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Neurological Emergencies Treatment Trials Network

Neurological Emergencies Treatment Trials Network. RAMPART Overview Robert Silbergleit. R apid A nticonvulsant M edication P rior to Ar rival T rial (RAMPART). Paramedic treatment of status epilepticus Standard treatment is IV benzodiazepine

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Neurological Emergencies Treatment Trials Network

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  1. Neurological EmergenciesTreatment Trials Network RAMPARTOverview RobertSilbergleit

  2. Rapid Anticonvulsant MedicationPrior to Arrival Trial (RAMPART) • Paramedic treatment of status epilepticus • Standard treatment is IV benzodiazepine • IV starts difficult / dangerous in the convulsing patient • Best IV agent, lorazepam, impractical for EMS • IM treatment is faster and easier • Best IM agent, midazolam, is practical for EMS

  3. Rapid Anticonvulsant MedicationPrior to Arrival Trial (RAMPART) • IM midazolam autoinjector v. IV lorazepam • Double dummy blinded design • Exception to consent for emergency research • Outcome: termination of seizure prior to ED arrival • Sample 700 patients (350 per group) • Intention to treat, non-inferiority analysis

  4. 120,000 to 200,000 cases / yr Mortality 22% at 30 days 55,000 deaths in the US 1st Yr cost $40,000 /patient Bassin S, et al. Crit Care 2002;6(2):137-42 Claassen J, et al. Neurology 2002;58(1):139-42 DeLorenzo RJ, et al. Neurology 1996;46(4):1029-35 Penberthy LT, et al. Seizure 2005;14(1):46-51 Wu YW, et al. Neurology 2002;58(7):1070-6 Status Epilepticus

  5. Pre-hospital care issues • PHTSE trial proved EMS treatment effective • Ideal agent and route remain unknown • Convulsions can make IV placement challenging • Lorazepam has stocking / cost concerns • Mass casualty / battlefield are special concerns

  6. Intramuscular midazolam • Favorable pharmacology for treatment of SE • Effectiveness • Rapidity • Better stability – lower cost • Increasing acceptance by EMS • Optimal agent for organophosphate toxicity

  7. Midazolam levels near 80% of peak as early as 5 minutes after IM administration Alfonzo-Echeverri, Anesth Prog 1990;37:277-281

  8. IM midazolam stops seizures 4 times faster than IM diazepam (in mice) Raines, Epilepsia. 1990;31:313-7

  9. Brain midazolam concentration remains high even as serum concentration is dropping Megarbane, Toxicology Letters 2005;159:22–31

  10. Duration of seizure suppression with midazolam is hours, and similar to that of diazepam Towne, J Emerg Med 1999;17:323–328

  11. Meta-analysis of IM/IN midazolam shows the same efficacy as IV diazepam Review: IV diazepam versus IM/IN midazolam for treatment of seizures Comparison: 01 Effectiveness of IM/IN MDZ as compared to IV DZP Outcome: 01 Termination of seizure IVDiazepam IM/INMidazolam RR (fixed) Weight RR (fixed) Study n/N n/N 95% CI % 95% CI Chamberlain 8.99 0.92 [0.69, 1.21] 11/13 12/13 Lahat 17.23 1.04 [0.87, 1.25] 24/26 23/26 Rainbow 19.96 0.73 [0.47, 1.12] 23/62 23/45 Mahmoudian 15.73 1.33 [0.97, 1.83] 28/35 21/35 38.10 0.92 [0.80, 1.07] Shah 54/65 45/50 Total (95% CI) 201 169 100.00 0.97 [0.86, 1.09] 0.5 0.7 1 1.5 2 Favors IM/IN MDZ Favors IV DZP Total events: 140 (IV Diazepam), 124 (IM/IN Midazolam) Test for heterogeneity: Chi² = 6.87, df = 4 (P = 0.14), I² = 41.8% Test for overall effect: Z = 0.54 (P = 0.59)

  12. Meta-analysis of IM/IN midazolam shows more rapid termination of seizures compared to IV diazepam Review: IV diazepam versus IM/IN midazolam for treatment of seizures Comparison: 01 Effectiveness of IM/IN MDZ as compared to IV DZP Outcome: 02 Time to seizure control IV DZP IM/IN MDZ WMD (fixed) Weight WMD (fixed) Study N Mean (SD) N Mean (SD) 95% CI % 95% CI 11 11.20(3.60) 13 7.80(4.10) 3.51 3.40 [0.32, 6.48] Chamberlain 26 8.00(4.10) 26 6.10(3.60) 7.58 1.90 [-0.20, 4.00] Lahat 65 4.20(2.30) 50 1.60(0.90) 88.91 2.60 [1.99, 3.21] Shah 102 89 100.00 2.58 [2.00, 3.15] Total (95% CI) -10 -5 0 5 10 Favors IM/IN MDZ Favors IV DZP Test for heterogeneity: Chi² = 0.68, df = 2 (P = 0.71), I² = 0% Test for overall effect: Z = 8.74 (P < 0.00001)

