Drug management for acute tonic‐clonic convulsions including convulsive status epilepticus in children

Amy McTague; Timothy Martland; Richard Appleton

doi:10.1002/14651858.CD001905.pub3

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Analysis 1.1

Comparison 1 Lorazepam versus diazepam, Outcome 1 Seizure cessation.

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Analysis 1.2

Comparison 1 Lorazepam versus diazepam, Outcome 2 Time from drug administration to stopping of seizures.

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Analysis 1.3

Comparison 1 Lorazepam versus diazepam, Outcome 3 Incidence of respiratory depression.

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Analysis 1.4

Comparison 1 Lorazepam versus diazepam, Outcome 4 Additional dose of the trial drug required to stop seizures.

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Analysis 1.5

Comparison 1 Lorazepam versus diazepam, Outcome 5 Additional drugs required to stop seizures.

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Analysis 1.6

Comparison 1 Lorazepam versus diazepam, Outcome 6 Seizure recurrence within 24 hours.

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Analysis 1.7

Comparison 1 Lorazepam versus diazepam, Outcome 7 Incidence of admissions to the intensive care unit (ICU).

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Analysis 2.1

Comparison 2 Intranasal lorazepam versus intramuscular paraldehyde, Outcome 1 Seizure cessation.

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Analysis 2.2

Comparison 2 Intranasal lorazepam versus intramuscular paraldehyde, Outcome 2 Additional drugs required to stop seizures.

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Analysis 2.3

Comparison 2 Intranasal lorazepam versus intramuscular paraldehyde, Outcome 3 Seizure recurrence within 24 hours.

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Analysis 3.1

Comparison 3 Intravenous lorazepam versus intravenous diazepam/intravenous phenytoin combination, Outcome 1 Seizure cessation.

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Analysis 3.2

Comparison 3 Intravenous lorazepam versus intravenous diazepam/intravenous phenytoin combination, Outcome 2 Incidence of respiratory depression.

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Analysis 3.3

Comparison 3 Intravenous lorazepam versus intravenous diazepam/intravenous phenytoin combination, Outcome 3 Additional drugs required to stop seizures.

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Analysis 4.1

Comparison 4 Intravenous lorazepam versus intranasal lorazepam, Outcome 1 Seizure cessation.

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Analysis 5.1

Comparison 5 Buccal midazolam versus rectal diazepam, Outcome 1 Seizure cessation.

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Analysis 5.2

Comparison 5 Buccal midazolam versus rectal diazepam, Outcome 2 Incidence of respiratory depression.

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Analysis 5.3

Comparison 5 Buccal midazolam versus rectal diazepam, Outcome 3 Additional drugs required to stop seizures.

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Analysis 6.1

Comparison 6 Buccal midazolam versus intravenous diazepam, Outcome 1 Seizure cessation within five minutes.

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Analysis 6.2

Comparison 6 Buccal midazolam versus intravenous diazepam, Outcome 2 Time from drug administration to stopping of seizures.

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Analysis 7.1

Comparison 7 Intranasal midazolam versus intravenous diazepam, Outcome 1 Seizure Cessation.

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Analysis 7.2

Comparison 7 Intranasal midazolam versus intravenous diazepam, Outcome 2 Time from drug administration to stopping of seizures [minutes].

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Analysis 8.1

Comparison 8 Intranasal midazolam versus rectal diazepam, Outcome 1 Seizure cessation.

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Analysis 8.2

Comparison 8 Intranasal midazolam versus rectal diazepam, Outcome 2 Additional drugs required to stop seizures.

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Analysis 9.1

Comparison 9 Intramuscular midazolam versus intravenous diazepam, Outcome 1 Seizure cessation.

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Analysis 9.2

Comparison 9 Intramuscular midazolam versus intravenous diazepam, Outcome 2 Time from drug administration to stopping of seizures (minutes).

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Analysis 9.3

Comparison 9 Intramuscular midazolam versus intravenous diazepam, Outcome 3 Additional drugs required to stop seizures.

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Analysis 9.4

Comparison 9 Intramuscular midazolam versus intravenous diazepam, Outcome 4 Seizure recurrence within 24 hours.

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Analysis 10.1

Comparison 10 Intramuscular midazolam versus rectal diazepam, Outcome 1 Seizure cessation.

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Analysis 11.1

Comparison 11 Intravenous midazolam versus intravenous diazepam, Outcome 1 Seizure cessation.

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Analysis 11.2

Comparison 11 Intravenous midazolam versus intravenous diazepam, Outcome 2 Time from drug administration to stopping of seizures.

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Analysis 11.3

Comparison 11 Intravenous midazolam versus intravenous diazepam, Outcome 3 Incidence of respiratory depression.

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Analysis 11.4

Comparison 11 Intravenous midazolam versus intravenous diazepam, Outcome 4 Additional dose of the trial drug required to stop seizures.

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Analysis 11.5

Comparison 11 Intravenous midazolam versus intravenous diazepam, Outcome 5 Seizure recurrence within 24 hours.

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Analysis 12.1

Comparison 12 Intravenous midazolam versus intravenous lorazepam, Outcome 1 Seizure cessation.

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Analysis 12.2

Comparison 12 Intravenous midazolam versus intravenous lorazepam, Outcome 2 Time from drug administration to stopping of seizures.

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Analysis 12.3

Comparison 12 Intravenous midazolam versus intravenous lorazepam, Outcome 3 Additional dose of the trial drug required to stop seizures.

