RAMPART

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Silbergleit R, et al. "Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus". The New England Journal of Medicine. 2012. 366(7):591-600.
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Clinical Question

For prehospitalized patients in status epilepticus, how effect is the use of IM midazolam compared with IV lorazepam for seizure termination?

Bottom Line

IM midazolam is superior to IV lorazepam for prehospital seizure cessation.

Major Points

The current definition of status epilepticus is more than 5 minutes of continuous seizure activity or recurrent seizure activity within this time. This definition is based on the knowledge that seizures extending past 5 minutes are much less likely to spontaneously terminate and animal studies suggested that permanent neuronal injury and resistance to treatment may set in between 5-30 minutes. [1] [2] [3]

The Veterans Affairs Status Epilepticus Cooperative Study Group showed better seizure control with lorazepam compared to phenytoin as an initial agent in the context of overt generalized convulsive status epilepticus in a paired analysis. The subsequent Prehospital Treatment of Status Epilepticus (PHTSE) trial [4] comparing diazepam, lorazepam and placebo for seizure termination failed to find a significant difference between lorazepam vs. diazepam though there was a trend toward better termination with lorazepam. When IM formulations of midazolam became readily available, it gained significant popularity with paramedics due to its convenience and easy of use. Also, unlike lorazepam, midazolam has good stability and a long shelf life when not refrigerated. This study showed that IM Midazolam is superior to IV lorazepam for seizure termination, not associated with any increases in adverse events and can be administered more quickly.

Guidelines

Emergent treatment for status epilepticus (Adapted from 2014 Neurocritical Care Society's Guidelines for the Evaluation and Management of Status Epilepticus):

  • Lorazepam (Class I, level A) Recommended dose: 0.1 mg/kg IV up to 4 mg per dose, may repeat in 5–10 min
  • Midazolam (Class I, level A) Recommended dose: 0.2 mg/kg IM up to maximum of 10 mg
  • Diazepam (Class IIa, level A) Recommended dose: 0.15 mg/kg IV up to 10 mg per dose, may repeat in 5 min
  • Phenytoin/fosphenytoin (Class IIb, level A) Recommended dose: 20 mg phenytoin equivalence/kg IV, may give additional 5 mg/kg
  • Phenobarbital (Class IIb, level A) Recommended dose: 20 mg/kg IV, may give an additional 5–10 mg/kg
  • Valproate Sodium (Class IIb, level A) Recommended dose: 20–40 mg/kg IV, may give an additional 20 mg/kg
  • Levetiracetam (Class IIb, level C) Recommended dose: 1,000–3,000 mg IV, 20–60 mg/kg IV in pediatrics

Design

  • Multicenter, randomized, double blind, phase 3, noninferiority clinical trial.
  • N=893
    • IM Midazolam: 448 in intention to treat (ITT) analysis and 362 in per-protocol (PP) analysis
    • IV Lorazepam: 445 in ITT and 370 in PP analysis
  • Setting: 33 EMS agencies, and 79 receiving hospitals across the United States.
  • Enrollment: Jun 2009 - Jan 2011
  • Analysis: Intention-to-treat
  • Primary outcome: Number of Subjects With Termination of Seizures at ED Arrival With no Rescue Therapy Given(average 20 minutes). Subjects did not reach the primary outcome if they were having seizures on arrival in the ED 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.

