Outcomes of deviation from treatment guidelines in status epilepticus: A systematic review

  • Preena Uppal
    Correspondence
    Corresponding author at: Sydney Children's Hospital, High Street, Randwick, NSW, 2031, Australia.
    Affiliations
    Sydney Children's Hospital, Department of Pediatric Neurology, High Street, Randwick, NSW, 2031, Australia

    University of New South Wales – Randwick Campus, School of Women's and Children's Health, High Street, Randwick, NSW, 2052, Australia
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  • Michael Cardamone
    Affiliations
    Sydney Children's Hospital, Department of Pediatric Neurology, High Street, Randwick, NSW, 2031, Australia

    University of New South Wales – Randwick Campus, School of Women's and Children's Health, High Street, Randwick, NSW, 2052, Australia
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  • John A. Lawson
    Affiliations
    Sydney Children's Hospital, Department of Pediatric Neurology, High Street, Randwick, NSW, 2031, Australia

    University of New South Wales – Randwick Campus, School of Women's and Children's Health, High Street, Randwick, NSW, 2052, Australia
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Open ArchivePublished:April 16, 2018DOI:https://doi.org/10.1016/j.seizure.2018.04.005

      Highlights

      • There is a gap between guidelines on status epilepticus and its management.
      • The proportion of variations ranged from 10.7% to 66%.
      • The most common variation was excessive benzodiazepine use.
      • 5.79 times higher odds of respiratory depression with excessive benzodiazepine use.

      Abstract

      Objective

      Due to a gap between published clinical guidelines on status epilepticus SE and clinician management of SE, a systematic review was performed to investigate treatment adherence to SE guidelines and its impact on patient outcomes.

      Methods

      Medline and Embase searches were conducted for studies appraising adherence to SE guidelines (from 1970 and 1st April 2018). The quality of eligible studies was assessed by QUADAS- 2 criteria. Comparison was made between patients where guidelines were followed and not followed. Various patient outcomes including intubation, ICU admission, morbidity and mortality were compared. A Forest plot was used to investigate the effect of adherence on outcome.

      Results

      A total of 3424 titles and abstracts were screened from the initial search after removal of duplicates. A total of 441 full text articles were reviewed in detail, and 22 articles were included in this study. The proportion of deviations ranged from 10.7% to 66.1%. Four studies were descriptive. Eighteen studies looked at the adverse effects of non-adherence. Eight studies showed respiratory depression and intubation were associated with excessive benzodiazepine use. A subset analysis showed 5.79 times higher odds of respiratory depression and intubation], if excessive benzodiazepines were given. The next most common variations were delayed management and insufficient treatment. These variations from the guidelines were associated with prolonged seizures.

      Conclusions

      This review provides preliminary evidence that non-adherence to SE guidelines negatively impacts on patient outcomes. Appropriate and timely treatment is imperative for rapid seizure termination and improving outcomes.

      Keywords

      1. Introduction

      Status epilepticus (SE) is a common neurological emergency with significant morbidity and mortality [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ]. There is a gap between evidence based best management and actual clinical practice [
      • Lenfant C.
      Clinical research to clinical practice—lost in translation?.
      ].To decrease this gap, clinical practice guidelines(CPGs), based on available evidence are employed [
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ,
      • NICEGuidelines E.
      Epilepsies: diagnosis and management.
      ,
      • Wilkes R.
      • Tasker R.C.
      Pediatric intensive care treatment of uncontrolled status epilepticus.
      ]. It is unclear if the available guidelines for SE have any impact on patient outcomes.
      Guidelines are systematically developed algorithms to assist clinical decision-making [
      • Jackson R.
      • Feder G.
      Guidelines for clinical guidelines: a simple, pragmatic strategy for guideline development.
      ]. Guidelines for the management of SE have been available for many years, yet a number of retrospective studies have confirmed that clinicians often do not follow recommended guidelines on the management of patients with SE [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ]. Common deviations from guidelines include delay in administration of anticonvulsants and excessive benzodiazepine use [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ].
      The prognosis of SE is related to many factors e.g. age, aetiology, history of prior seizures and type of seizure at SE onset [
      • Sutter R.
      • Kaplan P.W.
      • Ruegg S.
      Outcome predictors for status epilepticus–what really counts.
      ]. Several studies have evaluated the effect of adherence to treatment guidelines [
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ] and these studies have given conflicting results. However, adherence to guidelines has not been subject to systematic review previously. There has recently been a review published looking at the state of epilepsy practice guidelines [
      • Sauro K.M.
      • Wiebe S.
      • Dunkley C.
      • Janszky J.
      • Kumlien E.
      • Moshe S.
      • et al.
      The current state of epilepsy guidelines: a systematic review.
      ], however, the implementation of guidelines continues to be uncertain [
      • Dunkley C.
      • Cross J.H.
      NICE guidelines and the epilepsies: how should practice change?.
      ].
      This study aims to conduct a systematic review investigating adherence to SE clinical practice guidelines and its impact on patient morbidity including respiratory depression and ICU admission.

