Pharmacotherapy of Status Epilepticus

Full update February 2020

Despite the availability of several new anticonvulsants in recent years, the treatment of status epilepticus still involves the old standbys, particularly the benzodiazepines. The chart below provides anticonvulsant dosing and place in therapy of convulsive status epilepticus. Administration rates, monitoring, and other practical information is also provided. The chart is largely based on the 2016 American Epilepsy Society guidelines for the treatment of convulsive status epilepticus. The complete guidelines are available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749120/pdf/i1535-7511-16-1-48.pdf and include a sample treatment algorithm (page 58). Since publication of these guidelines, several new studies comparing fosphenytoin, levetiracetam, and valproate sodium for benzodiazepine-refractory status epilepticus have been published.9,14-16,18 They are likely equally effective, including in the elderly and children ≥2 years of age. Consider levetiracetam for ease of use and safety (i.e., relatively few drug interactions and adverse effects).16,17,19 Levetiracetam is a safer option than phenytoin or valproate sodium when past medication history is not readily available.

Dosing, administration rates, and other information may differ from product labeling

DRUG

DOSEb

COMMENTS

Initial Treatment Options if still seizing after stabilization (i.e., airway, breathing, circulation, blood glucose, etc addressed)1

Diazepam, intravenous

0.15 to 0.2 mg/kg/dose,
max 10 mg/dose; may repeat once,1
in 5 minutes2

Consider using actual weight in obese adults.7


Max administration rate: 5 mg/min.2

Contains propylene glycol.2,a

Monitor for hypotension and respiratory depression.2

Lorazepam, intravenous

0.1 mg/kg/dose, max 4 mg/dose; may repeat once,1 in 5 to 10 minutes2

Consider using actual weight in obese adults.7

Max administration rate: 2 mg/min.2

Contains propylene glycol.2,a

Dilute 1:1 with saline.2

Monitor for hypotension and respiratory depression.2

 

Midazolam, intramuscular

10 mg if >40 kg, 5 mg if 13 to 40 kg; single dose1

Consider using actual weight in obese adults.7


Monitor for respiratory depression and hypotension.2

Alternative Initial Treatment Options (if above options not available)1

Diazepam, rectal

0.2 to 0.5 mg/kg, max 20 mg; single dose1

Monitor for respiratory depression and hypotension.2

See our chart, Nasal Midazolam and Rectal Diazepam for Seizures, for information on Diastat.

 

Midazolam, intranasal or buccal

Intranasal: most studies used 0.2 mg/kg, with a max dose of 10 mg in some studies5

Buccal: most studies used 0.2 to 0.5 mg/kg, with a max 10 mg in some studies4

 

Monitor for respiratory depression and hypotension.2

Can use injection solution buccally or intransally.3,6

For intranasal use, administer with needleless syringe, or consider use of a nasal atomizer device for converting IV syringe for intranasal use.5,6 See our chart, Nasal Midazolam and Rectal Diazepam for Seizures, for information on Nayzilam.

Intranasal: solution typically dripped into each nostril equally.4

Buccal: solution typically placed between gum and cheek; cheek can be massaged.4

Most studies performed in children.4

 

Phenobarbital, intravenous

15 to 20 mg/kg/dose; single dose1,2

Administration rate: 50 to 100 mg/min.2

Contains propylene glycol.2,a

Monitor for hypotension and respiratory depression.2

 

Second-line Options if patient is still seizing after 20 minutes (or sooner).1 Failing one option, moving to a third (refractory) agent is recommended.2

Levetiracetam, intravenous

20 to 60 mg/kg, max 3,000 to 4,500 mg/dose; single dose1,2,9,14-18 Note that there is more evidence for
40 mg/kg (in pediatrics) and 60 mg/kg doses.9,15,16

 

Available in premixed bags.2 Multiple bags will often be needed
(1,500 mg in 100 mL is the most concentrated available).

Administration rate: 2 to 5 mg/kg/min.2

  • Alternatively, doses ≤2,500 mg can be infused over 5 minutes.20 Doses ≤4,500 mg can be infused over 10 minutes.9 However, it will take six minutes to infuse one premade bag (1,500 mg) due to most pump rate limitations.

Doses <1,000 mg can be given IV push over two minutes.19 But keep in mind that the vials contain only 500 mg.

