The clock is the treatment. A tonic-clonic seizure lasting 5 minutes is status epilepticus and needs treatment now; by 30 minutes the risk of lasting neuronal injury is real (ILAE 2015, t1 and t2). Give one full weight-based benzodiazepine dose, not small divided doses (AES 2016). If seizures continue, the second agent starts by 20 minutes, and the goal is definitive control within 60 minutes of onset (NCS 2012). All doses on this card are for adults unless stated.
Phase Timeline (AES 2016 algorithm, ESETT doses)
Phase
Agent
Adult Dose
Rate / Limit
0-5 min Stabilize
Airway, O2, monitor, IV access, fingerstick glucose
Thiamine 100 mg IV before dextrose; D50 50 mL IV if glucose <60 mg/dL (AES 2016).
Thiamine goes first (NCS 2012). Do not let this delay the benzodiazepine.
Intubate; anesthetic infusion (midazolam, propofol, pentobarbital) or repeat a second-line agent
See infusion table below. Start continuous EEG.
Sick or ICU patients may move through phases faster or skip the second phase (AES 2016).
Underlined entries jump to detail further down. AES 2016 names fosphenytoin, valproate, and levetiracetam as second-phase options with no clear evidence that one is better, and phenobarbital (15 mg/kg IV in the AES algorithm; NCS 2012 uses 20 mg/kg) as a reasonable alternative if none of the three is available. ACEP 2024 (Level A) adopted the ESETT doses above. Pediatric dosing is outside the scope of this card.
0.1 mg/kg (max 4 mg/dose), repeat once in 5-10 min
NCS 2012: the preferred IV agent. A 100 kg adult gets 4 mg, then 4 mg again if still seizing. Contains propylene glycol.
Midazolam IM
10 mg (>40 kg); NCS also lists 0.2 mg/kg, max 10 mg
RAMPART (NEJM 2012): seizures absent on ED arrival in 73.4% with IM midazolam vs 63.4% with IV lorazepam 4 mg, mainly because IV access takes time. Do not repeat (AES 2016).
Diazepam IV
0.15-0.2 mg/kg (AES 2016; NCS 2012 lists 0.15 mg/kg), max 10 mg/dose, repeat once in 5 min
Short effective duration from rapid redistribution; active metabolite; propylene glycol.
Trial data are mostly pediatric or prehospital. Nayzilam 5 mg spray is FDA-labeled for seizure clusters (age ≥12), may repeat once after 10 min, max 10 mg; it is not labeled for SE.
Diazepam rectal
0.2 mg/kg (age >12, NCS 2012); AES 2016: 0.2-0.5 mg/kg, max 20 mg, single dose
Only when no IV and no IM option (NCS 2012 prefers diazepam for the rectal route).
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The number-one error is underdosing. In ESETT, 81% of first lorazepam doses and 76% of first midazolam doses were below guideline doses (Sathe, Epilepsia 2021). The classic pattern is lorazepam 1-2 mg, wait, another 1-2 mg. AES 2016 says the initial dose should be a single full dose, and lists “insufficient anticonvulsant doses” as a cause of inadequate treatment. In fairness, the Sathe analysis did not find that higher benzodiazepine doses improved response to the second-line drug; the case for full dosing rests on the trials (RAMPART and others) that used full doses.
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Fear of respiratory depression is not a reason to underdose. In the prehospital lorazepam vs diazepam vs placebo trial (Alldredge, NEJM 2001), respiratory or circulatory complications occurred in about 11% and 10% of treated patients versus 22.5% on placebo (P=0.08). Ongoing seizures compromise the airway too. Have a bag-mask ready and give the full dose. AES 2016 allows one repeat of IV lorazepam or diazepam and no repeat of other initial agents; after that, move to stage 2.
100-150 mg PE/min (label). 1500 mg PE takes ≥10 min.
10 min in ESETT. NCS 2012: 3-6 mg/kg/min. Label: 60 min, ≤20 mg/min.
Seizure stop + improved responsiveness at 60 min
47%
45%
46%
Life-threatening hypotension
0.7%
3.2%
1.6%
Intubation
20%
26%
17%
Age >65 (Lancet 2020)
37%
35%
47%
Best fit
Common default. Minimal drug interactions, not hepatically metabolized (NCS 2012). Maintenance needs renal adjustment.
Hypotension and arrhythmia risk: needs cardiac monitoring. Many interactions (enzyme inducer).
Avoid in liver disease, pregnancy, POLG, urea cycle disorder, bleeding, or on a carbapenem. Fastest median time to seizure stop in ESETT (7.0 vs 10.5-11.7 min).
None of the efficacy or safety differences was statistically significant, including in the age-stratified analysis (Chamberlain, Lancet 2020). About half of patients fail any one of the three, so line up stage 3 while the second agent runs.