      2. Methods

      2.1 Search strategy

      This systematic review was performed according to the PRISMA guidelines [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ] (Fig. 1). Medline and EMBASE databases were searched for articles published between 1 January 1970 and 1 April 2018, investigating the adherence to SE treatment guidelines.
      Fig. 1
      Fig. 1Flowchart outlining searches strategy for the systematic review (The formatted figure is attached separately as another file).

      2.2 Identification

      The following text and MeSH terms were used in our search: (seizures/or status epilepticus and (guideline adherence/or guideline/or clinical protocols or practice guideline) and (deviation from guidelines.mp or benzodiazepines/ad,ae,to or anticonvulsant/ad,ae,to) and (intubation or ICU admission or length of stay or morbidity or mortality or treatment outcome). See detailed search strategy, e-1. The language was limited to English. Only human studies were included.
      The review question was broken down to help guide the development of search terms using the PICO structure. Possible synonyms and abbreviations for the terms of interest and subject headings (including MeSH headers) were included.

      2.3 Inclusion criteria

      • 1)
        All patients: with SE, seizure duration > 5 min
      • 2)
        Adult and paediatric studies (age >28 days)

      2.4 Exclusion criteria

      • 1)
        Personal views and letters to editors
      • 2)
        Studies with incomplete data
      • 3)
        Conference abstracts
      The Medline and Embase searches identified 3773 articles (Fig. 1). Bibliographic references of the studies were also searched. Scopus was hand searched to find relevant and highly cited papers in this area. We hand searched the first authors of included papers to find articles that may not have been appropriately indexed but were relevant to the questions. A total of 67 additional records identified through these searches.
      The authors have not included unpublished abstracts and other grey literature as the data is often incomplete and non-peer reviewed.

      2.5 Screening

      A total of 3424 records were screened after removal of 416 duplicates (Fig. 1). We screened titles and abstracts and excluded all irrelevant publications. If the paper was deemed relevant by any of the authors or the relevance was not clear from the title and abstract, then the full text was retrieved.

      2.6 Eligibility

      A total of 441 full-text articles were reviewed and 419 articles excluded; of these 233 were comparisons between medications and/or compared various routes of administration; 83 were opinions, review articles and letters to the editor; 77 were guidelines or comments on guidelines; 14 articles had duplicate or incomplete data; 10 were expert commentaries and 2 were physician perspectives.

      2.7 Study quality

      For quality assessment, a template based on Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) [
      • Whiting P.F.
      • Rutjes A.W.
      • Westwood M.E.
      • Mallett S.
      • Deeks J.J.
      • Reitsma J.B.
      • et al.
      QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.
      ] was used.

      3. Results

      The search strategy identified 22 articles, which were included in the systematic review. Included studies were appraised for their risk of bias and applicability (Fig. 2a & b). The quality assessment was used for evaluative purposes. No studies were excluded based on quality assessment.
      Fig. 2
      Fig. 2a Proportion of studies with risk of bias (%) as assessed by QUADAS-2. b Proportion of studies with low, high or unclear concerns regarding applicability (%) as assessed by QUADAS-2.