  13. Hypotheses Primary • IM midazolam is as effective as IV lorazepam at stopping convulsions prior to ED arrival Secondary • Convulsions stop more rapidly with treatment with IM midazolam versus IV lorazepam • There is no difference in safety between the two treatments

  14. Inclusion criteria • Continuous or repeated convulsive seizure activity for > 5 minutes • Patient is still seizing • Estimated weight > 13 kg

  15. Exclusion criteria • Major trauma precipitating seizure • Hypoglycemia • Known allergy to midazolam or lorazepam • Sensitivity to benzodiazepines • Cardiac arrest or heart rate <40 beats/minute • Known pregnancy • Prisoner

  16. Intervention - Dose • Two packages in each box, Child dose and Adult dose • Each package has one IM injector, one IV dose, one of which is active, the other is dummy • Child (13- 39 kg) – Lorazepam 2 mg or Midazolam 5 mg • Adult (40 kg and up)– Lorazepam 4 mg or Midazolam 10 mg • Midazolam is in an autoinjector • Lorazepam is given IV

  17. Providing data loggers, stepper controllers, data acquisition and custom engineering services to customers worldwide RAMPART Datalogger

  18. Intervention • Medic arrives on scene and evaluates patient • Ask bystanders duration of seizure and trauma • Look for medic alert jewelry • Check glucose and vital signs • For children, check estimated weight • If criteria are met, study box is opened to enroll • Medic states that entry criteria are met • Select child dose or adult dose based on weight • Give IM medication and verbalize

  19. Intervention (continued) • Start IV, give IV med, and verbalize • Monitor vital sings and transport • Verbalize if convulsions stop • At 10 minute after treatment, provide “rescue” meds per local protocol if still seizing en route, verbalize tha med was given • At ED arrival, verbailze whether patient is still seizing or not

  20. ED and inpatient treatment Attempt standardized post-intervention care For further seizures in the ED or secondary treatment of prior status… • Lorazepam 0.5-0.1 mg/kg plus • Phenytoin or Fosphenytoin 18-20 mg/kg

  21. ED and inpatient treatment If seizures continue then… • Intubate and ventilate, keep ≤ 37°C • Consider vecuronium 0.1 mg/kg • Then add: • Midazolam 0.2 mg/kg then 1.2 ug/kg/min or • Propofol 1 mg/kg then 1-5 mg/kg/hr or • Pentobarbital 5-15 mg/kg over 1 hr, then 0.5-5 mg/kg/hr • Admit to ICU, early EEG monitoring

  22. Study Activity and Data Collection • Study team activated on ED arrival of subject • Investigator or coordinator in ED • Collect the data logger • Complete as many CRF items as possible • Approach subject or family for consent to continue to collect and use data • Restock ambulance with new study kit • Follow patient in hospital for AE’s • Collect remaining data at discharge

  23. Primary outcome • Proportion of subjects with termination of clinically evident seizure determined at arrival in the Emergency Department (ED) after a single dose of study medication. • Non-inferiority analysis designed to detect greater than 10% absolute difference in proportion with termination at ED arrival.

  24. Secondary outcomes • Rapidity of seizure termination • Frequency of subsequent tracheal intubation • Frequency and duration of ICU and hospital stay

  25. Sample Size • Non-inferiority margin of 10% • Power of 0.85 • Significance at 0.05 • Inflation for data loss and recidivists at 15% • N = 700 (350 per group)

  26. Enrollment • 700 subjects over 36 months • 21 subjects per hub per year • If each hub recruits using 14 ambulances the rate is 0.13 subjects/ambulance*month • By comparison the PHTSE trial enrolled just over 0.20 subjects/ambulance*month and did not enroll children

  27. Human subjects protection Benefits • Both arms are accepted therapy • Potential for direct benefit to subjects Challenges • Exception to Informed Consent • IRB approval at all receiving hospitals

  28. Exception to Informed Consent • Community Consultation • Public Notification • Local Context • Centralized Support • Local Outreach – attend community meetings • Patient Focus Groups – survivors and clinics

  29. Emergency Exception • These regulations can improve the quality of research done in this network • NETT can help the FDA, NIH, and OHRP ensure the quality of the regulations • Build on experience, consensus, and innovation

  30. Timeline • 2007 • IND submission • IRB applications • Community consultations • Public notification • Acquire and test data loggers • EMS approvals

  31. Timeline • 2008-2010 • Enrollment • Initial and on-going EMS training • On-going AE reporting • One interim analysis at 350 subjects enrolled • 2011 • Last patient in – database lock • Analysis • Public notification again

  32. nett.umich.edu

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