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Analysis 12.4

Comparison 12 Intravenous midazolam versus intravenous lorazepam, Outcome 4 Seizure recurrence within 24 hours.

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Summary of findings for the main comparison. Summary of findings ‐ Lorazepam compared with diazepam

Lorazepam compared with diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Lorazepam Comparison: Diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Diazepam	Lorazepam
Seizure cessation Follow‐up: up to 24 hours	708 per 1000	765 per 1000 (694 to 850)	RR 1.08 (0.98 to 1.20)	439 (3 trials)	⊕⊕⊝⊝ low^{1, 2}	In two trials, drugs were administered intravenously. In a third trial, drugs were administered intravenously or rectally if intravenous access was not possible Subgroup analysis showed a significant difference by route of intervention (intravenous: RR 1.04 (95% CI 0.94 to 1.16) compared to rectally RR: 2.86 (95% CI 1.47 to 5.55), test of subgroups P = 0.003)
Time from drug administration to termination of seizures Follow‐up: up to 24 hours	The mean time to cessation of seizures was 84.94 seconds in the diazepam group	The mean time to cessation of seizures was 6.18 faster (7.83 slower to 20.19 faster) in the lorazepam group	NA	80 (1 trial)	⊕⊕⊕⊝ moderate³	Drugs were administered intravenously Another trial (where drugs were administered intravenously or rectally) reported similar mean times to seizure cessation. Standard deviations were not available so data could not be entered into analysis
Incidence of respiratory depression Follow‐up: up to 24 hours	356 per 1000	256 per 1000 (196 to 331)	RR 0.72 (0.55 to 0.93)	439 (3 trials)	⊕⊕⊕⊝ moderate¹	In two trials, drugs were administered intravenously. In a third trial, drugs were administered intravenously or rectally if intravenous access was not possible There was no difference between the routes of intervention (test of subgroups, P = 0.86)
Additional drugs required to terminate the seizure: additional dose of study drug Follow‐up: up to 24 hours	305 per 1000	268 per 1000 (195 to 366)	RR 0.88 (0.64 to 1.20)	439 (3 trials)	⊕⊕⊝⊝ low^{1, 2}	In two trials, drugs were administered intravenously. In a third trial, drugs were administered intravenously or rectally if intravenous access was not possible Subgroup analysis by route of intervention (intravenous: RR 0.97 (95% CI 0.71 to 1.33) compared to rectally RR: 0.11 (95% CI 0.01 to 1.56), test of subgroups P = 0.11). Two trials also reported whether additional (other) antiepileptic drugs were required to stop the seizure. There were no significant differences overall or by route of intervention
Seizure recurrence within 24 hours Follow‐up: up to 24 hours	266 per 1000	229 per 1000 (162 to 319)	RR 0.86 (0.61 to 1.20)	439 (3 trials)	⊕⊕⊕⊝ moderate¹	In two trials, drugs were administered intravenously. In a third trial, drugs were administered intravenously or rectally if intravenous access was not possible There was no difference between the routes of intervention (test of subgroups, P = 0.27)
Incidence of admissions to the ICU Follow‐up: up to 24 hours	116 per 1000	17 per 1000 (2 to 114)	RR 0.15 (0.02 to 0.98)	86 (1 trial)	⊕⊕⊝⊝ low^{1, 4}	In the included trial, drugs were administered intravenously or rectally if intravenous access was not possible There was no difference between the routes of intervention (test of subgroups P = 0.32).
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: one included study was quasi‐randomised, which may have led to selection bias and an intention‐to‐treat approach was not used in the study. ²Downgraded once due to inconsistency: a high proportion of heterogeneity was present in the analysis, probably due to differences in the route of administration and differences in definition of 'seizure cessation'. ³Downgraded once due to imprecision: wide confidence intervals around the effect size, ⁴Downgraded once due to imprecision: wide confidence intervals around the effect size (due to zero events in the intervention group).

Summary of findings for the main comparison. Summary of findings ‐ Lorazepam compared with diazepam

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Summary of findings 2. Summary of findings ‐ Intranasal lorazepam compared with intramuscular paraldehyde

Intranasal lorazepam compared with intramuscular paraldehyde for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intranasal lorazepam Comparison: Intramuscular paraldehyde
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intramuscular paraldehyde	Intranasal lorazepam
Seizure cessation: within 10 minutes Follow‐up: up to 24 hours	613 per 1000	747 per 1000 (606 to 931)	RR 1.22 (0.99 to 1.52)	160 (1 study)	⊕⊕⊕⊝ moderate¹	‐
Time from drug administration to termination of seizures Follow‐up: NA	Outcome not reported				NA	‐
Incidence of respiratory depression Follow‐up: up to 24 hours	No difference was found between either treatment group in terms of clinically important cardiorespiratory events.		NA	160 (1 study)	⊕⊕⊝⊝ low^{1, 2}	‐
Additional drugs required to terminate the seizure: 2 or more additional anticonvulsants required Follow‐up: up to 24 hours	263 per 1000	100 per 1000 (47 to 213)	RR 0.38 (0.18 to 0.81)	160 (1 study)	⊕⊕⊝⊝ low^{1, 3}	‐
Seizure recurrence within 24 hours Follow‐up: up to 24 hours	138 per 1000	100 per 1000 (43 to 235)	RR 0.73 (0.31 to 1.71)	160 (1 study)	⊕⊕⊝⊝ low^{1, 3}	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to applicability: a high proportion of the children recruited had either cerebral malaria or meningitis. These comorbidities may have impacted upon the results. ²Downgraded once due to imprecision: no numerical data reported. ³Downgraded once due to imprecision: wide confidence intervals around the effect size (due to low event numbers in one or both treatment groups).

