neurological emergencies treatment trials network rampart overview robert silbergleit
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Neurological EmergenciesTreatment Trials Network
RAMPARTOverview
Robert Silbergleit
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
• 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
Rapid Anticonvulsant MedicationPrior to Arrival Trial (RAMPART)
Status Epilepticus
120,000 to 200,000 cases / yrMortality 22% at 30 days55,000 deaths in the US
1st Yr cost $40,000 /patient
Bassin S, et al. Crit Care 2002;6(2):137-42Claassen J, et al. Neurology 2002;58(1):139-42
DeLorenzo RJ, et al. Neurology 1996;46(4):1029-35Penberthy LT, et al. Seizure 2005;14(1):46-51Wu YW, et al. Neurology 2002;58(7):1070-6
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
Intramuscular midazolam
• Favorable pharmacology for treatment of SE– Effectiveness– Rapidity
• Better stability – lower cost• Increasing acceptance by EMS• Optimal agent for organophosphate toxicity
Midazolam levels near 80% of peak as early as 5 minutes after IM administration
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intramuscular injection
submucosal injection
Alfonzo-Echeverri, Anesth Prog 1990;37:277-281
IM midazolam stops seizures 4 times faster than IM diazepam (in mice)
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lower dose0.2 mg DZP0.1 mg MDZ
higher dose0.4 mg DZP0.2 mg MDZ
90 ± 7 minRaines, Epilepsia. 1990;31:313-7
Brain midazolam concentration remains high even as serum concentration is dropping
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Megarbane, Toxicology Letters 2005;159:22–31
Duration of seizure suppression with midazolam is hours, and similar to that of diazepam
Towne, J Emerg Med 1999;17:323–328
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normal saline
midazolam 10mg IM
diazepam 10mg IV
diazepam 20mg IV
Review: IV diazepam versus IM/IN midazolam for treatment of seizuresComparison: 01 Effectiveness of IM/IN MDZ as compared to IV DZP
Outcome: 01 Termination of seizure
Study
IVDiazepam
IM/INMidazola
m RR (fixed) Weight RR (fixed)
n/N n/N 95% CI % 95% CI
Chamberlain 11/13 12/13
8.99 0.92 [0.69, 1.21] Lahat 24/26 23/26
17.23 1.04 [0.87, 1.25]
Rainbow 23/62 23/45
19.96 0.73 [0.47, 1.12] Mahmoudian
28/35 21/35
15.73 1.33 [0.97, 1.83] Shah 54/65 45/50
38.10 0.92 [0.80, 1.07]
Total (95% CI) 201 169 100.00 0.97 [0.86, 1.09]
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)
0.5 0.7 1 1.5 2
Favors IM/IN MDZ Favors IV DZP
Meta-analysis of IM/IN midazolam shows the same efficacy as IV diazepam
Review: IV diazepam versus IM/IN midazolam for treatment of seizuresComparison: 01 Effectiveness of IM/IN MDZ as compared to IV DZP
Outcome: 02 Time to seizure control Study
IV DZP IM/IN MDZ WMD (fixed) Weight WMD (fixed)N Mean (SD) N Mean (SD) 95% CI % 95% CI
Chamberlain 11 11.20(3.60) 13 7.80(4.10) 3.51 3.40 [0.32, 6.48]
Lahat 26 8.00(4.10) 26 6.10(3.60) 7.58 1.90 [-0.20, 4.00]
Shah 65 4.20(2.30) 50 1.60(0.90) 88.91 2.60 [1.99, 3.21]
Total (95% CI) 102 89 100.00 2.58 [2.00, 3.15]
Test for heterogeneity: Chi² = 0.68, df = 2 (P = 0.71), I² = 0%Test for overall effect: Z = 8.74 (P < 0.00001)
-10 -5 0 5 10
Favors IV DZP Favors IM/IN MDZ
Meta-analysis of IM/IN midazolam shows more rapid termination of seizures compared to IV diazepam
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
Inclusion criteria
• Continuous or repeated convulsive seizure activity for > 5 minutes
• Patient is still seizing
• Estimated weight > 13 kg
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
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
RAMPART Datalogger
Providing data loggers, stepper controllers, data acquisition and custom engineering services to customers worldwide
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
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
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
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
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
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.
Secondary outcomes
• Rapidity of seizure termination• Frequency of subsequent tracheal intubation• Frequency and duration of ICU and hospital stay
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)
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
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
Exception to Informed Consent
• Community Consultation• Public Notification
• Local Context• Centralized Support
• Local Outreach – attend community meetings• Patient Focus Groups – survivors and clinics
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
Timeline
• 2007– IND submission– IRB applications– Community consultations– Public notification– Acquire and test data loggers– EMS approvals
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
nett.umich.edu