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The caps are a 75 kg patient. 60, 20, and 40 mg/kg at 75 kg give exactly 4500 mg, 1500 mg PE, and 3000 mg. Anyone heavier than 75 kg gets the cap, which keeps obese-patient dosing simple. A matching home medication did not lower the chance of stopping seizures (Wabl, Neurology 2021), so a patient on home levetiracetam can still get the full levetiracetam load.
Phenytoin vs fosphenytoin
Feature
Fosphenytoin
Phenytoin
Units
Ordered in mg PE (phenytoin sodium equivalents). Vial is 50 mg PE/mL. The label warns not to confuse the PE dose with the vial concentration.
Ordered in mg phenytoin sodium.
Loading dose
20 mg PE/kg (label for SE: 15-20 mg PE/kg). NCS: may give 5 mg PE/kg more after 10 min.
20 mg/kg per NCS 2012 (additional 5-10 mg/kg allowed). The Dilantin label lists 10-15 mg/kg for adult SE.
Max rate
150 mg PE/min
50 mg/min. A 1500 mg load takes ≥30 min.
Diluent
Saline or D5W (label), to 1.5-25 mg PE/mL
Saline only (precipitates in dextrose); 0.22-0.55 micron in-line filter; flush before and after.
Purple glove syndrome
Reported, less common
Edema, discoloration, and pain distal to a peripheral IV site, sometimes days later; can progress to necrosis. Large vein or central line.
Other
Adds phosphate (0.0037 mmol per mg PE): matters in severe renal impairment. Not for IM use in SE (levels rise too slowly).
Propylene glycol vehicle (NCS 2012).
Both
Boxed warning: hypotension and arrhythmias with rapid infusion, including at recommended rates. Cardiac monitoring during and after the load. Highest risk in the elderly and critically ill; slow the rate for them. Contraindicated (labels) in sinus bradycardia, sinoatrial block, second- or third-degree AV block, Adams-Stokes syndrome, prior phenytoin-attributed hepatotoxicity, and with delavirdine.
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Timing the first level. Draw phenytoin levels no earlier than 2 hours after the end of an IV fosphenytoin infusion (4 h after IM). Before conversion is complete, common immunoassays overestimate phenytoin because they cross-react with fosphenytoin (Cerebyx label). Follow every load with maintenance dosing; adult starting maintenance is 4-6 mg PE/kg/day in divided doses.
Neural tube defects, other major malformations, lower IQ. Label: do not use in women of childbearing potential unless other medications have failed or are unacceptable. In SE, choose levetiracetam or fosphenytoin first.
Hyperammonemia
Can occur with normal LFTs. Check ammonia for unexplained lethargy, vomiting, or mental status change. Topiramate raises the risk.
Carbapenems
Meropenem, imipenem, and ertapenem drop valproate to subtherapeutic levels and seizures can recur. Pick another antibiotic or another antiseizure drug; do not count on dose increases.
Bleeding, platelets
Dose-related thrombocytopenia (risk rises at troughs ≥110 mcg/mL in women, ≥135 in men). Avoid in active bleeding or pending surgery.
Protein binding
Displaces phenytoin from albumin. On both drugs, follow free phenytoin.
Lacosamide and phenobarbital
Lacosamide
200-400 mg IV (NCS 2012, Class IIb). Off-label for SE and not tested in ESETT. Label allows infusion as fast as 15 min in adults. Dose-dependent PR prolongation; AV block and bradycardia reported, including one patient on a beta blocker during a 15 min infusion. Get an ECG in conduction disease or with other PR-prolonging drugs. CrCl <30: cut the maximum dose by 25%.
Phenobarbital
20 mg/kg IV at 50-100 mg/min (NCS 2012); additional 5-10 mg/kg allowed. AES 2016 uses 15 mg/kg single dose and reserves it for when none of the three ESETT agents is available. Expect hypotension and respiratory depression, especially after benzodiazepines.
Refractory SE means clinical or electrographic seizures continue after an adequate benzodiazepine and an adequate second agent. These doses come from observational data and expert opinion, and the guideline notes doses in practice may be higher, titrated to clinical and EEG response. All require a secured airway and continuous EEG.
Agent
Load
Infusion
Breakthrough
Watch for
Midazolam
0.2 mg/kg at 2 mg/min
0.05-2 mg/kg/h
0.1-0.2 mg/kg bolus; raise 0.05-0.1 mg/kg/h q3-4h
Tachyphylaxis; active metabolite accumulates in renal failure. No propylene glycol.
Propofol
1-2 mg/kg, start 20 mcg/kg/min
30-200 mcg/kg/min
Raise 5-10 mcg/kg/min q5 min, or 1 mg/kg bolus
PRIS: caution >80 mcg/kg/min for >48 h. Follow triglycerides, CK, lactate (q8h in some protocols). Hypotension.
Pentobarbital
5-15 mg/kg at ≤50 mg/min; may give 5-10 mg/kg more
0.5-3 mg/kg (EB Medicine 2025); 0.5-1 mg/kg (ACEP Now 2026)
0.1-5 mg/kg/h (EB Medicine 2025) or 1-5 mg/kg/h (ACEP Now 2026); up to 10 mg/kg/h reported in SRSE
Per neurology
No guideline dose: NCS 2012 lists it only as an alternative. Published regimens vary widely. NMDA antagonism makes sense once GABA-A receptors have internalized. Often paired with midazolam.