Few drug interactions.2 Good tolerability.1

 

Fosphenytoin, intravenous
(a phenytoin prodrug)

20 mg phenytoin equivalents/kg, max 1,500 to 2,000 mg phenytoin equivalents; single dose.1,12

Consider using an adjusted body weight for obese  patients.

Fosphenytoin can be administered intramuscularly, although the intravenous route is preferred for status epilepticus.10 Fosphenytoin is 100% bioavailable when given intramuscularly, but peak levels are lower than after intravenous administration, and pharmacokinetics are similar to orally administered phenytoin.6

Max administration rate: up to 150 mg phenytoin equivalents per min.2

Compatible with saline, dextrose, and Lactated Ringer’s solution.2

Monitor for hypotension and arrhythmias.2

Phenytoin is an alternative, but causes more injection-site pain, serious tissue damage, and arrhythmias, and is compatible only with normal saline.1-3 Contains propylene glycol.2 Max administration rate 50 mg/min.2 If diluted in a mini-bag of normal saline, dilute to not less than 5 mg/mL.6 Infuse with 0.22 to 0.55 micron in-line filter.6 Watch solution for precipitation.6 Use central access, or healthy antecubital fossa vein (or similar or larger vein) with 20-gauge catheter or larger.6 Administer through a free-flowing IV of normal saline.6 Flush line with saline before and after administration.6

The loading dose of 20 mg/kg should put the total phenytoin level in the target range of 20 to 25 mg/L.11

 

Valproate sodium, intravenous

20 to 40 mg/kg, max 3,000 mg/dose; single dose1,17,18

Administration rate: 3 to 6 mg/kg/min.2 A rate of 10 mg/kg/min may be as safe as a rate of 6 mg/kg/min.22 Can dilute in 100 mL saline.18

Consider after benzo for patients with a history of generalized epilepsy.2

 

Alternative Second-line Options (if above options not available)

Phenobarbital, intravenous

15 to 20 mg/kg/dose (single dose), if not already given1,2

Administration rate: 50 to 100 mg/min.2

Contains propylene glycol.2,a

Monitor for hypotension and respiratory depression.2

 

Lacosamide, intravenous8

Adults: 200 to 400 mg, single dose.2,8 400 mg is the most common dose, and may be more effective.8

Limited data in status epilepticus.2

Few drug interactions.2

Monitor for hypotension, PR prolongation, AV conduction disturbance, and asystole.2,3

Give 200 mg over 15 minutes.2 400 mg has been given over 30 minutes.13 Has also been given IV push at a rate of 80 mg/min.21

 

Continuous Infusion Options for Refractory Patients require ventilatory assistance, electroencephalogram monitoring, and cardiac monitoring.2 Try an alternative if the first one doesn’t work.2

Midazolam infusion

Bolus: 0.2 mg/kg at a rate of 2 mg/min2

Continuous infusion: 0.05 to 2 mg/kg/h.2

For breakthrough: consider a 0.1 to 0.2 mg/kg bolus and increasing rate by 0.05 to 0.1 mg/kg/h every three to four hours.2


Can cause hypotension (less than propofol).2

Tolerance with prolonged use.2

Propofol

Bolus: 1 to 2 mg/kg2

Continuous Infusion: 20 mcg/kg/min, initial.2 Range: 30 to 200 mcg/kg/min.2

For breakthrough: consider increasing rate by 5 to 10 mcg/kg/min every 5 minutes. Or give a 1 mg/kg bolus and increase infusion rate.2

 


Can cause hypotension, especially with loading doses.2

Watch for cardiac depression, rhabdomyolysis, metabolic acidosis, and renal failure. Use special caution with doses >80 mcg/kg/min for >48 hrs.2 In children, use caution with doses >65 mcg/kg/min.2

Provides 1.1 kcal/mL.2

Pentobarbital

Bolus: 5 to 15 mg/kg. May give an additional 5 to 10 mg/kg. Infuse at a rate ≤50 mg/min.2

Continuous infusion: 0.5 to 5 mg/kg/hr.2

For breakthrough: consider a 5 mg/kg bolus, then increasing continuous infusion by 0.5 to 1 mg/kg/h every 12 h.2


May be more effective than midazolam initially, but has more side effects.2

Can cause hypotension.2

Watch for cardiac depression and paralytic ileus.2

Contains propylene glycol.2

Ketamine

Bolus: 0.5 to 5 mg/kg (adults).23 In a case series, the median bolus dose was 1.5 mg/kg (adults and children).24

Continuous infusion: Consider at least
0.9 mg/kg/h.24 Up to 10 mg/kg/h has been used in adults.23 In a case series, the median dose was 2.75 mg/kg/h (adults and children).24

Evidence limited.23 Efficacy and optimal dose unclear.23 Studies ongoing.