      3.1 Studies included

      There were 22 studies included in the review (Fig. 1). Four articles described non-adherence to guidelines [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Martin-Gill C.
      • Hostler D.
      • Callaway C.W.
      • Prunty H.
      • Roth R.N.
      Management of prehospital seizure patients by paramedics.
      ,
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      ,
      • Kwong K.L.
      • Chang K.
      • Lam S.Y.
      Features predicting adverse outcomes of status epilepticus in childhood.
      ]. Eighteen studies also looked at the effect of non-adherence on various patient outcomes and morbidity including respiratory depression, intubation and ICU admission [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ,
      • Eriksson K.J.
      • Koivikko M.J.
      Status epilepticus in children: aetiology, treatment, and outcome.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Martin P.J.
      • Millac P.A.
      Status epilepticus: management and outcome of 107 episodes.
      ,
      • Orr R.A.
      • Dimand R.J.
      • Venkataraman S.T.
      • Karr V.A.
      • Kennedy K.J.
      Diazepam and intubation in emergency treatment of seizures in children.
      ,
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ]. This review did not investigate individual drug comparisons and nor did we look at impact of the route of administration.

      3.2 Characteristics of the target population and studies

      The definition of SE varied between studies. Eleven of the 22 included studies have used the classical definition of seizure duration >30 min (Table 1). Five out of the 22 studies have used the operational definition of SE to include >5 min of seizure activity [
      • Daniel Lowenstein H.
      • Bleck T.
      • Robert Macdonald L.
      It’s time to revise the definition of status epilepticus.
      ]. Two studies used >15 min [
      • Eriksson K.J.
      • Koivikko M.J.
      Status epilepticus in children: aetiology, treatment, and outcome.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ], two studies used failure of >2 antiepileptic drugs [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ,
      • Sanchez Fernandez I.
      • Jackson M.C.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • Carpenter J.L.
      • et al.
      Refractory status epilepticus in children with and without prior epilepsy or status epilepticus.
      ], one used the inclusion criteria of witnessed seizures and receiving at least one anticonvulsant [
      • Orr R.A.
      • Dimand R.J.
      • Venkataraman S.T.
      • Karr V.A.
      • Kennedy K.J.
      Diazepam and intubation in emergency treatment of seizures in children.
      ] and another used the chief complaint of seizure in emergency department as the inclusion criteria [
      • Martin-Gill C.
      • Hostler D.
      • Callaway C.W.
      • Prunty H.
      • Roth R.N.
      Management of prehospital seizure patients by paramedics.
      ]. Thirteen paediatric studies [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ,
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Kwong K.L.
      • Chang K.
      • Lam S.Y.
      Features predicting adverse outcomes of status epilepticus in childhood.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ,
      • Eriksson K.J.
      • Koivikko M.J.
      Status epilepticus in children: aetiology, treatment, and outcome.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Orr R.A.
      • Dimand R.J.
      • Venkataraman S.T.
      • Karr V.A.
      • Kennedy K.J.
      Diazepam and intubation in emergency treatment of seizures in children.
      ,
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ], eight adult studies [
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Martin-Gill C.
      • Hostler D.
      • Callaway C.W.
      • Prunty H.
      • Roth R.N.
      Management of prehospital seizure patients by paramedics.
      ,
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ,
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Martin P.J.
      • Millac P.A.
      Status epilepticus: management and outcome of 107 episodes.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ], and one study with both paediatric and adult populations [
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      ] were included (Table 1).
      Table 1Comparison of studies by patient characteristics, design and SE definition.
      Study (By year)YearPatients/numberDesignInclusion criteria/seizure durationSetting
      Paediatric Studies
      Gaínza-Lein, et al.
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      2018N = 218ProspectiveFailure of >2 AEDSHospital
      Fernandez, et al.
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      2015N = 81ProspectiveFailure of >2 AEDSHospital
      Shatirishvili, et al.
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      2014N = 48Prospective>30 minHospital
      Tirupathi, et al.
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      2009N = 47Retrospective>30 minTertiary Hospital/ICU
      Tobias, et al.
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      2008N = 100Prospective>30 minICU
      Chin, et al.
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      2008N = 182Prospective>30 minPopulation
      Eriksson, et al.
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      2005N = 184Retrospective>5 minED/Paed ICU
      Chin, et al.
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      2004N = 91Retrospective>30 minPaed ICU
      Kwong, et al.
      • Kwong K.L.
      • Chang K.
      • Lam S.Y.
      Features predicting adverse outcomes of status epilepticus in childhood.
      2004N = 25Retrospective>30 minPaed ICU
      Eriksson et al.
      • Eriksson K.J.
      • Koivikko M.J.
      Status epilepticus in children: aetiology, treatment, and outcome.
      1997N = 65Retrospective>15 minPaed ICU
      Alldredge, et al.
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      1995N = 38Retrospective>15 minHospital
      Chiulli, et al.
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      1994N = 146Retrospective>30 minED
      Orr, et al.
      • Orr R.A.
      • Dimand R.J.
      • Venkataraman S.T.
      • Karr V.A.
      • Kennedy K.J.
      Diazepam and intubation in emergency treatment of seizures in children.
      1991N = 98RetrospectiveWitnessed seizure+≥ 1 AEDHospital
      Adult Studies
      Rosetti, et al.
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      2013N = 263Prospective registry>5 minHospital
      Spatola, et al.
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      2013AdultsProspective registry>5 minHospital
      N = 202
      Aranda, et al.
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      2010N = 111Prospective>5 minPopulation
      Martin-Gill, et al.
      • Martin-Gill C.
      • Hostler D.