EEG targets and weaning (NCS 2012)
When to start cEEG
Within 1 h if ongoing seizures are suspected, and whenever the patient is not back to baseline >10 min after a clinical seizure. Monitor ≥48 h in comatose patients.
Target
Cessation of electrographic seizures (Class I, level B). Burst suppression (8-20 s interburst intervals) or complete suppression are options (Class IIb, level C); the best endpoint is unsettled.
How long
24-48 h of electrographic control, then a slow wean of the infusion while cEEG continues.
Hidden seizures
Ongoing nonconvulsive status despite stopped motor activity in 18-50%. A paralyzed or sedated patient can seize without moving.
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Super-refractory SE is SE that continues 24 h or more after anesthesia starts, or recurs on weaning (Shorvon and Ferlisi, Brain 2012). Options with limited data include ketamine, corticosteroids, IVIG or plasma exchange, inhaled anesthetics, ketogenic diet, hypothermia, ECT, and surgery (NCS 2012). These are epileptology decisions; pharmacy’s job is interactions, carbohydrate content of IV fluids for a ketogenic diet, and propylene glycol load.
Phenytoin Levels: Albumin Correction
Target total 10-20 mcg/mL, or free 1-2 mcg/mL (Dilantin label). The label says to follow free levels in hypoalbuminemia, renal disease, and hepatic disease. Use the equations only when a free level is unavailable or slow. Albumin in g/dL.
Equation
Corrected total =
Use
Classic Winter-Tozer
measured ÷ (0.2 × albumin + 0.1)
Repeatedly shown to overpredict.
Revised, neuro ICU
measured ÷ (0.29 × albumin + 0.1)
Kane, Ann Pharmacother 2013
Revised, elderly and trauma
measured ÷ (0.25 × albumin + 0.1)
Anderson, Ann Pharmacother 1997
ESRD / dialysis
measured ÷ (0.2 × albumin + 0.1)
Soriano, Ann Pharmacother 2017. The old 0.1 renal coefficient correlates poorly. Small sample: get a free level.
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Worked example: total phenytoin 8 mcg/mL, albumin 2.5. Classic Winter-Tozer says 13.3 (looks therapeutic). The 0.29 equation says 9.7 (subtherapeutic). Reloading decisions flip on which equation you use, which is why a free level wins.
Special Situations
Situation
Approach
Eclampsia
Magnesium sulfate 4-6 g IV over 20-30 min, then 1-2 g/h; adjust if creatinine ≥1 mg/dL. No IV: 10 g IM (5 g each buttock), then 5 g IM q4h. If seizures recur on magnesium: lorazepam 4 mg IV (or midazolam 10 mg IM), then fosphenytoin or levetiracetam. Magnesium toxicity: calcium gluconate 1 g IV over 3 min (ACOG algorithm 2023). Magnesium is the anticonvulsant for eclampsia; it is not a general SE drug.
Alcohol use disorder, malnutrition
Thiamine 100 mg IV before dextrose. Hypoglycemia is a reversible cause; check glucose in the first 5 minutes.
Pregnancy, not eclamptic
Standard benzodiazepine dosing. Prefer levetiracetam or fosphenytoin over valproate.
Renal failure
Levetiracetam maintenance is renally adjusted (label). Fosphenytoin adds phosphate. Midazolam has a renally eliminated active metabolite. Lacosamide maximum drops 25% at CrCl <30. Follow free phenytoin.
Small, divided benzodiazepine doses and a late second agent. Lorazepam 2 mg “and see” is the classic error, and ESETT showed underdosing is the norm, not the exception. Give 0.1 mg/kg (max 4 mg), repeat once if needed, and have the second agent hanging by minute 20 so control is achieved within 60 minutes.
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Phenytoin products given too fast or in the wrong units. Phenytoin above 50 mg/min or fosphenytoin above 150 mg PE/min causes hypotension, bradycardia, and arrhythmia. The fosphenytoin label carries a specific dosing-error warning: the dose is in mg PE and the vial is 50 mg PE/mL, so mg and mL get confused. Peripheral IV phenytoin can cause purple glove syndrome; use a large vein.
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Valproate in the wrong patient. POLG mitochondrial disease (fatal liver failure), urea cycle disorders (hyperammonemic coma), pregnancy, and any patient on a carbapenem (subtherapeutic levels and breakthrough seizures). Check the MAR and the history before loading.
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“Stopped shaking” is not “stopped seizing.” Up to half of patients have ongoing nonconvulsive status after motor activity stops. A patient given a paralytic for intubation shows nothing. If they are not waking up, get the EEG.
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Flumazenil in a patient being treated for SE. Using a benzodiazepine for a life-threatening indication such as SE is an absolute contraindication to flumazenil. See the Antidotes Quick Card.