Management of Refractory Status Epilepticus
Washington University Emergency Medicine Journal Club– January 20th, 2022
You’re working a shift during your community emergency medicine rotation when EMS rolls in with a 24-year-old female who is currently seizing. The paramedic reports that were called to the scene after the patient had a first ever generalized tonic-clonic seizure. On their arrival she was post-ictal but awake and alert. En route to the ED she began to seize again. They gave her two doses of diazepam, 10 mg each, five minutes apart, but the patient continues to have convulsive activity upon arrival with her eyes deviated to the left. Her current seizure has been ongoing now for a little more than 10 minutes.
The patient’s oxygen saturation on a non-rebreather is 100% and her BP is 160/90 with a heart rate of 116. You begin to ask the nurse to get fosphenytoin from the Pyxis (20 mg phenytoin equivalents (PE)/kg at a rate of 150 mg PE/minute) when your attending suggest giving levetiracetam instead (40 mg/kg at 500 mg/minute) as it can be infused more rapidly.
The nurse administers the levetiracetam as ordered and the patient ultimately stops seizing. As you breathe a huge sigh of relief, you wonder if your attending’s preference for second-line anticonvulsant was truly the better choice. You begin to hunt online for evidence to back up her decision, or to prove her wrong…
Population: Adult and pediatric patients with status epileptics refractory to benzodiazepine therapy
Intervention: IV levetiracetam
Comparison: IV phenytoin or fosphenytoin
Outcome: Cessation of seizure activity, improved responsiveness, need for intubation, hypotension, cardiac dystrhythmia, ICU admission, length of stay, long-term neurologic dysfunction
PubMed was searched using the terms levetiracetam AND (phenytoin OR fosphenytoin) AND “status epilepticus” (https://tinyurl.com/bdfxreta). This resulted in 221 citations, of which the four most relevant were selected. The Cochrane Database of Systematic Reviews was also searched and a single systematic review was identified from September 2014. As the most relevant trials identified in PubMed were published after this date, we elected not to include this report.
Article 1: Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, Rogers A, Barsan W, Cloyd J, Lowenstein D, Bleck TP, Conwit R, Meinzer C, Cock H, Fountain NB, Underwood E, Connor JT, Silbergleit R; Neurological Emergencies Treatment Trials; Pediatric Emergency Care Applied Research Network investigators. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020 Apr 11;395(10231):1217-1224. doi: 10.1016/S0140-6736(20)30611-5. Epub 2020 Mar 20. PMID: 32203691; PMCID: PMC7241415. Answer Key
Article 2: Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, Francis KL, Sharpe C, Harvey AS, Davidson A, Craig S, Phillips N, George S, Rao A, Cheng N, Zhang M, Kochar A, Brabyn C, Oakley E, Babl FE; PREDICT research network. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019 May 25;393(10186):2135-2145. doi: 10.1016/S0140-6736(19)30722-6. Epub 2019 Apr 17. PMID: 31005386. Answer Key
Article 3: Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Hickey H, Woolfall K, Roper L, Noblet J, Lee ED, Potter S, Tate P, Iyer A, Evans V, Appleton RE; Paediatric Emergency Research in the United Kingdom & Ireland (PERUKI) collaborative. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet. 2019 May 25;393(10186):2125-2134. doi: 10.1016/S0140-6736(19)30724-X. Epub 2019 Apr 17. PMID: 31005385; PMCID: PMC6551349. Answer Key
Article 4: Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113. doi: 10.1056/NEJMoa1905795. PMID: 31774955; PMCID: PMC7098487. Answer Key
Status epilepticus is a common neurologic emergency seen in our EDs, with a rising incidence observed between 1999 and 2010 (Betjemann 2015). While mortality is generally lower in pediatric patients than in adults (Dham 2014), approximately 20% of pediatric patients require intubation and ICU admission (Chin 2006). While clinical guidelines universally recommend benzodiazepines as a first-line treatment for status epilepticus in both pediatric and adult patients (Meierkord 2010, Brophy 2012, Glauser 2016), the optimal second-line agent when benzodiazepines fail is less clearly defined. While phenytoin was previously recommended as the second-line agent, the addition of propylene glycol, a known cardiac depressant, necessitated a rather slow maximum infusion rate of 50 mg/min. While the introduction of fosphenytoin in 1996 allowed for more rapid infusion, several recent studies have compared these two agents with intravenous levetiracetam or valproate for management of status epilepticus.
