Pharmacotherapy of Status Epilepticus

modified September 2024

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. An associated treatment algorithm is available at https://www.aesnet.org/images/default-source/default-album/cse-treatment-chart-final_rerelease.jpg?sfvrsn=f9e6cfd5_2. Since publication of these guidelines, several new studies comparing fosphenytoin, levetiracetam, and valproate sodium for benzodiazepine-refractory status epilepticus have been published.9 After a benzodiazepine, loading doses of these agents (levetiracetam 60 mg/kg, valproate sodium 40 mg/kg, or fosphenytoin 20 mg/kg [phenytoin equivalents]) are likely equally effective.9 Consider levetiracetam for ease of use and safety (i.e., drug interactions, adverse effects).14 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 Optionsif 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/min2

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,1in 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

Rectal gel is commercially available (Diastat).

Diazepam, nasal

(Valtoco [US])13

0.2 mg/kg (6 to 11 years of age), or 0.3 mg/kg
(≥12 years of age), max 20 mg.6

Divide dose equally between nostrils.6

There is little data on intranasal diazepam for status epilepticus.25

Midazolam, intranasal or buccal

Intranasal: most common dose
0.2 mg/kg to 0.3 mg/kg, with a max dose of
10 mg5,16,17

Buccal: 0.2 to 0.5 mg/kg,max 10 mg4,6

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 Nasal spray (5 mg/spray) is commercially available in US (Nayzilam).6 Divide dose equally between nostrils.4

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

Use 5 mg/mL concentration for fast onset.19

Most studies performed in children.4,18

Phenobarbital, intravenous

15 to 20 mg/kg/dose; single dose.1,2  Max 1,000 mg/dose in pediatrics.26

Administration rate: 50 to 100 mg/min.2  Max 1mg/kg/min in pediatrics.26

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

60 mg/kg, max 4,500 mg/dose9

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

  • Doses ≤4,500 mg have been given IV push to adults over as little as two minutes.24
  • Undiluted IV push doses up to 60 mg/kg have been given safely to children down to <1 year of age.29
  • Keep in mind practical limitations. USP <797> compounding regulations for immediate-use medications at the bedside limit three vials (500 mg each) to one syringe (1,500 mg total per syringe).27

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.1,15

Consider using actual body weight for obese patients.15

Fosphenytoin can be administered intramuscularly, although the intravenous route is preferred for status epilepticus.13 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 minute in adults.2 For pediatrics, up to 3 mg/kg phenytoin equivalents per minute, not to exceed adult max.28

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 in adults, or 1 mg/kg/min in pediatrics, not to exceed adult max.2,26 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

Valproate sodium, intravenous

40 mg/kg, max 3,000 mg (single dose)1,9,10

Administration rate: 3 to 6 mg/kg/min.2 A rate of 10 mg/kg/min may be as safe as 6 mg/kg/min.22 Can dilute in 100 mL saline.12

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

Hepatotoxicity is a concern, especially with children <2 years of age, and with rapid infusion.11,22

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

Phenobarbital, intravenous

15 to 20 mg/kg/dose (single dose), if not already given1,2 Max 1,0000 mg/dose in pediatrics.26

Administration rate: 50 to 100 mg/min.2  Max 1mg/kg/mmin in pediatrics.26

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

Pediatrics: Limited data. 3.3 to 10 mg/kg/dose has been used in children.30 Do not exceed adult dose.

Limited data in status epilepticus.2

Few drug interactions.2

Monitor for hypotension, PR prolongation, AV conduction disturbance, bradycardia, and asystole.2,3,30

Give 200 mg over 15 minutes.2 Doses of up to 400 mg have also been given IV push at a rate of 40 to 80 mg/min.6,21

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: 1 to 2.5 mg/kg.9  In a case series, the median bolus dose was 1.5 mg/kg (adults and children).20

Continuous infusion: 1 to 10 mg/kg/h.9,23 In a case series, the median dose was 2.75 mg/kg/h (adults and children).20

Evidence limited.11 Efficacy and optimal dose unclear.11  Studies ongoing.11

Appears well-tolerated; serious cardiorespiratory adverse effects are uncommon.11
  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.

