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En Route to the ER, an Autoinjector with Antiseizure Medications Found More Effective for Status Epilepticus

Talan, Jamie

doi: 10.1097/01.NT.0000413287.18270.c2
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Investigators reported that 73.4 percent of patients (329 of 448) randomized to receive midazolam through an autoinjector were seizure-free by the time they reached the hospital compared with 63.4 percent (282 of 445) of those who received IV lorazepam (p<0.001 for both noninferiority and superiority).

A federally-funded study that involved 4,314 paramedics, 33 emergency medical system agencies, 79 hospitals, and almost 900 patients in the throes of status epilepticus may change the future of how patients with prolonged and life-threatening seizures receive emergency care on the way to the hospital.

Results from the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) showed that an autoinjector filled with antiseizure medicine is faster and may be a more effective way to stop seizures. Currently, the routine plan during such calls is to deliver medicine through an IV, which can be difficult when the patient is thrashing about. The autoinjector, similar to an EpiPen, delivers medicine right into the thigh muscle.

The study, reported in the Feb. 16 New England Journal of Medicine, was designed to compare the benefits of the two delivery methods — an autoinjector and an IV — to see whether the autoinjector is just as safe and effective as delivering medicine directly into a vein. The study was designed and coordinated through the Neurological Emergencies Treatment Trials (NETT) network, which was developed at the NINDS. The investigators compared two medicines commonly used to control seizures, lorazepam and midazolam — both benzodiazepines. Midazolam was selected because it is rapidly absorbed from muscle. Lorazepam must be given by IV.

Paramedics throughout the country were trained in the study protocol, as they would be the ones to decide whether the patient seizing was a candidate for the clinical study. Enrollment was so smooth, study investigators said, that they had all of the patients they needed a year earlier than expected.

The RAMPART investigators found that 73.4 percent of patients (329 of 448) in the group that received midazolam through the autoinjector were seizure-free by the time they reached the hospital compared with 63.4 percent (282 of 445) of those who were randomized to receive IV lorazepam (p<0.001 for both noninferiority and superiority).

The study was designed to ensure that antiseizure medicines delivered through an autoinjector were not inferior to the IV approach. The primary outcome was absence of seizures by the time they arrived at the emergency room. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to when the prolonged seizures stopped.

Investigators did not expect that the patients would actually do better when they received the medicine intramuscularly. “We were pleasantly surprised,” said Daniel Lowenstein, MD, professor of neurology at the University of California, San Francisco (UCSF) and director of the UCSF Epilepsy Center. Dr. Lowenstein was a co-principal investigator with Robert Silbergleit, MD, a clinical care surgeon and emergency room physician at the University of Michigan.



While the autoinjector arm of the study led to fewer seizures upon arrival to the hospital, the two groups were similar in the need for endotracheal intubation (around 14 percent) and in the recurrence of seizures (11.4 percent for patients with intramuscular midazolam and 10.6 percent for those on IV lorezepam.)

The median time it took to deliver the treatment on the scene was 1.2 minutes for the intramuscular group and 4.8 minutes for the IV group. The time of the delivery to cessation of the seizures was 3.3 minutes for the intramuscular group and 1.6 minutes for the IV group.

There has been a growing use of intramuscular delivery of antiseizure medicines but no one knew for sure whether it was safe and as effective as the now-routine use of IV-delivered medicines, said Dr. Lowenstein. His group conducted the pivotal trial comparing the delivery of two benzodiazepines against placebo for pre-hospital treatment of seizures.

The authors wrote in the study: “Our data are consistent with a finding of statistical superiority of intramuscular midazolam. Regardless of whether it is noninferior or superior, this trial supports the clinical decision to use the more pragmatic intramuscular approach in the pre-hospital treatment of status epilepticus.”

Dr. Lowenstein added during a telephone interview that the idea to study neurological emergency treatments in the field works. “The results were so clean, the numbers so consistent. The NETT model is proving to be very effective.”

Prolonged status epilepticus can last for hours and result in brain damage and even death. If antiseizure medicines don't work, general anesthesia is prescribed to break the seizure. There are about 55,000 deaths a year due to status epilepticus.

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Walter Koroshetz, MD, deputy director of the NINDS, agreed that the study “was an incredibly productive effort between neurologists, neurosurgeons, ER physicians, and emergency medical services across the country.” The NETT clinical trials study group has about five studies underway.



He said as they were designing the study they learned that the military was interested in fast and effective ways to treat chemical bioterrorism attacks. Many of the chemicals that can be used during these attacks can trigger prolonged seizures. The NINDS provided funding for the study in collaboration with the NIH Countermeasures Against Chemical Threats program and the Biomedical Advanced Research and Development Authority. The Department of Defense provided the autoinjectors for the study. And the trial was performed under an Investigational New Drug application with the FDA.

Dr. Koroshetz said that it might one day be possible for patients and their families to carry around an autoinjector filled with antiseizure medicine for emergency situations. But that may not be feasible with the current drug tested as midazolam has a strong sedative effect and requires “on-site medical supervision,” he noted.

“The earlier treatment is initiated for seizure clusters and status epilepticus; the more likely that the episode can be aborted, the less likely the event will be associated with prolonged hospitalization, brain injury, and other adverse consequences,” said Jacqueline A. French MD, director of the clinical trials consortium at the New York University Comprehensive Epilepsy Center, and a member of the editorial advisory board of Neurology Today.

“The availability of a treatment that can be administered through an intramuscular injection and does not need initiation of an IV line is an important advance. Time to administration of the dose was much faster for the intramuscular than the IV route, and even in the experienced hands of the EMT providers, in 31 of 445 patients randomized to lorazepam, an IV could not be started prior to arrival at the hospital. There is no question that seizures will not be aborted if the medication never reaches the patient, or is substantially delayed.”

Prior to this study, Dr. French added, “EMS treatment has been variable, and not always optimized. This study should create a standard for safe and effective pre-hospital treatment of ongoing seizure activity.”

She said that there are other studies underway looking at the safety and effectiveness of acute in-home treatment of seizure clusters with benzodiazepines. “This might include an EpiPen type approach, or intranasal or buccal administration,” Dr. French said. “All of these require further study, but hopefully will eventually lead to earlier and better treatment of status epilepticus and seizure clusters, and improved outcome for patients.”



The new finding that an autoinjector filled with antiseizure medicine is faster and may be a more effective way to stop seizures en route to the emergency room is an important advance, experts say. Listen here as the two lead investigators — neurologist Dr. Daniel Lowenstein (left), of the University of California, and Dr. Robert Silbergleit, a clinical care surgeon and emergency room physician at the University of Michigan — describe their findings and what it could mean for emergency care for status epilepticus:

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• Silbergleit R, Durkalski V, Lowenstein D, et al, for the NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600.
    ©2012 American Academy of Neurology