By CHUCK RANGEL
Scenario: You and your child are at the park when suddenly your child begins to have a seizure. You quickly call 911 and wait for emergency medical services (EMS). As you hear the fire engine siren getting closer, the seizure subsides, only to start up again. The fire department arrives on scene, quickly assesses the situation, gives your child oxygen, and administers an intravenous (IV) line in preparation for medication administration. A single dose of lorazepam stops the seizure. Your child is then transported to the hospital for further evaluation and treatment.
Imagine this same scenario but with one small change: When your child begins to seize and you call 911, you then reach into your pocket and take out an auto injector preloaded with midazolam and administer it to your child. As you hear the siren getting closer, your child stops seizing, and no more seizure activity occurs. The fire crew arrives with the same auto injector, in case you did not have yours. There is no need to wait for the seizure to stop or delay medication administration waiting to establish IV access.
In March 2009, 15 San Jose (CA) Fire Department (SJFD) engine crews were trained by Stanford University staff to begin a double blind study in the field, considered the first multicenter prehospital study of its kind. This is a clinical trial, known as Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), a study to determine whether intramuscular (IM) midazolam is as effective and safe as IV lorazepam in the prehospital treatment of status epilepticus by fire department crews. This study’s goal is to scientifically evaluate the effectiveness of IM midazolam. The trial’s results could allow the United States Food and Drug Administration (FDA) to approve IM midazolam for treating seizures, a condition for which it has not been approved. Currently, caregivers of children and adults with a significant seizure disorder have only rectal diazepam for breakthrough seizures; this is not as effective as IV medications for terminating seizures. If IM midazolam works as well as IV meds and receives FDA approval, caregivers may be able to someday carry a midazolam auto injector for use in case of emergency, which would tremendously benefit patients.
Most seizures terminate voluntarily and cause no long-term harm. Continuous or multiple seizures, where the patient does not have an interlude of being conscious and awake, comprise a condition called status epilepticus, a life-threatening medical emergency that requires prompt treatment. More than 10 years ago, another San Francisco area clinical trial called the Prehospital Treatment of Status Epilepticus (PHTSE) demonstrated that paramedics can effectively treat status epilepticus with a class of anticonvulsant medications called benzodiazepines. PHTSE compared placebo (plain saline injection) against two benzodiazepines (diazepam and lorazepam). Both benzodiazepines worked better than placebo, and the study also suggested that lorazepam may be more effective than diazepam. Lorazepam is most commonly used in emergency departments and inpatient settings as an emergency anticonvulsant medication, but it is a poor choice for prehospital use because it requires refrigerated storage, is thick and difficult to prepare, and requires IV administration.
A number of smaller clinical studies have suggested that another benzodiazepine—midazolam—is also highly effective as an anticonvulsant even when given intramuscularly. Because its features make it ideal for prehospital use (i.e., it does not require refrigeration, has a longer shelf life, and is easy to draw up and administer), many EMS systems use midazolam in their seizure protocols, even though it is not FDA approved for this purpose. To date, there have not been any large-scale clinical trials to test whether prehospital use of midazolam as an anticonvulsant is effective and safe. That is what RAMPART was designed to determine.
The RAMPART trial is being run through the Neurological Emergencies Treatment Trials (NETT), a clinical trials network comprised of 17 academic medical center hubs throughout the country. NETT is funded by the National Institutes of Health (NIH) to conduct research that will reduce the burden of acute neurologic illnesses and injuries. The RAMPART trial is being led by Robert Silbergleit, M.D., of the University of Michigan and Daniel Lowenstein, M.D., of the University of California, San Francisco. Stanford University is one of the hubs chosen to participate in the NETT network and is led by James Quinn, M.D., a researcher and practicing emergency physician at Stanford Hospital, with assistance from EMS Coordinator Peter D’Souza, M.D., also an emergency physician at Stanford.
The National Institute of Neurological Disorders and Stroke at the NIH in partnership with the Department of Health and Human Services Biomedical Advanced Research and Development Authority and the Department of Defense funded the RAMPART study. The RAMPART trial has been approved by the California State EMS agency and David Ghilarducci, M.D., who was the Santa Clara (CA) County EMS Agency’s medical director at that time. Current County EMS Medical Director Eric Rudnick has also been supportive of the study. Stanford researchers chose the SJFD as one of the participating agencies in the Bay area.
The RAMPART study is a special type of research performed under federal regulations called “Exception from Informed Consent (EFIC) for Emergency Research,” as stipulated by Title 21 CFR 50.24. It allows for research in emergency conditions when it is not possible to obtain consent. In compliance with this regulation—before the study began—investigators ensured that the study risks were minimized, performed community consultation involving the Epilepsy Foundation, and did widespread public disclosure including several articles and advertisements in the local newspapers and on the radio. Those who did not want to participate in the study could wear a bracelet to opt out.