Summary of findings 2. Summary of findings ‐ Intranasal lorazepam compared with intramuscular paraldehyde

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Summary of findings 3. Summary of findings ‐ Intravenous lorazepam compared with intravenous diazepam/intravenous phenytoin combination

Intravenous lorazepam compared with intravenous diazepam/intravenous phenytoin combination for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intravenous lorazepam Comparison: Intravenous diazepam/intravenous phenytoin combination
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous diazepam/intravenous phenytoin combination	Intravenous lorazepam
Seizure cessation: within 10 minutes Follow‐up: up to 24 hours	Seizures were stopped for all individuals in the Intravenous diazepam/intravenous phenytoin combination group	Seizures were stopped for all individuals in the Intravenous lorazepam group	RR 1.00 (0.98 to 1.02)	178 (1 trial)	⊕⊕⊕⊝ moderate¹	‐
Time from drug administration to stopping of seizures Follow‐up: up to 24 hours	There was no significant difference in the median time to seizure cessation (20 seconds in each group).		NA	178 (1 trial)	⊕⊕⊕⊝ moderate²	‐
Incidence of respiratory depression Follow‐up: up to 24 hours	57 per 1000	44 per 1000 (13 to 160)	RR 0.78 (0.22 to 2.82)	178 (1 trial)	⊕⊕⊕⊝ moderate³	‐
Additional drugs required to stop the seizure Follow‐up: up to 24 hours	159 per 1000	67 per 1000 (27 to 165)	RR 0.42 (0.17 to 1.04)	178 (1 trial)	⊕⊕⊕⊝ moderate³	‐
Seizure recurrence within 24 hours Follow‐up: up to 24 hours	There were no seizure recurrences in either group.		NA	178 (1 trial)	⊕⊕⊕⊝ moderate⁴	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due toapplicability: Both treatment arms showed a 100% seizure cessation rate, which is higher than expected. Unclear whether this high success rate was due to a particular element of the trial design. ²Downgraded once due to imprecision: limited numerical data reported. ³Downgraded once due to imprecision: wide confidence intervals around the effect size (due to low event numbers in one or both treatment groups). ⁴Downgraded once due to applicability: the control intervention included a long‐acting anti‐convulsant (phenytoin) which may have influenced the seizure recurrence rate in the control group.

Summary of findings 3. Summary of findings ‐ Intravenous lorazepam compared with intravenous diazepam/intravenous phenytoin combination

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Summary of findings 4. Summary of findings ‐ Intravenous lorazepam compared with intranasal lorazepam

Intravenous lorazepam compared with intranasal lorazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intravenous lorazepam Comparison: Intranasal lorazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intranasal lorazepam	Intravenous lorazepam
Seizure cessation: within 10 minutes Follow‐up: up to 24 hours	696 per 1000	744 per 1000 (536 to 1000)	RR 1.07 (0.77 to 1.49)	58 (1 trial)	⊕⊕⊕⊝ moderate ¹	There was also no significant difference between treatments for seizure cessation at 1 hour: RR 0.70 (95% CI 0.43 to 1.17)
Time from drug administration to stopping of seizures Follow‐up: up to 24 hours	Median time to achieve seizure control from drug administration was 4 minutes in both groups.		NA	58 (1 trial)	⊕⊕⊕⊝ moderate²	Time taken to achieve intravenous access ranged from 1 to 25 minutes with a median of 4 minutes across all participants in the trial. If this had been included in the response time for the intravenous lorazepam, the results would have been skewed significantly in favour of intranasal lorazepam
Incidence of respiratory depression Follow‐up: up to 24 hours	One child required respiratory support	Two children required respiratory support	NA	141 (1 trial, see comment)	⊕⊕⊕⊝ moderate³	Incidence of respiratory depression was not reported for the subgroup of participants with generalised tonic‐clonic seizures in the trial, therefore these results refer to all participants (including 83 participants without generalised tonic‐clonic seizures).
Additional drugs required to stop the seizure Follow‐up: NA	Outcome not reported				NA	‐
Seizure recurrence within 24 hours Follow‐up: NA	Outcome not reported				NA	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Downgraded once due to imprecision: imbalance in the number of participants randomised to each intervention with generalised tonic‐clonic seizures and overall direction of effect seems to change when measured at 10 minutes or at 1 hour ²Downgraded once due to imprecision: limited numerical data reported. ³Downgraded once due to imprecision: Low event numbers and outcome data not available for the subgroup participants with generalised tonic‐clonic seizures in the trial

Summary of findings 4. Summary of findings ‐ Intravenous lorazepam compared with intranasal lorazepam

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Summary of findings 5. Summary of findings ‐ Buccal midazolam compared with rectal diazepam

