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Healthcare Professionals
About the study
Full Protocol
Patient Involvement
Sources
About the Study
Thank you for your interest in this study. As you may know, there are approximately 50,000 to 60,000 episodes of status epilepticus (SE) annually in the United States in children and adults. 1 It is estimated that 4 to 8 children per 1,000 may be expected to experience an episode of SE before 15 years of age. 2 In the pediatric population, SE may present in patients with a known seizure disorder (epilepsy), or may occur in patients without epilepsy who experience a febrile seizure, metabolic imbalance, acute infection of the central nervous system, or a traumatic head injury.
Patients who present in SE are treated with pharmacologic agents designed to terminate the seizure activity. Termination of the seizure activity with pharmacologic treatment may result in immediate benefit through improved maintenance of vital functions and long-term benefit through a decrease in neurologic sequelae. Benzodiazepines in general are considered to be the most effective agents for the initial treatment of SE, achieving lasting control in 80 percent of patients. 3, 4 They work by enhancing the inhibitory effect of the neurotransmitter GABA, by specific binding to the benzodiazepine-GABA-phenobarbital receptor complex. 5 Several studies have examined the use of benzodiazepines for pediatric SE, with results suggesting shortened duration and reduced seizure recurrence. 6, 7, 8
Three specific benzodiazepines, Diazepam, Lorazepam and Midazolam, have all been reported to be effective in treating pediatric patients with SE. 9 These findings are important in initial seizure management since longer seizure duration has been associated with difficulty in controlling future seizure activity and risk for neurological damage. 10 However, benzodiazepines have serious side effects, most importantly respiratory depression. Management of respiratory depression and respiratory failure are the most common complications of benzodiazepine administration in the emergency setting; data on pediatric efficacy and safety are scant. 11
Textbooks and expert opinion recommend both Diazepam and Lorazepam as initial therapy for children in SE and provide recommended doses that are commonly used. 12, 13 However, unlike Diazepam, Lorazepam is only FDA-approved for treatment for SE in patients over 18 years of age. Despite this fact, many experts support the use of Lorazepam over Diazepam in pediatric SE. 14, 15, 16, 17, 18 Increased duration of action, increased effectiveness in terminating SE, and a lower incidence of respiratory depression have been cited as potential advantages of Lorazepam over Diazepam. However, data to support firm recommendations for one medication over another are lacking. Thus, either Diazepam (Food and Drug Administration (FDA) approved) or Lorazepam can be considered first-line agents for pediatric SE, and the physician’s choice of agent depends on local practice patterns and individual treatment styles. In the pre-hospital (Emergency Medical Services) setting, Diazepam is commonly chosen because of a longer shelf life without refrigeration.
The fact that there are few data demonstrating the superiority of one benzodiazepine over another in the treatment of children with SE results in individual and institutional variation in the treatment of pediatric SE. While many experts prefer Lorazepam for the initial treatment of SE in both adults and children for the reasons discussed above, many published protocols still advise using Diazepam as the initial agent. 19, 20, 21 In a recent study looking at existing published guidelines for the management of childhood SE, it was noted that none used the same three initial drugs in the same order. 22, 23 In fact, the management of SE in children is based largely, if not wholly, on the management of SE in adults, including an extrapolation of the dosages of the anticonvulsant drugs. This may be inappropriate for a number of reasons, including different etiologies of seizures in children, unique airway considerations in children, the wide range of body weights in children and intravenous access issues resulting in different routes of administration in children. In addition, there may be differences in the pharmacokinetics and metabolism of the anticonvulsant drugs when treating children in SE. In fact, the sparse data that exist on the pharmacokinetics of Lorazepam in neonates and children suggest that both the volume of distribution (normalized for body weight) and the mean serum half-life may differ from that found in adults. 24, 25, 26 Data are needed to determine the pharmacology of the benzodiazepines commonly used to treat SE (Diazepam and Lorazepam) in children, and to determine if there is a difference in the effectiveness and safety between these drugs when used to treat children with SE.
Federal legislation, including regulations of the FDA, require that drugs be tested for safety and efficacy before they are approved for clinical use. This testing must take place in all populations in which the drug will be used. Since both the qualitative and quantitative aspects of pharmacodynamics and pharmacokinetics are different in immature individuals, and clinical efficacy and safety may not be extrapolated from older patient populations to pediatric populations, studies must be conducted in the appropriate pediatric population before pediatric use information may be appropriately incorporated in the label. The Best Pharmaceuticals for Children Act (BPCA) was enacted to enhance pediatric clinical studies leading to new pediatric labeling in accordance with FDA rules and regulations. Lorazepam as a therapy for pediatric SE has been chosen by the Secretary of the Department of Health and Human Services (DHHS), acting through the Director of the National Institutes of Health (NIH) and the Health Resources and Services Administration (HRSA) and in consultation with the commissioner of the FDA and experts in pediatric research, as a priority "off-patent" drug for which pediatric studies are most urgently needed. We propose to conduct the second of two clinical trials designed to achieve these objectives.
