National seizure study to identify best treatment for children
The scenario unfolds almost every day in the United States. A crowd gathers at a playground, or perhaps on a soccer field. A child has fallen to the ground, gripped by a seizure. Usually, the twitching and jerking stop within a few minutes. If they do not, the condition becomes status epilepticus, continuous unrelenting seizures that can lead to brain damage — or even death — if not treated. An ambulance rushes the child to a nearby hospital emergency department. There, doctors do their best to administer life-saving treatment as quickly as possible. Before they can treat the patient, however, they must choose between one of two drugs commonly prescribed to treat the condition.
Yet no reliable information exists to determine which of the two drugs — diazepam and lorazepam — is more effective. But a large-scale national study planned by the National Institutes of Health will soon determine which of the two medications is the safest, most effective treatment for children with status epilepticus. The condition is life-threatening, and even with the best treatment, is fatal in 4 percent of cases. The study is the most comprehensive of its kind and UC Davis is among 11 hospitals around the country participating.
Comparing standard treatments
Lorazepam and diazepam are both administered to treat status epilepticus. Although both medications are regarded as standard treatment, no large-scale comparison has been conducted to determine which is the safest, most effective treatment. The Pediatric Seizure Study will compare the safety and effectiveness of the two medications in treating status epilepticus in children admitted to hospital emergency departments.
"Currently, the choice of treatment for status epilepticus depends upon the best judgment of the treating physician," said Cheryl Vance, professor of emergency medicine and principal investigator of the study at UC Davis. "The Pediatric Seizure Study seeks to provide the most definitive information possible on which medication offers the greater chance for successful treatment."
Status epilepticus affects between 50,000 to 60,000 children and adults in the United States each year, explained the study's principal investigator, James Chamberlain, Division Chief of Emergency Medicine at Children's National Medical Center in Washington, D.C. which is leading the national study. He added that four to eight children per every 1,000 will experience status epilepticus before age 15. Status epilepticus may occur in patients with epilepsy or in patients without epilepsy who experience a seizure due to a high fever, low blood sugar, an infection of the central nervous system, or a head injury. Children who have no apparent risk factors may also develop status epilepticus.
Diazepam, more commonly known as Valium, has been approved by the U.S. Food and Drug Administration for use in adults and children. Lorazepam, marketed under the name Ativan, is only approved by the FDA to treat seizures in adult patients but is widely prescribed off label for children. Once a drug has been approved by the FDA for a particular use, physicians may use their best judgment to prescribe it for other uses, known as "off label" uses, in other patients whom they believe might benefit.
"We want to hold these two medications to the highest standard and ensure that children are receiving the most appropriate medication for their condition," Chamberlain said.
To conduct the study, researchers will randomly assign children who are in status epilepticus to be treated with either lorazepam or diazepam. Usually, the choice of which drug to prescribe would rest with the treating physician. During the study, however, the medication will be assigned randomly by a computer, to eliminate any potential human bias in assigning the medication. A roughly equal number of the children will receive each medication.
"Status epilepticus must be treated within 5 minutes or less of a child's arrival in an emergency department," said Vance. "Without prompt treatment, brain injury or death could result. This means that it will not be possible to obtain permission from a child's parent or guardian before enrolling the child in the study."
Normally, researchers first ask the parent or guardian for permission to enroll a child in a study, explain the details and procedures of the study, its potential risks and benefits, and alternatives, and enroll the child only after the parent or guardian agrees. For this study, however, it is not possible to explain the study details and obtain parental permission in advance because of the urgent need to provide treatment within 5 minutes of the child's arrival in the emergency department. Moreover, status epilepticus may occur when a child is away from his or her parents; a parent may not be present when the child is taken to the emergency department.
Children admitted to UC Davis and other participating institutions who meet study criteria will be automatically enrolled in the study without prior parental consent. This sequence of events is little different than what would take place in an emergency department not involved in the study. Under typical circumstances, the admitting physician would decide on whether the patient would receive lorazepam or diazepam. In the study, a computer program will decide which drug the child received. The principle is to assign the drug without any preference, to avoid any potential human bias. At the end of the study, roughly equal numbers of children will have been assigned to receive each drug, and a large enough number of children will have been studied to allow the researchers to draw definitive conclusions about each medication.
After the doctor has made sure that the child has received treatment and has been stabilized, the doctor or a representative from the study team will contact the parent to let them know that his or her child has been enrolled in this study. At this time, the details of the study will be explained to the parent, and the parent can choose to allow the child to continue in the study or can withdraw the child from the study.
If the parent agrees to continue, small blood samples will be taken from the child and the parent will be interviewed by phone 48 hours later and then 30 days after the child is enrolled to ask about the child's condition.
UC Davis' Instutional Review Board is overseeing the study at the hospital and ensuring that all procedures comply with ethics and safety standards. Other independent reviewers will look for overall trends in study data. If it becomes clear that one drug is more effective at treating seizures, the study will be ended early.
A public information campaign has been designed at each instiution to inform the public about the study. At UC Davis a variety of meetings with community and patient groups are being held to provide information about the study to all interested families whose children may be enrolled in the study. During the meetings, questions are answered and the community's concerns are heard.
The NICHD is funding the study in accordance with the Best Pharmaceuticals for Children Act (BPCA), explained Donald Mattison, M.D., Chief of the Obstetric and Pediatric Pharmacology Branch. Under the BPCA, the NIH consults with the U.S. Food and Drug Administration to determine which approved drugs should be prioritized for further testing in children. Dr. Mattison added that roughly two-thirds of drugs prescribed for children have never been specifically tested in children.