The Stanford investigators maintain an active Web site (https://med.stanford.edu/survey/rampart) for others to learn more and voice their opinion. Patients and their families in the local community have overwhelmingly supported the study. Although one can appreciate the importance of individual autonomy when participating in research, others can also appreciate that, without the ability to conduct trials of new treatments, advances could not be made. Placing defibrillators for use in public spaces is the best known example of a treatment studied under EFIC. As one would expect, such research is very carefully monitored by Institutional Review Boards, the NIH, the FDA, and the Office of Human Research Protections. Throughout the study, Data Safety and Monitoring Boards analyzed study data to ensure that treatments are as safe and effective as expected and that the health, safety, and rights of patients enrolled in the study are protected. Within our fire department and community, Stanford University maintains overall responsibility for the study, and Quinn is the principal investigator.
All patients, for whom a participating SJFD engine company is dispatched, are screened for eligibility in the study. The research protocol calls for each actively seizing patient to receive an IM auto injector and an IV carpuject (prefilled syringe system). Patients randomly receive either IM midazolam by an auto injector or IV lorazepam by preload carpuject. The study design is double blind, meaning that one of the devices (preload auto injector or carpuject) contains medication and the other, a placebo. Paramedics do not know which delivery device contains medication. Such a study design avoids bias on the part of paramedics and researchers and helps ensure that the results are fairly evaluated. Although RAMPART is a randomized study, no seizing patient is randomized to receive only a placebo. Considering all seizing patients enrolled in the study, if the patient stops seizing, the study stops and no further medication is given. Subjects are followed through discharge from the hospital. To date, the SJFD has enrolled 19 patients in the study.
The SJFD started its field study in August 2009. Within a few days of the study’s launch, the SJFD enrolled the first patient. Preparing for and participating in the study have presented many challenges because of the trial’s unique nature. The SJFD has had to help coordinate training to make sure all the medics assigned to an engine with a RAMPART box had special skills and knowledge. Each participating medic has undergone several hours of study on topics pertinent to the trial including protection of human subjects involved in research studies, review of seizures, protocol review, and hands-on training with the medication box.
In 2009, the SJFD responded to more than 42,000 emergency medical incidents, of which 775 were seizure related. To continue with the agency’s successful participation and to strengthen its relationship with the Stanford hub, 10 more SJFD engine crews will be trained in the near future. The NETT hopes that further prehospital studies will demonstrate the effectiveness of early intervention in cases such as traumatic brain injury, traumatic spinal cord injury, and neurologic injury postcardiac arrest. Researchers are continuing to work on designing simple trials that could be carried out at multiple centers.
The SJFD is proud to participate in developing new ways to assist the public. Providing cutting-edge emergency medicine demands research and clinical study to demonstrate the effectiveness of what we do. SJFD considers EMS advancement an important component of its duty as it continues to serve the community.
Author’s note: Special thanks to the following for their technical and editorial assistance in developing this article and in the study: Robert Silbergleit, M.D. (University of Michigan); Daniel Lowenstein, M.D. (University of California, San Francisco); James Quinn, M.D. (Stanford Hospital; Palo Alto, CA); Peter D’Souza, M.D. (Stanford University); Stanford Medical Center Research Nurse Stephanie Casal; and SJFD Chief William McDonald, Chief (Ret.) Darryl Von Raesfeld, Firefighter/Paramedic Dan Williams, Captain/Med30 Mike Van Elgort, Assistant Chief Teresa Deloach Reed, Deputy Chief Dana Reed, Battalion Chief Stew McGehee, Captain Reggie Williams, Registered Nurse Audrey Crouch, and Captain Dave Huseman.
REFERENCES
1. Millikan, D.; Rice, B; Silbergleit, R. Emergency treatment of status epilepticus: current thinking. Emerg Med Clin North Am. 2009;27(1):101-13.
2. Alldredge, BK; Gelb, AM; Isaacs, SM; et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. New England Journal of Medicine. 2001;345(9):631-7.
3. Duvivier, EH; Pollack, CV. Chapter 100: Seizures, p.1346-1355 in Rosen’s Emergency Medicine, 7th edition: Marx, JA; Hockberger, RS; Walls, RM; et al. editors, copyright 2010, Mosby, Philadelphia, PA.
CHUCK RANGEL is a captain and the public information officer for the San Jose (CA) Fire Department, where he has served for 22 years. He has a B.S. in occupation studies from California State University in Long Beach and an A.S. in fire science from Mission College in Santa Clara, California.
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