PDF: RAMPART
(2012)Objective
To compare intramuscular midazolam with intravenous lorazepam for prehospital treatment of status epilepticus.
Study Summary
• The advantage was driven by faster time to active treatment (median 1.2 vs 4.8 min) despite slightly slower onset after dosing (3.3 vs 1.6 min)
• IM midazolam reduced hospitalization (57.6% vs 65.6%) and ICU admission (28.6% vs 36.2%); intubation rates were similar (14.1% vs 14.4%)
Intervention
IM midazolam 10 mg via autoinjector (5 mg if 13-40 kg) vs IV lorazepam 4 mg (2 mg if 13-40 kg), double-dummy; N=893
Inclusion Criteria
Age ≥13 years (≥40 kg), generalized convulsive seizures >5 min still convulsing on EMS arrival, no IV access established.
Study Design
Arms: IM Midazolam vs IV Lorazepam (active control)
Patients per Arm: IM Midazolam: 448, IV Lorazepam: 445
Outcome
• Hospitalization RR 0.88 (95% CI 0.79-0.98); ICU admission RR 0.79 (95% CI 0.65-0.95)
• Intubation 14.1% vs 14.4%; recurrent seizures 11.4% vs 10.6%
• Time to treatment median 1.2 min (IM) vs 4.8 min (IV)
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.
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, noninferiority trial with double-dummy design
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy (IM injection + IV injection, one active and one placebo)
- Sample Size
- 893
- Follow-up
- Through hospital discharge
- Centers
- 33 EMS agencies, 79 receiving hospitals
- Countries
- United States
Primary Outcome
Definition: Absence of seizures at ED arrival without rescue therapy
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| IV Lorazepam: 282/445 (63.4%) | IM Midazolam: 329/448 (73.4%) | - (Absolute difference 10.0 percentage points (95% CI 4.0 to 16.1)) | <0.001 (both noninferiority and superiority) |
Limitations & 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
Citation
Silbergleit R et al. N Engl J Med. 2012;366(7):591-600. DOI: 10.1056/NEJMoa1107494