PDF: RAMPART
(2012)Objective
To determine if intramuscular midazolam is noninferior to intravenous lorazepam for prehospital treatment of status epilepticus
Study Summary
• IM midazolam reduced hospitalization (57.6% vs 65.6%) and ICU admission (28.6% vs 36.2%); identical safety: intubation 14.1% vs 14.4%, hypotension 2.7% vs 2.9%
Intervention
IM midazolam 10 mg (5 mg if 13-40 kg) via autoinjector vs IV lorazepam 4 mg (2 mg if 13-40 kg)
Inclusion Criteria
Children (>=13 kg) or adults with convulsive seizures lasting >5 minutes or intermittent seizures without regaining consciousness >5 minutes
Study Design
Arms: IM Midazolam vs IV Lorazepam
Patients per Arm: IM Midazolam: 448, IV Lorazepam: 445
Outcome
• Time to treatment: IM 1.2 min vs IV 4.8 min; time to cessation: IM 3.3 min vs IV 1.6 min
• Hospitalization: 57.6% vs 65.6%; ICU: 28.6% vs 36.2%; intubation: 14.1% vs 14.4% (NS); recurrent seizure: 11.4% vs 10.6% (NS)
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