Treatment Of Acute Status Epilepticus Research Articles

Benzodiazepines in the Management of Seizures and Status Epilepticus: A Review of Routes of Delivery, Pharmacokinetics, Efficacy, and Tolerability.

Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA)A receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs—such as intranasal administration—have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE.Graphical

Costs and cost-driving factors of acute treatment of status epilepticus in children and adolescents: A cohort study from Germany.

To provide data on inpatient costs and cost-driving factors in children and adolescents due to non-refractory (NSE), refractory (RSE), and super-refractory status epilepticus (SRSE). All children and adolescents treated for status epilepticus (SE) between 2011 and 2018 at the Frankfurt University Hospital were analyzed for health care utilization. We evaluated 223 admissions in 174 patients (6.8±5.1 years, median 5.5 years, range 0.1-17.5 years, 109 males [62.6%]) treated for SE. Mean costs of hospital treatment were €5,711 (median €2,330, range=€654-€102,414) per patient per admission, with a mean length of stay (LOS) of 9.2 days (median 5.0, range=1-101), resulting in mean costs of €621 per SE treatment day. Course of SE had a significant impact on the mean costs, which were €3,386 in NSE (median €2,139, range €654-€38,236, €529 per treatment day; 37% of total inpatient costs due to SE), €7,409 in RSE (median €2,772, range €700-€38,236; €612 per treatment day, 38% of total inpatient costs due to SE) and €17,436 in SRSE (median €6,911, range €2,138-102,414; €842 per treatment day, 25% of total inpatient costs due to SE). Independent cost-driving factors were three or more treatment steps, acute-symptomatic etiology, and unfavorable modified Rankin Scale score at admission. Increased LOS was predicted by three or more treatment steps and unfavorable modified Rankin Scale score at admission. Overall mortality at discharge was 1.3% (three patients). Acute treatment of SE, and particularly RSE and SRSE, is associated with high hospital costs and prolonged LOS. Patients with disabilities are at risk for an unfavorable course of SE, resulting in prolonged LOS. In general, mortality associated with SE is low in children and adolescents, however three or more treatment steps are associated with high treatment costs.

Efficacy and safety of levetiracetam in Japanese epilepsy patients: A retrospective cohort study

Levetiracetam is an antiepileptic drug with good tolerability that is used for focal and generalized epilepsy as well as acute treatment of status epilepticus; it is also a first-line antiepileptic drug for patients with concomitant medical conditions. The effect of blood levetiracetam concentration on its efficacy and safety in Japanese patients with epilepsy is unknown. This retrospective cohort study compared the efficacy and safety of levetiracetam alone and in combination with other antiepileptic drugs in 255 outpatients with epilepsy treated with levetiracetam. Electronic medical records were accessed to analyse clinical parameters including blood concentrations of levetiracetam and concomitant antiepileptic drugs, clinical laboratory values and adverse reactions. Combination of levetiracetam with antiepileptic drugs, even those that alter cytochrome P450 activity, did not affect blood levetiracetam concentrations. Similarly, levetiracetam use did not significantly affect blood concentrations of concomitantly used antiepileptic drugs. Although blood levetiracetam concentration was significantly increased in older patients and those with renal dysfunction, the rates of adverse reactions were not increased. Levetiracetam may be used effectively and safely without dose adjustment using blood concentration monitoring even when administered in combination with other antiepileptics for Japanese patients with epilepsy.

Recurrent seizures in cats: Treatment - which antiepileptic drugs are recommended?

This review of recurrent seizures in cats is intended for all veterinarians who are facing the challenges of seizure diagnosis and management in the feline patient. Evidence base: Recommendations for diagnosis and management of feline seizure disorders have historically been extrapolated from the canine and human literature. The information and guidance provided in this two-part series is based on a review of the recent published literature addressing seizure disorders and antiepileptic treatment in cats, as well as the authors' clinical experience.

Costs and cost-driving factors for acute treatment of adults with status epilepticus: A multicenter cohort study from Germany.

