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What Is the Issue?
- Emergency treatment for prolonged seizures or status epilepticus must be swift and effective to prevent lasting brain damage or fatality.
- Benzodiazepines such as midazolam, Ativan (lorazepam), diazepam, and clonazepam are widely recognized as the first-line medications for managing acute seizures.
- Various delivery methods exist for these drugs, but the differences in clinical effectiveness and safety among these routes remain unclear.
- Decision-makers are evaluating whether paramedics treating seizures in prehospital settings with intramuscular (IM) midazolam should transition to intravenous (IV) Ativan, which is commonly used by nurses and doctors in clinical environments.
What Did We Do?
- We reviewed and summarized the available research on the clinical effectiveness and safety of midazolam compared to Ativan in adults for seizure control.
- A comprehensive search was conducted across key resources, including journal citation databases and targeted internet sources, focusing on evidence published since 2019. One reviewer screened relevant studies, critically assessed their quality, and provided a narrative summary of the findings.
What Did We Find?
- A systematic review (SR) was identified that included four randomized controlled trials (RCTs), but only one was relevant to this analysis. This double-blind RCT demonstrated that IM midazolam was not inferior to IV Ativan in treating seizures when administered by paramedics in a mixed population of adults (89%) and children (11%).
- The SR authors performed a subanalysis using participant-level data, confirming that IM midazolam was as effective and safe as IV Ativan for stopping seizures in adults in prehospital settings. The findings in adults mirrored those observed in the overall randomized population, including both adults and children.
What Does This Mean?
- Given the shorter time required to administer midazolam via the IM route compared to Ativan via the IV route, along with their comparable efficacy and safety, IM midazolam may be the preferred option in prehospital settings when IV access is difficult to establish.
- Transitioning from IM midazolam to IV Ativan for seizure treatment by paramedics may not be a practical approach.
Characteristics of Midazolam and Ativan
Midazolam is a short-acting benzodiazepine with a rapid onset (within two minutes of IM injection) and a short half-life of 1 to 4 hours. Its duration of action is approximately 1 to 2 hours. This drug has anxiolytic, muscle relaxant, anticonvulsant, sedative, hypnotic, and amnesic effects. Midazolam is available in oral (tablet or syrup), rectal, intranasal, IM, IV, or buccal formulations. Midazolam injection (solution, 1 mg/mL and 5 mg/mL, IV and IM) is approved for use in surgical or diagnostic procedures, anesthesia, endoscopic procedures, and sedation for mechanical ventilation in ICU settings. The IM route is recommended for treating adult status epilepticus in prehospital scenarios where IV access is difficult or unavailable.
Ativan (lorazepam) is a benzodiazepine with a fast onset (1 to 3 minutes after IV injection) and an intermediate half-life of 8 to 25 hours. Its effects last approximately 10 to 20 hours. Ativan has anticonvulsant, sedative, hypnotic, and anti-anxiety properties. It is available in oral, sublingual, IM, and IV forms. Ativan injection (solution, 4 mg/mL, IM and IV) is approved for anxiety relief in adults, treatment of anxiety neurosis, pre-surgical sedation, and as an anticonvulsant for managing status epilepticus.
Why Is This Review Important for mountainspringsdental.com ?
The American Epilepsy Society provides a treatment algorithm for status epilepticus, beginning with a stabilization phase (0 to 5 minutes), followed by an initial therapy phase (5 to 20 minutes), where benzodiazepines are the first-choice treatment for both children and adults in prehospital and in-hospital settings. One of the three equivalent first-line options includes IM midazolam (10 mg for individuals over 40 kg, 5 mg for those weighing 13 to 40 kg, single dose), IV Ativan (0.1 mg/kg, with a maximum single dose of 4 mg, which may be repeated once), or IV diazepam (0.15 to 0.2 mg/kg, with a maximum single dose of 10 mg, which may also be repeated once). If these three options are unavailable, the guidelines recommend IV phenobarbital, rectal diazepam, or intranasal midazolam.
In prehospital settings, many emergency paramedic services primarily use IM midazolam instead of IV Ativan, even though IV Ativan is the most effective and widely used option in emergency departments (EDs) for seizure treatment. The preference for IM midazolam among paramedics highlights its faster and easier administration compared to IV access and the fact that Ativan requires refrigeration, reducing its shelf-life in field settings. Decision-makers want to determine whether IM midazolam is as effective and safe as IV Ativan for stopping seizures before hospital arrival and whether paramedic protocols should shift to IV Ativan to align with in-hospital treatment guidelines.
Objective
The goal of this review is to support decision-making on whether paramedics should transition from IM midazolam to IV Ativan by summarizing and critically evaluating studies comparing the clinical effectiveness and safety of these two drugs in adults for seizure control.
Research Question
How do midazolam and Ativan compare in terms of clinical effectiveness and safety for controlling seizures in adults?
Methods
Literature Search Strategy
A specialized information expert conducted a search across key resources, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, and websites of major Canadian and international health technology agencies. Additionally, a targeted internet search was performed. The search strategy was designed to ensure a balance between comprehensiveness and relevance. It incorporated both controlled vocabulary (e.g., Medical Subject Headings [MeSH]) and keyword-based search queries. The primary search concepts included midazolam, Ativan, and seizures. The search was completed on September 19, 2024, and limited to English-language publications since January 1, 2019.
Patient Population
The systematic review focused on adults with convulsive status epilepticus based on data from the RAMPART trial by Silbergleit et al., which included 89% adults and 11% children, all weighing at least 13 kg. The review authors accessed participant-level data from the RAMPART trial and extracted information on 782 participants aged 16 years and older. The mean age was 48 years for those receiving IM midazolam and 49 years for those treated with IV Ativan. The male-to-female ratio was similar in both groups, and approximately 90% of patients in both treatment arms had status epilepticus.