Appears well-tolerated. Adverse effects reported include arrhythmias and drooling.23

  1. Propylene glycol-containing products pose a higher risk of hypotension.2
  2. Unless otherwise specified, dosing recommendations are intended for both children and adults.

Project Leader in preparation of this clinical resource (360219): Melanie Cupp, Pharm.D., BCPS

References

  1. Glauser T, Shinnar S, Gloss D, 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.
  2. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23.
  3. Trinka E, Hofler J, Leitinger M, Brigo F. Pharmacotherapy for status epilepticus. Drugs 2015;75:1499-521.
  4. Jain P, Sharma S, Dua T, et al. Efficacy and safety of anti-epileptic drugs in patients with active convulsive seizures when no IV access is available: systematic review and meta-analysis. Epilepsy Res 2016;122:47-55.
  5. Humphries LK, Eiland LS. Treatment of acute seizures: is intranasal midazolam a viable option? J Pediatr Pharmacol Ther 2013;18:79-87.
  6. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2020. http://www.clinicalkey.com. (Accessed January 16, 2019).
  7. Leykin Y, Miotto L, Pellis T. Pharmacokinetic considerations in the obese. Best Pract Res Clin Anaesthesiol 2011;25:27-36.
  8. Stzelczyk A, Zollner JP, Willems LM, et al. Lacosamide in status epilepticus: systematic review of current evidence. Epilepsia 2017;58:933-50.
  9. Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med 2019;381:2103-13.
  10. Roth JL. Status epilepticus. Updated February 13, 2018. https://emedicine.medscape.com/article/1164462-overview. (Accessed January 16, 2019).
  11. Epilepsy Foundation. Phenytoin. April 2004. http://www.epilepsy.com/information/professionals/co-existing-disorders/cerebrovascular-disease/treatment-seizures/phenytoin. (Accessed January 16, 2020).
  12. Erstad BL. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensive Care Med 2004;30:18-32.
  13. Ramsay RE, Sabharwal V, Khan F, et al. Safety and pK of IV loading dose of lacosamide in the ICU. Epilepsy Behav 2015;49:340-2.
  14. Chakravarthi S, Goyal MK, Modi M, et al. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci 2015;22:959-63.
  15. Dalziel SR, Borland ML, Furyk J, 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.
  16. Lyttle MD, Rainford NE, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLIPSE): a multicenre, open-label, randomised trial. Lancet 2019;393:2125-34.
  17. Zaccara G, Giorgi FS, Amantini A, et al. Why we prefer levetiracetam over phenytoin for treatment of status epilepticus. Acta Neurol Scand 2018;137:618-22.
  18. Nene D, Mundlamuri RC, Satishchandra P, et al. Comparing the efficacy of sodium valproate and levetiracetam following initial lorazepam in elderly patients with generalized convulsive status epilepticus (GCSE): a prospective randomized controlled pilot study. Seizure 2019;65:111-7.
  19. Morgan O, Medenwald B. Safety and tolerability of rapid administration undiluted levetiracetam. Neurocrit Care 2019 Mar 27. doi: 10.1007/s12028-019-00708-5.
  20. Ramael S, Daoust A, Otoul C, et al. Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetics study. Epilepsia 2006;47:1128-35.
  21. Davidson KE, Newell J, Alsherbini K, et al. Safety and efficiency of intravenous push lacosamide administration. Neurocrit Care 2018;29:491-5.
  22. Limdi NA, Knowlton RK, Cofield SS, et al. Safety of rapid intravenous loading of valproate. Epilepsia 2007;48:478-83.
  23. Hofler J, Trinka E. Intravenous ketamine in status epilepticus. Epilepsia 2018;59 Suppl 2:198-206.
  24. Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multi-center study. Epilepsia 2013;54:1498-503.

Cite this document as follows: Clinical Resource, Pharmacotherapy of Status Epilepticus. Pharmacist’s Letter/Prescriber’s Letter. February 2020.

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