Ospedaliera-Universitaria Delle Marche, Ancona, Italy.
⁵ Pediatric Anesthesia and Intensive Care Unit, IRCCS, Azienda Ospedaliera-Universitaria di Bologna, Bologna, Italy.
⁶ IRCCS Istituto Delle Scienze Neurologiche di Bologna, Neuropsichiatria Dell'età Pediatrica, Bologna, Italy.
⁷ Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
⁸ Pediatric Intensive Care Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
⁹ Pediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.
¹⁰ Pediatric Intensive Care Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.
¹¹ Anesthesia and Critical Care Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹² Pediatric Neurorehabilitation Department, full member of European Reference Network EpiCARE, IRCCS San Raffaele, Rome, Italy.
¹³ Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children's Hospital, Full member of European Reference Network EpiCARE, IRCCS, Rome, Italy.
¹⁴ University Hospitals, Leuven, Belgium.
¹⁵ Child Neuropsychiatric Unit, Department of Engineering for Innovation Medicine, University of Verona, full member of European Reference Network EpiCARE, Verona, Italy.
¹⁶ Department of Neonatal and Pediatric Intensive Care, University of Verona, Verona, Italy.
¹⁷ Pediatric Anesthesia and Intensive Care Unit, G. Salesi Pediatric Hospital, Azienda Ospedaliera-Universitaria Delle Marche, Ancona, Italy.
¹⁸ Anesthesia and Critical Care Medicine, Buzzi Children's Hospital, via Ludovico Castelvetro, Milan, Italy.
¹⁹ Child Neurology Unit, Buzzi Children's Hospital, Milan, Italy.
²⁰ Department of Cardiothoracic and Vascular Anesthesia and Intensive Care Unit, IRCCS, Policlinico San Donato, Milan, Italy.
²¹ Pediatric Intensive Care Unit, Pediatric Trauma Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.
²² Child Neurology and Psychiatric Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.
²³ Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
²⁴ Neonatal and Pediatric Intensive Care Unit, Emergency Department, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²⁵ Intermediate Care Unit, Emergency Department, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²⁶ Institute for Maternal and Child Health, IRCCS, Trieste, Italy.
²⁷ Department of Pediatrics, Regina Margherita Children's Hospital, Turin, Italy.
²⁸ Pediatric Intensive Care Unit, Anesthesia, Resuscitation, and Emergency Department, University of Turin, Turin, Italy.

PMID: 40377450
DOI: 10.1111/epi.18455

Abstract

Objective: This study was undertaken to describe a cohort of pediatric patients with status epilepticus (SE) in Italy over the past decade, focusing on the variability of treatment protocols among centers, adherence to guidelines, and potential predictors of refractoriness.

Methods: This is a multicenter retrospective observational cohort study including patients aged 1 month to 18 years who experienced convulsive SE (CSE) between January 2010 and June 2022. Variables analyzed included age at CSE onset, etiology, and treatment.

Results: We included 1374 CSE episodes in 1071 patients (median age = 3.3 years); 46% occurred in the first 3 years of life. The prominent etiology was remote symptomatic (32%). Resolution was obtained only with benzodiazepine administration in 19.2% of SE episodes. Phenytoin, phenobarbital, and midazolam by infusion were the drugs most frequently used. Maximum therapeutic response occurred with low-dose (<.2 mg/kg/h) midazolam infusion administered at an early stage, following a single dose of benzodiazepine or an antiseizure medication (ASM; 59%). Midazolam effectiveness decreased to 37% when it was used after multiple ASMs, even at high doses. CSE was refractory in 39% of cases. Predictors of refractoriness included nonadherence to current guidelines, type of CSE, and etiology.

Significance: This study emphasizes that low-dose midazolam infusion, not requiring endotracheal intubation and administered at an early phase, appears to be effective in permanently stopping seizure and preventing the evolution toward a refractory CSE. Given its proven efficacy and widespread use in many hospitals, early midazolam infusion could be considered in the management of pediatric CSE. Adherence to treatment protocols, specific etiologies, and type of CSE are correlated with refractoriness; thus, when facing SE in infants, these factors should guide treatment protocol selection, including medication choice and timing.

Keywords: guideline adherence; midazolam infusion; pediatric status epilepticus; refractory status epilepticus; status epilepticus etiology.

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References

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Optimizing pediatric status epilepticus management: The role of early midazolam infusion and adherence to clinical practice guidelines

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Optimizing pediatric status epilepticus management: The role of early midazolam infusion and adherence to clinical practice guidelines

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