The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus

The Established Status Epilepticus Treatment Trial was a blinded, comparative‐effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine‐refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight‐based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight‐normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54‐1.51) or >90 kg (OR = 0.85, 95% CI = 0.42‐1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings

Behaviour of motor unit action potential rate, estimated from surface EMG, as a measure of muscle activation level

BACKGROUND: Surface electromyography (EMG) parameters such as root-mean-square value (RMS) are commonly used to assess the muscle activation level that is imposed by the central nervous system (CNS). However, RMS is influenced not only by motor control aspects, but also by peripheral properties of the muscle and recording setup. To assess motor control separately, the number of motor unit action potentials (MUAPs) per second, or MUAP Rate (MR) is a potentially useful measure. MR is the sum of the firing rates of the contributing MUs and as such reflects the two parameters that the CNS uses for motor control: number of MUs and firing rate. MR can be estimated from multi-channel surface EMG recordings. The objective of this study was to explore the behaviour of estimated MR (eMR) in relation to number of active MUs and firing rate. Furthermore, the influence of parameters related to peripheral muscle properties and recording setup (number of fibers per MU, fiber diameter, thickness of the subcutaneous layer, signal-to-noise-ratio) on eMR was compared with their influence on RMS. METHODS: Physiological parameters were varied in a simulation model that generated multi-channel EMG signals. The behaviour of eMR in simulated conditions was compared with its behaviour in experimental conditions. Experimental data was obtained from the upper trapezius muscle during a shoulder elevation task (20–100 N). RESULTS: The simulations showed strong, monotonously increasing relations between eMR and number of active MUs and firing rate (r(2 )> 0.95). Because of unrecognized superimpositions of MUAPs, eMR was substantially lower than the actual MUAP Rate (aMR). The percentage of detected MUAPs decreased with aMR, but the relation between eMR and aMR was rather stable in all simulated conditions. In contrast to RMS, eMR was not affected by number of fibers per MU, fiber diameter and thickness of the subcutaneous layer. Experimental data showed a strong relation between eMR and force (individual second order polynomial regression: 0.96 < r(2 )< 0.99). CONCLUSION: Although the actual number of MUAPs in the signal cannot be accurately extracted with the present method, the stability of the relation between eMR and aMR and its independence of muscle properties make eMR a suitable parameter to assess the input from the CNS to the muscle at low contraction levels non-invasively

The tetanic depression in fast motor units of mammalian skeletal muscle can be evoked by lengthening of one initial interpulse interval

A lower than expected tetanic force (the tetanic depression) is regularly observed in fast motor units (MUs) when a higher stimulation frequency immediately follows a lower one. The aim of the present study was to determine whether prolongation of only the first interpulse interval (IPI) resulted in tetanic depression. The experiments were carried out on fast MUs of the medial gastrocnemius muscle in cats and rats. The tetanic depression was measured in each case as the force decrease of a tetanus with one IPI prolonged in relation to the tetanic force at the respective constant stimulation frequency. Force depression was observed in all cases studied and was considerably greater in cats. For cats, the mean values of force depression amounted to 28.64% for FR and 10.86% for FF MUs whereas for rats 9.30 and 7.21% for FR and FF motor units, respectively. Since the phenomenon of tetanic depression in mammalian muscle is commonly observed even after a change in only the initial interpulse interval within a stimulation pattern, it can effectively influence processes of force regulation during voluntary activity of a muscle, when motoneurones progressively increase the firing rate

Amyotrophic Lateral Sclerosis: An Emerging Era of Collaborative Gene Discovery

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS

Underdosing of Benzodiazepines in Patients With Status Epilepticus Enrolled in Established Status Epilepticus Treatment Trial

Benzodiazepines, including diazepam (DZP), lorazepam (LZP), and midazolam (MDZ), are considered the initial drugs of choice for status epilepticus (SE) treatment. A number of trials have demonstrated their safety and efficacy; however, the failure rate ranges from 10‐55%.1,2 This may be attributable, in part, to sub‐optimal benzodiazepine dosing and timing of administration. The Neurocritical Care Society (NCS) and American Epilepsy Society (AES) have published evidence‐based guidelines for benzodiazepine use in SE that specify drugs, doses, and routes of administration

Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial

Objective This study was undertaken to describe patterns of benzodiazepine use as first‐line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second‐line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). Methods Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second‐line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline‐recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second‐line agent. Results Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second‐line medications in these benzodiazepine‐refractory seizures. Significance Benzodiazepines as first‐line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.

Surface EMG Fatigue Analysis by Means of Homomorphic Deconvolution

In this paper we use homomorphic deconvolution to obtain the power spectrum of the motor unit action potential (MUAP) from the surface electromyography (sEMG) signal. This spectrum is then used to extract the parameters of a time-domain model of the MUAP itself, in particular its amplitude and time scale. The analysis of the extracted parameters leads to the estimation of cadence and muscle fatigue. The methodology is tested with a sEMG signal recorded during biceps curl exercises