Buccal midazolam compared with rectal diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Buccal midazolam Comparison: Rectal diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Rectal diazepam	Buccal midazolam
Seizure cessation: within 5 minutes to 1 hour Follow‐up: up to 24 hours	584 per 1000	730 per 1000 (660 to 806)	RR 1.25 (1.13 to 1.38)	648 (4 trials) 690 seizure episodes	⊕⊝⊝⊝ very low^{1, 2, 3}	The measurement time of seizure cessation was examined in a subgroup analysis 5 minutes: RR 1.22 (95% CI 1.07 to 1.40, P = 0.004); 10 minutes: RR 1.07 (95% CI 0.95 to 1.21, P = 0.26); 1 hour; RR 2.05 (95% CI 1.45 to 2.91, P < 0.001). There was a significant difference between the subgroups (P = 0.002)
Time from drug administration to of seizures Follow‐up: up to 24 hours	One trial found no difference between groups in the time from drug administration to seizure cessation One trial reported that both the median treatment initiation time and drug effect time were significantly shorter in the buccal midazolam group than the rectal diazepam group.		NA	141 (2 trials)	⊕⊕⊝⊝ low^{1, 4}	No numerical data presented for either trial
Incidence of respiratory depression Follow‐up: up to 24 hours	76 per 1000	67 per 1000 (46 to 94)	RR 0.88 (0.61 to 1.25)	648 (4 trials) 690 seizure episodes	⊕⊕⊝⊝ low^{1, 3}	‐
Additional drugs required to stop the seizure: intravenous lorazepam required Follow‐up: up to 24 hours	573 per 1000	332 per 1000 (241 to 452)	RR 0.58 (0.42 to 0.79)	177 (1 trial) 219 seizure episodes	⊕⊕⊝⊝ low^{3, 5}	A second trial reported that there was no difference between groups in the need for a second drug
Seizure recurrence within 24 hours Follow‐up: NA	Outcome not reported				NA	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: one included study was quasi‐randomised and one study did not conceal allocation. Both of these studies were at risk of selection bias. ²Downgraded once due to inconsistency: a high proportion of heterogeneity was present in analysis, probably due to differences in the measurement times of the outcome and potentially also the doses of the drugs across the studies and comorbidities of participants recruited. ³Downgraded once due to imprecision: Results are not available at the participant level so results reported for McIntyre 2005 are at the episode level. This is a limitation, as meta‐analysis assumes independence between measurements, and more than one treated seizure per participant would not be statistically independent. A result of ignoring this unit‐of‐analysis issue could be overoptimistic confidence intervals. ⁴Downgraded once due to imprecision: no numerical data reported. ⁵Downgraded once due to risk of bias: the included study was quasi‐randomised, did not conceal allocation and was at risk of selection bias.

Summary of findings 5. Summary of findings ‐ Buccal midazolam compared with rectal diazepam

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Summary of findings 6. Summary of findings ‐ Buccal midazolam compared with intravenous diazepam

Buccal midazolam compared with intravenous diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Buccal midazolam Comparison: Intravenous diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous diazepam	Buccal midazolam
Seizure cessation Follow‐up: up to 24 hours	933 per 1000	849 per 1000 (747 to 961)	RR 0.91 (0.80 to 1.03)	120 (1 trial)	⊕⊕⊕⊕ high	‐
Time from drug administration to termination of seizures Follow‐up: up to 24 hours	The mean time to cessation of seizures was 1.13 minutes in the intravenous diazepam group.	The mean time to cessation of seizures was 0.56 minutes higher in the buccal diazepam group (0.29 to 0.83 minutes higher).	NA	120 (1 trial)	⊕⊕⊕⊝ moderate¹	The mean time for initiation of treatment was significantly shorter in the buccal midazolam group (MD ‐1.09 minutes, 95% CI ‐1.31 to ‐0.87) and therefore the mean total time to controlling the seizures was significantly shorter in the buccal midazolam group compared to the intravenous diazepam group (MD ‐0.59, 95% CI ‐0.96 to ‐0.22)
Incidence of respiratory depression Follow‐up: up to 24 hours	There were no adverse events in either group		NA	120 (1 trial)	⊕⊕⊕⊕ high	‐
Additional drugs required to stop the seizure Follow‐up: NA	Outcome not reported				NA	‐
Seizure recurrence within 24 hours Follow‐up: NA	Outcome not reported				NA	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; MD: Mean difference; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to applicability: the route of intervention of the drug has been shown to influence the outcome.

Summary of findings 6. Summary of findings ‐ Buccal midazolam compared with intravenous diazepam

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Summary of findings 7. Summary of findings ‐ Intranasal midazolam compared with intravenous diazepam

Intranasal midazolam compared with intravenous diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intranasal midazolam Comparison: Intravenous diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous diazepam	Intranasal midazolam
Seizure cessation Follow‐up: up to 24 hours	967 per 1000	948 per 1000 (880 to 1000)	RR 0.98 (0.91 to 1.06)	122 (2 trials)	⊕⊕⊕⊝ moderate¹	‐
Time from drug administration to stopping of seizures Follow‐up: up to 24 hours	The mean time to cessation of seizures ranged from 2.5 to 2.94 minutes in the intravenous diazepam group.	The mean time to cessation of seizures was 0.62 minutes higher in the intranasal midazolam group (0.14 lower to 1.38 minutes higher).	NA	122 (2 trials)	⊕⊕⊕⊝ moderate²	One trial reports that the time for initiation of treatment was significantly shorter in the intranasal midazolam group (MD ‐2.00 minutes, 95% CI ‐3.03 to ‐0.97). The other trial also reports that time for initiation of treatment was significantly shorter in the intranasal midazolam group but does not account for this in analysis
Incidence of respiratory depression Follow‐up: up to 24 hours	No adverse events including respiratory depression occurred in either group.		NA	122 (2 trials)	⊕⊕⊕⊕ high	‐
Additional drugs required to stop the seizure Follow‐up: NA	Outcome not reported				NA	‐
Seizure recurrence within 24 hours Follow‐up: NA	Outcome not reported				NA	‐
Incidence of admissions to the ICU Follow‐up: up to 24 hours	There were no admissions to the ICU in either group		NA	52 (1 trial)	⊕⊕⊕⊕ high	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; MD: Mean difference; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: one of the studies included in this comparison did not report this outcome. As this is an expected outcome, this may be selective reporting. Additionally, in one trial both treatment arms showed a 100% seizure cessation rate, which is higher than expected. Unclear whether this high success rate was due to a particular element of the trial design. ²Downgraded once due to applicability: the route of intervention of the drug has been shown to influence the outcome.

