Status Epilepticus
Conditions
Keywords
Status Epilepticus, Emergency Medical Services, Anticonvulsants, Drug Administration Routes, Seizures
Brief summary
The goal of this non-inferiority trial is to determine which type of routine care is the best for paramedics to stop someone from seizing.
Detailed description
Seizures are a common medical problem. Although they can be frightening to watch, most seizures are brief and stop by themselves. Seizures that don't stop in seconds or minutes are a dangerous life-threatening medical emergency. Paramedics often have medications that can stop seizures, but the best way to give the medicines is not known. Paramedics often give medicine directly into a vein, which is called intravenous (IV) administration. This works well, but can be hard to do in a person who is seizing. It can also take some time and delay treatment. Another way to give the medicine is as a shot given into a muscle, which is called intramuscular (IM) administration. Giving the medicine this way is faster, but it may not stop the seizure as quickly. This clinical trial, the Rapid Anti-convulsant Medication Prior to ARrival Trial (RAMPART), is designed to figure out whether giving anti-seizure medicine works similarly well and more quickly when given through an IV or when given as a shot in the muscle. Two similar medicines will be used. Both are already used by paramedics in the field and by doctors in the hospital to stop seizures. One is commonly given by IV, and the other is commonly given as a shot in the muscle. In this study, the shot will be given using a device similar to an EpiPen-which is an autoinjector used by people with severe allergies. Approximately 1,024 persons whose seizures are continuing after emergency medical service (EMS) arrival and who meet all eligibility criteria will be enrolled in the trial. Every participant will be treated with anti-seizure medicine by the paramedics. At random, half the participants will be in one group and half in another. Half the participants will receive the study medicine through an IV and will be given a shot in the muscle without medicine (placebo). The other half will receive the medicine as a shot in the muscle plus an IV without medicine (placebo). In September 2010, more rapid than expected enrollment made it feasible to increase the sample size of the study from 800 to 1,024 with the already available funding. The goals of the expansion were to enroll more pediatric subjects (since the trial was enrolling slightly fewer than anticipated) and to improve the power of the study to 90%, which was initially desired. It is important to understand that the extended enrollment was not a sample size re-estimation in any way. The opportunity to extend the trial is pragmatic, based solely on the early enrollment success of the trial. It is not informed by the planned interim analyses that have been performed, the results of which remain sequestered, and there have been no unscheduled interim analyses. The firewall that prevents the blinded leadership from any knowledge of the outcome data has been diligently maintained throughout the process of proposing and implementing this extension.
Interventions
DRUGIntramuscular route of active treatment
IM administration by autoinjector of midazolam 5 mg for subjects under estimated weight of 40 kg or midazolam 10 mg for subjects with estimated weight of 40 kg or above, IV administration of matching volume of IV flush.
DRUGIntravenous route of active treatment
IV administration of lorazepam 2 mg for subjects under estimated weight of 40 kg or midazolam 4 mg for subjects with estimated weight of 40 kg or above, IM administration by autoinjector of matching volume of saline.
Sponsors
Medical University of South Carolina
University of California, San Francisco
National Institute of Neurological Disorders and Stroke (NINDS)
Robert Silbergleit
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Paramedics or reliable witnesses verify 5 minutes of either continuous seizure activity or of repeated convulsive seizure activity where the patient does not regain consciousness (operationally defined as meaningful speech or obeying commands) between seizures. * Patient is still seizing at the time of paramedic treatment with study medications. * Estimated weight equal to or greater than 13 kg. * Subject to be transported to a RAMPART participating hospital.
