|
 
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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 19
| Issue : 4 | Page : 269-273 |
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Time is brain: Review of emergency management of status epilepticus in adults
Mamta Madhiyazhagan
Department of Emergency Medicine, Narayana Health Multispeciality Hospital, Bengaluru, Karnataka, India
| Date of Submission | 10-May-2021 |
| Date of Decision | 30-May-2021 |
| Date of Acceptance | 12-Jun-2021 |
| Date of Web Publication | 07-Dec-2021 |
Correspondence Address:
Dr. Mamta Madhiyazhagan
Department of Emergency Medicine, Narayana Health Multispeciality Hospital, HSR Layout, Bengaluru, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_53_21
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 |
| Introduction | |  |
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 | | |
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.
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]
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 | | |
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.
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| Status Epilepticus in Pregnancy | | |
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 | | |
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.
| References | | |
| 1. | Nair PP, Kalita J, Misra UK. Status epilepticus: Why, what, and how. J Postgrad Med 2011;57:242-52.  [ PUBMED] [Full text] |
| 2. | Kalita J, Nair PP, Misra UK. A clinical, radiological and outcome study of status epilepticus from India. J Neurol 2010;257:224-9. |
| 3. | Prasad K, Krishnan PR, Al-Roomi K, Sequeira R. Anticonvulsant therapy for status epilepticus. Br J Clin Pharmacol 2007;63:640-7. |
| 4. | Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA 1993;270:854-9. |
| 5. | Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League against Epilepsy. Epilepsia 1993;34:592-6. |
| 6. | Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, et al. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia 2015;56:1515-23. |
| 7. | Leitinger M, Trinka E, Giovannini G, Zimmermann G, Florea C, Rohracher A, et al. Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes. Epilepsia 2019;60:53-62. |
| 8. | Aminoff MJ, Simon RP. Status epilepticus. Causes, clinical features and consequences in 98 patients. Am J Med 1980;69:657-66. |
| 9. | Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, Wirbatz A, et al. Incidence of status epilepticus in adults in Germany: A prospective, population-based study. Epilepsia 2001;42:714-8. |
| 10. | Sathe AG, Tillman H, Coles LD, Elm JJ, Silbergleit R, Chamberlain J, et al. Underdosing of benzodiazepines in patients with status epilepticus enrolled in established status epilepticus treatment trial. Acad Emerg Med 2019;26:940-3. |
| 11. | Uppal P, Cardamone M, Lawson JA. Outcomes of deviation from treatment guidelines in status epilepticus: A systematic review. Seizure 2018;58:147-53. |
| 12. | Alshehri A, Abulaban A, Bokhari R, Kojan S, Alsalamah M, Ferwana M, et al. Intravenous versus nonintravenous benzodiazepines for the cessation of seizures: A systematic review and meta-analysis of randomized controlled trials. Acad Emerg Med 2017;24:875-83. |
| 13. | Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23. |
| 14. | Crawshaw AA, Cock HR. Medical management of status epilepticus: Emergency room to intensive care unit. Seizure 2020;75:145-52. |
| 15. | Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591-600. |
| 16. | |
| 17. | Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792-8. |
| 18. | Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med 2019;381:2103-13. |
| 19. | Appleton RE, Gill A. Adverse events associated with intravenous phenytoin in children: A prospective study. Seizure 2003;12:369-72. |
| 20. | Rao VK, Feldman PD, Dibbell DG. Extravasation injury to the hand by intravenous phenytoin. Report of three cases. J Neurosurg 1988;68:967-9. |
| 21. | Hall EA, Wheless JW, Phelps SJ. Status epilepticus: The slow and agonizing death of phenytoin. J Pediatr Pharmacol Ther 2020;25:4-6. |
| 22. | Fischer JH, Patel TV, Fischer PA. Fosphenytoin: Clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet 2003;42:33-58. |
| 23. | Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016;16:48-61. |
| 24. | Madhiyazhagan M, Ramgopal R, Geratala Dhanapal S, Vijay JJ, Mathew V, Abhilash KPP. Early Management of Active Seizure in the Emergency Department. Unpublished manuscript. 2021. |
| 25. | Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27-34. |
| 26. | Eriksson K, Metsäranta P, Huhtala H, Auvinen A, Kuusela AL, Koivikko M. Treatment delay and the risk of prolonged status epilepticus. Neurology 2005;65:1316-8. |
| 27. | Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534-9. |
| 28. | Maegaki Y, Kurozawa Y, Hanaki K, Ohno K. Risk factors for fatality and neurological sequelae after status epilepticus in children. Neuropediatrics 2005;36:186-92. |
| 29. | Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): An open-label, multicentre, randomised controlled trial. Lancet 2019;393:2135-45. |
| 30. | Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Hickey H, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): A multicentre, open-label, randomised trial. Lancet 2019;393:2125-34. |
| 31. | Kuisma M, Roine RO. Propofol in prehospital treatment of convulsive status epilepticus. Epilepsia 1995;36:1241-3. |
| 32. | Rossetti AO, Reichhart MD, Schaller MD, Despland PA, Bogousslavsky J. Propofol treatment of refractory status epilepticus: A study of 31 episodes. Epilepsia 2004;45:757-63. |
| 33. | |
| 34. | Legriel S, Oddo M, Brophy GM. What's new in refractory status epilepticus? Intensive Care Med 2017;43:543-6. |
| 35. | Harden CL, Hopp J, Ting TY, Pennell PB, French JA, Hauser WA, et al. Practice parameter update: Management issues for women with epilepsy – focus on pregnancy (an evidence-based review): Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:126-32. |
| 36. | Jagoda A, Riggio S. Emergency department approach to managing seizures in pregnancy. Ann Emerg Med 1991;20:80-5. |
| 37. | Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev 2010;(10):CD000128. doi: 10.1002/14651858.CD000128.pub2. PMID: 20927719. |
| 38. | Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011;305:1996-2002. |
[Figure 1]
[Table 1], [Table 2]
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