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John M. Pellock, MD Professor and Chairman Division of Child Neurology

Acute, Prolonged Seizures: Identification and Treatment Strategies Is there a need for further trials? . John M. Pellock, MD Professor and Chairman Division of Child Neurology Interim Senior Associate Dean for Professional Education and CEO of UHS-PEP Children’s Hospital of Richmond

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John M. Pellock, MD Professor and Chairman Division of Child Neurology

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  1. Acute, Prolonged Seizures: Identification and Treatment StrategiesIs there a need for further trials? John M. Pellock, MD Professor and Chairman Division of Child Neurology Interim Senior Associate Dean for Professional Education and CEO of UHS-PEP Children’s Hospital of Richmond Virginia Commonwealth University/Medical College of Virginia Richmond, VA USA

  2. Division of Child Neurology Children’s Pavilion 1001 East Marshall Street, First Floor Richmond, Virginia 23298-0211

  3. John M. Pellock, MD Professor and Chairman, Division of Child Neurology Virginia Commonwealth University/ Medical College of Virginia Children’s Hospital of Richmond Richmond, Virginia Dr. Pellock has received grants/research support in excess of $10,000 and is a paid consultant as listed below. All grants, research support, consultant fees and honoraria are paid to Virginia Commonwealth University or the physician practice plan (MCV Physicians). Dr. Pellock has NO equity, stock or any other ownership interest in any of these companies. 10/2013

  4. Status Epilepticus: Epidemiology • A prolonged seizure or recurrent seizures without recovery of consciousness • Annual Incidence of status epilepticus is 41-61 / 100,000 • Annual mortality of Status Epilepticus is 19 / 100,000 From Delorenzo et al. Neurology 1996 46: 1029-1035 Other studies report lower incidence, see: A systematic review of Epidemiology of SE, European Journal of Neurology 2004, 11: 800-810.

  5. Mortality After Initial Pediatric Status Epilepticus % 1 Age (Years) 1 Logroscino G et al, Epilepsia, 1997; 38: 1344-1349. Barry E, Hauser WA, Neurol., 1993; 43: 1473-1478.

  6. Treatment of Status Epilepticus 1. Lorazepam 0.1 mg/Kg at 2 < mg/min; if seizures stop, no other therapy may be required if cause is corrected. 2. Fosphenytoin 20 mg PE/Kg at 3 mg PE/Kg/min (150 mg PE/min max) 3. Fosphenytoin 5-10 mg PE/Kg Lowenstein DH, Alldredge BK. N Engl J Med, 1998: 970-976. Cochrane Database Syst Rev. 2008;16 (3): CD001905

  7. Treatment of Status Epilepticus (cont’d) 4. Phenobarbital 20 mg/Kg at 50-75 mg/min 5. Phenobarbital 10 mg/Kg 6. Anesthesia: Phenobarbital Midazolam Propofol Midazolam 0.2 mg/Kg, then 1-10 µm/Kg/min Lowenstein DH, Allredge BK. N Engl J Med, 1998: 970-976.

  8. SE: Treatment Overview Rossetti & Lowenstein Lancet Neurol 2011

  9. Treatment of Convulsive Status Epilepticus in Adults and Children: A Systematic Review and Treatment Algorithm Tracy Glauser, MD, ShlomoShinnar, MD, PhD, Lisa Garrity, PharmD,Jacquelyn Bainbridge, PharmD, Mary Bare, MD, Thomas Bleck, MD, W. Edwin Dodson, MD, Andy Jagoda, MD, Daniel Lowenstein, MD, John Pellock, MD, James Riviello, MD, Edward Sloan, MD, David Treiman, MD

  10. Glauser, et. al., in press, 2014 Proposed treatment algorithm for status epilepticus Interventions IV Access Available Seizure continues

  11. Methods • Randomized, double blind comparison of fosphenytoin(FOS) levetiracetam (LVT), and valproic acid (VPA). • Primary Outcome: Clinical determination of cessation of seizures, as defined by the termination of clinical seizures within 20 minutes of beginning of drug infusion and improving mental status, and without further intervention, sustained hypotension or cardiac arrhythmias, maintained until 1 hour after starting treatment. • Secondary Outcomes: 1) efficacy in children; 2) duration of SE; 3) intubation within 24 hours; 4) admission to ICU within 24 hours; 4) mortality.

