Delayed first-line treatment of refractory convulsive status epilepticus (SE) led to a higher frequency of death, a 5-year observational study from the Pediatric Status Epilepticus Research Group found.
Pediatric patients who received first-line benzodiazepine treatment 10 minutes or more after SE onset had a much higher chance of death (adjusted OR 11.0), greater odds of receiving continuous infusion (adjusted OR 1.8), longer convulsive seizure durations (adjusted OR 2.6), and more frequent hypotension (adjusted OR 2.3), reported Tobias Loddenkemper, MD, director of Clinical Epilepsy Research at Boston Children’s Hospital. and colleagues.
First-line treatment delays also were linked to delays in administering second- and third-line treatments.
“These findings may change the perception of acute seizure and status epilepticus treatment, tentatively converting it into an extremely time-sensitive emergency that is similar to stroke or other cardiovascular events,” the team wrote online in JAMA Neurology.
“This is the first pediatric study on refractory convulsive SE that demonstrates a link between delayed treatment and poor outcomes and suggests that timely treatment may be a method to prevent or improve such outcomes,” commented Anup D. Patel, MD, section chief of Neurology at Nationwide Children’s Hospital in Columbus, OH, writing in an accompanying editorial.
“Status epilepticus is life threatening and affects a high percentage of children. Both short-term and long-term morbidity and mortality risks are present for children who experience SE. Methods to improve these outcomes are thus desperately needed.”
Current SE treatment protocols recommend that patients receive first-line treatment — a benzodiazepine — within 5 to 10 minutes of seizure onset. This usually is followed by a second-line treatment of a non-benzodiazepine anti-seizure medication 10 to 20 minutes later. If SE persists, patients may receive a third-line treatment — anesthetic agents by continuous infusion — within 30 to 70 minutes of seizure onset.
The rationale is to stop seizures quickly and reduce the risk of brain damage and other complications. Studies have shown that seizures usually last less than 10 minutes; seizures lasting longer often do not stop spontaneously.
While time to treatment has been associated independently with SE duration, the effects on other outcome measurements like death were unknown.
To discover how timing mattered, Loddenkemper et al performed an observational study of 218 children admitted with refractory convulsive SE to 11 pediatric tertiary hospitals in the United States from June 1, 2011, to July 31, 2016. Patients were stratified into two groups: those who received timely first-line benzodiazepine (i.e., given within less than 10 minutes of seizure onset); and those who received treatment within 10 or more minutes.
Patients were ages 1 month to 21 years, had focal or generalized convulsive epileptic seizures at onset, and had treatment failure with two or more anti-seizure medications or started continuous infusion for seizure control.
The median age of the group was 4, and 53.2% were male. Of the 218 patients studied, 33.9% received first-line benzodiazepine treatment in less than 10 minutes, and 66.1% received it in 10 minutes or more. In 63.8% of patients, refractory convulsive SE started in a pre-hospital setting.
The median time to first-line benzodiazepine treatment was 17 minutes; it was longer in the pre-hospital group than the in-hospital cohort (25 minutes versus 8 minutes). The median time to the first administration of non-benzodiazepine anti-seizure medications was 63 minutes — that, too, was longer for the pre-hospital group (82 minutes) than the in-hospital group (40 minutes).
During hospital admission, seven patients (3.2%) died. All seven received untimely first-line benzodiazepine treatment, and five of the seven had pre-hospital SE onset. Multivariate analysis showed that untimely first-line benzodiazepine treatment had an adjusted OR of death of 11.0 (95% CI 1.43 to ∞; P=0.02.).
About half of the patients in the study — 112, or 51.4% — received a continuous infusion; of these, 71.4% had received untimely first-line treatment (P=0.09). The untimely treatment group was more likely to receive one or more continuous infusions (adjusted OR, 1.8; 95% CI 1.01-3.36; P=0.047).
The median convulsion duration was 48.5 minutes longer for patients who received untimely first-line benzodiazepine treatment (91 versus 139.5 minutes; P=0.03).
More work is needed to improve outcomes, especially in the pre-hospital setting, Patel noted: “Evidence-based guidelines exist for the pre-hospital treatment of seizures and most emergency medical services have independent protocols, but it is not known if these guidelines are implemented uniformly by emergency medical services personnel.
“Standardization of these protocols using guidelines may improve outcomes and is a good first step.”
The study has several limitations, the researchers noted. They did not determine the association between the dose of benzodiazepine and outcomes, and the small number of overall deaths in the study limited the number of confounders in the analysis; other confounders may have influenced mortality and other outcomes. In the pre-hospital setting, times to treatment were based on information provided by families, although the researchers corroborated data with emergency medical services reports and medical records when available.
In addition, the team said, the findings do not include patients whose seizures spontaneously stopped, or stopped after medication before coming to the hospital; the findings apply only to pediatric patients with refractory convulsive SE.
The study and the Pediatric Status Epilepticus Research Group consortium of 11 tertiary pediatric hospitals in the United States are funded by the Epilepsy Research Fund and the Pediatric Epilepsy Research Foundation.
The researchers reported financial relationships with Ovation Pharmaceuticals, King Pharmaceuticals, PRA International/Eisai, Johnson & Johnson, Lily, GlaxoSmithKline, Pfizer, Siemens, General Electric, Supernus, AssureX Health, Sage Therapeutics, GWPharm, Novartis, Lundbeck, Upsher-Smith, Acorda, and Zogenix.
Patel reported financial relationships with Greenwich Biosciences, UCB Pharma, Supernus, LivaNova, and Upsher-Smith.