What is the lowest dose for midazolam IV to be given for active seizure if patient is not on telemetry or monitored? Can midazolam be given IM for active seizure?

Comment by InpharmD Researcher

Current literature does not establish a lowest effective or safe intravenous (IV) midazolam dose for active seizures in patients who are not on telemetry or otherwise continuously monitored; prescribing information and clinical reviews emphasize that IV midazolam requires continuous respiratory and cardiac monitoring due to risk of severe respiratory depression and arrest. Studies report effective IV doses ranging from approximately 0.1 to 0.3 mg/kg in children and 2.5 to 10 mg in adults, though all were administered in monitored settings. Notably, the 2016 American Epilepsy Society guideline identifies intramuscular (IM) midazolam as an effective first-line option for convulsive status epilepticus, particularly when IV access has not yet been established. Preshospital trials similarly demonstrate that IM midazolam is comparable in safety and effectiveness to IV benzodiazepines, while the question of a minimal unmonitored IV dose remains unanswered.

Background

According to the 2016 American Epilepsy Society guidelines on the treatment of convulsive status epilepticus in children and adults, a comprehensive analysis was conducted to evaluate the efficacy, safety, and tolerability of various anticonvulsants. This evidence-based guideline synthesized data from 38 randomized controlled trials (RCTs), of which only four provided class I evidence of efficacy. The analysis focused on convulsive status epilepticus, defined as continuous seizure activity lasting more than 30 minutes or two or more sequential seizures without full recovery of consciousness between episodes. The guideline emphasizes the importance of rapid termination of both clinical and electrical seizure activities to reduce associated mortality and morbidity. In the context of initial therapy, intramuscular (IM) midazolam, intravenous (IV) lorazepam, IV diazepam, and IV phenobarbital were established as efficacious options for adults, while IV lorazepam and IV diazepam were deemed effective for children, with potential efficacy demonstrated for other routes of midazolam administration. Notably, the guideline identifies IM midazolam as having superior effectiveness to IV lorazepam in adults without established IV access, with a standard IM dose of 10 mg for adults or 5 mg for patients weighing 13 to 40 kg. Recommended IV benzodiazepine doses used in class I trials include IV lorazepam 0.1 mg/kg and IV diazepam 0.15 to 0.2 mg/kg, which may be repeated once. The guideline supports the use of IM midazolam as a first-line option in patients without established IV access. No recommendations are made regarding a lowest monitored vs. unmonitored dose; rather, dosing reflects those used in randomized controlled trials. [1]

The third edition of the National Association of State EMS Officials (NASEMSO) National Model EMS Clinical Guidelines outlines anticonvulsant treatment that includes midazolam 0.2 mg/kg (maximum 10 mg) IM or Intranasal (IN) when vascular access is absent, and when IV or intraosseous (IO) access is present recommends diazepam 0.2 mg/kg (maximum 10 mg), lorazepam 0.1 mg/kg (maximum 4 mg), or midazolam 0.1 mg/kg (maximum 4 mg). Recent evidence indicates that IM midazolam is at least as safe and effective as IV lorazepam for stopping seizures in prehospital settings. This suggests that midazolam administered via the IM route can be a viable alternative to IV lorazepam, offering comparable safety and effectiveness for seizure cessation before reaching a hospital. [2]

According to a 2025 source from the National Center for Biotechnology Information, StatPearls, intravenous midazolam, a potent sedative, carries a risk of causing severe respiratory depression and arrest, which can lead to fatal outcomes or hypoxic encephalopathy if not addressed immediately. Its administration requires a setting equipped for continuous respiratory and cardiac monitoring, with access to resuscitation drugs, ventilation and intubation equipment, and trained personnel. In pediatric patients under deep sedation, constant monitoring by skilled clinicians is essential to ensure safety and mitigate risks. [3]

References:

[1] Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. doi:10.5698/1535-7597-16.1.48
[2] National Association of State EMS Officials (NASEMSO), Medical Directors Council. National Model EMS Clinical Guidelines. Version 3.0. National Highway Traffic Safety Administration; 2022. Accessed December 5, 2025.
[3] Lingamchetty TN, Hosseini SA, Patel P, Saadabadi A. Midazolam. In: StatPearls. StatPearls Publishing; 2025. Accessed December 5, 2025.
Relevant Prescribing Information

BOXED WARNING [4]
WARNINGS
Personnel and Equipment for Monitoring and Resuscitation
Adults and Pediatrics: Intravenous midazolam hydrochloride has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam hydrochloride should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, e.g., pulse oximetry. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS). For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

References:

[4] Midazolam hydrochloride (injection). Prescribing information. Belcher Pharmaceuticals, LLC.; 2025.
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the lowest dose for midazolam IV to be given for active seizure if patient is not on telemetry or monitored? Can midazolam be given IM for active seizure?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-6 for your response.

Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus
Design

Double-blind, randomized, noninferiority trial

N= 893
Objective To determine whether intramuscular midazolam is as effective as intravenous lorazepam, with a similar degree of safety, for terminating status epilepticus seizures before arrival at the hospital
Study Groups

Intramuscular midazolam (n= 448)

Intravenous lorazepam (n= 445)
Inclusion Criteria Children with an estimated body weight of 13 kg or more and adults requiring treatment with benzodiazepines for status epilepticus in the prehospital setting; convulsive seizures at the time of treatment by paramedics
Exclusion Criteria Major trauma, hypoglycemia, cardiac arrest, heart rate <40 bpm, known allergy to midazolam or lorazepam, known pregnancy, prisoner status, participation in another study, opted out by wearing a medical-alert tag marked “RAMPART declined”
Methods

Subjects were given either 10 mg of intramuscular midazolam or 4 mg of intravenous lorazepam for adults and children over 40 kg, and 5 mg of intramuscular midazolam or 2 mg of intravenous lorazepam for children 13 to 40 kg. Intramuscular administration was via autoinjector, followed by intravenous administration if needed. Paramedics recorded treatment times and seizure cessation.
Duration June 15, 2009, to January 14, 2011
Outcome Measures

Primary: Termination of seizures before arrival in the emergency department without rescue therapy

Secondary: Time from study-box opening to termination of convulsions, frequency of endotracheal intubation, recurrent seizures, hospital and ICU admission duration
Baseline Characteristics   Intramuscular midazolam (n= 448) Intravenous lorazepam (n= 445)
Age, years (mean) Not specified Not specified
History of epilepsy Not specified Not specified
Diagnosis of status epilepticus Not specified Not specified
Results   Intramuscular midazolam (n= 448) Intravenous lorazepam (n= 445) p-value
Seizures absent without rescue therapy 73.4% 63.4% <0.001
Need for endotracheal intubation 14.1% 14.4% Not specified
Recurrent seizures 11.4% 10.6% Not specified
Adverse Events Adverse-event rates were similar in the two groups
Study Author Conclusions Intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. It is a practical, safe, and effective alternative to the intravenous route for treating prolonged convulsive seizures in the prehospital setting.
Critique The study's strengths include its large sample size and rigorous double-blind, randomized design. However, the study may be limited by the lack of detailed baseline characteristics and potential variability in paramedic training and adherence to protocol. Additionally, the study did not explore the long-term outcomes of the treatments.
References:

Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600. doi:10.1056/NEJMoa1107494

Parenteral Midazolam is Superior to Diazepam for Treatment of Prehospital Seizures
Design

Retrospective cohort study

N= 440
Objective To compare the effectiveness of midazolam and diazepam in treating prehospital seizures during periods of drug scarcity
Study Groups

Diazepam (n= 237)