Summary of findings 7. Summary of findings ‐ Intranasal midazolam compared with intravenous diazepam

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Summary of findings 8. Summary of findings ‐ Intranasal midazolam compared with rectal diazepam

Intranasal midazolam compared with rectal diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intranasal midazolam Comparison: Rectal diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Rectal diazepam	Intranasal midazolam
Seizure cessation: within 10 minutes Follow‐up: up to 24 hours	591 per 1000	869 per 1000 (591 to 1000)	RR 1.47 (1.00 to 2.16)	45 (1 trial)	⊕⊕⊝⊝ low^{1, 2}	‐
Time from drug administration to termination of seizures Follow‐up: NA	Outcome not reported				NA	‐
Incidence of respiratory depression Follow‐up:	There was no significant difference between the two groups for of cardiorespiratory or adverse effects.		NA	45 (1 trial)	⊕⊕⊝⊝ low^{1, 3}	No numerical data reported
Additional drugs required to stop the seizure Follow‐up: up to 24 hours	409 per 1000	131 per 1000 (41 to 421)	RR 0.32 (0.10 to 1.03)	45 (1 trial)	⊕⊕⊝⊝ low^{1, 4}	‐
Seizure recurrence within 24 hours Follow‐up: NA	Outcome not reported				NA	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: one included study was quasi‐randomised, which may have led to selection bias. Additionally, the description of the seizure type and aetiology of the included children was unclear, so it is unclear if the population of this study is generalisable. ²Downgraded once due to imprecision: wide confidence intervals around the effect size (due to high event rates in both treatment groups). ³Downgraded once due to imprecision: no numerical data reported. ⁴Downgraded once due to imprecision: wide confidence intervals around the effect size (due to low event rates in both treatment groups).

Summary of findings 8. Summary of findings ‐ Intranasal midazolam compared with rectal diazepam

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Summary of findings 9. Summary of findings ‐ Intramuscular midazolam compared with intravenous diazepam

Intramuscular midazolam compared with intravenous diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intramsucular midazolam Comparison: Intravenous diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous diazepam	Intramsucular midazolam
Seizure cessation Follow‐up: up to 24 hours	929 per 1000	901 per 1000 (808 to 1000)	RR 0.97 (0.87 to 1.09)	105 (2 trials)	⊕⊕⊝⊝ low^1,2	‐
Time from drug administration to stopping of seizures: total time to seizure cessation Follow‐up: up to 24 hours	The mean total time to cessation of seizures was 2.68 minutes lower (3.94 to 1.42 minutes lower) in the intramuscular midazolam group compared to the intravenous diazepam group		NA	105 (2 trials)	⊕⊝⊝⊝ very low^{1, 2, 3}	One trial also showed that the initiation of treatment was significantly shorter in the intramuscular midazolam group (MD ‐4.50 minutes (‐6.68 to ‐2.32)) but there was no significant difference between treatments for the time to drug effect (MD 1.10 minutes (95% CI ‐0.91 to 3.11)
Incidence of respiratory depression Follow‐up: up to 24 hours	There were no adverse events or complications in either trial		NA	105 (2 trials)	⊕⊕⊝⊝ low^{1, 2}	‐
Additional drugs required to terminate the seizure Follow‐up: up to 24 hours	71 per 1000	96 per 1000 (25 to 366)	RR 1.34 (0.35 to 5.13)	105 (2 trials)	⊕⊝⊝⊝ very low^{1, 2, 4}	‐
Seizure recurrence within 24 hours: within one hour Follow‐up: up to 24 hours	364 per 1000	309 per 1000 (98 to 983)	RR 0.85 (0.27 to 2.62)	24 (1 trial)	⊕⊝⊝⊝ very low^{1, 2, 4}	There was also no significant difference between treatments at within 15 minutes (RR: 0.85 (95% CI 0.06,to12.01)
Incidence of admissions to the ICU Follow‐up: up to 24 hours	There were no admissions to the ICU		NA	81 (1 trial)	⊕⊕⊕⊝ moderate¹	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; MD: Mean difference; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: in both included trials, methods of randomisation were unclear so the trials may be at risk of selection bias. ²Downgraded once due to applicability: one child was randomised twice in one trial and included in both groups. It was not possible to identify this child in analysis and results are not adjusted for the correlation between measurements from the same child. ³Downgraded once due to applicability: the route of intervention of the drug has been shown to influence the outcome. ⁴Downgraded once due to imprecision: wide confidence intervals around the effect size or pooled effect size (due to low event rates in both treatment groups).