      • Callaway C.W.
      • Prunty H.
      • Roth R.N.
      Management of prehospital seizure patients by paramedics.
      2009N = 87RetrospectiveAcute seizurePrehospital & ED
      Rossetti, et al.
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      2009N = 54Prospective>5 minPeripheral/Central Hosp.
      Muayqil, et al.
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      2007N = 45Retrospective>30 minEmergency
      Martinet al.
      • Martin P.J.
      • Millac P.A.
      Status epilepticus: management and outcome of 107 episodes.
      1995N = 43Retrospective>30 minHospital
      Scholtes, et al.
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      1994N = 346Retrospective>30 minHospital, multicentre
      Adult and Paediatric
      Pellock, et al.
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      2004N = 889Prospective registry>30 minPopulation
      AED: Anti-Epileptic Drug; ED: Emergency Department; ICU: Intensive care Unit; Paed = Paediatric.
      The SE clinical practice guidelines followed by all the various studies used similar first and second line anticonvulsant recommendations. The first line agent was always a benzodiazepine (BZD) e.g. lorazepam or midazolam and the second line was a long acting anticonvulsant e.g. phenytoin. However, there were slight variations in the guidelines. In two studies, levetiracetam [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ] and in another two studies valproate [
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ,
      • Martin P.J.
      • Millac P.A.
      Status epilepticus: management and outcome of 107 episodes.
      ] was considered as appropriate second line treatments along with phenytoin. In four studies, intramuscular fosphenytoin was the second line agent [
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ].
      Seven studies were prospective [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ,
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ], twelve were retrospective [
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Martin-Gill C.
      • Hostler D.
      • Callaway C.W.
      • Prunty H.
      • Roth R.N.
      Management of prehospital seizure patients by paramedics.
      ,
      • Kwong K.L.
      • Chang K.
      • Lam S.Y.
      Features predicting adverse outcomes of status epilepticus in childhood.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ,
      • Eriksson K.J.
      • Koivikko M.J.
      Status epilepticus in children: aetiology, treatment, and outcome.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Martin P.J.
      • Millac P.A.
      Status epilepticus: management and outcome of 107 episodes.
      ,
      • Orr R.A.
      • Dimand R.J.
      • Venkataraman S.T.
      • Karr V.A.
      • Kennedy K.J.
      Diazepam and intubation in emergency treatment of seizures in children.
      ,
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ] and in three, data was extracted from a prospectively collected database [
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      ]. There were no case-control studies investigating adherence to guidelines. The studies where odds ratios were available [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ], were graphically represented (Table 2 & Fig. 3).
      Table 2Studies describing the deviation from protocol (%) and the effect of deviation on the patient outcomes (if measured).
      Study (By year)YearPatients description/number(% Deviations Noted)Adverse Outcome
      Descriptive data
      Pellock, et al.
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      2004Adults and Paed64.9% delayed treatment; >30 mins of seizure onset
      N = 889
      Non-adherence
      Rosetti, et al.
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      2013Age > 16 yrs.62% (139/225) delayed treatment >1 h of seizure onsetMortality
      N = 263
      Aranda, et al.
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      2010AdultsInadequate first line treatment: 62% (62/100); inadequate second line treatment 25.9% (14/54)Need for next line treatment
      N = 111
      Tirupathi, et al.
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      2009Paediatric53.2%; non compliance with protocolICU admission
      N = 47
      Tobias, et al.
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      2008Paediatric, N = 10022.5% Incorrect BZD doseIntubation
      Delayed management
      Gaínza-Lein, et al.
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      2018Paediatric66.1% delayed treatment
      N = 2018
      Fernandez, et al.
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      2015Paediatric39.7%; delayed treatmentLonger SE duration
      N = 81
      Muayqil, et al.
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      2007Adults66%; delayed treatmentLonger SE duration
      N = 45
      Eriksson, et al.
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      2005Paediatric16.6%; delayed treatmentLonger SE duration
      N = 184
      Excessive Benzodiazepines
      Shatirishvili, et al.
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      2014Paediatric44%; >one dose of benzodiazepineIntubation
      N = 48
      Spatola, et al.
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      2013Adult14.3% (29/202); >30% above the recommended doseIntubation
      202
      Tirupathi, et al.
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      2009Paediatric48.9% (23/47); >2 doses of benzodiazepinesICU admission
      N = 47
      Chin, et al.
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      2008Paediatric47.6%; >2 doses of benzodiazepinesRespiratory depression
      N = 182
      Chin, et al.
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      2004Paediatric58.2%; >2 doses of benzodiazepinesRespiratory insufficiency
      N = 91
      Insufficient treatment
      Aranda, et al.
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      2010Adults62%; inadequate first line treatmentProlonged seizure
      N = 111
      Scholtes, et al.
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      1994>15 years10.7%; insufficient treatmentMorbidity
      N = 3468%; inadequate dosage of AEDs
      Hospital Setting
      Rossetti, et al.
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      2009Adults > 16Up to 22% were deviating from guidelines in peripheral centres; vs. 3% in large academic centre.Outcome and neurological sequelae
      N = 54
      ICU: Intensive care Unit; Paed = Paediatric.
      Fig. 3
      Fig. 3Forest plot – the odds ratios (95%CI), of adverse outcomes due to non-adherence to treatment guidelines. With non-adherence, these results suggest there are higher odds of adverse outcome for most deviations from guidelines. For excessive benzodiazepines in particular, the pooled OR shows much higher odds for adverse outcomes (OR = 5.79).

