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Development of benzodiazepines for out-of-hospital management of seizure emergencies.

ABSTRACT: Management of seizure emergencies substantially changed after the introduction of rectal diazepam in Europe in the 1970s and in the United States in the 1990s. Although safe and effective, social objections and legal concerns have limited use of rectal diazepam products in out-of-hospital treatment of seizure emergencies. Shortly after the introduction of Diastat (diazepam rectal gel), commercial development of innovative formulations began involving several benzodiazepines and routes of administration, including buccal, IM, nasal, and subcutaneous. All benzodiazepines have the same mechanism of action; however, there are major differences in physicochemical properties and pharmacokinetic characteristics, which affect the choice of drug and route. This article highlights some of those differences and their effect on selection of therapies for treating seizure emergencies. We also present results from key clinical studies of these drugs and provide an update on current status of new products under development.

SUBMITTER: Agarwal SK

PROVIDER: S-EPMC5764431 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Development of benzodiazepines for out-of-hospital management of seizure emergencies.

Agarwal Suresh K SK Cloyd James C JC

Neurology. Clinical practice 20150201 1

Management of seizure emergencies substantially changed after the introduction of rectal diazepam in Europe in the 1970s and in the United States in the 1990s. Although safe and effective, social objections and legal concerns have limited use of rectal diazepam products in out-of-hospital treatment of seizure emergencies. Shortly after the introduction of Diastat (diazepam rectal gel), commercial development of innovative formulations began involving several benzodiazepines and routes of adminis ...[more]

PMID: 29443201

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Project description:Patients with epilepsy may experience seizure clusters, which are described by the US Food and Drug Administration (FDA) as intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. Untreated seizure clusters may increase the risk for status epilepticus, as well as decrease quality of life and increase burden on patients and care partners. Benzodiazepine therapies are the mainstay for acute treatment of seizure clusters and are often administered by nonmedical care partners outside a healthcare facility. Three rescue therapies are currently FDA-approved for this indication, with diazepam rectal gel being the first in 1997, for patients aged ≥ 2 years. Limitations of rectal administration (e.g., positioning and disrobing the patient, which may affect ease of use and social acceptability; interpatient variation in bioavailability) led to the investigation of the potential for nasal administration as an alternative. Midazolam nasal spray (MDS) was approved by the FDA in 2019 for patients aged ≥ 12 years and diazepam nasal spray (DNS) in 2020 for patients aged ≥ 6 years; these two intranasal therapies have differences in their formulations [e.g., organic solvents (MDS) vs. Intravail and vitamin E for absorption and solubility (DNS)], effectiveness (e.g., proportion of seizure clusters requiring only one dose), and safety profiles. In clinical studies, the proportion of seizure clusters for which only one dose of medication was used varied between the three approved rescue therapies with the highest single-dose rate for any time period for DNS; however, although studies for all three preparations enrolled patients with highly intractable epilepsy, inclusion and exclusion criteria varied, so the three cannot be directly compared. Treatments that have been used off-label for seizure clusters in the USA include midazolam for injection as an intranasal spray (indicated for sedation/anxiolysis/amnesia and anesthesia) and tablet forms of clonazepam (indicated for treatment for seizure disorders) and lorazepam (indicated for anxiety). In the European Union, buccal and intranasal midazolam are used for treating the indication of prolonged, acute convulsive seizures and rectal diazepam solution for the indication of epileptic and febrile convulsions; duration of effectiveness for these medications for the treatment of seizure clusters has not been established. This paper examines the literature context for understanding seizure clusters and their treatment and provides effectiveness, safety, and administration details for the three FDA-approved rescue therapies. Additionally, other medications that are used for rescue therapy in the USA and globally are discussed. Finally, the potential benefits of seizure action plans and candidates for their use are addressed. This paper is intended to provide details about the unique characteristics of rescue therapies for seizure clusters to help clarify appropriate treatment for individual patients.

