Table 2.
Comparison of different studies regarding nonintravenous benzodiazepines.
|
Kay et al., current study |
Silbergleit et al., NEJM 2012 |
Lahat et al., BMJ 2000 |
Alldredge et al., NEJM 2001 |
Thakker et al., J Neurol 2013 | Holsti et al., Arch Pediatr Adolesc Med 2010 | de Haan et al., Epilepsia 2010 | Nakken et al., Acta Neurol Scand 2011 | Hardmeier et al., Clin Pharmacol Ther 2012 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Design | EEG‐based, single arm, r | RCT, p | RCT, p | RCT, p | RCT, p | RCT, p | randomized crossover, p | randomized, partly crossover, p | EEG‐based, healthy probands, p | |||||||||
| Year | 2015–2018 | 2009 –2011 | n.a.; 12 months | 1994–1999 | 2006 | 2006–2008 | n.a. | n.a.; 8 months | n.a. | |||||||||
| Country (city) |
Germany (Frankfurt) |
USA (multicenter) | Israel (Zerifin) | USA (multicenter) | India (Mumbai) | USA (Salt Lake City) | Netherlands (Heemstede) | Norway (Baerum) | Switzerland (Basel) | |||||||||
| Inclusion criteria | Children or adults with EEG‐proven SE (>5 minb,> 10 minc) | Children or adults with convulsions lasting> 5 min | Children with prolonged febrile seizures (> 10 min) | Adults with prolonged (>5 min) or repetitive generalized convulsions | Children with seizures> 10 min | Pediatric patients who were prescribed a home rescue medication | Adults with refractory epilepsy, who require rescue medication | Patients with seizures lasting more than 5 min | Healthy volunteers | |||||||||
| Primary outcome measure | Cessation of SE in EEG | Termination of seizures before arrival in the ED | Cessation of seizures | SE termination on arrival in the ED | Cessation of seizures and time from treatment to cessation | Total seizure time after medication administration | No clinical visible seizure activity within 15 minutes | Cessation of seizure activity within 10 minutes | Pharmacokinetic and pharmacodynamic measures | |||||||||
| Setting | IH | OH and ED | OH and ED | ED | OH | REC | REC | REC | IH | |||||||||
| Drug investigated | in‐MDZ | im‐MDZ | iv‐LZP | in‐MDZ | iv‐DZP | iv‐DZP | iv‐LZP | Placebo | in‐MDZ | iv‐DZP | in‐MDZ | r‐DZP | in‐MDZ | r‐DZP | r‐DZP | b‐MDZ | in‐MDZ | iv‐MDZ |
| Dose | 6.4 ± 2.6 mg (2.5–15) | 5 or 10 mg | 2 or 4 mg | 0.2 mg/kg | 0.3 mg/kg | 5 mg | 2 mg | 0.2 mg/kg | 0.3 mg/kg | 0.2 mg/kg | 0.3–0.5 mg/kg | 10 mg | 10 mg | 26 mg* (10–30 mg | 16 mg* (10–20 mg) | 3 or 6 mg | 5 mg | |
| Patients included | 42 | 448 | 445 | 21 | 23 | 68 | 66 | 71 | 27 | 23 | 50 | 42 | 21 (61)a | 21 (63)a | 18 (37)a | 16 (43)a | 12 (24)a | 12 |
|
Mean age in years (range) |
52.7 ± 22.7 (5–92) |
43 ± 22 (0–102) |
44 ± 22 (1v94) |
16* (6–38) months | 18* (6–40) months | 50.4 ± 19.1 | 49.9 ± 20.1 | 52.0 ± 18.2 | 3.8 ± 2.9 | 4.0 ± 3.3 | 5.6* (2.5–0.7)# | 6.9* (3.8–10.8)# | 40.2 | 40.2 | 42.4 | 29 (20–45) | ||
| Male gender, n (%) | 19; 45% | 198; 44% | 238; 53% | 13; 62% | 12; 52% | 41; 60% | 46; 70% | 42; 59% | 15; 56% | 12; 52% | 24; 48% | 22; 52% | 13; 62% | 13; 62% | 12; 55% | 12; 100% | ||
| History of seizures | 25; 60% | 293; 65% | 295; 66% | 17; 81% | 17; 74% | 48; 70% | 36; 55% | 47; 66% | 7; 26% | 6; 26% | 41; 82% | 32; 76% | 21; 100% | 21; 100% | 22; 100% | n.a. | ||
| Convulsive SE | 33% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | n.a. | n.a. | 100% | 100% | 46% | ‐ | ||
| Efficacy rate BZP | 24; 57% | 329; 73% | 282; 63% | 23/26; 88% | 24/26; 92% | 29; 43% | 39; 59% | 15; 21% | 18; 67% | 15; 65% | n.a. | n.a. | 50; 82% | 56; 89% | 30; 81% | 32; 74% | n.a. | |
| ß‐band increase | 04:07 mins (±01:09) | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | 6.9 and 5.5 mins | 1.2 mins |
| Time to SE end | 05:05 mins (± 03:10) | n.a. | n.a. | 3.1 mins (± 1.8) | 2.5 mins (± 1.9) | n.a. | n.a. | n.a. | 3.0 mins (± 2.8) | 2.7 mins (± 2.3) | 3.0* mins (1.0–10)# | 4.3* mins (2.0–14.5)# | 4.6 mins (± 3.4) | 4.3 mins (± 3.4) | 5.0 min and 9 min | 2.8 min and 9.3 min | n.a. | |
| Adverse events (%) | 6; 14.3% nasal irritation | No acute side effects documented; total SAE in study: | None | None | Out‐of‐hospital complications: (hypotension, cardiac dysrhythmia, respiratory intervention) | Respiratory depression | Intubation |
Drowsiness, local irritation |
Tiredness, bitter taste, numbness in mouth | Local irritation | ||||||||
|
137/ 514; 26.7% |
156/ 509; 30.6% |
7; 10.3% | 7; 10.6% | 16; 22.5% | None | 1; 4.3% | 1; 0.02% | None |
40; 68% 17 (29%) |
34; 55% None |
18; 49% None |
9; 21% 9; 21% |
17; 71% | None | ||||
| Case fatality rate | 5; 11.9% | n.a. | 0; 0% | 0; 0% | 5; 7.7% | 3; 4.5% | 11; 15.7% | n.a. | n.a. | 0; 0% | 0; 0% | n.a. | None | |||||
Data are presented in the format of mean ± SD or as “number; percentage”; deviations are displayed as follows: *median # interquartile range
R,retrospective; RCT, randomized controlled trial; p, prospective; n.a., not available; IH, inhospital; OH, out‐of‐hospital; ED, emergency department; REC, residential epilepsy center; SE, status epilepticus; BZP, benzodiazepines; in‐, intranasal; r‐, rectal; b‐, buccal; im‐, intramuscular; iv‐, intravenous; MDZ, midazolam; LZP, lorazepam; DZP: diazepam.
Number of seizure episodes.
For convulsive SE.
For nonconvulsive SE.