Alldredge SE
A Comparison of Lorazepam, Diazepam, and Placebo for the Treatment of Out-of-Hospital Status Epilepticus
Clinical Question
In patients with out-of-hospital status epilepticus, is intravenous lorazepam or diazepam more effective than placebo for terminating seizures before hospital arrival?
Bottom Line
Both IV lorazepam and diazepam were significantly more effective than placebo for prehospital SE: seizure termination 59.1% (lorazepam) vs 42.6% (diazepam) vs 21.1% (placebo; P<0.001 for both vs placebo). Lorazepam was the most effective. Paradoxically, benzodiazepine-treated patients had better outcomes on ED arrival — shorter SE duration, lower intubation rate, and shorter ICU stay — disproving concerns about prehospital respiratory depression.
Major Points
- Seizure termination before ED: lorazepam 59.1% vs diazepam 42.6% vs placebo 21.1% (P<0.001 for both drugs vs placebo).
- Lorazepam vs diazepam: 59.1% vs 42.6% (P=0.08, NS) — lorazepam numerically but not significantly superior.
- Respiratory/circulatory complications: lorazepam 10.6%, diazepam 10.3%, placebo 22.5% — paradoxically FEWER with treatment.
- ICU admission: lorazepam 10.6%, diazepam 9.6%, placebo 27.5% — treated patients had better ED disposition.
- SE duration from treatment to termination: lorazepam/diazepam ~5 min vs placebo ~25 min in ED.
- Double-blind, randomized, placebo-controlled. 205 patients. San Francisco paramedics, 1994-1998.
- Paramedic administration was safe and feasible — established paradigm for prehospital SE treatment.
- Lorazepam dose: 2mg IV; diazepam dose: 5mg IV. Repeated once if seizure continued after 4 min.
- Only included adults ≥18 years with convulsive seizures >5 min. Excluded known pregnancy.
- Landmark trial: led to RAMPART (IM midazolam) and established prehospital benzodiazepine as standard of care.
Design
Study Type: Randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind. Identical prefilled syringes in sequentially numbered kits.
Enrollment Period: August 1994 to March 1998
Follow-up Duration: Hospital discharge
Centers: 1
Countries: United States
Sample Size: 205
Analysis: Intention-to-treat. Chi-square and Fisher exact for proportions. Logistic regression for adjusted analyses.
Inclusion Criteria
- Age ≥18 years.
- Convulsive seizures lasting ≥5 minutes witnessed by paramedics, OR ≥3 seizures without full recovery between episodes.
- IV access obtainable in the field.
- Transported by San Francisco EMS.
Exclusion Criteria
- Known pregnancy.
- Seizures secondary to major trauma.
- Unable to obtain IV access.
Arms
| Field | Lorazepam | Diazepam | Control |
|---|---|---|---|
| Intervention | Lorazepam 2 mg IV, repeated once after 4 min if seizure continued (max 4 mg). | Diazepam 5 mg IV, repeated once after 4 min if seizure continued (max 10 mg). | Normal saline IV, identical syringe. |
| Duration | Prehospital | Prehospital | Prehospital |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Termination of SE before ED arrival | Primary | 15/71 (21.1%) | Lorazepam 39/66 (59.1%); Diazepam 29/68 (42.6%) | Lorazepam NNT ~3; Diazepam NNT ~5 | <0.001 overall |
| Respiratory/circulatory complications | Secondary | 16/71 (22.5%) | LZP 7/66 (10.6%); DZP 7/68 (10.3%) | NS | |
| ICU admission | Secondary | 19/71 (27.5%) | LZP 7/66 (10.6%); DZP 6/68 (9.6%) | <0.05 | |
| SE still active on ED arrival | Secondary | 56/71 (78.9%) | LZP 27/66 (40.9%); DZP 39/68 (57.4%) | ||
| Intubation | Adverse | ~22% | LZP ~11%; DZP ~10% | ||
| Death | Adverse | ~7% | LZP ~3%; DZP ~4% |
Subgroup Analysis
No significant interaction by seizure type, duration, or history of epilepsy.
Criticisms
- Single-center (San Francisco) — may not generalize to all EMS systems.
- Only IV route studied — IM route (later studied in RAMPART) may be more practical.
- Low single doses (LZP 2mg, DZP 5mg) — may underestimate efficacy of higher doses.
- Placebo arm: ethical concerns about withholding treatment in SE (justified by equipoise at time).
- Small sample (205) — underpowered for lorazepam vs diazepam comparison.
- Adults only — pediatric prehospital SE not addressed.
- Short follow-up (hospital discharge only).
Funding
NIH/NINDS (NS01651).
Based on: Alldredge SE (The New England Journal of Medicine, 2001)
Authors: Brian K. Alldredge, Daniel H. Gelb, S. Marshelle Isaacs, ..., Daniel H. Lowenstein
Citation: N Engl J Med 2001;345:631-637.
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