Summary of findings 9. Summary of findings ‐ Intramuscular midazolam compared with intravenous diazepam

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Summary of findings 10. Summary of findings ‐ Intramuscular midazolam compared with rectal diazepam

Intramuscular midazolam compared with rectal diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intramuscular midazolam Comparison: Rectal diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Rectal diazepam	Intramuscular midazolam
Seizure cessation Follow‐up: up to 24 hours	940 per 1000	959 per 1000 (874 to 1000)	RR 1.02 (0.93 to 1.12)	100 (1 trial)	⊕⊕⊕⊝ moderate¹	‐
Time from drug administration to stopping of seizures Follow‐up: up to 24 hours	There was a significant difference in time from administration to seizure cessation in favour of midazolam (median 66 seconds, diazepam, median 130 seconds, P < 0.001)		NA	100 (1 trial)	⊕⊕⊕⊝ moderate¹	It is noted that the speed of administration was similarly fast for both medications, so this seems to reflect a medication difference.
Incidence of respiratory depression Follow‐up: up to 24 hours	No patients developed respiratory depression except for one patient who received an accidental double dose of intramuscular midazolam.		NA	100 (1 trial)	⊕⊕⊕⊝ moderate¹	‐
Additional drugs required to stop the seizure Follow‐up: NA	Outcome not reported				NA	‐
Seizure recurrence within 24 hours Follow‐up: up to 24 hours	Among those with seizures terminated, there were no recurrences at 24 hours		NA	100 (1 trial)	⊕⊕⊕⊝ moderate¹
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: the included study did not conceal allocation so is at risk of selection bias.

Summary of findings 10. Summary of findings ‐ Intramuscular midazolam compared with rectal diazepam

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Summary of findings 11. Summary of findings ‐ Intravenous midazolam compared with intravenous diazepam

Intravenous midazolam compared with intravenous diazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intravenous midazolam Comparison: Intravenous diazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous diazepam	Intravenous midazolam
Seizure cessation Follow‐up: up to 24 hours	900 per 1000	972 per 1000 (873 to 1000)	RR 1.08 (0.97 to 1.21)	80 (1 trial)	⊕⊕⊕⊝ moderate¹	‐
Time from drug administration to stopping of seizures Follow‐up: up to 24 hours	The mean time to cessation of seizures was 84.94 seconds in the intravenous diazepam group.	The mean time to cessation of seizures was 7.68 seconds higher in the intravenous midazolam group (6.73 seconds lower to 22.09 seconds higher) .	NA	80 (1 trial)	⊕⊕⊕⊝ moderate²	‐
Incidence of respiratory depression Follow‐up: up to 24 hours	25 per 1000	8 per 1000 (0 to 199)	RR 0.33 (0.01 to 7.95)	80 (1 trial)	⊕⊕⊕⊝ moderate³	‐
Additional drugs required to stop the seizure: additional dose of the trial drug required Follow‐up: up to 24 hours	100 per 1000	25 per 1000 (3 to 214)	RR 0.25 (0.03 to 2.14)	80 (1 trial)	⊕⊕⊕⊝ moderate³	‐
Seizure recurrence within 24 hours Follow‐up: up to 24 hours	100 per 1000	50 per 1000 (10 to 258)	RR 0.50 (0.10 to 2.58)	80 (1 trial)	⊕⊕⊕⊝ moderate³	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: the definition of the 'seizure cessation' outcome is not an appropriate criterion for judging seizure cessation. This definition is likely to have impacted upon results. ²Downgraded once due to imprecision: wide confidence intervals around the effect size. ³Downgraded once due to imprecision: wide confidence intervals around the effect size (due to low event rates in both treatment groups).

Summary of findings 11. Summary of findings ‐ Intravenous midazolam compared with intravenous diazepam

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Summary of findings 12. Summary of findings ‐ Intravenous midazolam compared with intravenous lorazepam

Intravenous midazolam compared with intravenous lorazepam for children with acute tonic‐clonic seizures
Patient or population: Children with acute tonic‐clonic seizures Settings: Hospital inpatients Intervention: Intravenous midazolam Comparison: Intravenous lorazepam
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intravenous lorazepam	Intravenous midazolam
Seizure cessation Follow‐up: up to 24 hours	Seizures were terminated for all children in the Intravenous lorazepam group	Seizures were terminated for 39 out of 40 children in the intravenous midazolam group	RR 0.98 (0.91 to 1.04)	80 (1 trial)	⊕⊕⊕⊝ moderate¹	‐
Time from drug administration to termination of seizures Follow‐up: up to 24 hours	The mean time to cessation of seizures was 91.12 seconds in the intravenous lorazepam group.	The mean time to cessation of seizures was 1.50 seconds higher in the intravenous midazolam group (9.37 seconds lower to 12.37 seconds higher) .	NA	80 (1 trial)	⊕⊕⊕⊝ moderate²	‐
Incidence of respiratory depression Follow‐up: up to 24 hours	There were no occurrences of respiratory depression in either group		NA	80 (1 trial)	⊕⊕⊕⊕ high	‐
Additional drugs required to terminate the seizure: additional dose of the trial drug required Follow‐up: up to 24 hours	No children in the intravenous lorazepam group required an additional dose of the trial drug.	One child in the intravenous midazolam group required an additional dose of the trial drug.	RR 3.00 (0.13 to 71.51)	80 (1 trial)	⊕⊕⊕⊝ moderate³	‐
Seizure recurrence within 24 hours Follow‐up: up to 24 hours	50 per 1000	50 per 1000 (8 to 338)	RR 1.00 (0.15 to 6.76)	80 (1 trial)	⊕⊕⊕⊝ moderate³	‐
Incidence of admissions to the ICU Follow‐up: NA	Outcome not reported				NA	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive Care Unit; NA: Not applicable; RR: Risk Ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Downgraded once due to risk of bias: the definition of the 'seizure cessation' outcome is not an appropriate criterion for judging seizure cessation. This definition is likely to have impacted upon results. ²Downgraded once due to imprecision: wide confidence intervals around the effect size. ³Downgraded once due to imprecision: wide confidence intervals around the effect size (due to low event rates in both treatment groups).

