Expert Opinion on Pharmacotherapy

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Pharmacologic treatment of status epilepticus Eugen Trinka, Julia Höfler, Markus Leitinger, Alexandra Rohracher, Gudrun Kalss & Francesco Brigo To cite this article: Eugen Trinka, Julia Höfler, Markus Leitinger, Alexandra Rohracher, Gudrun Kalss & Francesco Brigo (2016) Pharmacologic treatment of status epilepticus, Expert Opinion on Pharmacotherapy, 17:4, 513-534, DOI: 10.1517/14656566.2016.1127354 To link to this article:

Accepted author version posted online: 02 Dec 2015. Published online: 09 Feb 2016. Submit your article to this journal

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Date: 26 November 2017, At: 10:14



Pharmacologic treatment of status epilepticus Eugen Trinkaa,b, Julia Höflera, Markus Leitingera, Alexandra Rohrachera, Gudrun Kalssa and Francesco Brigoc a

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Department of Neurology, Christian Doppler Medical Centre, Paracelsus Medical University Salzburg, and Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria; bInstitute of Public Health, Medical Decision Making and HTA, University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria; cDepartment of Neurological, Biomedical, and Movement Sciences, University of Verona, Verona, Italy ABSTRACT


Introduction: Status epilepticus (SE) requires rapid identification of its cause and urgent pharmacological treatment. Despite an estimated incidence of up to 61 per 100,000 per year, evidence from high-class clinical trials is only available for the early stages of SE. Areas covered: Following a four-stage approach of SE (early, established, refractory and superrefractory), we present pharmacological treatment options and their clinical utility. Expert opinion: Intravenous lorazepam and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal midazolam has emerged as first-line non-intravenous drug with similar efficacy and safety to other intravenous or rectal benzodiazepines. In established SE intravenous antiepileptic drugs are in use. There are no double-blind, but six randomized open studies with valproate and two with levetiracetam. A meta-analysis found higher rates of seizure cessation with valproate 75.7% (95% CI 63.7–84.8) and phenobarbital 73.6%, (95% CI 58.3–84.8) than with levetiracetam (68.5%, 95% CI 56.2–78.7) or phenytoin (50.2%, 95% CI 34.2–66.1). Based on the favourable tolerability profile of levetiracetam and valproate, the authors prefer these drugs in established SE over phenytoin. Treatment options in refractory SE are intravenous anaesthetics. In super-refractory SE ketamine, magnesium, steroids and other drugs have been used with variable outcomes. At this stage therapeutic decisions are based on doctors’ preferences, patient factors such as age and comorbidity, and cause of SE, if identified.

Received 11 September 2015 Accepted 30 November 2015 Published online 5 February 2016

1. Introduction Seizures are one of the most common neurological emergencies. They are always a consequence of pathophysiological processes of the brain, either as a permanent or transient disturbance of brain function or on the basis of a structural pathology. The International League against Epilepsy (ILAE) defined a seizure as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Seizures are usually brief and by definition self-limited. Generalized tonic clonic seizures usually last less than 3 minutes [1–4] and focal complex seizures less than 10 minutes.[1] In the clinical context, there are three important steps: first, one has to identify the nature of the event (epileptic vs nonepileptic). Second, if epileptic, the type of seizure and its topography have to be identified (left or right, frontal, temporal, parietal, or occipital), and third, the actual cause has to be identified as early as possible and treated appropriately (e.g. acute ischemic stroke). Furthermore, it has to be decided whether symptomatic emergency treatment of the seizure is needed. As seizures are self-limited, CONTACT Eugen Trinka © 2016 Taylor & Francis

[email protected]


Status epilepticus; antiepileptic drugs; benzodiazepines; anaesthetics; outcome

there is no need for urgent treatment. However, once seizures exceed a certain duration, they are called status epilepticus (SE) and need to be managed as such. A new ILAE definition of SE gives a good guidance, when emergency treatment must be considered: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures..[5]

In general, time point t1 is the time when treatment should be started, which is at 5 minutes for generalized tonic clonic seizures and at 10 minutes for focal seizures with or without impairment of consciousness. Time point t2 marks the time at which neuronal damage or self-perpetuating alteration of neuronal networks may begin and indicates that SE should be controlled latest by that time. The pharmacological management of repetitive seizures and SE still represents an area with