Midazolam (n= 203)
Inclusion Criteria Adult patients who received at least 1 parenteral dose of diazepam or midazolam for treatment of seizures
Exclusion Criteria Patients younger than 18 years, interfacility transfers, administrations for indications other than active seizure, or cases with incomplete data
Methods Retrospective chart review of a single EMS agency during a 29-month period. Ambulances were stocked with either diazepam or midazolam based on availability. The regional prehospital protocol recommended 5 mg IV diazepam, 5 mg IM diazepam, 5 mg IM midazolam, or 2.5 mg IV midazolam. Medication effectiveness was compared with respect to seizure cessation without repeat seizure during the prehospital encounter
Duration January 2011 to May 2013
Outcome Measures Primary: Cessation of seizure without repeat seizure during the prehospital encounter
Baseline Characteristics  

Diazepam (n= 237)

Midazolam (n= 203)
Number 237 203
Male gender 50.6% 53.7%
Mean age 48.4 47.8
Dispatch for seizure 69.2% 70.0%
History of seizure 74.3% 75.9%
Patient taking seizure medications 44.3% 40.9%
Alcohol use noted 7.6% 7.4%
Trauma noted 4.2% 4.4%
Seizure prior to arrival 78.5% 81.8%
Mean patient contact time 0:30 0:29
Mean time to first benzodiazepine administration 0:17 0:15
Results  

Diazepam (n= 237)

Midazolam (n= 203)

 p-value
Seizure stopped; no further seizures 49% 65% 0.002
Seizure stopped with first dose IM 25% 69% <0.0001
Seizure stopped with first dose IV 58% 62% 0.294
Adverse Events Not specifically reported in the abstract
Study Author Conclusions For parenteral administration, midazolam demonstrated superior first-dose seizure suppression compared to diazepam. This study demonstrates how periods of drug scarcity can be utilized to study prehospital medication effectiveness.
Critique The study utilized a natural experiment due to drug scarcity, providing a unique opportunity to compare medications. However, the retrospective design and reliance on existing data may limit the ability to control for all variables. The study did not evaluate hospital outcomes, which could provide additional insights into the long-term effectiveness of the treatments.

 

References:

Clemency BM, Ott JA, Tanski CT, Bart JA, Lindstrom HA. Parenteral midazolam is superior to diazepam for treatment of prehospital seizures. Prehospital Emergency Care. 2015;19(2):218-223. doi:10.3109/10903127.2014.959220

Assessment of First-line Therapy With Midazolam for Prehospital Seizures in Children
Design

Retrospective cohort study

N= 1172
Objective To assess the effectiveness of midazolam treatment in terminating pediatric seizures in the prehospital setting
Study Groups

