Super-refractory status epilepticus (SE) is a stage of refractory SE characterized by unresponsiveness to initial anesthetic therapy. It is a new concept that has been the focus of recent basic and therapeutic work, and is defined as "SE that continues or recurs 24 hours or more after the onset of anesthesia, including those cases in which SE recurs on the reduction or withdrawl of anesthesia." It is encountered typically, but not exclusively, in two quite distinctive clinical situations: (1) in patients with severe acute brain injury, and (2) in patients with no history of epilepsy in whom status epilepticus develops out of the blue with no overt cause. There are a variety of treatments used, almost entirely based on open observational studies or case reports. Therapy includes anesthesia, antiepileptic drug therapy, hypothermia and ICU therapy, other medical, immunological, and physical therapies. In this review, the range of possible therapies is outlined and an approach to therapy is discussed.
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Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset of anaesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia. It is an uncommon but important clinical problem with high mortality and morbidity rates. This article reviews the treatment approaches. There are no controlled or randomized studies, and so therapy has to be based on clinical reports and opinion. The published world literature on the following treatments was critically evaluated: anaesthetic agents, anti-epileptic drugs, magnesium infusion, pyridoxine, steroids and immunotherapy, ketogenic diet, hypothermia, emergency resective neurosurgery and multiple subpial transection, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, electroconvulsive therapy, drainage of the cerebrospinal fluid and other older drug therapies. The importance of treating the identifying cause is stressed. A protocol and flowchart for managing super-refractory status epilepticus is suggested. In view of the small number of published reports, there is an urgent need for the establishment of a database of outcomes of individual therapies.
Super-refractory status epilepticus is a neurological emergency with high potential for morbidity and mortality if not recognized early. Approximately 23% to 48% of established patients with SE progress to RSE, and 22% of patients with RSE transition to SRSE.5 In some cases, SRSE may develop because of inadequate treatment of RSE, but in others, the progression to SRSE is due to the underlying etiology such as infection, inflammatory, or anatomical/structural cause.4 A small retrospective study of SRSE in children found that 47% had immune-mediated encephalitis.6
Super-refractory status epilepticus carries a substantial risk of poor neurological outcomes. In a review of 596 cases, 35% returned to baseline, 13% had a severe neurological deficit, 13% had mild neurological deficit, 4% had undefined deficit, and 35% died.7 One study found progressive brain atrophy in 19 patients with SRSE who underwent serial imaging.8
When SE persists after the first 24 hours and fail typical treatments, the evidence is more diluted. In desperation to offer a therapy for these patients, clinicians have explored multiple unconventional treatments that lack evidence of efficacy or safety. Among the therapies reviewed here, we found mostly class IV studies. Some therapies carry a significant health risk. For example, therapeutic hypothermia may cause venous thrombosis and pulmonary embolism; inhalation anesthetics may cause neurotoxicity. Other therapies such as lidocaine, PGB, perampanel, and VNS had very little data to support their use. Ketogenic diet has been used mainly in children with class IV evidence. Brain surgery may be reserved for patients with a well-defined super-refractory seizure focus in a noneloquent cortex after other treatments have failed.
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The loading dose of midazolam in the treatment of refractory status epilepticus is 0.2-0.4 mg/kg IV every 5 minutes until seizures are controlled with a maximum dose of 2 mg/kg [6]. Its maintenance infusion rate is 0.1-2.0 mg/kg/h [6]. Adverse effects include respiratory depression, in which patients often require intubation and mechanical ventilation [10], and hypotension, in which 30-50% of patients will require pressors [11]. For the treatment of pediatric SE, a recent study involving 34 Japanese children was conducted in which an initial bolus of 0.15 mg/kg midazolam was given, with additional doses of 0.1-0.3 mg/kg to a cumulative dose of 0.6 mg/kg [12]. For high-risk patients, a continuous infusion at 0.1 mg/kg/h, with a maximum of 0.4 mg/kg/h, was administered [12]. This dosing regimen achieved a good cessation rate of 88%, suggesting that midazolam is suitable for pediatric patients as a first-line treatment [12].
Gaspard and his colleagues investigated the use of ketamine in seven patients critically ill with SRSE and found that the drug produced electroencephalographic control of the crisis in 50% of cases without causing hemodynamic instability [34]. Shet and Gidal found that the use of ketamine in refractory cases was able to keep seizures under control [31]. Furthermore, Gaspard et al. showed in a retrospective study that the use of ketamine in refractory status epilepticus resulted in 57% (34/60) of cases in which seizures were resolved, 32% (19/60) of cases in which seizures were terminated, and approximately 13% (8/60) of cases in which seizures were controlled with the administration of intravenous ketamine [34]. The loading dose of ketamine is 1-3 mg/kg and the maintenance dose is 5-7.5 mg/kg/h [35].
Status epilepticus is defined as super-refractory when seizures continue clinically or electrographically on continuous video EEG monitoring for more than 24 hours despite induction of pharmacologically induced coma with highly sedating anesthetic agents, or recurrence of seizures when weaning off from anesthetics [4,5].
Management of super-refractory status epilepticus requires monitoring in the intensive care unit with anesthetics and anticonvulsants. Benzodiazepines remain the first-line agents in status epilepticus and require midazolam with assisted mechanical ventilation with continued seizure activity. Second-line anticonvulsants may follow. The commonly used second-line anticonvulsants are phenytoin, phenobarbital, and levetiracetam. There is limited evidence that one is superior to the other when compared in clinical trials. The choice depends on the existing comorbidities in each patient. Levetiracetam is avoided in patients with renal failure, and phenytoin and phenobarbital are avoided in patients with hepatic dysfunction. Super-refractory status epilepticus warrants the need for third-line agents and if needed. Additional options including hypothermia, electroconvulsive therapy, and infusions of pyridoxine and magnesium. Lesionectomy and resective epilepsy surgery are indicated in the case of an identified lesion being the epileptogenic focus including tumors, cavernous malformations, medial temporal sclerosis, or in cases of herpes encephalitis with a predilection for the temporal lobe. CSF drainage is also used in limited cases. Neuromodulation techniques are used in select cases including transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation [4,5]. 2351a5e196
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