The recently published ESETT trial was a multicenter, double-blind, randomized controlled trial conducted at 57 EDs across the US between November 3, 2015 and October 31, 2017 (Kapur 2019). All patients aged 2 years and older with status epilepticus refractory to benzodiazepine therapy were eligible for enrollment. Out of 400 cases, levetiracetam was administered in 145 cases, fosphenytoin was given in 118 cases, and valproate was given in 121 cases. The primary outcome—cessation of clinically apparent seizure activity with improved responsiveness at 60 minutes after the start of the study drug infusion—was seen in 47% (95% CI 38% to 56%) of patients in the levetiracetam group , 45% (95% CI 36% to 54%) in the fosphenytoin group, and 46% (95% CI 38% to 55%) of the valproate group. There was also no difference in median time to seizure determination (measured in a subset of patients), seizure recurrence, need for ICU admission, median length of hospital or ICU stay, or the prevalence of life-threatening hypotension, arrhythmia, need for endotracheal intubation, mortality, or other safety outcomes.
The authors of the ESETT trial published a second report a year later, including the same cohort plus an additional 78 cases from another ED (Chamberlain 2020). While these additional cases did not have a significant impact on previously reported outcomes (47%, 46%, and 49% for the primary outcome, respectively), endotracheal intubation was noted to occur more frequently in pediatric patients in the fosphenytoin group (33%) compared to the levetiracetam group (8%) and the valproate group (11%).
Further research in pediatric status epilepticus include the ConSEPT and EcLiPSE trials, both of which were published in Lancet in 2019. the ConSEPT trial was an open-label, multicenter, randomized controlled trial conducted at 13 emergency departments in New Zealand and Australia between March 19, 2015 and November 29, 2017. Children aged 3 months to 16 years presenting in convulsive status epilepticus despite receiving two dozes of benzodiazepines were eligible for enrollment. A total of 234 children were enrolled, of whom 115 were randomized to receive phenytoin as second-line agent and 119 were randomized to receive levetiracetam. For the primary outcome—cessation of seizure activity within 5 minutes after completion of the infusion of the first study medication—there was a non-statistically significant trend toward improved rates of cessation in the phenytoin compared to the levetiracetam group (60% vs. 50%; Risk Difference [RD] -9.2%, 95% CI -21.9 to 3.5%). However, it should be noted that the 5-minute time-frame began after administration of the study drug was completed; this seems an unfair comparison given that phenytoin administration occurred over 20 minutes while levetiracetam was administered over only 5 minutes. No differences were seen in need for cessation of seizure activity at 2 hours, need for alternate study drug at 2 hours, median time to seizure cessation, intubation rates at any time, or ICU/hospital length of stay.
The EcLiPSR trial was another open-label, multicenter, randomized controlled trial comparing IV phenytoin with levetiracetam. Conducted at 30 emergency departments in the United Kingdom between July 17, 2015 and April 7, 2018, this trial enrolled pediatric patients aged 6 months to 17 years presenting with convulsive status epilepticus requiring second-line treatment. The modified intention to treat analysis included 152 patients who received levetiracetam and 134 patients who received phenytoin. For the primary outcome, the median time from randomization to seizure cessation was 35 minutes in the levetiracetam group and 45 minutes in the phenytoin group (p = 0.20; unadjusted hazard ratio 1.20 in favor of levetiracetam, 95% CI 0.91 to 1.60). There was no statistically significant difference in the proportion of patients receiving additional anticonvulsants, need for intubation, critical care admission, or adverse events.
Overall, the existing data suggest that levetiracetam is at least as efficacious as fosphenytoin/phenytoin in the management of status epilepticus in both children and adults. There may be some added benefit in children, with one study showing a decreased need for intubation with levetiracetam compared to fosphenytoin.