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REVIEW ARTICLE
Year : 2021  |  Volume : 19  |  Issue : 4  |  Page : 269-273

Time is brain: Review of emergency management of status epilepticus in adults


Department of Emergency Medicine, Narayana Health Multispeciality Hospital, Bengaluru, Karnataka, India

Date of Submission10-May-2021
Date of Decision30-May-2021
Date of Acceptance12-Jun-2021
Date of Web Publication07-Dec-2021

Correspondence Address:
Dr. Mamta Madhiyazhagan
Department of Emergency Medicine, Narayana Health Multispeciality Hospital, HSR Layout, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_53_21

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  Abstract 


Status epilepticus (SE) is a serious complication of epilepsy that warrants both rapid and appropriate emergency management for better outcomes in terms of mortality and morbidity. The initial management of SE in emergency department (ED) involves a rapid neurological assessment and initiation of supportive therapy. Benzodiazepines are the recommended first-line treatment based on high-quality evidence, among them intramuscular (IM) midazolam IM was found to be as effective as intravenous lorazepam. However, it is important to understand that speedy drug delivery and adequate initial dose are of prime importance than selection of drug. Recent evidence shows all three second-line drugs, namely, valproate, fosphenytoin, and levetiracetam are alike in cessation of SE with similar incidence of adverse events. In refractory SE, the therapeutic options include the use of bolus dose followed by infusion of propofol, midazolam, ketamine, lacosamide, and phenobarbital. Magnesium sulfate is safe and superior in the management of eclamptic SE prompt and appropriate management in ED is the key to early cessation of SE, leading to better outcomes.

Keywords: Status epilepticus, antiepileptic drugs, emergency department, refractory status epilepticus


How to cite this article:
Madhiyazhagan M. Time is brain: Review of emergency management of status epilepticus in adults. Curr Med Issues 2021;19:269-73

How to cite this URL:
Madhiyazhagan M. Time is brain: Review of emergency management of status epilepticus in adults. Curr Med Issues [serial online] 2021 [cited 2022 May 24];19:269-73. Available from: https://www.cmijournal.org/text.asp?2021/19/4/269/331831




  Introduction Top


Status epilepticus (SE) is a challenging neurological emergency both diagnostically and therapeutically. It is often associated with high mortality and substantial morbidity,[1],[2] and 12%–30% of adults present with SE as the first epilepsy presentation.[3] SE was defined earlier as 30 min of continuous seizure like activity or multiple episodes with no recovery between episodes.[4],[5] Task Force of the International League Against Epilepsy (ILAE) in 2015 proposed SE as seizures activity exceeding 5 min for tonic–clonic variety and 10 min for absence and focal SE.[6] As per this new definition, a recent study found that the incidence of a first convulsive SE was 36.1/100,000 adults/year while that of the nonconvulsive SE was 12.1/100,000 adults/year.[7] The etiology of SE differs widely in different geographical regions. Stroke (16.7%–60%) is an important cause of SE in adults in developed countries,[8],[9] while infections, birth, and head injuries and poor compliance to antiepileptics in the developing countries. In India, a study done by Kalita et al. found that infection in 53.8%, metabolic in 14.5%, and stroke in 12.8% were most encountered etiologies.[2] The Task Force of the ILAE 2015 stressed the necessity for prompt SE treatment in order to minimize the risk of permanent damage.[6] Despite current guidelines emphasizing the need for the same, several studies showed initial underdosing and delayed management of SE, especially in emergency department (ED).[10],[11] In this review, we will discuss regarding the acute management of SE in ED and address certain gray areas encountered by emergency physicians such as choice of antiepileptic drugs and management of SE in special situations such as refractory SE (RSE) and SE in pregnancy.