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Exception from Informed Consent
This study is presented with exactly these challenges:
• Seizures are a life-threatening emergency that requires immediate therapy
• There is insufficient time to obtain informed consent within the therapeutic window
• Parents may not be present
• Even when parents are present, seizures are very distressing and trigger significant emotional distress
• Patients with seizures are frequently transported via ambulance in an environment that is very noisy and chaotic, preventing the opportunity to present a research study in a calm, systematic manner
In recognition of the unique circumstances pertaining to research in emergency situations, the FDA has established regulations that provide a narrow exception to the requirement for informed consent from subjects or their legally authorized representatives in such situations. These regulations, known as the Exception from Informed Consent (EFIC) for Emergency Research (21 CFR 50.24), are harmonized with the regulations set forth by the DHHS and known as the Waiver of Informed Consent Requirements in Certain Emergency Research (45 CFR 46.101(i)). Both sets of regulations, often referred to as the “Final Rule,” represent a single common standard for this type of research and were published together in the Federal Register on October 2, 1996. [21 CFR 50.24 and 45 CFR 46 in Federal Register].
The use of EFIC requires that the protocol meet the following standards:
• Study of a life threatening condition
• Current standard of treatment is unproven or unsatisfactory
• There is prospect of direct benefit to the patient
• Informed consent is not possible within the therapeutic window
• The research cannot practicably be conducted without utilizing the EFIC guidelines.
The regulations also provide additional processes to ensure the protection of human subjects. These include:
• Community consultation
• Public disclosure
• Contact of the legally authorized representative as soon as reasonably possible.
Study Methods
This will be a double-blinded, randomized, controlled trial of Lorazepam and Diazepam. Patients will be enrolled when they present to the ED or in a hospital unit with status epilepticus (SE). Diazepam will be administered in a dose of 0.2 mg/kg IVP for a maximum of 8 mg and Lorazepam will be administered 0.1 mg/kg IVP for a maximum of 4 mg. Age criteria includes children from three months to less than 18 years of age.
Eligibility:
Children presenting with generalized tonic-clonic status epilepticus, defines as one or more if the following:
a) Three or more generalized tonic-clonic seizures within the last hour and currently experiencing a convulsion; or
b) Two or more generalized tonic-clonic seizures in succession with no recovery of consciousness between seizures and currently experiencing a convulsion; or
c) A single ongoing generalized tonic-clonic seizure of at least five minutes duration
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Patient Involvement
If a child comes to an emergency department (ED) at one of the participating centers with a seizure, an ED doctor will evaluate the child to see if he or she qualifies for the study. If the child qualifies, he or she will automatically be enrolled in the study.
If a parent does not want his or her child to participate in the research study, he or she may exercise his or her right to refuse participation in this study by letting the study staff know prior to or during the ED visit (see Refusal of Patient Participation )
In any case in which a parent refuses his/her child’s participation in this study, the treating ED physician will treat the child as they normally would to control the seizures.
Since Lorazepam and Diazepam both have the same side effects, the child’s pediatrician will still be able to take care of the child as he or she normally would. Please note that the study physicians will not contact a participating child’s pediatrician. It is the parent’s choice to inform his or her child’s pediatrician of the child’s involvement in this study.
If an emergency situation arises, and a child’s pediatrician needs to know which drug the patient received, he or she will be able to obtain that information from the study physicians.
After the doctor in the ED has made sure that the child has been treated medically, the doctor or someone from the research team will find the child’s parent or guardian to let him or her know that the child has been enrolled in this research study. At this time, the child’s parent or guardian will be given all of the details about participation and can choose to continue or end the child’s participation.
Refusal of Patient Participation
If a parent does not want a child to participate, he or she can inform us in one of three ways:
• By calling us at 866-377-8557
• Completing the refusal form
• Informing the doctor if the parent is present with his or her child when admitted to the ED.
