RAMPART
Intramuscular Versus Intravenous Therapy for Prehospital Status Epilepticus
Bottom Line
IM midazolam was not only noninferior but superior to IV lorazepam for prehospital status epilepticus (73.4% vs 63.4% seizure cessation by ED arrival, p<0.001). The IM route advantage was driven by faster time to active treatment (median 1.2 vs 4.8 minutes) despite slower onset after administration (3.3 vs 1.6 minutes). IM midazolam also reduced hospitalization and ICU admission rates. This trial established IM midazolam as first-line prehospital treatment for SE.
Major Points
- IM midazolam noninferior to IV lorazepam for prehospital SE: 73.4% vs 63.4% seizure cessation (absolute diff 10.0%; 95% CI 4.0-16.1%; noninferiority P<0.001, superiority P=0.001).
- IM midazolam FASTER because no IV needed: median time to treatment 1.2 min (IM) vs 4.8 min (IV).
- 893 patients, 79 EMS agencies, 33 US sites. Double-blind, double-dummy. NETT Network.
- IM midazolam 10 mg (autoinjector) vs IV lorazepam 4 mg. Weight-adjusted for 13-40 kg (5 mg IM / 2 mg IV).
- Need for intubation similar: 14.1% vs 14.4%. Recurrence: 11.4% vs 10.6%.
- ED seizure-free without rescue: 64.8% (IM MDZ) vs 52.9% (IV LZP).
- Hospitalization rate similar: ~60% both groups. ICU admission: ~15% both.
- Landmark trial: shifted SE treatment paradigm — IM route preferred when IV not available.
- Published NEJM 2012 (Silbergleit et al.). Largest prehospital SE trial at time.
- Led to FDA approval of midazolam autoinjector for SE and guideline updates.
Design
Study Type: Phase 3, multicenter, randomized, double-blind, noninferiority trial with double-dummy design
Randomization: 1
Blinding: Double-blind, double-dummy (IM injection + IV injection, one active and one placebo)
Enrollment Period: June 15, 2009 to January 14, 2011
Follow-up Duration: Through hospital discharge
Centers: 33 EMS agencies, 79 receiving hospitals
Countries: United States
Sample Size: 893
Analysis: Intention-to-treat; noninferiority margin 10 percentage points; power 90%, alpha 0.025 (one-sided); NCT00809146
Inclusion Criteria
- Age ≥13 years (weight ≥40 kg).
- Generalized convulsive seizures lasting >5 minutes witnessed by EMS.
- Active convulsions on EMS arrival.
- No IV access established.
Exclusion Criteria
- IV already established.
- Known seizure secondary to major trauma.
- Prisoners.
- Known pregnancy.
Arms
| Field | IM Midazolam | Control |
|---|---|---|
| Intervention | Adults/children >=40 kg: 10 mg midazolam via autoinjector IM + IV placebo; children 13-40 kg: 5 mg midazolam IM + IV placebo | Adults/children >=40 kg: IM placebo autoinjector + 4 mg lorazepam IV; children 13-40 kg: IM placebo + 2 mg lorazepam IV |
| Duration | Single administration | Single administration |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Absence of seizures at ED arrival without rescue therapy | Primary | IV Lorazepam: 282/445 (63.4%) | IM Midazolam: 329/448 (73.4%) | 10 | <0.001 (both noninferiority and superiority) |
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| Adverse | 13 (2.9%) | 12 (2.7%) | |||
| Adverse | 2 (0.5%) | 4 (0.9%) | |||
| Adverse | 3 (0.7%) | 0 (0%) |
Subgroup Analysis
Not separately reported; 13% re-enrollment rate; both adults and children included (dose-tiered)
Criticisms
- Dose inequivalence: IM midazolam dose (10 mg adults) pharmacologically higher relative to IV lorazepam dose (4 mg adults)
- Faster delivery biased IM arm: median 1.2 min vs 4.8 min to active treatment due to IV access delays
- Prehospital setting limitations: seizure duration estimated by paramedics; only 317/893 had documented treatment-to-cessation times
- 13% re-enrollment rate could introduce correlation between observations
- Predominantly Black population (50-51%) may limit generalizability
- Non-epileptic spells included: 7% of each group had final diagnosis of non-epileptic events
- No long-term outcomes reported: follow-up ended at hospital discharge
Funding
NINDS (U01NS056975, U01NS059041); NIH Office of the Director CounterACT Program; BARDA
Based on: RAMPART (New England Journal of Medicine, 2012)
Authors: Silbergleit R, Durkalski V, Lowenstein D, ..., Barsan W; NETT Investigators
Citation: Silbergleit R et al. N Engl J Med. 2012;366(7):591-600. DOI: 10.1056/NEJMoa1107494
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