      3.3 Adherence to SE guidelines

      Rates of adherence were reported in all the 22 included studies. The proportion of deviations ranged from 10.7% [
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ] to 66.1% [
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ]. In a recent multicentre, prospective study of 218 patients in the United States 66.1% patients received the first line benzodiazepines 10 min or more after the seizure onset [
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ]. In a prospective study of 111 adults [
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ] from France the odds of seizure termination with first-line treatment was 11 times greater if the protocol was adhered to (Fig. 3) [
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ]. Similarly, a retrospective study of 47 children in Ireland [
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ] reported a non-adherence rate of 53.2% and the odds of ICU admission were 3.1 times higher if there was non-adherence to the protocol (Fig. 3). A Swiss study of 263 adults reported that adherence to treatment guidelines had no effect on morbidity, mortality or likelihood of seizure control [
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ].
      Excessive benzodiazepine use [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ] was the most commonly reported reason for non-adherence, followed by delayed management [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ], insufficient treatment [
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ], prehospital treatment [
      • Cabana M.D.
      • Rand C.S.
      • Powe N.R.
      • Wu A.W.
      • Wilson M.H.
      • Abboud P.-A.C.
      • et al.
      Why don't physicians follow clinical practice guidelines?: A framework for improvement.
      ] and location of treatment i.e. large academic vs. peripheral hospital [
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ].
      The data from studies was summarized in the form of a forest box-plot (see Fig. 3) where odds ratios could be calculated. These results suggest there are higher odds of adverse outcome for most deviations from guidelines. Worse outcomes were seen in both paediatric [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ] and adult studies [
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ].