Exclusion criteria
* Major trauma as the precipitant of the seizure * Hypoglycemia (as defined by local EMS protocol or a glucose \< 60 mg/dL) * Known allergy to midazolam or lorazepam * Cardiac arrest or heart rate (HR) \<40 beats per minute * Sensitivity to benzodiazepines * Medical alert tag marked with RAMPART declined * Prior treatment of this seizure with diazepam autoinjector as part of another study * Known pregnancy * Prisoners
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Termination of Seizures at ED Arrival With no Rescue Therapy Given | Duration of prehospital care, outcome is determined upon arrival at the ED on the day of enrollment (average 20 minutes). | The primary outcome was termination of seizures before arrival in the emergency department (ED) without the need for the paramedics to provide rescue therapy. Subjects did not reach the primary outcome if they were having seizures on arrival in the emergency department or if they received rescue medication before arrival. Termination of seizures on arrival was determined according to the clinical judgment of the attending emergency physician and was based on examination of the subjects, their clinical course, and results of any routine diagnostic testing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Hospitalized | at ED disposition on day of enrollment | Hospital and ICU admission from the ED, and length of stay, is abstracted from the hospital admission record. ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient. |
| Number of Subjects Admitted to an Intensive Care Unit (ICU) | at time of disposition on day of enrollment | Hospital and ICU admission from the ED, and length of stay, is abstracted from the hospital admission record. ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient. |
| Number of Subjects With Recurrent Seizure Within 12 Hours After ED Arrival | within 12 hours after ED arrival | Acute seizure recurrence is defined as any further convulsive or electrographic seizures occurring in the first 12 hours of hospitalization, if they require additional antiepileptic medications, in subjects that had been determined not to be having seizures on ED arrival. |
| Number of Subjects With Hypotension | participants were followed for the duration of hospital stay, an average of 6 days | Acute hypotension is defined as a systolic blood pressure of \< 90 mmHg sustained for greater than 5 minutes and for which the patient was treated with a continuous IV infusion of a vasopressor. |
| Number of Subjects With Endotracheal Intubation Within 30 Min After ED Arrival | anytime before 30 minutes after ED arrival | Endotracheal intubation performed or attempted by EMS or within 30 minutes after ED arrival is abstracted from the ED record physician and nursing records. Endotracheal intubation includes placement of a definitive tracheal airway (oro-, naso-, cricothyroidotomy, or tracheostomy) for support of respirations or protection of airway. Non-definitive and/or non-tracheal airways (oral or nasal airways, laryngeal mask airways, or esophageal obturator airways) are not included if the patient is not subsequently intubated unless specifically deemed to have been used in lieu of tracheal intubation. |
| Number of Subjects With IV Injection-site Complications | participants were followed for the duration of hospital stay, an average of 6 days | IV insertion site complications are defined as any symptoms or signs of injury or reaction at the site of the study IV placed by paramedics and used for study medication. This includes thrombosis, phlebitis, or skin infection requiring specific treatment including compresses, antibiotics, or wound care. |
| Length of Intensive Care Unit (ICU) Stay in Days | participants were followed for the duration of hospital stay, an average of 6 days | Continuous days of initial ICU stay from time of admission |
| Length of Hospital Stay in Days | participants were followed for the duration of hospital stay, an average of 6 days | Continuous acute care inpatient hospital days from day of admission until discharge |
| Number of Subjects With IM Injection-site Complications | participants were followed for the duration of hospital stay, an average of 6 days | IM injection site complications are defined as any symptoms or signs of injury or reaction at the site of the study IM injection requiring treatment. This includes extensive hematoma requiring treatment (decompression, pressure dressings, or discontinuation of anticoagulant or antithrombotic medications). Treatment does not include imaging without other interventions. This definition also includes wound infection requiring antibiotic therapy, retained foreign bodies requiring exploration and removal, or other similar wound problems. |
Countries
United States
Participant flow
Recruitment details
Subjects treated for status epilepticus in the prehospital setting by paramedics were enrolled at the scene between June 2009 and January 2011. A total of 1023 subject enrollments represented 893 unique subjects with a reenrollment rate of 13%. RAMPART involved 4314 paramedics, 33 EMS agencies, and 79 receiving hospitals across the United States.
Pre-assignment details
Number of patients enrolled includes any repeat enrollments for those who presented to emergency medical services (EMS) with status epilepticus more than once. The number assigned to treatment in the intention-to-treat analysis includes every patient who was enrolled in the study but only the initial enrollment for those enrolled more than once.