1 Dose (n= 713)

2 Doses (n= 306)

3 Doses (n= 113)

>3 Doses (n= 40)
Inclusion Criteria Patients aged 0 to 18 years for whom a mobile intensive care unit was dispatched due to a seizure between January 1, 2017, and December 31, 2019
Exclusion Criteria Not seizing on MICU arrival, incomplete data on midazolam, treated with intraosseous midazolam, trauma, drug intoxication, heat stroke, nonepileptic seizures
Methods Retrospective analysis using the INEMS database, assessing the administration of rescue therapy following the first midazolam administration. Midazolam dosages: IV route 0.11 mg/kg, IN route 0.25 mg/kg, IM route 0.21 mg/kg. Data analyzed with SPSS statistical software
Duration January 1, 2017, to December 31, 2019
Outcome Measures Administration of rescue therapy
Baseline Characteristics   1 Dose (n= 713) 2 Doses (n= 306) 3 Doses (n= 113) >3 Doses (n= 40)
Age, mean (SD), y 5.9 (4.8) 5.1 (4.5) 5.4 (4.8) 5.5 (4.2)
Sex - Male 435 (61.01%) 166 (54.25%) 70 (61.95%) 26 (65.00%)
Sex - Female 278 (38.99%) 140 (45.75%) 43 (38.05%) 14 (35.00%)
O2 saturation on arrival, median (IQR), % 95 (90-98) 95 (88-98) 93 (87-98) 91 (83-95)
Glucose level on arrival, median (IQR), mg/dL 122 (101-153) 140 (107-161) 142 (111-156) 143 (106-188)
MICU time of arrival from dispatch to scene, median (IQR), min 9.1 (6.1-13.4) 9.5 (6.4-14.3) 8.4 (6.2-13.1) 10.4 (6.5-14.6)
MICU time of arrival from scene to the hospital, median (IQR), min 14.3 (9.4-23.4) 14.4 (9.3-23.4) 16.3 (10.1-25.3) 17.1 (10.3-30.0)
Patient background - Previously healthy 190 (26.65%) 95 (31.05%) 32 (28.32%) 11 (27.50%)
Patient background - Convulsive disorder 259 (36.33%) 109 (35.62%) 51 (45.13%) 18 (45.00%)
Patient background - Cerebral palsy 52 (7.29%) 22 (7.19%) 3 (2.66%) 1 (2.50%)
Patient background - Developmental disorder 85 (11.92%) 25 (8.17%) 11 (9.73%) 2 (5.00%)
Patient background - Congenital genetic or metabolic disorder 54 (7.57%) 21 (6.86%) 4 (3.54%) 5 (12.50%)
Patient background - Structural brain abnormality 36 (5.05%) 18 (5.88%) 5 (4.43%) 1 (2.50%)
Patient background - Other 37 (5.19%) 16 (5.23%) 7 (6.19%) 2 (5.00%)
Midazolam route of administration - Intravenous 307 (43.06%) 97 (31.70%) 33 (29.20%) 14 (35.00%)
Midazolam route of administration - Intranasal 234 (32.82%) 146 (47.71%) 54 (47.79%) 20 (50.00%)
Midazolam route of administration - Intramuscular 172 (24.12%) 63 (20.59%) 26 (23.01%) 6 (15.00%)
Results          

Rescue therapy was administered to 144 of 451 patients (31.93%) using the intravenous route, 220 of 454 patients (48.46%) using the intranasal route, and 95 of 267 patients (35.58%) using the intramuscular route. Rescue therapy failed in 153 of 1172 patients (13.05%), who required a third dose of midazolam or more to terminate the seizures.
Adverse Events High proportion of patients required rescue therapy (39.16%). Respiratory support was needed in some cases: bag-mask ventilation (31 patients), endotracheal intubation (5 patients)
Study Author Conclusions The effectiveness of midazolam to terminate prehospital pediatric seizures was suboptimal, with a high proportion of patients requiring rescue therapy. The intranasal route was associated with a higher risk for rescue therapy.
Critique

The study provides valuable insights into the effectiveness of midazolam in the prehospital setting, highlighting the need for rescue therapy in a significant proportion of cases. However, the retrospective design and lack of data on the timing of treatment relative to seizure onset limit the ability to draw definitive conclusions. Additionally, the study's findings may not be generalizable to settings where home rescue treatment is common.

 

References:

Shavit D, Strugo R, Siman-Tov M, Nov S, Shavit I. Assessment of First-line Therapy With Midazolam for Prehospital Seizures in Children. JAMA Netw Open. 2023;6(4):e236990. Published 2023 Apr 3. doi:10.1001/jamanetworkopen.2023.6990

Real-World Midazolam Use and Outcomes With Out-of-Hospital Treatment of Status Epilepticus in the United States
Design

Retrospective cohort study

N= 7,634
Objective

To examine the effectiveness of midazolam in a national out-of-hospital cohort, focusing on the route and dose of administration and their impact on clinical outcomes
Study Groups

Intranasal (IN) midazolam (n= 1,500)

Intravenous (IV) midazolam (n= 3,462)

Intramuscular (IM) midazolam (n= 2,635)
Inclusion Criteria

Patients ≥18 years with an out-of-hospital diagnostic impression of status epilepticus who received midazolam as the initial benzodiazepine during the out-of-hospital encounter from January 1, 2019, to December 31, 2019
Exclusion Criteria Patients who received diazepam or lorazepam as the initial medication, and patients with cardiac arrest
Methods