      3.4 Effect of excessive benzodiazepines (BZDs)

      Benzodiazepines are a widely recognized first-line treatment for SE, but may also be associated with respiratory depression [
      • Novorol C.L.
      • Chin R.F.
      • Scott R.C.
      Outcome of convulsive status epilepticus: a review.
      ]. Of the 22 studies, eight [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ,
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ] reported excessive BZD use. For excessive benzodiazepines, the pooled OR (Fig. 3) shows much higher odds (OR = 5.79) for adverse outcomes including respiratory depression, intubation and ICU admission [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ]. A recent prospective observational study at nine tertiary paediatric hospitals in the USA [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ], showed 39.7% (31/78) received at least three doses of benzodiazepines prior to escalation to non-benzodiazepine medications. An American study done prospectively in paediatric ICU patients, found respiratory compromise was more common in patients who received a BZD dose greater than recommended guidelines [
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ]. A paediatric emergency department study in New York looked at type of benzodiazepine and intubation rates. This study reported that diazepam use resulted in a higher number of intubations as compared to lorazepam [
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ]. The New York study demonstrated 12 out of 26 patients required endotracheal intubation that the authors considered was related to excessive BZD administration [
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ].
      A prospective study investigated BZD over dosage in SE and its relationship with the need for intubation and length of hospitalization [
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ]. It compared 173 adult patients who received standard BZD doses to those receiving excessive doses (>30% above recommended dose, n = 29) and quantitated the morbidity and mortality. The study found a statistically significant increase in the intubation rate with 45% (13/29) of the “excessive” BZD patients intubated for airway protection, versus only 8% (13/173) where the BZD dose was appropriate (p < .001) (Box plot1). A Georgian paediatric study found that 13/17 patients who received excessive BZDs required to be intubated [
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ]. None of the 31 patients who received appropriate BZD required intubation (p < .049) [
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ].
      A paediatric study of 47 children, found three times higher odds of excessive benzodiazepines in the children with convulsive SE admitted to intensive care, when compared to the ward group [
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ]. Two other studies found higher odds of respiratory depression [
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ] and respiratory insufficiency [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ] when excessive BZDs were given. For excessive benzodiazepine use, the pooled OR shows much higher odds (OR = 5.79) for adverse outcomes including respiratory depression, intubation and ICU admission.

      3.5 Delay in initiation of treatment of SE

      Five out of 22 studies examined if there was a delay in initiation of treatment. These include delay in pre-hospital treatment, delay in arrival to emergency department, or delay in administration of first and second line antiepileptic agent. In a recent multicentre, prospective study 66.1% patients received the first line benzodiazepines 10 min or more after the seizure onset [
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ]. The multivariate analysis showed these patients higher odds of death after adjusting for confounders (adjusted odds ratio, 11.0), In another study, treatment was initiated after an hour following the onset of SE in 62/225 patients [
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ]. A delay in presentation to the emergency department was associated with a longer duration of seizure. For a delay in treatment of every minute from onset of SE, there was a 5% increase in the risk of the episode being longer lasting, in excess of 60 min [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ]. A recent In a retrospective study of 45 adults, delayed management was associated with significantly longer seizure duration (median: 95 versus 38 min); compared to where management was instituted in the recommended timeframes (p ≤ 0.02) [
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ].

      3.6 Effect of pre-hospital treatment

      Two studies showed that the initiation of SE therapy frequently started pre-hospital [
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ]. One study described up to 64% of the patients received pre-hospital treatment [
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ]. Pre-hospital therapy of SE with diazepam decreased the duration of SE [
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ]. It also reduced the risk of recurrent seizures in the hospital [
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ].

      3.7 Effect of insufficient treatment

      Only one study looked at insufficient treatment [
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ]. The criteria for insufficient treatment included the doses administered were too low, wrong route of administration was used, or a delay to move on to the next line of treatment. Of the 346 patients (≥15years) of SE looked at retrospectively “insufficient” treatment was found in 22.5% in patients who had negative sequelae. In patients with good outcome, insufficient treatment was seen in only 8% [
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ]. Treatment was deemed to be insufficient in the 17 of the 38 patients (44%) who died [
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ].

      3.8 Effect of hospital setting

      There was a single study looking at hospital setting and adherence to guidelines [
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ]. It was a prospective study comparing management and prognosis of SE according to the academic tertiary versus peripheral hospital setting, done in Switzerland [
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ]. The treatment in 22% of patients in peripheral hospitals was not in accordance the guidelines as compared to 3% in Centre Hospital, p = .04 [
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ]. There was no significant difference in the patient outcomes [
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ].

