Beating the Seizure Countdown
Marshaling the efforts of 4,314 paramedics, 79 receiving hospitals and 33 EMS agencies across the country, an NIH study coordinated by the U-M charts a new standard for treating seizures that won’t stop.
It’s a scene familiar to paramedics across the country: a man lies in the grass at a local park, his body wracked by seizures. They note that he is in status — shorthand for status epilepticus — meaning that unlike most seizures, which are fleeting, these convulsions have been going on for more than five minutes and are creating a feedback loop that will require medical intervention to short circuit.
The clock is ticking. The longer the seizure is allowed to continue, the less effective the medics’ go-to drugs will be, and the harder the seizure will be to break. As the minutes wear on, his overtaxed neurons will start to die, lowering his chances of survival and putting him at risk for permanent brain damage if he does survive.
The best way to speed medication into his system is through an IV line, but he’s thrashing so violently, the paramedics know it will be difficult and time consuming to place a needle safely into one of his veins. They have a few backup options: administer the medicine rectally, or squirt it into his mouth or nose, where it can be absorbed through mucous membranes — though they know those routes aren’t nearly as effective and risk the medication being expelled.
Soon, first responders may be able to count on a safe, easy-to-administer alternative, thanks to a National Institutes of Health-sponsored study co-led by Robert Silbergleit (M.D. 1992), associate professor of emergency medicine in the Medical School. The findings “should lead to a systematic change in the way patients in status epilepticus are treated en route to the hospital,” proclaimed an editorial that accompanied the study in the February 16 issue of the New England Journal of Medicine.
Journal Watch, a publication that highlights key research from more than 250 medical journals, referred to the Rapid Anticonvulsant Medications Prior to Arrival Trial (RAMPART) paper as a “landmark article.” The research also holds important implications for military and civilian chemical defense preparedness.
A Tale of Three Drugs
For the last three decades, paramedics’ primary tool for halting seizures has been benzodiazepines, a class of sedating drugs that includes household names like Valium and Xanax. Although similar to each other, each medication has a unique molecular structure and distinctive properties. Prior to RAMPART, a lack of definitive data had fueled a sibling rivalry of sorts between medications and delivery methods, with no clear answer for front-line medics as to what was best for status patients.
Diazepam, popularly known as Valium, became the flagship benzodiazepine in the 1960s, touching off a wave of development for similar drugs. “It was discovered to be a great anticonvulsant and was the mainstay of treatment for many years,” says Silbergleit. Lorazepam, marketed under the name Ativan, came along in the late 1970s as an anti-anxiety medication and gradually was recognized for its power to stop seizures.
Comparison studies came later: In 1998, a hospital-based study found lorazepam to be the more effective first-line treatment. Then, in 2001, RAMPART’s other principal investigator, Daniel H. Lowenstein, M.D., director of the University of California, San Francisco’s Epilepsy Center, was the first author of a study that showed both drugs were superior to a placebo when used by first responders in the field — with lorazepam again appearing to be the superior choice. “Today, lorazepam is the standard of care in hospitals,” Silbergleit says.
But the same is not true of emergency medical services, he adds. Most EMS providers still rely on diazepam, because refrigerated storage is recommended for lorazepam, which loses its potency while stored in ambulances, especially in warmer months. “And with either one, it can be very hard or impossible to get an IV started in someone who’s having a violent convulsion,” says Silbergleit.
“Eventually people started recognizing that there’s another benzodiazepine that is known to be extremely well absorbed transmucosally and intramuscularly,” Silbergleit explains. “Midazolam, which has also been around for decades, gets absorbed and distributed to the brain quite rapidly. Its fat solubility helps it cross the blood-brain barrier.”
Silbergleit co-authored a 2010 meta-analysis of a handful of small studies in children and young adults that showed non-IV midazolam, formerly sold under the trade name Versed, was as safe and effective as diazepam by any delivery route.