Study investigators conducted a retrospective analysis of patient demographic and clinical data collected from electronic medical records using the ESO Data Collaborative public-use research database. Statistical analyses were used to examine outcomes based on the midazolam route and dose. 
Duration

January 1, 2019, to December 31, 2019
Outcome Measures

Primary: Administration of rescue therapy (additional benzodiazepine)

Secondary: Provision of ventilatory support (endotracheal intubation, supraglottic airway, CPAP [continuous positive airway pressure device], or bag valve mask)
Baseline Characteristics

 

 IN midazolam (n= 1,500) IV midazolam (n= 3,462) IM midazolam (n= 2,635)

Age, years

 46 ± 17 46 ± 18 45 ± 18

Female sex

 781 (52.2%) 1,660 (48.1%) 1,311 (49.9%)

Race

White

Black

Other

 

849 (56.6%)

556 (37.1%)

95 (6.3%)

 

2,155 (62.2%)

1,036 (29.9%)

271 (7.8%)

 

1,398 (53.1%)

996 (37.8%)

241 (9.1%)

Hispanic ethnicity

 115 (7.7%) 233 (6.7%) 170 (6.5%)

Suspected alcohol/drug use

 109 (7.3%) 232 (6.7%) 219 (8.3%)

Systolic BP, mmHg

 145 ± 30 144 ± 31 142 ± 29

Oxygen saturation

 95% ± 6% 95% ± 6% 95% ± 7%

Pulse, beats/min

 110 ± 27 107 ± 25 109 ± 27

GCS category

3-8

9-12

12-15

 

686 (47.3%)

333 (23.0%)

430 (29.7%)

 

1,463 (43.8%)

712 (21.3%)

1,162 (34.8%)

 

1,229 (48.3%)

545 (21.4%)

772 (30.3%)

Initial midazolam dose, median (IQR), mg

 5.0 (3.0 to 5.0) 3.0 (2.0 to 5.0) 5.0 (5.0 to 5.0)

Time from on-scene arrival to treatment, median (IQR), mins

 8.6 (4.9 to 14.6) 14.8 (9.3 to 21.7) 8.6 (5.0 to 15.6)

Abbreviations: BP= blood pressure. IQR= interquartile range.
Results

Compared with IM administration, IN midazolam increased (risk difference [RD] 6.5%, 95% confidence interval [CI] 2.4% to 10.5%), and IV midazolam decreased (RD −11.1%, 95% CI −14.7% to −7.5%) the risk of rescue therapy.

The differences in ventilatory support were not statistically significant (IN midazolam RD −1.5%, 95% CI −3.2% to 0.3%; IV midazolam RD −0.3%, 95% CI −1.9% to 1.2%).

Higher doses were associated with a lower risk of rescue therapy (RD −2.6%, 95% CI −3.3% to −1.9%) and increased ventilatory
support (RD 0.4%, 95% CI 0.1% to 0.7%).
Adverse Events

Not specified.
Study Author Conclusions

The route and dose of midazolam affect clinical outcomes. Compared with intramuscular administration, intranasal administration may be less effective and intravenous administration more effective in terminating status epilepticus, although the differences between these and previous results may reflect the nature of real-world data as opposed to randomized data.
Critique

The study provides valuable insights into real-world midazolam use, highlighting the impact of administration route and dose on outcomes. However, the retrospective design and reliance on electronic medical records may introduce biases and limit the ability to establish causality. The lack of data on emergency department and hospital outcomes is a limitation, as is the potential for misclassification of outcomes and exposures.
References:

Guterman EL, Sporer KA, Newman TB, et al. Real-World Midazolam Use and Outcomes With Out-of-Hospital Treatment of Status Epilepticus in the United States. Ann Emerg Med. 2022;80(4):319-328. doi:10.1016/j.annemergmed.2022.05.024
Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus
Design