Population

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

Baseline Characteristics

Given for IM Midazolam group, IV lorazepam group similar

  • Mean age (range) yr: 43±22 (0–102)
  • Age:
    • 0–5 yr: 7%
    • 6–10 yr: 3%
    • 11–20 yr: 6%
    • 21–40 yr: 25%
    • 41–60 yr: 38%
    • ≥61 yr: 20%
  • Male sex (%) 56%
  • Race:
    • Black 229 (51) 224 (50)
    • White 165 (37) 183 (41)
    • Other, mixed, or unknown 54 (12) 38 (9)
  • Dose tier (%):
    • Low 14%
    • High 86%
  • History of epilepsy (%):
    • Yes 65%
    • No 25%
    • Not documented 10%
  • Final diagnosis (%):
    • Status epilepticus: 90%
    • Nonepileptic spell: 7%
    • Undetermined: 3%
  • Precipitating cause of status epilepticus (%)
    • Noncompliance with or discontinuation of anticonvulsant therapy: 31%
    • Idiopathic or breakthrough status epilepticus: 27%
    • Coexisting condition that lowered seizure threshold: 7%

Interventions

  • Patients greater than 40 kgs were randomized to 10 mg of intramuscular midazolam followed by intravenous placebo or intramuscular placebo followed by 4 mg of intravenous lorazepam
  • Patients between 13 to 40 kg were randomized to either 5 mg of intramuscular midazolam followed by intravenous placebo or intramuscular placebo followed by 2 mg of intravenous lorazepam.
  • When it was difficult to obtain IV access, continue attempts were made for at least 10 minutes. Intraosseous access were permitted at any time in lieu of intravenous access and considered equivalent to intravenous access.
  • Rescue therapy, was recommended if patient was still convulsing 10 minutes after the administration of the last study medication.

Outcomes

Results given IM midazolam vs. IV lorazepam

Primary Outcome

 % of Subjects (95% CI) With Termination of Seizures at ED Arrival With no Rescue Therapy Given
73.4 (69.3–77.5) vs. 63.4 (58.9–67.9), difference=10%; 95% CI=4.0 to 16.1; P<0.001 for noninferiority and P<0.001 for superiority

Secondary Outcomes

 % of Subjects With Endotracheal Intubation Within 30 Min After ED Arrival
14.1% vs. 14.4%, RR=0.98 (95% CI: 0.70–1.34)
 % of Subjects hospitalized
57.6% vs. 65.6%, RR=0.88 (95% CI: 0.79–0.98)
 % of Subjects admitted to an Intensive Care Unit (ICU)
28.6% vs. 36.2%, RR=0.79 (95% CI: 0.65–0.95)
 % of Subjects with recurrent seizure within 12 Hours after ED arrival
11.4% vs. 10.6%, RR= 1.08 (95% CI: 0.74–1.56)
 % of Subjects with Hypotension SBP < 90 mmHg sustained for greater than 5 minutes and for which the patient was treated with a continuous IV infusion of a vasopressor
2.7% vs. 2.9%, RR=0.92 (95% CI: 0.42–1.98)
Number of Subjects With IM Injection-site Complications
4 vs. 2, RR=1.99 (95% CI: 0.30–10.70)
Number of Subjects With IV Injection-site Complications
0 vs. 3
Mean length of Intensive Care Unit (ICU) Stay in Days
5.7±9.5 vs. 4.1±4.7
Mean length of Hospital Stay in Days
6.7±10.0 vs. 5.5±6.4
Median time to administration
1.2 minutes vs. 4.8 minutes
Onset of action (termination of convulsions)
3.3 minutes vs. 1.6 minutes

Criticisms

  • Due to study design, unable to conclude if superior seizure termination was due to IM route of administration vs. IV route or due to superiority of midazolam as an agent to lorazepam.
  • An autoinjector was used in this study and results may be not fully translatable to conventional intramuscular injections

Funding

  • The National Institute of Neurological Disorders and Stroke
  • IM injectors were provided by the U.S. Department of Defense

Further Reading

  1. Lowenstein DH. Current concepts: status epilepticus. N Engl J Med. 1998;338(14):970
  2. Meldrum BS, Horton RW. Physiology of status epilepticus in primates. Arch Neurol. 1973;28(1):1–9.
  3. Mazarati AM. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res. 1998;814(1–2):179
  4. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of hospital status epilepticus. N Engl J Med 2001;345:631-7. [Erratum, N Engl J Med 2001;345:1860.]