Intervention and Comparator
The RAMPART trial was a double-blind, randomized, noninferiority study comparing the efficacy and safety of IM midazolam with IV Ativan in children and adults with status epilepticus treated by paramedics. Patients estimated to weigh over 40 kg received either 10 mg IM midazolam followed by an IV placebo or an IM placebo followed by IV Ativan.
Clinical Effectiveness Outcomes: Midazolam vs. Ativan for Seizure Control
Seizure Cessation
Seizures stopped without requiring additional rescue therapy before hospital arrival in:
- 73.9% (289 of 391) of adults treated with IM midazolam
- 62.4% (244 of 391) of adults treated with IV Ativan
Although statistical comparisons were not reported, the results were consistent with those observed in the full intention-to-treat (ITT) population, where seizure cessation rates were:
- 73.4% for IM midazolam vs. 63.4% for IV Ativan (P < 0.001).
Among adults whose seizures stopped before ED arrival, the median time from drug administration to seizure cessation (onset of action) was:
- 3 minutes (range: 2 to 6.3 minutes) for IM midazolam
- 2 minutes (range: 1 to 4.4 minutes) for IV Ativan
Similarly, in the ITT population, the time to onset of action was longer for IM administration compared to IV:
- 3.3 minutes for IM midazolam vs. 1.6 minutes for IV Ativan
However, the time required for drug administration was shorter for the IM route:
- 1.2 minutes for IM midazolam vs. 4.8 minutes for IV Ativan
Despite these differences, the overall time from the start of drug administration to seizure termination was similar between the two treatment groups (presented in graphical form).
Seizure Recurrence
Within 12 hours of arriving at the emergency department (ED), seizures recurred in 12.0% (47 out of 391) of adult patients who received intramuscular (IM) midazolam, compared to 10.7% (42 out of 391) of those who were given intravenous (IV) Ativan. Similar results were observed in the intent-to-treat (ITT) population, with recurrence rates of 11.4% for IM midazolam and 10.6% for IV Ativan. However, no statistical comparisons were provided.
Safety Outcomes of Midazolam Versus Ativan in Adults for Seizure Control
Table 5 summarizes the safety outcomes, primarily based on data from the ITT population as reported in the RAMPART trial. The SR21 review only documented mortality rates for the adult population.
Respiratory Depression
Among all randomized patients, respiratory depression was observed in 6.4% (33 out of 514) of those who received IM midazolam and in 10.0% (47 out of 509) of those who were given IV Ativan. No statistical comparisons were reported.
Mortality
Mortality rates for adult patients were 2.8% (11 out of 391) in the IM midazolam group and 2.0% (8 out of 391) in the IV Ativan group. Again, statistical comparisons were not provided, and mortality data for the ITT population was not reported.
Gaps in Evidence
No direct clinical trials comparing the efficacy and safety of midazolam and Ativan for treating seizures in adults were found. The authors of the SR21 review were able to access participant-level data from the RAMPART trial, which included 782 participants aged 16 years or older. However, the subanalysis performed for the adult population lacked a statistical plan for comparing outcomes between treatment groups.
Generalizability of Findings
Because the findings were derived from a single study—the RAMPART trial, published in 2012—their applicability to the broader adult population remains limited. Nevertheless, the available evidence suggests that IM midazolam is as effective and safe as IV Ativan for terminating seizures in prehospital settings for both children and adults.
Certainty of Evidence
The overall certainty regarding the comparative effectiveness and safety of midazolam and Ativan in adults with seizures remains unclear. The adult sample size extracted from the RAMPART trial may not have been sufficient to detect significant differences between the two medications.
Conclusions and Policy Implications
This review examined one systematic review (SR21) that included four randomized controlled trials (RCTs), but only one—the RAMPART trial—was directly relevant to the research question. The RAMPART study was a double-blind, randomized, noninferiority trial comparing the efficacy and safety of IM midazolam to IV Ativan for treating seizures in children and adults in prehospital settings. The SR authors obtained participant-level data, extracting information on 782 individuals aged 16 or older, and provided a narrative summary of the results without conducting statistical comparisons. To supplement the findings, the original RAMPART trial data was referenced.
Among the adult population, seizure cessation without the need for additional rescue therapy occurred in 73.9% of patients treated with IM midazolam and 62.4% of those who received IV Ativan. The ITT population showed similar results, with IM midazolam proving at least as effective as IV Ativan (73.4% vs. 63.4%; P < 0.001). The study also indicated that key safety outcomes—such as seizure recurrence, respiratory depression, and the need for endotracheal intubation—were comparable between the two groups. Additionally, fewer patients in the IM midazolam group required hospitalization or ICU admission compared to those in the IV Ativan group, although there was no significant difference in hospital length of stay.
Since the overall time from drug administration to seizure termination was similar in both groups, but IM midazolam was easier to administer and more stable at room temperature, switching from IM midazolam to IV Ativan for prehospital seizure treatment by paramedics may not be a practical approach.
Future Research Considerations
Additional clinical trials comparing midazolam and Ativan through different routes of administration would help refine seizure management strategies in adults, particularly in prehospital settings where IV access may be challenging.
Clinical Practice Implications
Although IV administration results in a slightly faster onset of action, the time required to establish IV access in prehospital settings may delay treatment. Given that IM midazolam is easier to administer and has a similar efficacy and safety profile to IV Ativan, intramuscular midazolam may be the preferred choice for seizure management in prehospital care.