Open-label, prospective, multicenter study

N= 34
Objective To evaluate the efficacy, safety, and pharmacokinetics of bolus and continuous midazolam infusion in Japanese children with status epilepticus unresponsive to diazepam
Study Groups All patients (n= 34)
Inclusion Criteria Patients aged between 45 weeks, corrected gestational age, and 16 years with status epilepticus unresponsive to diazepam, seizure episode lasting for 15 min or longer, or multiple seizures lasting for 5 min or longer
Exclusion Criteria Patients with non-convulsive status epilepticus, acute narrow angle glaucoma, myasthenia gravis, receiving combination therapy with HIV protease inhibitor or HIV reverse transcriptase inhibitor, hypersensitivity to MDL or benzodiazepine
Methods

An initial bolus of 0.15 mg/kg midazolam was given, with additional doses of 0.1–0.3 mg/kg up to a cumulative dose of 0.6 mg/kg. Continuous infusion was initiated at 0.1 mg/kg/h (maximum 0.4 mg/kg/h) for patients at high risk of recurrence or in whom seizure reduction was achieved, continued for 24 h after seizure cessation.

 
Duration October 2010 to December 2012
Outcome Measures

Primary: Seizure cessation rate by intravenous bolus

Secondary: Cumulative dose required for seizure cessation, adverse events
Baseline Characteristics   All patients (n= 34)
Mean age, years (SD) 6.0 (4.2)
Mean body weight, kg (SD) 19.9 (17.0)
Male 19 (55.9%)
Seizure type - Partial seizures 26 (76.5%)
Seizure type - Generalized seizures 8 (23.5%)
Etiology - Epilepsy 30 (88.2%)
Etiology - Acute diseases 4 (11.8%)
Results   Seizure cessation rate
Bolus iv period 88.2% (30/34)
By cumulative dose during bolus iv period - ≤0.15 mg/kg 52.9% (18/34)
By cumulative dose during bolus iv period - ≤0.2 mg/kg 70.6% (24/34)
By cumulative dose during bolus iv period - ≤0.3 mg/kg 82.4% (28/34)
By cumulative dose during bolus iv period - ≤0.4 mg/kg 85.3% (29/34)
By cumulative dose during bolus iv period - ≤0.5 mg/kg 85.3% (29/34)
By cumulative dose during bolus iv period - > 0.5 mg/kg 88.2% (30/34)
Adverse Events Adverse events were observed in three patients; one had mild respiratory depression that required supplemental oxygen and bag-valve-mask ventilation. Other events included fever and rash
Study Author Conclusions The efficacy and safety of midazolam were demonstrated in children with status epilepticus, suggesting that intravenous midazolam is suitable as first-line treatment.
Critique The study was limited by its small sample size and lack of a control group. However, it provided valuable insights into the dosing regimen and safety profile of midazolam in pediatric status epilepticus. The open-label design may introduce bias, and the results may not be generalizable to all pediatric populations due to the specific inclusion criteria.

 

References:

Hamano SI, Sugai K, Miki M, Tabata T, Fukuyama T, Osawa M. Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus. J Neurol Sci. 2019;396:150-158. doi:10.1016/j.jns.2018.09.035

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus
Design

Randomized, blinded, adaptive trial

N= 384
Objective

To compare the efficacy and safety of three intravenous (IV) anticonvulsive agents — levetiracetam, fosphenytoin, and valproate — in children and adults with convulsive status epilepticus (CSE) that was unresponsive to treatment with benzodiazepines
Study Groups

Levetiracetam (n= 145)

Fosphenytoin (n= 118)

Valproate (n= 121)
Inclusion Criteria

Patients ≥2 years treated with a cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes, with persistent or recurrent convulsions in the emergency department at least 5 minutes after the last dose of benzodiazepine and no more than 30 minutes after the last dose of benzodiazepine
Exclusion Criteria

Patients with acute seizure due to major trauma, hypoglycemia, hyperglycemia, cardiac arrest, or postanoxia, already treated with anticonvulsant agents other than benzodiazepines, intubated, pregnant, or incarcerated
Methods

Patients were randomly assigned to receive levetiracetam (60 mg/kg, max 4,500 mg), fosphenytoin (20 mgPE/kg, max 1,500 mgPE), or valproate (40 mg/kg, max 3,000 mg) via IV infusion over 10 minutes. After 10 minutes, the infusion of the trial drug was discontinued.