Project description:Most Medicare patients seeking emergency medical transport are treated by ambulance providers trained in advanced life support (ALS). Evidence supporting the superiority of ALS over basic life support (BLS) is limited, but some studies suggest ALS may harm patients.To compare outcomes after ALS and BLS in out-of-hospital medical emergencies.Observational study with adjustment for propensity score weights and instrumental variable analyses based on county-level variations in ALS use.Traditional Medicare.20% random sample of Medicare beneficiaries from nonrural counties between 2006 and 2011 with major trauma, stroke, acute myocardial infarction (AMI), or respiratory failure.Neurologic functioning and survival to 30 days, 90 days, 1 year, and 2 years.Except in cases of AMI, patients showed superior unadjusted outcomes with BLS despite being older and having more comorbidities. In propensity score analyses, survival to 90 days among patients with trauma, stroke, and respiratory failure was higher with BLS than ALS (6.1 percentage points [95% CI, 5.4 to 6.8 percentage points] for trauma; 7.0 percentage points [CI, 6.2 to 7.7 percentage points] for stroke; and 3.7 percentage points [CI, 2.5 to 4.8 percentage points] for respiratory failure). Patients with AMI did not exhibit differences in survival at 30 days but had better survival at 90 days with ALS (1.0 percentage point [CI, 0.1 to 1.9 percentage points]). Neurologic functioning favored BLS for all diagnoses. Results from instrumental variable analyses were broadly consistent with propensity score analyses for trauma and stroke, showed no survival differences between BLS and ALS for respiratory failure, and showed better survival at all time points with BLS than ALS for patients with AMI.Only Medicare beneficiaries from nonrural counties were studied.Advanced life support is associated with substantially higher mortality for several acute medical emergencies than BLS.National Science Foundation, Agency for Healthcare Research and Quality, and National Institutes of Health.

Project description:ObjectiveTo determine the clinical characteristics, management and outcomes of patients taken to hospital by emergency ambulance after a suspected seizure.DesignQuantitative cross-sectional retrospective study of a consecutive series of patients.SettingAn acute hospital trust in a large city in England.ParticipantsIn 2012-2013, the regions' ambulance service managed 605 481 emergency incidents, 74 141/605 481 originated from Sheffield (a large city in the region), 2121/74 141 (2.9%) were suspected seizures and 178/2121 occurred in May 2012. We undertook detailed analysis of the medical records of the 91/178 patients who were transported to the city's acute hospital. After undertaking a retrospective review of the medical records, the best available aetiological explanation for the seizures was determined.ResultsThe best available aetiological explanation for 74.7% (68/91) of the incidents was an epileptic seizure, 11.0% (10/91) were psychogenic non-epileptic seizures and 9.9% (9/91) were cardiogenic events. The epileptic seizures fall into the following four categories: first epileptic seizure (13.2%, 12/91), epileptic seizure with a historical diagnosis of epilepsy (30.8%, 28/91), recurrent epileptic seizures without a historical diagnosis of epilepsy (20.9%, 19/91) and acute symptomatic seizures (9.9%, 9/91). Of those with seizures (excluding cardiogenic events), 2.4% (2/82) of patients were seizing on arrival in the Emergency Department (ED), 19.5% (16/82) were postictal and 69.5% (57/82) were alert. 63.4% (52/82) were discharged at the end of their ED attendance and 36.5% (19/52) of these had no referral or follow-up.ConclusionsMost suspected seizures are epileptic seizures but this is a diagnostically heterogeneous group. Only a small minority of patients require emergency medical care but most are transported to hospital. Few patients receive expert review and many are discharged home without referral to a specialist leaving them at risk of further seizures and the associated morbidity, mortality and health services costs of poorly controlled epilepsy.

Project description:BACKGROUND:The aims of this study were to survey the occurrence of acute medical situations in Dutch orthodontic practice and to examine the self-perceived competence of orthodontists in managing acute medical emergencies. METHODS:A self-designed questionnaire was distributed among all 149 Dutch orthodontists attending the spring meeting of the Dutch Society for Orthodontists. The questionnaire was divided into three parts, addressing background information of the orthodontist, precautions against and experiences in acute medical situations, and self-perceived competence of nine common medical emergencies. The statistical analysis was performed using the chi-square test and a multiple logistic regression analysis. RESULTS:The response rate was 74.5% (105 out of 149). The male to female ratio in this population was 55:50. Mean age of all participants was 46.9 years (SD 10.4 years) with on average 16.7 years of working experience (SD 10.6 years). The most common medical emergency reported by Dutch orthodontists was vasovagal collapse (n = 219), followed by acute allergic reaction (n = 163) and hyperventilation (n = 83). On average, 75% (n = 79) of the orthodontists felt competent to handle any acute medical situation with an average occurrence of 0.36 acute medical emergencies per orthodontist per year. Male participants were more likely to send patients towards the emergency department (p = 0.049). Moreover, a statistically significant negative correlation was observed between self-perceived competence handling hypoglycemia and years of clinical experience. The longer orthodontists were clinically active, the less competent they felt when encountered with a hypoglycemia (p = 0.031). CONCLUSIONS:Medical emergencies may be rare but challenging occurrences in the orthodontic practice. It is strongly recommended for all orthodontists and supporting staff to be trained regularly in the management of medical emergencies and to possess up-to-date evidence-based knowledge. Familiarity with and availability of appropriate drugs and equipment are deemed essential to the management of acute medical emergencies that may arise in the orthodontic practice.

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Development of benzodiazepines for out-of-hospital management of seizure emergencies.

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Development of benzodiazepines for out-of-hospital management of seizure emergencies.

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