If a parent refuses participation prior to visiting the ED, we will provide a bracelet that the child can wear to identify that he or she is not participating in the study. While the child does not have to wear the bracelet, we strongly suggest that he or she does. We don’t always know a child’s name when we first treat them in the ED. Our focus is on treating the child’s medical condition. That is why he or she must wear the bracelet so we can make the child is not enrolled in the study.
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Sources
1. Hauser WA. Status epilepticus: Epidemiologic considerations. Neurology 1990;40(suppl)9-13.
2. Shinnar S, Berg AT, Moshe SL, et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up. Pediatrics 1996;98:216-225.
3. De Negri M, Baglietto MG. Treatment of Status Epilepticus in Children. Pediatric Drugs 2001;3(6):411-420.
4. Treiman DM. The role of benzodiazepines in the management of status epilepticus. Neurology 1990; 40(5 Suppl 2):32-42.
5. McDonald RE, McLean MJ. Anticonvulsant drugs: mechanisms of action. In: Delgado-Escueta AV, Ward JR AA, Woodbury DM, et al; editors. Basic Mechanisms of the Epilepsies: molecular and cellular approaches. Advances in neurology. New York (NY): Raven Press, 1986;Vol 44;115-25.
6. Alldredge BK, Wall DB, Ferriero DM. Effect of prehospital treatment on the outcome of status epilepticus in children, Pediatric Neurology 1995;12:213-216.
7. Dieckmann RA. Rectal diazepam for prehospital pediatric status epilepticus. Ann Emerg Med 1994;23:216-223.
8. Lacey DJ, Singer WD, Horwitz SJ, Gilmore H. Lorazepam therapy of status epilepticus in children and adolescents. J Peds 1986;108:771-774.
9. The Status epilepticus working party. The treatment of convulsive status epilepticus in children. Arch Dis Child 2000;83:415-419.
10. Lowenstein DH, Alldredge BK, Status Epilepticus at an urban public hospital in the 1980’s, Neurology 1993;43:483-488.
11. Mitchell WG. Status Epilepticus and Acute Repetitive Seizures in Children, Adolescents, and Young Adults: Etiology, Outcome and Treatment. Epilepsia 1996;37(1):S74-80.
12. Graneto JW, Strange, GR. Seizures. In: Fleisher GR, Ludwig S eds. Textbook of Pediatric Emergency Medicine (3rd ed.) Baltimore. Williams and Wilkins. 1993;468
13. The Harriet Lane Handbook. A Manual for Pediatric House Officers. Gunn VL, Nechyba C. eds. St Louis. Mosby. 2002.
14. The Status epilepticus working party. The treatment of convulsive status epilepticus in children. Arch Dis Child 2000;83:415-419.
15. Mitchell WG. Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia 1996;37(Suppl 1):S74-80.
16. Bleck TP. Management approaches to prolonged seizures and status epilepticus. Epilepsia 1999;40 Suppl 1:S59-63.
17. Sabo-Graham T, Seay AR. Management of status epilepticus in children. Peds Rev 1998;19(9):306-9.
18. Manno EM. New management strategies in the treatment of status epilepticus. Mayo Clinic Proc 2003;78(4):508-18.
19. Shorvon SD. Emergency treatment of epilepsy: acute seizures, serial seizure clusters and status epilepticus. In: Handbook of Epilepsy Treatment. 1st edn. Oxford, Blackwell Science, 2000.
20. Dodson WE, DeLorenzo RJ, Pedley TA, Shinnar S, Treiman DM, Wannamaker BB. Treatment of convulsive status epilepticus: recommendations of the epilepsy foundation of America working group on status epilepticus. JAMA 1993; 270:854–9.
21. Sabo-Graham T, Seay AR. Management of status epilepticus in children. Pediatrics in Review. 1998;19(9):306-9.
22. Martland T, Baxter P, Rittey C. Is there an agreed treatment for children in status epilepticus. Dev Med Child Neurol 1998;40:286-287.
23. Ativan injection (lorazepam) (package insert). Philadelphia, Wyeth-Ayerst Laboratories, 2002.
24. McDermott CA, Kowalczyk AL, Schnitzler ER, Mangurten HH, Rodvold KA, Metrick S. Pharmacokinetics of Lorazepam in Critically Ill neonates with seizures. J Peds. 1992;120(3):479-483.
25. Relling MV, Mulhern RK, Dodge RK, Johnson D, Pieper JA, Rivera GK, Evans WE. Lorazepam pharmacodynamics and pharmacokinetics in children. J Peds. 1989;114(4 Pt.1):641-646.
26. Food and Drug Administration. Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors. Exception from Informed Consent Requirements for Emergency Research. March 2000.
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