May 23, 2007
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.
At a briefing at the National Institutes of Health, researchers today outlined plans for a large-scale national study to 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 11 hospitals around the country will participate.
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 Duane Alexander, M.D., Director of the NIH’s National Institute of Child Health and Human Development, which is sponsoring the study. “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, M.D., Division Chief of Emergency Medicine at Children's National Medical Center in Washington, D.C. 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,” Dr. Chamberlain said.
To conduct the study, researchers at the 11 participating hospitals will randomly assign children who are in status epilepticus to be treated with either lorazepam or diazepam, explained the study’s co-principal investigator, Jill Baren, M.D., of the Division of Emergency Medicine, Department of Pediatrics, The Children's Hospital of Philadelphia, PA. 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.
Dr. Baren added that status epilepticus must be treated within 5 minutes or less of a child’s arrival in an emergency department. 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 participating institutions and who meet study criteria will be automatically enrolled in the study without prior parental consent. Dr. Baren stressed that 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.
The independent board or research review committee at each hospital will oversee the study and ensure 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.
“We have consulted a wide range of ethicists, experts and government officials about this study to ensure that we protect patients’ safety,” Dr. Baren said.
The researchers have designed a public information campaign to inform the public about the study in the various communities where it will be performed, Dr. Baren said. They will hold community meetings to provide information about the study to all interested families that might be included in the study. During the meetings they will answer questions and listen to concerns of community members.
Dr. Baren stressed the importance of proper research on all emergency treatments to be sure of their effectiveness. The FDA has emphasized the need to test all drugs used for children so that those used are known to be safe and effective.
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.
In-depth information about the Pediatric Seizure Study is available from the accompanying set of Questions and Answers, available at http://www.nichd.nih.gov/news/releases/Pages/study_pediatric_seizure_QA_052207.aspx.
The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.