Rescue therapy was given for persistent seizures after 20 minutes from the start of the trial-drug infusion.
Duration

November 3, 2015, to October 31, 2017
Outcome Measures

Primary: Cessation of seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication

Secondary: Time to termination of seizures, admission to ICU, length of ICU, length of hospital stay

Safety: Life-threatening hypotension or cardiac arrhythmia within 60 minutes, endotracheal intubation within 60 minutes
Baseline Characteristics  

Levetiracetam (n= 145)

 Fosphenytoin (n= 118) Valproate (n= 121)
Age, years

33.3 ± 26.0

 32.8 ± 25.4 32.2 ± 25.4
Female

68 (46.9%)

 47 (39.8%) 56 (46.3%)

Race

Black

White

Other, more than one, or unknown

 

62 (42.8%)

62 (42.8%)

21 (14.5%)

 

49 (41.5%)

49 (41.5%)

20 (16.9%)

 

54 (44.6%)

49 (40.5%)

18 (14.9%)
Hispanic ethnic group

23 (15.9%)

 18 (15.3%) 22 (18.2%)
History of epilepsy

97 (66.9%)

 80 (67.8%) 83 (68.6%)

Diagnosis

Seizure or status epilepticus

Non-epileptic spell

Unable to adjudicate

 

128 (88.3%)

13 (9.0%)

4 (2.8%)

 

104 (88.1%)

11 (9.3%)

3 (2.5%)

 

102 (84.3%)

13 (10.7%)

6 (5.0%)

Duration of seizure at enrollment, median (IQR), min

62.0 (43.0–85.0)

59.0 (43.0–94.0)

61.5 (38.5–86.5)
Benzodiazepines given before arrival

89 (61.4%)

 68 (57.6%) 62 (51.2%)
Results  

Levetiracetam (n= 145)

 Fosphenytoin (n= 118) Valproate (n= 121)
Cessation of seizures and improvement in consciousness at 60 minutes

68 (47%)

 53 (45%) 56 (46%)
Time to termination of seizures, median (IQR), minutes

10.5 (5.7–15.5)

 11.7 (7.5–20.9) 7.0 (4.6–14.9)
Admission to ICU

87 (60.0%)

 70 (59.3%) 71 (58.7%)
Length of ICU stay, median (IQR), days

1 (0–3)

 1 (0–3) 1 (0–3)
Length of hospital stay, median (IQR), days

3 (1–7)

 3 (1–6) 3 (2–6)
Life-threatening hypotension within 60 minutes 0.7% 3.2% 1.6%
Cardiac arrhythmia within 60 minutes

0.7%

 0% 0%
Endotracheal intubation within 60 minutes

20%

 26.4% 16.8%

Abbreviations: ICU= intensive care unit. IQR= interquartile range.
Adverse Events

Deaths: 4.7% in levetiracetam, 2.4% in fosphenytoin, 1.6% in valproate.

Numerically, more episodes of hypotension and intubation occurred in the fosphenytoin group, and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.
Study Author Conclusions

In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events.
Critique

The study's strengths include a large sample size and adaptive design, which increased the likelihood of detecting differences if they existed. Limitations include the need for unblinding in some cases, the inclusion of patients with psychogenic seizures, and the lack of electroencephalographic confirmation of seizure cessation. Additionally, the study did not explore different dosing regimens that might affect efficacy.
References:

Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019;381(22):2103-2113. doi:10.1056/NEJMoa1905795