      4. Discussion

      This systematic review is the first to investigate the effect of clinician adherence to SE clinical practice guidelines and its impact on patients. Although there are clinical practice guidelines for SE, it is clear from this systematic review that SE clinical practice guidelines are not being followed. All of the studies in this systematic review confirmed the management of status epilepticus varied from the clinical practice guidelines. Non-adherence to SE management guidelines were associated with an increased chance of worse outcome including ICU admission [
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ] and mortality [
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ].
      Adherence to the treatment guidelines is associated with faster seizure termination and better seizure control [
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ]. The systematic review found that most studies violated the guidelines and the main protocol deviations were excessive benzodiazepine use and delay to treatment [
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ]. An excessive use of benzodiazepines is related to higher odds of respiratory depression and intubation. (Fig. 3).
      Appropriate and timely treatment is imperative for early seizure termination [
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ]. Comparisons between medications and/or various routes of administration were not examined in this systematic review. For example important randomized controlled trials such as RAMPART [
      • Alldredge B.K.
      • Gelb A.M.
      • Isaacs S.M.
      • Corry M.D.
      • Allen F.
      • Ulrich S.
      • et al.
      A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
      ] which looked at route of administration of benzodiazepines could not be included in the review. RAMPART [
      • Alldredge B.K.
      • Gelb A.M.
      • Isaacs S.M.
      • Corry M.D.
      • Allen F.
      • Ulrich S.
      • et al.
      A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
      ] found that IM midazolam is no different to IV lorazepam for the management of SE. Intramuscular administration can be given more rapidly than IV administration but this was not felt to be an important contributor to guideline violations and was not examined. This systematic review included both adult and paediatric age groups. Our study shows that there was deviation from guidelines seen in both paediatric studies [
      • Chin R.F.
      • Neville B.G.
      • Peckham C.
      • Wade A.
      • Bedford H.
      • Scott R.C.
      Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Tobias J.D.
      • Berkenbosch J.W.
      Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines.
      ,
      • Sanchez Fernandez I.
      • Abend N.S.
      • Agadi S.
      • An S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Time from convulsive status epilepticus onset to anticonvulsant administration in children.
      ,
      • Shatirishvili T.
      • Tatishvili N.
      • Lomidze G.
      • Kipiani T.
      Effect of treatment of convulsive status epilepticus on outcome in children.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Kwong K.L.
      • Chang K.
      • Lam S.Y.
      Features predicting adverse outcomes of status epilepticus in childhood.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ,
      • Eriksson K.J.
      • Koivikko M.J.
      Status epilepticus in children: aetiology, treatment, and outcome.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Orr R.A.
      • Dimand R.J.
      • Venkataraman S.T.
      • Karr V.A.
      • Kennedy K.J.
      Diazepam and intubation in emergency treatment of seizures in children.
      ,
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ,
      • Gainza-Lein M.
      • Sanchez Fernandez I.
      • Jackson M.
      • Abend N.S.
      • Arya R.
      • Brenton J.N.
      • et al.
      Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus.
      ], adult studies [
      • Spatola M.
      • Alvarez V.
      • Rossetti A.O.
      Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.
      ,
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Rossetti A.O.
      • Alvarez V.
      • Januel J.-M.
      • Burnand B.
      Treatment deviating from guidelines does not influence status epilepticus prognosis.
      ,
      • Martin-Gill C.
      • Hostler D.
      • Callaway C.W.
      • Prunty H.
      • Roth R.N.
      Management of prehospital seizure patients by paramedics.
      ,
      • Rossetti A.O.
      • Novy J.
      • Ruffieux C.
      • Olivier P.
      • Foletti G.B.
      • Hayoz D.
      • et al.
      Management and prognosis of status epilepticus according to hospital setting: a prospective study.
      ,
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Martin P.J.
      • Millac P.A.
      Status epilepticus: management and outcome of 107 episodes.
      ,
      • Aranda A.
      • Foucart G.
      • Ducassé J.L.
      • Grolleau S.
      • McGonigal A.
      • Valton L.
      Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice.
      ], and a study with both paediatric and adult populations [
      • Pellock J.M.
      • Marmarou A.
      • DeLorenzo R.
      Time to treatment in prolonged seizure episodes.
