Table 1.
Main randomized, controlled clinical trials conducted in different stages of status epilepticus (SE)
| Study | Country | Definition of SE | Participants and age | Interventions | Clinical seizure cessation | Adverse effects |
|---|---|---|---|---|---|---|
| Early SE: Stage I | ||||||
| Remy et al. [53] | France | Seizures >20 min or 2 GTCS within 20 min | Adults 16–65 years |
Rectal DZP 30 mg vs. rectal DZP 20 mg | DZP 30 mg 13/18 DZP 20 mg 6/21 |
DZP 30 mg 10/18 DZP 20 mg 13/21 |
| Dreifuss et al. [52] | USA | Acute repetitive seizures | Adults >18 years |
Rectal DZP 0.2 mg/kg vs. placebo | DZP 31/46 Placebo 14/49 |
DZP 19/46 Placebo 13/49 |
| Cereghino et al. [50] | USA | Multiple seizures within 12–24 h | Adults 18–76 years |
Rectal DZP 0.2 mg/kg vs. placebo | DZP 22/31 Placebo 11/39 |
DZP 10/31 Placebo 9/39 |
| Shaner et al. [117] | California | GTCS >30 min or 3 GTCS within 1 h or GTCS >5 min | Adults >15 years |
IV DZP 2–20 mg + IV PHT 6–18 mg/kg based on initial drug levels vs. IV PB 10–30 mg/kg IV | DZP + PHT 10/18 PB 16/18 |
DZP + PHT 9/18 PB 9/18 |
| Alldredge et al. [40] | USA | Seizures >5 min | Adults >18 years |
IV DZP 5 mg or LZP 2 mg vs. placebo | LZP 39/66 DZP 29/68 Placebo 15/71 |
LZP 7/66 DZP 7/68 Placebo 16/71 |
| Chamberlain et al. [43] | USA | Seizures >5 min | Children 3 months–18 years |
IV DZP 0.2 mg/kg vs. IV LZP 0.1 mg/kg | DZP 101/140 LZP 97/133 |
DZP 157** LZP 155** |
| Leppik et al. [41] | USA | ≥3 GTCS in 1 h; confusional state with ongoing EEG abnormalities | Adults >18 years |
IV LZP 2 mg vs. IV DZP 5 mg | LZP 33/37 DZP 25/32 |
LZP 0/37 DZP 4/32 |
| Treiman et al. [81] | USA | Seizures >10 min or 2 GTCS within 10 min or subtle generalized convulsive SE (coma and ictal discharges on EEG) | Adults >18 years |
IV LZP vs. IV PB vs. IV DZP + PHT vs. IV PHT | LZP 63/97 PB 53/91 DZP + PHT 53/95 PHT 44/101 |
LZP 42/97 PB 46/91 DZP + PHT 48/95 PHT 44/101 |
| Arya et al. [48] | India | Seizures at arrival at emergency department | Children 6–14 years |
IN LZP 0.1 mg/kg vs. IV LZP 0.1 mg/kg | IN LZP 59/71 IV LZP 56/70 |
IN LZP 0/71 IV LZP 0/70 |
| Gathwala et al. [58] | India | Seizures at arrival at emergency department | Children 6 months–14 years |
IV MDZ 0.1 mg/kg vs. IV DZP 0.3 mg/kg vs. IV LZP 0.1 mg/kg | MDZ 36/40 DZP 29/40 LZP 38/40 |
MDZ 4/40 DZP 24/40 LZP 4/40 |
| Lahat et al. [59] | Israel | Febrile seizures >10 min | Children 6 months–5 years |
IN MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg | MDZ 23/26 DZP 24/26 |
MDZ 0/26 DZP 0/26 |
| Fisgin et al. [62] | Turkey | Seizures at arrival at emergency department | Children 1 month–13 years |
IN MDZ 0.2 mg/kg vs. rectal DZP 0.3 mg/kg | MDZ 20/23 DZP 13/22 |
MDZ 2/23 DZP 0/22 |
| Mahmoudian and Zadeh [60] | Iran | Seizures at arrival at emergency department | Children 2 months–15 years |
IN MDZ 5 mg/ml vs. IV DZP 0.2 mg/kg | MDZ 35/35 DZP 35/35 |
MDZ 0/35 DZP 0/35 |
| Thakker and Shanbag [61] | India | Seizures >10 min | Children 1 month–12 years |
IN MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg | MDZ 18/27 DZP 15/23 |
MDZ 0/27 DZP 1/23 |
| Scott et al. [65] | UK | Seizures at arrival of paramedics | Children/adults 5–22 years |
Buccal MDZ 10 mg vs. rectal DZP 10 mg | MDZ 30/40* DZP 23/39 |
MDZ: 0/40 DZP 0/40 |
| McIntyre et al. [63] | UK | Seizures at arrival at emergency department | Children 7 months–15 years |
Buccal MDZ 0.5 mg/kg vs. rectal DZP 0.5 mg/kg | MDZ 71/109* DZP 45/110 |
MDZ 5/109 DZP 7/110 |
| Mpimbaza et al. [66] | Uganda | Seizures at arrival at emergency department or >5 min | Children 3 months–12 years |
Buccal MDZ 0.5 mg/kg vs. rectal DZP 0.5 mg/kg | MDZ 125/165 DZP 114/165 |
MDZ 1/165 DZP 0/165 |
| Talukdar and Chakrabarty [64] | India | Seizures at arrival at emergency department | Children Birth to 12 years |
Buccal MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg | MDZ 51/60 DZP 56/60 |
MDZ 0/60 DZP 0/60 |
| Chamberlain et al. [217] | USA | Seizures >10 min | Children Birth to 18 years |
IM MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg | MDZ 12/13 DZP 10/11 |