  12. Initial treatment of generalized convulsive SE: Benzodiazepines PHTSE 60 Lorazepam Diazepam Placebo 40 Number of patients 20 0 Convusions stopped Ongoing RAMPART 400 Lorazepam 300 Midazolam Number of patients 200 100 0 Ongoing Seizure stopped 1) PECARN study: Use of lorazepamfor the treatment of pediatric status epilepticus: a randomized, double-blinded trial of lorazepamand diazepam

  13. RAMPART Selbergleit, et al. NEJM, 366;7, Feb 2012

  14. Intramuscular Midazolam Is The Best Option For The Prehospital Treatment Of Status Epilepticus R. Sibergleit et al. Epilepsia. 54 (Suppl. 6):74-77, 2013

  15. Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools? Cross JH, Wait S, Arzimanoglou A, Beghi E, Bennett C, Lagae L, Mifsud J, Schmidt D, Harvey G. Source UCL Institute of Child Health, Great Ormond Street Hospital NHS Foundation Trust, , London, UK. Abstract OBJECTIVE: This paper explores the issues that arise from the discussion of administering rescue medication to children who experience prolonged convulsive seizures in mainstream schools in the UK. SITUATION ANALYSIS: Current guidelines recommend immediate treatment of children with such seizures (defined as seizures lasting more than 5 min) to prevent progression to status epilepticus and neurological morbidity. As children are unconscious during prolonged convulsive seizures, whether or not they receive their treatment in time depends on the presence of a teacher or other member of staff trained and able to administer rescue medication. However, it is thought that the situation varies between schools and depends mainly on the goodwill and resources available locally. RECOMMENDATIONS: A more systematic response is needed to ensure that children receive rescue medication regardless of where their seizure occurs. Possible ways forward include: greater use of training resources for schools available from epilepsy voluntary sector organisations; consistent, practical information to schools; transparent guidance outlining a clear care pathway from the hospital to the school; and implementation and adherence to each child's individual healthcare plan. IMPLICATIONS: Children requiring emergency treatment for prolonged convulsive seizures during school hours test the goals of integrated, person-centred care as well as joined-up working to which the National Health Service (NHS) aspires. As changes to the NHS come into play and local services become reconfigured, every effort should be made to take account of the particular needs of this vulnerable group of children within broader efforts to improve the quality of paediatric epilepsy services overall. Arch Dis Child. 2013 Oct;98(10):777-80. doi: 10.1136/archdischild-2013-304089. Epub 2013 Jul 30.

  16. Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. Chin RF, Verhulst L, Neville BG, Peters MJ, Scott RC. Source Neurosciences Unit, Institute of Child Health, University College London, WC1N 1EH, UK. r.chin@ich.ucl.ac.uk Abstract OBJECTIVES: To characterise the clinical features, emergency pre-paediatric intensive care (PIC) treatment, and course of status epilepticus (SE) in children admitted to PIC. This may provide insight into reasons for admission to PIC and provide a framework for the development of strategies that decrease the requirement for intensive care. DESIGN: Cross sectional, retrospective study. SETTING: A tertiary paediatric institution's intensive care unit. PARTICIPANTS: The admission database and all discharge summaries of each admission to a tertiary paediatric institution's PIC over a three year period were searched for children aged between 29 days and 15 years with a diagnosis of SE or related diagnoses. The case notes of potential cases of SE were systematically reviewed, and clinical and demographic data extracted using a standard data collection form. RESULTS: Most children with SE admitted to PIC are aged less than 5 years, male to female ratio 1:1, and most (77%) will have had no previous episodes of SE. Prolonged febrile convulsions, SE related to central nervous system infection, and SE associated with epilepsy occur in similar proportions. Contrary to the Advanced Paediatric Life Support guidelines many children admitted to PIC for SE receive over two doses, or inadequate doses, of benzodiazepine. There is a risk of respiratory depression following administration of over two doses of benzodiazepine (chi2 = 3.4, p = 0.066). Children with SE admitted to PIC who had prehospital emergency treatment are more likely to receive over two doses of benzodiazepines (chi2 = 11.5, p = 0.001), and to subsequently develop respiratory insufficiency (chi2 = 6.2, p = 0.01). Mortality is low. Further study is required to determine the morbidity associated with SE in childhood requiring intensive care. CONCLUSIONS: As the risk of respiratory depression is greater with more than two doses of benzodiazepines, clinicians should not disregard prehospital treatment of SE. As pre-PIC treatment of SE is inadequate in many cases, appropriate audit and modifications of standard guidelines are required. J NeurolNeurosurg Psychiatry. 2004 Nov;75(11):1584-8.