  Initial Emergency Department Management Top


The initial management of SE in ED involves a rapid neurological assessment and initiation of supportive therapy. A rapid neurological assessment involves finding out the time of onset, duration of seizure(s), type and number of episodes of seizures, level of sensorium, past medical history, and drug history. This should be done in parallel to rapid-focused medical examination stabilizing airway, breathing, circulation, and treating any physical injuries sustained during seizure activity. Most SE patients will benefit from oxygen therapy in lateral lie to maintain adequate saturation and prevent aspiration. Attempts at placement of advance airway in actively seizing patient may be difficult due to laryngeal spasm and should be avoided to prevent injury, unless rapidly worsening oxygenation necessitates mechanical ventilation. Vital signs should be monitored along with cardiac monitoring, and a rapid fingerstick glucose should always be obtained to rule out hypoglycemia or hyperglycemia as possible cause of SE. Hypertensive encephalopathy, severe hyperthermia (heat stroke) as well as history of pregnancy in young females (eclampsia) should be considered as possible cause of SE intravenous (IV) access must be secured. Blood samples should be sent for electrolytes (Na+, Ca++, and Mg++), creatinine, liver function test, and appropriate toxicology studies. Measurement of arterial blood gases helps to rapidly detect hypoxemia and dyselectrolytemia. Consider crystalloid bolus infusions with or without inotropes for hypotension. Once the patient is stabilized, subsequently computed tomography head, lumbar puncture to be planned to look for intracranial pathology and central nervous system infections. The initial intervention should ideally be done within few minutes of ED arrival. It would be better to seek help early by getting more members of ED team as these steps could be simultaneously done in parallel. These tasks will need at least 2–5 min by which time if the seizure persists, we should consider administration of first dose of antiepileptic drug (AED).

First-line pharmacological treatment

The agent of choice according to current guidelines is benzodiazepines.[12],[13] However, there is dilemma in the selection of drug, dosage, and route of administration. Traditionally, IV administration of benzodiazepines is preferred when feasible, especially in in-hospital setting. A meta-analysis done by Alshehri et al. found that non-IV benzodiazepines terminate seizure faster and have lesser side effects.[12] Thus, the prompt use of non-IV routes, namely, intramuscular (IM), rectal, nasal, or buccal routes should be considered in both in-hospital and pre-hospital setting.[13] It is important to understand that adequate initial dosing and quick drug administration are more important than choice of drug.[14] Hence, in resource limited settings, it is advisable to administer the available benzodiazepine at appropriate dose. Lorazepam (0.1 mg/kg, maximum 4 mg) is the preferred agent for IV therapy and can be repeated 4 hourly with a maximum cumulative dose of 8 mg.[14] For IM therapy, midazolam is preferred (10 mg once only). Midazolam IM was found to be as effective as lorazepam IV.[15] Other drugs that can be given are diazepam IV (0.15 mg/kg), diazepam per rectal: 0.2–0.5 mg/kg, maximum 20 mg, single dose), midazolam intranasal (IN) (0.2 mg/kg, maximum 10 mg), or buccal (0.3 mg/kg, maximum 10 mg).[16] Other class of AED such as phenobarbital, levetiracetam, sodium valproate, and phenytoin have been evaluated as alternatives to benzodiazepines as first-line agent. A landmark randomized control trial (RCT) done by “;Veteran Affairs SE Cooperative Study Group,” had shown that lorazepam was more effective than pheytoin.[17] Although this study had shown phenobarbital to be equally effective, it is scarcely used due to long-term side effects and respiratory depression.[14] Although sodium valproate and levetiracetam are effective and safe, there is inadequate evidence in their favor as first-line agents.[14] Thus, phenobarbital, levetiracetam, sodium valproate, and phenytoin can be considered for use as initial agent only in cases where benzodiazepine is not readily available for treatment in ED.

Second-line pharmacological treatment

Although benzodiazepines are the recommended first-line agents, nearly one-third of the patients do not respond to benzodiazepines.[18] Commonly used AEDs in ED are levetiracetam, phenytoin, fosphenytoin, and sodium valproate. Until recently, due to a lack of clear evidence, the choice of second-line agent was largely decided based on availability. To identify which is the best second-line agent in the management of SE, “;Established SE Treatment Trial” was conducted.[18] This was a large multicentric randomized blinded comparative-effectiveness trial of fosphenytoin, levetiracetam, and valproate for the SE treatment in ED. The study showed the above three AEDs were equally effective in seizure cessation and improved sensorium by 60 min in almost half the patients and had similar incidences of adverse events.[18] It is also important to use a different AED in a known epileptic who was previously compliant on one particular AED. [Table 1] compares three second-line drugs in the treatment of SE.
Table 1: Second-line drugs in treatment of status epilepticus

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Phenytoin versus fosphenytoin