To provide first data on inpatient costs and cost-driving factors due to nonrefractory status epilepticus (NSE), refractory status epilepticus (RSE), and super-refractory status epilepticus (SRSE). In 2013 and 2014, all adult patients treated due to status epilepticus (SE) at the university hospitals in Frankfurt, Greifswald, and Marburg were analyzed for healthcare utilization. We evaluated 341 admissions in 316 patients (65.7 ± [standard deviation]18.2 years; 135 male) treated for SE. Mean costs of hospital treatment were €14,946 (median €5,278, range €776-€152,911, €787 per treatment day) per patient per admission, with a mean length of stay (LOS) of 19.0 days (median 14.0, range 1-118). Course of SE had a significant impact on mean costs, with €8,314 in NSE (n = 137, median €4,597, €687 per treatment day, 22.3% of total inpatient costs due to SE), €13,399 in RSE (n = 171, median €7,203, €638/day, 45.0% of total costs, p < 0.001), and €50,488 in SRSE (n = 33, median €46,223, €1,365/day, 32.7% of total costs, p < 0.001). Independent cost-driving factors were SRSE, ventilation, and LOS of >14 days. Overall mortality at discharge was 14.4% and significantly higher in RSE/SRSE (20.1%) than in NSE (5.8%). Acute treatment of SE, and particularly SRSE and ventilation, are associated with high hospital costs and prolonged LOS. Extrapolation to the whole of Germany indicates that SE causes hospital costs of >€200 million per year. Along with the demographic change, incidence of SE will increase and costs for hospital treatment and sequelae of SE will rise.

Benzodiazepine selection in the management of status epilepticus: a review.

The choice and route of administration of benzodiazepines for the treatment of acute status epilepticus (SE) in both prehospital and emergency department (ED) settings often vary by provider and institution. Prehospital and ED care often involves intramuscular, intravenous, or rectal administration of these medications. Diazepam, lorazepam, and midazolam are available as parenteral formulations in the United States. A literature review of clinical trials and SE treatment guidelines was conducted in an attempt to identify which benzodiazepine and route are the best treatment option for adult patients with SE. For initial treatment of SE in adults, intravenous lorazepam is the recommended drug of choice. However, evidence suggests that intramuscular midazolam has at least equal efficacy in prehospital settings and may be more appropriate for use in this environment. Despite the support of multiple clinical trials and treatment guidelines, inconsistencies in the treatment of acute SE continue to occur in both the prehospital and ED settings.

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.

Clinical review: status epilepticus.

Status epilepticus (SE) has an annual incidence exceeding 100,000 cases in the United States alone, of which more than 20% result in death. Thus, increased awareness of presentation, etiologies, and treatment of SE is essential in the practice of critical care medicine. This review discusses current definitions of SE, as well as its clinical presentation and classification. The recent literature on epidemiology is reviewed, including morbidity and mortality data. An overview of the systemic pathophysiologic effects of SE is presented. Finally, significant studies on the treatment of acute SE and refractory SE are reviewed, including the use of anticonvulsants, such as benzodiazepines, and other drugs.

The acute effect of valproate on cerebral energy metabolism in mice

Sodium valproate (VPA) is used in the acute treatment of status epilepticus and mania. We studied the acute effect of VPA on cerebral energy metabolism in awake mice that received VPA 400 mg kg −1 and [1- 13C]glucose or [2- 13C]acetate. At 25 min, 13C NMR spectroscopy of brain extracts indicated inhibition of the tricarboxylic acid (TCA) cycle, as could be seen from the accumulation of [4- 13C]glutamate and reduction in [ 13C]aspartate formation. Concomitantly, the level of ATP was reduced by 40%. To identify the enzymatic step at which the TCA cycle was inhibited [U- 14C]α-ketoglutarate was injected intracerebrally. Inhibition of α-ketoglutarate dehydrogenase was evident at 25 min, as shown by accumulation of [ 14C]glutamate. At 45 min the inhibition of α-ketoglutarate dehydrogenase was reversed, shown by both 13C- and 14C-labeling, and the ATP level was normalized. The study shows for the first time that acute administration of VPA causes inhibition of the TCA cycle activity in vivo. The reduction in brain ATP would be expected to reduce neuronal excitability through modulation of sodium channels which may be clinically advantageous in the initial phase of VPA treatment.

Diazepam: intravenous infusion in the treatment of status epilepticus.

As the anticonvulsant plasma level of diazepam (DZP) after intravenous injection is maintained only for a short period, it is profitable to administer DZP as an intravenous infusion. It has, however, been claimed that DZP cannot be mixed with dextrose injection as DZP would precipitate. As this is in contrast to our clinical experience we added DZP of various brands to dextrose injections. A precipitate was in fact found in dextrose injections containing Valium and Stesolid whereas Diazepam A.L. was not only slightly cloudy. The concentration of DZP was, however, the same in all the samples and corresponded to the calculated concentration. The precipitate in the solutions with Valium and Stesolid which did not pass the filter must therefore be due to additives, most probably benzoates. On the basis of these findings and our clinical experience of this mode of administration we recommend the infusion method as one of the most effective in the acute treatment of status epilepticus.