Participants by arm
| Arm | Count |
|---|---|
| Intramuscular (IM) Anticonvulsant This group gets active treatment with an anticonvulsant by the intramuscular route of administration. IM administration by autoinjector of midazolam 5 mg for subjects under estimated weight of 40 kg or midazolam 10 mg for subjects with estimated weight of 40 kg or above, IV administration of matching volume of IV flush. | 448 |
| Intravenous (IV) Anticonvulsant This group gets active treatment with an anticonvulsant by the intravenous route of administration. IV administration of lorazepam 2 mg for subjects under estimated weight of 40 kg or midazolam 4 mg for subjects with estimated weight of 40 kg or above, IM administration by autoinjector of matching volume of saline. | 445 |
| Total | 893 |
Baseline characteristics
| Characteristic | Intramuscular (IM) Anticonvulsant | Intravenous (IV) Anticonvulsant | Total |
|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 22 | 44 years STANDARD_DEVIATION 22 | 43 years STANDARD_DEVIATION 22 |
| Age, Customized 0-5 years | 32 participants | 29 participants | 61 participants |
| Age, Customized 11-20 years | 28 participants | 21 participants | 49 participants |
| Age, Customized 21-40 years | 114 participants | 112 participants | 226 participants |
| Age, Customized 41-60 years | 169 participants | 169 participants | 338 participants |
| Age, Customized 6-10 years | 15 participants | 20 participants | 35 participants |
| Age, Customized >61 years | 90 participants | 94 participants | 184 participants |
| Dose tier Children estimated >40kg and All Adults | 386 participants | 386 participants | 772 participants |
| Dose tier children with an estimated weight of 13 to 40 kg | 62 participants | 59 participants | 121 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 49 Participants | 57 Participants | 106 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 310 Participants | 290 Participants | 600 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 89 Participants | 98 Participants | 187 Participants |
| Final diagnosis Nonepileptic spell | 31 participants | 32 participants | 63 participants |
| Final diagnosis Status epilepticus | 404 participants | 399 participants | 803 participants |
| Final diagnosis Undetermined | 13 participants | 14 participants | 27 participants |
| History of epilepsy No | 111 participants | 103 participants | 214 participants |
| History of epilepsy Not documented | 44 participants | 47 participants | 91 participants |
| History of epilepsy Yes | 293 participants | 295 participants | 588 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 14 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 229 Participants | 224 Participants | 453 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 32 Participants | 13 Participants | 45 Participants |
| Race (NIH/OMB) White | 165 Participants | 183 Participants | 348 Participants |
| Region of Enrollment United States | 448 participants | 445 participants | 893 participants |
| Sex: Female, Male Female | 198 Participants | 207 Participants | 405 Participants |
| Sex: Female, Male Male | 250 Participants | 238 Participants | 488 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 514 | 95 / 509 |
| serious Total, serious adverse events | 137 / 514 | 156 / 509 |
Outcome results
Primary
Number of Subjects With Termination of Seizures at ED Arrival With no Rescue Therapy Given
The primary outcome was termination of seizures before arrival in the emergency department (ED) without the need for the paramedics to provide rescue therapy. Subjects did not reach the primary outcome if they were having seizures on arrival in the emergency department or if they received rescue medication before arrival. Termination of seizures on arrival was determined according to the clinical judgment of the attending emergency physician and was based on examination of the subjects, their clinical course, and results of any routine diagnostic testing.
Time frame: Duration of prehospital care, outcome is determined upon arrival at the ED on the day of enrollment (average 20 minutes).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects With Termination of Seizures at ED Arrival With no Rescue Therapy Given | 329 participants |
| IV Lorazepam | Number of Subjects With Termination of Seizures at ED Arrival With no Rescue Therapy Given | 282 participants |
Comparison: The null hypothesis of inferiority was tested with a one-sided z statistic. Sample size was estimated assuming independent proportions, 2 interim analyses, 70% control event rate; 90% power; a noninferiority margin of 10%; and a 1-sided test with type I error probability of 0.025. A sample size of 890 (445 per treatment group) was inflated by 15% (1024 subjects) to account for inadvertent repeated enrollment of the same subjects. Repeated enrollments of the same subject were not analyzed.p-value: <0.00195% CI: [0.04, 0.16]one-sided z statistic
Secondary
Length of Hospital Stay in Days
Continuous acute care inpatient hospital days from day of admission until discharge
Time frame: participants were followed for the duration of hospital stay, an average of 6 days
Population: All subjects with hospital length of stay data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IM Midazolam | Length of Hospital Stay in Days | 6.7 days | Standard Deviation 10 |
| IV Lorazepam | Length of Hospital Stay in Days | 5.5 days | Standard Deviation 6.4 |
p-value: 0.11t-test, 2 sided
Secondary
Length of Intensive Care Unit (ICU) Stay in Days
Continuous days of initial ICU stay from time of admission
Time frame: participants were followed for the duration of hospital stay, an average of 6 days
Population: All participants with ICU length of stay data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IM Midazolam | Length of Intensive Care Unit (ICU) Stay in Days | 5.7 days | Standard Deviation 9.5 |
| IV Lorazepam | Length of Intensive Care Unit (ICU) Stay in Days | 4.1 days | Standard Deviation 4.7 |
p-value: 0.09t-test, 2 sided
Secondary
Number of Subjects Admitted to an Intensive Care Unit (ICU)
Hospital and ICU admission from the ED, and length of stay, is abstracted from the hospital admission record. ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient.
