PDF: Chamberlain SE
(2014)Objective
To determine if IV lorazepam is superior to IV diazepam for pediatric status epilepticus
Study Summary
• Only significant finding: lorazepam caused MORE sedation (66.9% vs 50.0%, difference 16.9%, 95% CI 6.1-27.7%); no differences in recurrence, time to cessation, or return to baseline
Intervention
IV lorazepam 0.1 mg/kg (max 4 mg) vs IV diazepam 0.2 mg/kg (max 8 mg), with half-dose repeat option
Inclusion Criteria
Children 3 months to <18 years with generalized tonic-clonic SE (>=5 min seizure, successive seizures without recovery, or >=3 seizures in 1 hour)
Study Design
Arms: Lorazepam vs Diazepam
Patients per Arm: Lorazepam: 133, Diazepam: 140
Outcome
• Primary safety: Assisted ventilation: LZP 17.6% vs DZP 16.0% (NS)
• Lorazepam caused significantly MORE sedation: 66.9% vs 50.0% (difference 16.9%, 95% CI 6.1-27.7%)
• No differences in recurrence, time to cessation, or return to baseline mental status
Bottom Line
Lorazepam and diazepam were equally effective for pediatric SE: 72.9% vs 72.1% cessation by 10 minutes without recurrence (absolute difference 0.8%, 95% CI -11.4 to 9.8%). Assisted ventilation rates were also similar (17.6% vs 16.0%). However, lorazepam caused significantly more sedation (66.9% vs 50.0%, difference 16.9%). This trial showed no reason to prefer lorazepam over diazepam in pediatric SE, challenging the assumption that lorazepam is superior.
Major Points
- Lorazepam and diazepam equally effective for pediatric SE: 72.9% vs 72.1% cessation by 10 min (absolute diff 0.8%; 95% CI -11.4 to 9.8%).
- No difference in assisted ventilation: 17.6% vs 16.2% (P=NS).
- Lorazepam dose: 0.1 mg/kg IV (max 4 mg). Diazepam dose: 0.2 mg/kg IV (max 8 mg).
- 273 children randomized (140 LZP, 133 DZP). 9 US pediatric EDs, 2008-2012.
- Mean age 3 years. 56% male. 44% with known seizure disorder.
- Secondary outcomes: sedation similar (50% vs 48%), recurrence within 4h similar (4.7% vs 3.0%).
- Established therapeutic equivalence — either drug acceptable as first-line pediatric SE treatment.
- Double-blind, randomized. Published Lancet 2014.
Study Design
- Study Type
- Randomized, double-blind (quadruple-masked), Phase 2/3 clinical trial
- Randomization
- Yes
- Blinding
- Double-blind (quadruple-masked)
- Sample Size
- 273
- Follow-up
- 4 hours after study medication
- Centers
- 11
- Countries
- United States
Primary Outcome
Definition: Cessation of SE by 10 minutes without recurrence within 30 minutes (efficacy); assisted ventilation rate (safety)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Diazepam: 72.1% (101/140) efficacy; 16.0% assisted ventilation | Lorazepam: 72.9% (97/133) efficacy; 17.6% assisted ventilation | - (Efficacy difference: 0.8% (95% CI -11.4 to 9.8%); Safety difference: 1.6% (95% CI -9.9 to 6.8%)) | Not significant for either |
Limitations & Criticisms
- Powered for superiority, not equivalence or non-inferiority: negative result does not formally prove equivalence (CI of -11.4 to 9.8% includes clinically meaningful differences)
- IV access required for both drugs, may not reflect real-world scenarios with IM/IN/rectal routes
- Exception-from-informed-consent cohort introduces ethical and methodological complexities
- Sample size of 273 may be insufficient to detect modest but clinically relevant differences (e.g., 10% absolute)
- Higher sedation rate with lorazepam (66.9% vs 50%) is clinically relevant but was somewhat underemphasized
- Did not assess outcomes beyond 4 hours
- Differential rates of rescue medication use (fosphenytoin) not prominently reported
Citation
Chamberlain JM et al. JAMA. 2014;311(16):1652-1660. DOI: 10.1001/jama.2014.2625