Summary of findings 12. Summary of findings ‐ Intravenous midazolam compared with intravenous lorazepam

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Table 1. Event rates for seizure cessation, respiratory depression and additional drugs required

Study	Drug	Seizure cessation			Respiratory Depression			Additional drugs required
Study	Drug	No. of Events	No. of Children	%	No. of Events	No. of Children	%	No. of Events	No. of Children	%
Ahmad 2006	IN lorazepam	60	80	75	0	80	0	8	80	10
Ahmad 2006	IM paraldehyde	49	80	60	0	80	0	21	80	26
Appleton 1995	IV lorazepam	19	27	70	1	27	4	1	27	4
	Rectal lorazepam	6	6	100	0	6	0	0	6	0
	IV diazepam	22	34	65	7	34	21	5	34	15
	Rectal diazepam	6	19	32	1	19	5	12	19	63
Arya 2011 *	IN lorazepam	16	23	70	1	71	1	NR	23	NA
Arya 2011 *	IV lorazepam	26	35	74	2	70	3	NR	35	NA
Ashrafi 2010	Buccal midazolam	49	49	100	0	49	0	0	49	0
Ashrafi 2010	Rectal diazepam	40	49	82	0	49	0	9	49	18
Baysun 2005	Buccal midazolam	18	23	78	0	23	0	5	23	22
Baysun 2005	Rectal diazepam	17	20	85	1	20	5	3	20	15
Chamberlain 1997	IM midazolam	12	13	92	0	13	0	1	13	8
Chamberlain 1997	IV diazepam	10	11	91	0	11	0	1	11	9
Chamberlain 2014	IV diazepam	101	140	72	26	140	16	21	140	15
Chamberlain 2014	IV lorazepam	97	133	73	26	133	18	21	133	16
Fişgin 2002	IN midazolam	20	23	87	0	23	0	3	23	13
Fişgin 2002	Rectal diazepam	13	22	60	0	22	0	9	22	40
Gathwala 2012	IV diazepam	36	40	90	1	40	3	4	40	10
	IV midazolam	39	40	98	0	40	0	1	40	3
	IV lorazepam	40	40	100	0	40	0	0	40	0
Javadzadeh 2012	IN midazolam	NR	30	NA	NR	30	NA	NR	30	NA
Javadzadeh 2012	IV diazepam	NR	30	NA	NR	30	NA	NR	30	NA
Lahat 2000	IN midazolam	23	26	88	0	26	0	NR	26	NA
Lahat 2000	IV diazepam	24	26	92	0	26	0	NR	26	NA
Mahmoudian 2004	IN midazolam	35	35	100	0	35	0	0	35	0
Mahmoudian 2004	IV diazepam	35	35	100	0	35	0	0	35	0
McIntyre 2005	Buccal midazolam	61	109	56	5	109	5	36	109	33
McIntyre 2005	Rectal diazepam	30	110	27	7	110	6	63	110	57
Momen 2015	IM midazolam	48	50	96	1	50	2	NR	50	NA
Momen 2015	Rectal diazepam	47	50	94	0	50	0	NR	50	NA
Mpimbaza 2008	Buccal midazolam	125	165	76	2	165	1	NR	165	NA
Mpimbaza 2008	Rectal diazepam	114	165	69	2	165	1	NR	165	NA
Shah 2005	IM midazolam	45	50	90	0	50	0	5	50	10
Shah 2005	IV diazepam	29	31	90	0	31	0	2	31	6
Sreenath 2010	IV lorazepam	90	90	100	4	90	4	6	90	7
Sreenath 2010	IV diazepam with phenytoin	88	88	100	5	88	6	14	88	16
Talukdar 2009	Buccal midazolam	51	60	85	0	60	0	9	60	15
Talukdar 2009	IV diazepam	56	60	93	0	60	0	4	60	7
Abbreviations: IM: Intramuscular; IN: Intranasal; IV: Intravenous; NR: Not reported; NA: Not available (percentages could not be calculated where event rate was NR) *Occurences of respiratory depression were not reported for the subgroup of participants with generalised tonic‐clonic seizures in Arya 2011, therefore these results refer to all participants (including 83 participants without generalised tonic‐clonic seizures).

Table 1. Event rates for seizure cessation, respiratory depression and additional drugs required

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Comparison 1. Lorazepam versus diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	3	439	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.98, 1.20]

1.1 Intravenous	3	414	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.94, 1.16]
1.2 Rectal	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	2.86 [1.47, 5.55]
2 Time from drug administration to stopping of seizures Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 Intravenous	1	80	Mean Difference (IV, Fixed, 95% CI)	6.18 [‐7.83, 20.19]
3 Incidence of respiratory depression Show forest plot	3	439	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.55, 0.93]

3.1 Intravenous	3	414	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.55, 0.92]
3.2 Rectal	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.04, 20.78]
4 Additional dose of the trial drug required to stop seizures Show forest plot	3	439	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.64, 1.20]

4.1 Intravenous	3	414	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.71, 1.33]
4.2 Rectal	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 1.56]
5 Additional drugs required to stop seizures Show forest plot	2	359	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.45, 1.24]

5.1 Intravenous	2	334	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.54, 1.55]
5.2 Rectal	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 1.69]
6 Seizure recurrence within 24 hours Show forest plot	3	439	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.61, 1.20]