Phenytoin is one of the recommended second-line agents for SE. Its alkaline pH makes the infusion painful or leads to phlebitis with chronic administration.[19] Vasospasm near the infusion site can cause infiltration and/or extravasation with subsequent tissue necrosis.[20] Propylene glycol, a pharmaceutical solvent in phenytoin, restricts its solubility in parenteral solutions and limits the rate of loading dose, also large doses are associated with lactic acidosis, acute kidney injury, and multiorgan failure.[21] IM use is not recommended due to delayed and erratic absorption. Fosphenytoin, a phenytoin prodrug, is more expensive but has fewer local infusion site reactions and is available as an IM formulation for quicker administration.[22] As per the American Epilepsy Society guidelines 2016, fosphenytoin is preferred over phenytoin as first-line antiseizure therapy for convulsive SE whenever both are available.[23] A recent study (yet to be published) by Madhiyazhagan et al. found that the mean time to cessation of seizure in patients receiving fosphenytoin (17.48 + 49.24 min) was nearly half of that in patients receiving phenytoin (37.20 + 58.17 min).[24] [Table 2] summarizes the important differences between phenytoin and fosphenytoin. Both phenytoin and fosphenytoin act by sodium channel blockade, which is similar to mechanism of action of few toxidromes such as tricyclic antidepressants and cocaine overdose. The additional sodium channel blockade by phenytoin and fosphenytoin in patients with these toxidromes can result in cardiac dysrhythmias and cardiovascular collapse. Hence, it is advisable to avoid phenytoin and fosphenytoin in cases of SE with suspected toxicological etiology.[16]
Table 2: Phenytoin versus fosphenytoin

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Propofol as second-line agent in status epilepticus treatment

All the current recommended second-line AED agents require longer duration of IV administration and hence take longer time of onset of action. Longer duration of SE is associated with poorer neurological prognosis.[25],[26],[27],[28] ConSEPT and the EcLiPSE trial showed that the recommended second-line AEDs took nearly 20–30 min for cessation of SE.[29],[30] Propofol, a general anesthetic agent, is a familiar drug which is readily available in most ED. It has been recently tried as a second-line agent in SE, given that the fact that it can be administered quickly and has a rapid onset of action (30–60 s) and can also be used safely in suspected toxidromes. Although there is strong underlying biological basis which is backed by observational data,[31],[32] there is a need for stronger evidence comparing propofol with currently recommended second-line agents. Furthermore, administration of propofol needs continuous hemodynamic monitoring as it is known to cause hypotension, propofol infusion syndrome. Hence, its use is not recommended in areas where continuous hemodynamic monitoring is not available.

Advanced airway management in status epilepticus

Most patients needing second-line agent will demand definitive airway intervention due to risk of rapid desaturation. Despite initial oxygen therapy, if the patient has low saturation (<95%), rapid sequence airway is recommended. Laryngeal mask airway is inserted after bolus dose of propofol and subsequently an endotracheal tube is inserted when stable. In patients with adequate oxygen saturation, endotracheal intubation by rapid sequence intubation (RSI) is recommended.[33] It should be kept in mind that paralytics given with RSI will conceal ongoing seizure, thus converting convulsive SE (CSE) into Non convulsive SE (NCSE).


  Refractory Status Epilepticus Top


RSE is special type of SE, wherein the SE is persistent and resistant to both first-line and second line AEDs.[34] ED physician can initiate therapy for RSE. The therapeutic options include the use of bolus dose followed by infusion of propofol, midazolam, ketamine, lacosamide, and phenobarbital [Figure 1].
Figure 1: Algorithm for treatment of status epilepticus in emergency department.

Click here to view



  Status Epilepticus in Pregnancy Top


In pregnant women with known epilepsy history, evidence is insufficient to support or refute pregnancy as increased risk of SE, but rapid seizure control in the mother is associated with good fetal outcome.[35],[36] In eclampsia, delivering the fetus as soon as possible is the best therapy and magnesium sulfate is superior to other AEDs.[37] Exposure to AEDs in first trimester, particularly, valproate sodium, phenobarbital, and phenytoin substantially increases the risk associated with birth defects and hence should be avoided. However, newer generation AEDs such as levetiracetam are considered relatively safe.[38]

Future potential areas for research

There are potential avenues for future research in the treatment of SE. There is a need for better evidence, preferably RCTs, to evaluate efficacy of propofol as a second-line agent with regard to the current recommended second-line agents. Furthermore, there is a need to explore the use of ketamine in early course of management of SE. This might be useful in patients who present in shock along with SE. Another potential area of interest is the use of rapid EEG in ED to differentiate CSE from NCSE and to occasionally diagnose psychogenic nonepileptic seizure, which would help in aggressive, appropriate antiepileptic management. RSE is generally associated with poor prognosis and its treatment is discussed in other reviews.


  Conclusion Top


Speed of administration and adequate initial dosing of AED are crucial in treatment of SE. Based on current evidence, lorazepam IV or midazolam IM remains the first-line treatment, whereas levetiracetam, phenytoin, and valproate are equally effective as second-line treatment.

Ethical statement

This review article uses only publicly accessible documents as evidence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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