  17. FEBSTAT Treatment • Recognition • EMS on arrival did not recognize 12% of seizure (18 children) • EMS during transport did not recognize 20 % of seizure (31 children) • Only 40% (73 children) were given AED by EMS • Median seizure duration 68 minutes for subjects given medication prior to ED and median seizure duration 72 minutes for subjects given treatment ONLY by ED • Median time from the seizure onset to the first dose of medication by EMS or ED was 30 minutes • 2.72 minute delay in administration of 1st AED is associated with a 1.32 minute increase in seizure duration Seinfeld et al. in press

  18. FEBSTAT Treatment (continued) • 83 children given lorazepam as 1st AED • Optimal dose: > 0.05 mg/kg IV/IO/IM • 24 suboptimal doses • 83 children given diazepam as 1st AED • Optimal dose: > 0.3 mg/kg pr OR > 0.1 mg/kg IV/IO/IM • 32 suboptimal dose • Children given respiratory support had more AEDs (p = <0.0001) • Median seizure duration for respiratory support group 83 minutes; non-respiratory support group 58 minutes (p= 0.0003) Seinfeld et al. in press

  19. Benzodiazapine for Acute Seizures • Which • Preparation • Route of administration • Time to seizure cessation or to next event

  20. Studies of Prolonged/Recurrent Seizures • Carefully define inclusion • Age • Etiology • Time to treatment • Dosing • Ethical considerations (Equipoise?) • Exclusion • Medication failure (adequate Rx?) • Single or multiple events/recurrence

  21. Studies of Prolonged/Recurrent Seizures • Outcome measures • Clinical cessation • EEG (how) • Stop event versus seizure freedom for X hours • Tolerability • Ease of use • Statistical reliability (controlled, non-inferiority, etc.)

  22. Treatment of Acute Seizures:Practical Considerations: • Medication availability • Licensure (adults/pediatrics/age) • Pharmacometric characteristics • Ease of administration • Social acceptance • Cost • Public acceptance

  23. Status Epilepticus : ThinkTime • Time to treatment needs to be shorter. • Response to treatment is time dependent. • Morbidity and mortality are related to etiology and duration (time) of status epilepticus. • Subsequent epilepsy may depend on the duration (length of time) of the status epilepticus. • Prolonged seizures predict future prolonged seizures.

  24. Acute, Prolonged Seizures: Identification and Treatment StrategiesIs there a need for further trials? Do we need further studies? YES!!!! • Neonates • 1st line, 2nd line, refractory SE? • Public health practices • Education, recognition • Following emergency protocols

  25. Acute, Prolonged Seizures: Identification and Treatment StrategiesIs there a need for further trials? Challenges – • Controlled but probably not DBPC • Large consortia; well defined study criteria and endpoints; observational • Stratify by age, time to treatment, etiology

  26. Status Epilepticus This is a medical emergency. Have a treatment plan. You can do it. Stay calm. Persons with epilepsy should have an individualized emergencyplan in place.

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