Associate Professor of Neurology, Weill Cornell Medical College; Associate Attending Neurologist; NewYork-Presbyterian Hospital; Adjunct Associate Professor, University of Utah
SYNOPSIS: In an analysis of a large group of patients hospitalized with status epilepticus, based on an administrative database, patients who required a third line of intravenous anesthetic agents had the highest mortality and highest hospital costs.
SOURCE: Guterman EL, Betjemann JP, Aimetti A, et al. Association between treatment progression, disease refractoriness, and burden of illness among hospitalized patients with status epilepticus. JAMA Neurol 2021;78:588-595.
Status epilepticus (SE) is a life-threatening condition affecting 12 to 61 cases per 100,000 population.1-4 SE is treated with benzodiazepines as the first-line antiseizure drug (ASD) followed by intravenous ASDs (i.e., brivaracetam, fosphenytoin, lacosamide, levetiracetam, phenobarbital, phenytoin, and valproic acid).5 If SE does not abate, treatment is continued with intravenous anesthetics (i.e., etomidate, ketamine, midazolam, methohexital, pentobarbital, propofol, and thiopental).5 Often, patients with SE require treatment in an intensive care unit (ICU) setting. Additionally, SE can become refractory SE (RSE) when it requires third-line therapy with intravenous anesthetic infusions to achieve seizure control, or super-refractory SE (SRSE) when SE persists after 24 hours of anesthetic infusion or recurs after weaning of intravenous anesthetic agents.6,7 Therefore, SE often is associated with high morbidity and mortality because of the need for a prolonged ICU stay and mechanical ventilation and its associated medical complications.6-8 These authors investigated differences in clinical outcomes and costs associated with hospitalization for SE of varying degrees of refractoriness.
In a descriptive cross-sectional study of SE using the Premier Healthcare Database from Jan. 1, 2016, to Dec. 31, 2018, the investigators analyzed 43,988 U.S. hospitalizations (of any age) with a primary or secondary ICD-10 diagnosis of SE. Disease refractoriness was classified as low, moderate, or highly refractory based on the use of intravenous ASDs vs. continuously infused intravenous anesthetics. For example, midazolam would be a first-line therapy if administered as an initial bolus injection, but it would be considered a third-line intravenous anesthetic if administered in the ICU on the same day as an intravenous infusion.
Three cohorts were defined: low refractory SE was treatment with none or one intravenous ASD and no third-line intravenous anesthetic; moderate refractory SE was defined as treatment with more than one intravenous ASD and no third-line intravenous anesthetic; and highly refractory SE was defined as treatment with at least one intravenous ASD and at least one third-line intravenous anesthetic. Outcome measures were discharge disposition, need for mechanical ventilation, adverse events, hospital and ICU length of stay (LOS), and cost. A series of pairwise comparisons was done between different groups (basic SE characteristics and outcome data) using a bootstrap-based analysis of variance for parametric data, Kruskal-Wallis tests for nonparametric data, and χ2 tests for categorical data.
From the included 43,988 U.S. SE hospitalizations, 22,851 patients (51.9%) were male with mean age 49.9 years (95% confidence interval, 49.7 to 50.1 years). There were 14,694 admissions (33.4%) for low refractory SE, 10,140 (23.1%) for moderate refractory SE, and 19,154 (43.5%) for highly refractory SE. Overall in-hospital mortality was 11.2%, with the highest mortality rates in highly refractory SE (18.9%) compared with moderate refractory SE (6.3%) and low refractory SE (4.6%). The P value was < 0.001 for all comparisons. Median hospital LOS was five days (interquartile range [IQR], 2 to 10 days) with a greater length of stay in highly refractory SE (eight days; IQR, 4 to 15 days) compared with moderate refractory SE (four days; IQR, 2 to 8 days) and low refractory SE (three days; IQR, 2 to 5 days). Patients with highly refractory SE had greater hospital costs, with median costs of $25,105 (mean, $41,858; standard deviation [SD], $59,063) in the high refractory SE cohort, $10,592 (mean, $18,328; SD, $30,776) in the moderate refractory SE cohort, and $6,812 (mean, $11,532; SD, $17,228) in the low refractory SE cohort.
This study describes the range of morbidity, mortality, and costs associated with SE, with the burden increasing with the higher level of refractoriness. The three cohorts of low, moderate, and highly refractory SE were based on medication treatment and only approximate clinically defined early SE, RSE, and SRSE. About 43.5% of inpatients with SE required more antiseizure and anesthetic medications as a result of refractory disease. They also had higher clinical and financial costs and a higher mortality rate of 18.9% (which was more than 10% higher than moderate and low refractory SE). Patients with high refractory SE also had a longer hospital stay, and, therefore, higher total costs for acute hospitalization.
- Beg JM, Anderson TD, Francis K, et al. Burden of illness for super-refractory status epilepticus patients. J Med Econ 2017;20:45-53.
- Betjemann JP, Josephson SA, Lowenstein DH, Burke JF. Trends in status epilepticus-related hospitalizations and mortality: Redefined in US practice over time. JAMA Neurol 2015;72:650-655.
- Dham BS, Hunter K, Rincon F. The epidemiology of status epilepticus in the United States. Neurocrit Care 2014;20:476-483.
- Logroscino G, Hesdorffer DC, Cascino G, et al. Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus. Epilepsia 2001;42:1031-1035.
- Nelson SE, Varelas PN. Status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Continuum (Minneap Minn) 2018;24:1683-1707.
- Hunter G, Young GB. Status epilepticus: A review, with emphasis on refractory cases. Can J Neurol Sci 2012;39:157-169.
- Ochoa JG, Dougherty M, Papanastassiou A, et al. Treatment of super-refractory status epilepticus: A review. Epilepsy Curr 2021; Mar 10. Doi: 10.1177/1535759721999670. [Online ahead of print].
- Neligan A, Shorvon SD. Frequency and prognosis of convulsive status epilepticus of different causes: A systematic review. Arch Neurol 2010;67:931-940.