MDZ 1/13 DZP 1/11 |
| Shah and Deshmukh [67] | India | Seizures at arrival at emergency department | Children 1 month–12 years |
IM MDZ 0.2 mg/kg vs. IV DZP 0.2 mg/kg | MDZ 45/50 DZP 54/65 |
MDZ 0/50 DZP 7/65 |
| Silbergleit et al. [44] | USA | Seizures >5 min | Children and adults 0–102 years |
IM MDZ 5–10 mg (according to body weight) vs. IV LZP 2–4 mg (according to body weight) | MDZ 329/448 LZP 282/445 |
MDZ 75/448 LZP 77/445 |
| Misra et al. [82] | India | Seizures >10 min | Children/adults 1–85 years |
IV VPA 30 mg/kg bolus vs. IV PHT 18 mg/kg | VPA 23/35 PHT 14/33 |
VPA 4/35 PHT 6/33 |
| Gilad et al. [84] | Israel | Seizures >30 min | Adults >18 years |
IV VPA 30 mg/kg bolus vs. IV PHT 18 mg/kg bolus | VPA 13/18 PHT 7/9 |
VPA 0/18 PHT 2/9 |
| Misra et al. [116] | India | Seizures >5 min | Children/adults 1–75 years |
IV LEV 20 mg/kg over 15 min vs. IV LZP 0.1 mg/kg over 2–4 min | LEV 29/38 LZP 31/41 |
LEV 62** LZP 94** |
| Established SE: stage II | ||||||
| Shaner et al. [117] | California | GTCS >30 min or 3 GTCS within 1 h or GTCS >5 min | Adults >15 years |
IV DZP 2–20 mg + IV PHT 6–18 mg/kg based on initial drug levels vs. IV PB 10–30 mg/kg | DZP + PHT 10/18 PB 16/18 |
DZP + PHT 9/18 PB 9/18 |
| Treiman et al. [81] | USA | Seizures >10 min or 2 GTCS within 10 min or subtle generalized convulsive SE (coma and ictal discharges on EEG) | Adults >18 years |
IV LZP vs. IV PB vs. IV DZP + PHT vs. IV PHT | LZP 63/97 PB 53/91 DZP + PHT 53/95 PHT 44/101 |
LZP 42/97 PB 46/91 DZP + PHT 48/95 PHT 44/101 |
| Agarwal et al. [83] | India | Seizures >5 min refractory to IV DZP | Children/adults >2 years |
IV VPA 20 mg/kg bolus vs. IV PHT 20 mg/kg | VPA 44/50 PHT 42/50 |
VPA 4/50 PHT 8/50 |
| Chen et al. [218] | China | Seizures >5 min refractory to IV DZP | Adults 15–99 years |
IV VPA 30 mg/kg bolus followed by infusion at 1–2 mg/kg vs. IV DZP 0.2 mg/kg bolus followed by infusion at 4 mg/h for 3 min and then increased every 3 min by 1 μg/min until seizure cessation or maximal duration (1 h) reached | VPA 15/30 DZP 20/36 |
VPA 5/30 DZP 4/36 |
| Malamiri et al. [219] | Iran | Seizures >5 min, not controlled by DZP | Children 3–16 years |
IV VPA 20 mg/kg bolus vs. IV PB 20 mg/kg bolus | VPA 27/30 PB 23/30 |
7/30 22/30 |
| Refractory SE: stage III | ||||||
| Singhi et al. [127] | India | Motor seizures uncontrolled after 2 doses of DZP and PHT infusion | Children 2–12 years |
IV MDZ 0.2 mg/kg bolus followed by 2–10 μg/kg/min infusion vs. DZP 0.01–0.1 mg/kg/min infusion | MDZ 18/21 DZP 17/19 |
MDZ 8/21 DZP 9/19 |
| Mehta et al. [220] | India | Seizures >30 min, not controlled by DZP and PHT | Children 5 months–12 years |
IV VPA 30 mg/kg bolus vs. IV DZP 10 μg/Kg/min increased by 10 μg/kg/h every 5 min | VPA 16/20 DZP 17/20 |
VPA 0** DZP 22** |
| Rossetti et al. [135] | Switzerland, USA | Seizures >30 min, not controlled by benzodiazepine and PHT or VPA or PB or LEV | Adults 16–87 years |
IV PRO 2 mg/kg bolus then titrated toward burst-suppression or 2 mg/kg/h vs. IV PTB 5 mg/kg bolus then titrated toward burst-suppression or 2 mg/kg/h or IV THP 2 mg/kg bolus then titrated toward burst-suppression or 4 mg/kg/h | PRO 6/14 PTB or THP 2/9 |
PRO15** PTB or THP 12** |
| Super-refractory SE: stage IV | ||||||
| No randomized, controlled clinical trials available to inform clinical decisions | ||||||
| Studies not explicitly reporting a definition of SE | ||||||
| Appleton et al. [42] | UK | SE not defined | Children | LZP 0.0.5–0.1 mg/kg IV vs. DZP 0.3–0.4 mg/kg IV | LZP 26/27 DZP 29/34 |
LZP 0/27 DZP 0/34 |
| McCormick et al. [221] | USA | SE not defined | Children 1 month–15 years |
MDZ 0.2 mg/kg IV vs. LZP 0.1/kg IV | MDZ 14/15 LZP 8/12 |
MDZ 1/15 LZP 2/12 |
DZP diazepam, GTCS generalized tonic-clonic seizures, IM intramuscular, IN intranasal, IV intravenous, LZP lorazepam, mo months, PB phenobarbital, PHT phenytoin, PRO propofol, PTB pentobarbital, SE status epilepticus, THP thiopental, VPA valproate
* Expressed as number of episodes
** Expressed as number of episodes; some patients experienced more than one adverse effects