      ]. The included studies were mostly emergency department and ICU based studies and did not look at if the diagnosis or initiation of treatment was made in consultation with a specialist neurologist. The guidelines are designed to enable early initiation of treatment and seeking speciality consultation may delay this.
      This systematic review is not without limitations. This systematic review did not include unpublished data, abstracts from conferences and clinician personal communications. Low-level evidence studies have not been included in this review.
      Twelve of the 22 included studies are retrospective studies [
      • Muayqil T.
      • Rowe B.H.
      • Ahmed S.N.
      Treatment adherence and outcomes in the management of convulsive status epilepticus in the emergency room.
      ,
      • Chin R.F.M.
      • Verhulst L.
      • Neville B.G.R.
      • Peters M.J.
      • Scott R.C.
      Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.
      ,
      • Tirupathi S.
      • McMenamin J.B.
      • Webb D.W.
      Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children.
      ,
      • Martin-Gill C.
      • Hostler D.
      • Callaway C.W.
      • Prunty H.
      • Roth R.N.
      Management of prehospital seizure patients by paramedics.
      ,
      • Kwong K.L.
      • Chang K.
      • Lam S.Y.
      Features predicting adverse outcomes of status epilepticus in childhood.
      ,
      • Eriksson K.
      • Metsaranta P.
      • Huhtala H.
      • Auvinen A.
      • Kuusela A.L.
      • Koivikko M.
      Treatment delay and the risk of prolonged status epilepticus.
      ,
      • Eriksson K.J.
      • Koivikko M.J.
      Status epilepticus in children: aetiology, treatment, and outcome.
      ,
      • Alldredge B.K.
      • Wall D.B.
      • Ferriero D.M.
      Effect of prehospital treatment on the outcome of status epilepticus in children.
      ,
      • Scholtes F.B.
      • Renier W.O.
      • Meinardi H.
      Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients.
      ,
      • Martin P.J.
      • Millac P.A.
      Status epilepticus: management and outcome of 107 episodes.
      ,
      • Orr R.A.
      • Dimand R.J.
      • Venkataraman S.T.
      • Karr V.A.
      • Kennedy K.J.
      Diazepam and intubation in emergency treatment of seizures in children.
      ,
      • Chiulli D.A.
      • Terndrup T.E.
      • Kanter R.K.
      The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus.
      ]. Various studies have chosen different inclusion criteria for status epilepticus (Table 1) and different outcome measures (Table 2). We were unable to conduct a meta-analysis due to the heterogeneity of the included studies.
      The need to understand why clinicians do not follow SE clinical practice guidelines is paramount. One of the outstanding characteristics of our current health care systems is the gap between what should be done and what is delivered [
      • Wilson R.
      • Harrison B.
      What is clinical practice improvement?.
      ]. It is commonly known that guidelines are not translated into clinical practice [
      • Cabana M.D.
      • Rand C.S.
      • Powe N.R.
      • Wu A.W.
      • Wilson M.H.
      • Abboud P.-A.C.
      • et al.
      Why don't physicians follow clinical practice guidelines?: A framework for improvement.
      ]. The barriers in one setting may be different from another [
      • Cabana M.D.
      • Rand C.S.
      • Powe N.R.
      • Wu A.W.
      • Wilson M.H.
      • Abboud P.-A.C.
      • et al.
      Why don't physicians follow clinical practice guidelines?: A framework for improvement.
      ]. This review would form the basis for quality improvement in the management of status epilepticus, to understand and improve the factors responsible for non-adherence to guidelines.

      5. Conclusions

      Implementation of SE guidelines may improve management. To provide maximum benefit to the patients, it is imperative that appropriate care is instituted for patients presenting with a seizure. This review highlights that deviations from guidelines exist and have been studied to some extent. The adverse effect of non-compliance and its impact on patient care has not been vigorously and systematically studied. This review provides evidence that non-adherence to SE guidelines leads to adverse outcomes. Most of the studies consistently showed adverse outcomes were related to the use of excess benzodiazepines.

      Conflicts of interest

      None.

      Disclosure

      The authors report no disclosures relevant to the manuscript.

      Author contributions

      Preena Uppal contributed to the study design, literature review, data analysis, data interpretation, and writing. Michael Cardamone contributed to the study design, literature review, data interpretation, and writing. John Lawson, contributed to the study design, data interpretation, and writing.

      Study funding

      No funding was received for this study.

      Acknowledgments

      The authors thank Dr. Nancy Briggs, Senior Statistical Consultant, UNSW for statistical analysis.
      The authors thank Dr. Tejaswi Kandula, Paediatric neurologist for suggestions and proofreading.
      The authors thank Robyn Howard for proofreading.
      The authors thank Toni Le Roux & Cheng Siu from the UNSW Library for assistance with the search strategy.

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