6.1 Intravenous	3	414	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.65, 1.27]
6.2 Rectal	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 2.92]
7 Incidence of admissions to the intensive care unit (ICU) Show forest plot	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.02, 0.98]

7.1 Intravenous	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.00, 1.22]
7.2 Rectal	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.03, 10.51]

Comparison 1. Lorazepam versus diazepam

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Comparison 2. Intranasal lorazepam versus intramuscular paraldehyde

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Within 10 minutes	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.99, 1.52]
2 Additional drugs required to stop seizures Show forest plot	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.18, 0.81]

3 Seizure recurrence within 24 hours Show forest plot	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.31, 1.71]

Comparison 2. Intranasal lorazepam versus intramuscular paraldehyde

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Comparison 3. Intravenous lorazepam versus intravenous diazepam/intravenous phenytoin combination

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Within 10 minutes	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.98, 1.02]
2 Incidence of respiratory depression Show forest plot	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.22, 2.82]

3 Additional drugs required to stop seizures Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 More than one dose of the trial drug required	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.17, 1.04]

Comparison 3. Intravenous lorazepam versus intravenous diazepam/intravenous phenytoin combination

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Comparison 4. Intravenous lorazepam versus intranasal lorazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Within 10 minutes	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.77, 1.49]
1.2 Within 1 hour	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.43, 1.17]

Comparison 4. Intravenous lorazepam versus intranasal lorazepam

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Comparison 5. Buccal midazolam versus rectal diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	4	690	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [1.13, 1.38]

1.1 Within 5 minutes	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [1.07, 1.40]
1.2 Within 10 minutes	2	373	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.95, 1.21]
1.3 Within one hour	1	219	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [1.45, 2.91]
2 Incidence of respiratory depression Show forest plot	4	690	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.61, 1.25]

3 Additional drugs required to stop seizures Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Intravenous lorazepam required	1	219	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.42, 0.79]

Comparison 5. Buccal midazolam versus rectal diazepam

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Comparison 6. Buccal midazolam versus intravenous diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation within five minutes Show forest plot	1	120	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.80, 1.03]

2 Time from drug administration to stopping of seizures Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 Treatment initiation time (minutes)	1	120	Mean Difference (IV, Fixed, 95% CI)	‐1.09 [‐1.31, ‐0.87]
2.2 Time for drug effect (minutes)	1	120	Mean Difference (IV, Fixed, 95% CI)	0.56 [0.29, 0.83]
2.3 Total time to seizure cessation (minutes)	1	120	Mean Difference (IV, Fixed, 95% CI)	‐0.59 [‐0.96, ‐0.22]

Comparison 6. Buccal midazolam versus intravenous diazepam

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Comparison 7. Intranasal midazolam versus intravenous diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure Cessation Show forest plot	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.91, 1.06]

2 Time from drug administration to stopping of seizures [minutes] Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 Treatment initiation time (minutes)	1	52	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐3.03, ‐0.97]
2.2 Time for drug effect (minutes)	2	122	Mean Difference (IV, Fixed, 95% CI)	0.62 [‐0.14, 1.38]
2.3 Total time to seizure cessation (minutes)	2	112	Mean Difference (IV, Fixed, 95% CI)	0.80 [0.24, 1.35]

Comparison 7. Intranasal midazolam versus intravenous diazepam

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Comparison 8. Intranasal midazolam versus rectal diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Within 10 minutes	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.00, 2.16]
2 Additional drugs required to stop seizures Show forest plot	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.10, 1.03]

Comparison 8. Intranasal midazolam versus rectal diazepam

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Comparison 9. Intramuscular midazolam versus intravenous diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.87, 1.09]

2 Time from drug administration to stopping of seizures (minutes) Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 Treatment initiation time (minutes)	1	24	Mean Difference (Fixed, 95% CI)	‐4.5 [‐6.68, ‐2.32]
2.2 Time for drug effect (minutes)	1	24	Mean Difference (Fixed, 95% CI)	1.1 [‐0.91, 3.11]
2.3 Total time to seizure cessation (minutes)	2	105	Mean Difference (Fixed, 95% CI)	‐2.68 [‐3.94, ‐1.42]
3 Additional drugs required to stop seizures Show forest plot	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.35, 5.13]

4 Seizure recurrence within 24 hours Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Within 15 minutes	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.06, 12.01]
4.2 Within one hour	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.27, 2.62]

Comparison 9. Intramuscular midazolam versus intravenous diazepam

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Comparison 10. Intramuscular midazolam versus rectal diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Within 1 hour	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.93, 1.12]

Comparison 10. Intramuscular midazolam versus rectal diazepam

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Comparison 11. Intravenous midazolam versus intravenous diazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.97, 1.21]

2 Time from drug administration to stopping of seizures Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	7.68 [‐6.73, 22.09]

3 Incidence of respiratory depression Show forest plot	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.95]

4 Additional dose of the trial drug required to stop seizures Show forest plot	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.14]

5 Seizure recurrence within 24 hours Show forest plot	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.10, 2.58]

Comparison 11. Intravenous midazolam versus intravenous diazepam

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Comparison 12. Intravenous midazolam versus intravenous lorazepam

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Seizure cessation Show forest plot	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.91, 1.04]

2 Time from drug administration to stopping of seizures Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐9.37, 12.37]

3 Additional dose of the trial drug required to stop seizures Show forest plot	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 71.51]

4 Seizure recurrence within 24 hours Show forest plot	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.15, 6.76]

Comparison 12. Intravenous midazolam versus intravenous lorazepam

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