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Early treatment of status epilepticus (SE) is effectively controlled in with intravenous lorazepam or intramuscular midazolam in 64 to 73%. Intravenous clobazam might be a useful alternative, but high-class randomized trials are missing. In children, buccal midazolam can be used as an alternative whenever intravenous or intramuscular application of other benzodiazepines is not possible. After failure of benzodiazepines in the early stage, phenytoin (or fosphenytoin), valproate, levetiracetam, phenobarbital, and lacosamide are in use. Currently, there is no high-class evidence available to prefer one to the other; valproate and levetiracetam have a favorable safety profile compared to phenobarbital and phenytoin; lacosamide is now increasingly used, but available evidence is still very little and restricted to a few retrospective series, which do not allow to give stronger recommendations for its use. In refractory SE propofol, continuous midazolam infusion, thiopental/pentobarbital is in use. There is no randomized trial available, but retrospective series suggest a higher morbidity with thiopental/pentobarbital, compared to midazolam or propofol. In super-refractory SE, ketamine, magnesium, and immunomodulatory treatments should be considered early. The identification of a cause and its appropriate treatment is of utmost importance at this stage.

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limited robust evidence derived from high-quality, adequately powered randomized controlled trials (RCTs) to inform clinical practice. Most evidence in this topic regards the treatment of early SE, which has been the subject of several RCTs and critical assessment in systematic reviews with meta-analyses [6–13] and included in treatment protocols or practical guidelines.[14–17] All treatment protocols recognize a staged approach to treatment with different drugs used in early (stage I), established (stage II), refractory (stage III), and superrefractory SE (stage IV) (Figures 1 and 2). All treatment protocols emphasize prompt recognition and treatment of persisting seizure activity at each stage to prevent death or irreversible brain damage and reduce morbidity and mortality. The aim of this narrative review is to give an overview on the pharmacological emergency treatment with practical treatment recommendations. As a general remark, these recommendations refer to general convulsive SE (GCSE). Evidence for nonconvulsive SE (NCSE) is even more limited and treatment protocols for NCSE just represent inferences from GCSE so far. Importantly, aggressive treatment with

Lorazepam 0.07 to 0.1 mg/kg (usually 4 to 8 mg) IV bolus (maximum rate 2 mg/min); if necessary can be repeated once.

Diazepam 5–10 mg IV bolus (maximum rate 5 mg/ min); if necessary can be repeated once up to 20 mg.

Clonazepam 1 mg IV bolus (maximum rate 0.5 mg/min); if necessary can be repeated once after 5 min.

Phenobarbital 10 mg/kg (range 10–20) IV bolus infusion at a max. rate of 100 mg/min

Phenytoin 18 mg/kg (range 15–20) IV loadingdose at max. rate of 50 mg/min. Fosphenytoin15 mg PE/kg (range 15–20) IV bolus infusion at max. rate of 100 mg PE/min

Valproate 30 mg/kg (range 15–30) IV rapid loading dose at 3–6 mg/kg/min.

Levetiracetam3 0 mg/kg (range 30–60) IV rapid loading dose over 10 min.

Lacosamide 200–400 mg IV rapid loading doseover 3–5 min.

Propofol 2 mg/kg IV loading dose, repeated if necessary, and then followed by a continuous infusion of 5–10 mg/kg/h initially, reducing to a dose sufficient to maintain a burst-suppression pattern (usually 1–3mg/kg/h).

Midazolam 0.1–0.3 mg/kg IV loadingdoseat max. rate of 4 mg/min, followed by a continuous IV infusion at a dose sufficient to suppress ictal discharges (usually 0.05–0.4 mg/ kg/h).

Thiopental 100–250 mg IV loadingdoseover 20 s with further 50-mg boluses every 2–3 min until seizure control, followed by a continuous IV infusion at a dose to maintain a burstsuppression pattern (usually 3–5 mg/kg/h).

Pentobarbital 5–15 mg/kg IV bolus, followed by a continuous IV infusion at a dose to maintain aburst-suppression pattern on the EEG (usually 0.5–3 mg/kg/h).

Figure 1. Staged treatment protocol for early (Stage I), established (Stage II), and refractory (Stage III) convulsive status epilepticus. Timelines for stage I to III given are general approximations and may vary depending on clinical circumstances, cause, and age of the patient.

Midazolam 10 mg buccal (5 mg in the elderly or inpatients

Pharmacologic treatment of status epilepticus.

Status epilepticus (SE) requires rapid identification of its cause and urgent pharmacological treatment. Despite an estimated incidence of up to 61 pe...
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