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 Jan-Feb;16(1):48-61.
  2. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012 Aug;17(1):3-23.
  3. Trinka E, Höfler J, Leitinger M, Brigo F. Pharmacotherapy for Status Epilepticus. Drugs. 2015 Sep;75(13):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 May;122:47-55.
  5. Humphries LK, Eiland LS. Treatment of acute seizures: is intranasal midazolam a viable option? J Pediatr Pharmacol Ther. 2013 Apr;18(2):79-87.
  6. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2024. http://www.clinicalkey.com. (Accessed July 2, 2024).
  7. Leykin Y, Miotto L, Pellis T. Pharmacokinetic considerations in the obese. Best Pract Res Clin Anaesthesiol. 2011 Mar;25(1):27-36.
  8. Strzelczyk A, Zöllner JP, Willems LM, et al. Lacosamide in status epilepticus: Systematic review of current evidence. Epilepsia. 2017 Jun;58(6):933-950.
  9. Vossler DG, Bainbridge JL, Boggs JG, et al. Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee. Epilepsy Curr. 2020 Sep;20(5):245-264.
  10. Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113.
  11. Coles L, Rosenthal ES, Bleck TP, et al. Why ketamine. Epilepsy Behav. 2023 Apr;141:109066.
  12. 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 Feb;65:111-117.
  13. Drislane FW. Convulsive status epilepticus in adults: management. (Last updated March 10, 2022). In UpToDate, Post TW (ed), UpToDate, Waltham, MA 02013.
  14. Webb CA, Wanbon R, Otto ED. Levetiracetam for Status Epilepticus in Adults: A Systematic Review. Can J Hosp Pharm. 2022 Winter;75(1):46-53.
  15. Keats K, Powell R, Rocker J, et al. Evaluation of phenytoin loading doses in overweight patients using actual versus adjusted body weight. Epilepsy Behav. 2022 Sep;134:108833.
  16. Northwest Healthcare Response Network. Intranasal (IN) medication administration MBED clinical practice guideline. November 2020. https://nwhrn.org/wp-content/uploads/2020/11/1_E_Intranasal-Medication-Administration-MBED-Clinical-Practice-Guidelines.pdf. (Accessed June 19, 2024).
  17. McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med. 2010 Jun;17(6):575-82.
  18. Bailey AM, Baum RA, Horn K, et al. Review of Intranasally Administered Medications for Use in the Emergency Department. J Emerg Med. 2017 Jul;53(1):38-48.
  19. Rech MA, Barbas B, Chaney W, Greenhalgh E, Turck C. When to Pick the Nose: Out-of-Hospital and Emergency Department Intranasal Administration of Medications. Ann Emerg Med. 2017 Aug;70(2):203-211.
  20. Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013 Aug;54(8):1498-503.
  21. Torian SC, Jones GM. Safety Profile of High-Dose Intravenous Push Lacosamide. Neurohospitalist. 2023 Jul;13(3):278-282.
  22. Trinka E, Höfler J, Zerbs A, Brigo F. Efficacy and safety of intravenous valproate for status epilepticus: a systematic review. CNS Drugs. 2014 Jul;28(7):623-39.
  23. Hofler J, Trinka E. Intravenous ketamine in status epilepticus. Epilepsia 2018;59 Suppl 2:198-206.
  24. Koons M, Koehl J, Johnson R, et al. Efficiency and safety of high-dose undiluted intravenous push levetiracetam loading doses compared to intravenous infusion in seizing patients: A retrospective cohort study. Epilepsia. 2024 Aug 10. doi: 10.1111/epi.18079.
  25. Boddu SHS, Kumari S. A Short Review on the Intranasal Delivery of Diazepam for Treating Acute Repetitive Seizures. Pharmaceutics. 2020 Nov 30;12(12):1167.
  26. McKenzie KC, Hahn CD, Friedman JN. Emergency management of the paediatric patient with convulsive status epilepticus. Paediatr Child Health. 2021 Jan 21;26(1):50-66.
  27. ASHP. USP <797> Key changes. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/compounding/docs/USP-797-Key-Changes.pdf. (Accessed September 5, 2024).
  28. Tanaka J, Kasai H, Shimizu K, et al. Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers. Eur J Clin Pharmacol. 2013 Mar;69(3):489-97.
  29. Price L, Garrity L, Stiehl S. Evaluation of the safety and tolerability of intravenous undiluted levetiracetam at a pediatric institution. Pharmacotherapy. 2024 Feb;44(2):141-148.
  30. Messahel S, Bracken L, Appleton R. Optimal Management of Status Epilepticus in Children in the Emergency Setting: A Review of Recent Advances. Open Access Emerg Med. 2022 Sep 17;14:491-506.

Cite this document as follows: Clinical Resource, Pharmacotherapy of Status Epilepticus. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. July 2024. [400764]

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