Time frame: at time of disposition on day of enrollment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects Admitted to an Intensive Care Unit (ICU) | 128 participants |
| IV Lorazepam | Number of Subjects Admitted to an Intensive Care Unit (ICU) | 161 participants |
95% CI: [0.65, 0.95]
Secondary
Number of Subjects Hospitalized
Hospital and ICU admission from the ED, and length of stay, is abstracted from the hospital admission record. ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient.
Time frame: at ED disposition on day of enrollment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects Hospitalized | 258 participants |
| IV Lorazepam | Number of Subjects Hospitalized | 292 participants |
95% CI: [0.79, 0.98]
Secondary
Number of Subjects With Endotracheal Intubation Within 30 Min After ED Arrival
Endotracheal intubation performed or attempted by EMS or within 30 minutes after ED arrival is abstracted from the ED record physician and nursing records. Endotracheal intubation includes placement of a definitive tracheal airway (oro-, naso-, cricothyroidotomy, or tracheostomy) for support of respirations or protection of airway. Non-definitive and/or non-tracheal airways (oral or nasal airways, laryngeal mask airways, or esophageal obturator airways) are not included if the patient is not subsequently intubated unless specifically deemed to have been used in lieu of tracheal intubation.
Time frame: anytime before 30 minutes after ED arrival
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects With Endotracheal Intubation Within 30 Min After ED Arrival | 63 participants |
| IV Lorazepam | Number of Subjects With Endotracheal Intubation Within 30 Min After ED Arrival | 64 participants |
95% CI: [0.7, 1.34]
Secondary
Number of Subjects With Hypotension
Acute hypotension is defined as a systolic blood pressure of \< 90 mmHg sustained for greater than 5 minutes and for which the patient was treated with a continuous IV infusion of a vasopressor.
Time frame: participants were followed for the duration of hospital stay, an average of 6 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects With Hypotension | 12 participants |
| IV Lorazepam | Number of Subjects With Hypotension | 13 participants |
95% CI: [0.42, 1.98]
Secondary
Number of Subjects With IM Injection-site Complications
IM injection site complications are defined as any symptoms or signs of injury or reaction at the site of the study IM injection requiring treatment. This includes extensive hematoma requiring treatment (decompression, pressure dressings, or discontinuation of anticoagulant or antithrombotic medications). Treatment does not include imaging without other interventions. This definition also includes wound infection requiring antibiotic therapy, retained foreign bodies requiring exploration and removal, or other similar wound problems.
Time frame: participants were followed for the duration of hospital stay, an average of 6 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects With IM Injection-site Complications | 4 participants |
| IV Lorazepam | Number of Subjects With IM Injection-site Complications | 2 participants |
95% CI: [0.3, 10.7]
Secondary
Number of Subjects With IV Injection-site Complications
IV insertion site complications are defined as any symptoms or signs of injury or reaction at the site of the study IV placed by paramedics and used for study medication. This includes thrombosis, phlebitis, or skin infection requiring specific treatment including compresses, antibiotics, or wound care.
Time frame: participants were followed for the duration of hospital stay, an average of 6 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects With IV Injection-site Complications | 0 participants |
| IV Lorazepam | Number of Subjects With IV Injection-site Complications | 3 participants |
Secondary
Number of Subjects With Recurrent Seizure Within 12 Hours After ED Arrival
Acute seizure recurrence is defined as any further convulsive or electrographic seizures occurring in the first 12 hours of hospitalization, if they require additional antiepileptic medications, in subjects that had been determined not to be having seizures on ED arrival.
Time frame: within 12 hours after ED arrival
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Midazolam | Number of Subjects With Recurrent Seizure Within 12 Hours After ED Arrival | 51 participants |
| IV Lorazepam | Number of Subjects With Recurrent Seizure Within 12 Hours After ED Arrival | 47 participants |
Comparison: All participants were included in this analysis of rate of recurrence because this is the most clinically relevant denominator, although, by definition, only participants who stopped could have recurrent seizures.95% CI: [0.74, 1.56]