EPILEPSY
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`0733-8619/01 $15.00 + .OO
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`TREATMENT OF
`STATUS EPILEPTICUS
`Brien J. Smith, MD
`
`Status epilepticus (SE) is a medical emergency that may result in sig-
`nificant morbidity and mortality if not addressed in a timely and effective
`manner. Because a single seizure and SE are viewed as two extremes in a
`spectrum of seizure frequencies,” it is important to determine when a pro-
`longed seizure or repetitive seizures may cause harm and should be consid-
`ered SE. Medical therapy has been the mainstay for treating SE, but other
`treatments with reported success include surgical
`multiple
`subpial transection;’ electroconvulsive therapy,% caudate stimulation,3’
`and a~upuncture.4~ In reviewing treatment options available for SE, the
`physician needs to consider not only the definition of SE, specifically du-
`ration, but also the type of status, and the milieu in which treatment is
`provided.
`The approval of eight new antiepileptic medications in the United
`States over the last decade has resulted in significant changes in the ap-
`proaches and options available when treating patients with epilepsy.
`Unfortunately, many of these agents are limited to chronic oral admin-
`istration, and the development of newer parenteral agents for the acute
`treatment of seizures in emergency settings (i.e., status epilepticus) has not
`occurred. Understanding the need for rapid intervention, modifications to
`existing agents have been made enabling their potential use in SE. These in-
`clude intravenous valproic acid and the prodrug fosphenytoin. Diazepam
`solution has been administered rectally in the past, and now a rectal gel de-
`livery system (Diastat) is available. Use of the anesthetic agents, propofol
`
`From the Department of Neurology, Henry Ford Hospital and Medical Centers; and Director,
`Epilepsy Monitoring Unit, Henry Ford Hospital and Medical Centers, Detroit, Michigan,
`Assistant Professor of Neurology, Case Western Reserve University, Cleveland, Ohio
`
`NEUROLOGIC CLINICS
`VOLLTME 19 NLlMBER 2 MAY 2001
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`~
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`348
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`SMITH
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`and midazolam, has received more attention and allowed other options
`for treating refractory status epilepticus barbiturates.
`Many protocols for the treatment of SE have been postulated in the
`past and require frequent review. The approach to the patient in general-
`ized convulsive SE is being modified by changing concepts regarding the
`definition of SE, and studies justifying more aggressive treatment, with
`earlier intervention outside the emergency room. The authors will focus
`on agents available for the treatment of generalized convulsive SE in the
`adult population, with some caution concerning the care of children.
`
`DEFINITION
`Status epilepticus was defined in the first International Classification
`of Epileptic Seizures16 as a condition in which ”a seizure persists for a
`sufficient length of time or is repeated frequently enough to produce a
`fixed and enduring epileptic condition.” Slight modifications, in 1981, by
`the International League Against Epilep~y’~ still left practical uncertainty
`in the definition of SE, specifically concerning duration of seizure activ-
`ity. Recommendations of the Epilepsy Foundation of America’s Working
`Group onstatus Epilepticus, in 1993, defined SE as more than 30 minutes of:
`a, continuous seizure activity, orb, two or more sequential seizures without
`full recovery of consciousness.’24 The concept of potential neuronal injury
`related solely to the duration of SE is based in part on animal studies. De-
`spite optimal circumstances during SE, with animals paralyzed and venti-
`lated, neuronal damage may occur after 30 minutes in the substantia nigra
`pars reticularis, and after 45-60 minutes in the third and fourth layers of the
`cerebral cortex and the CA-1 and CA-4 sublayers of the hippocampus.7°,n*%
`Bleck6 defined SE as a state in which seizures last, or are frequently
`repeated without clinical recovery, for a period exceeding 20 minutes.
`This was based on pathophysiologic data regarding changes in tissue oxy-
`genation presented at an international workshop on the management of
`SE in 1980. Recent studies, including the VA Cooperative Trial on Treat-
`ment of Generalized Convulsive Status Epilepticus”’ and the Pre-Hospital
`Treatment of Status Epilepticus (PHTSE) study,@ used seizure duration of
`10 and 5 minutes respectively as inclusion criterion for SE.
`Lowenstein, Bleck, and Macdonald@ proposed an operational defini-
`tion for generalized convulsive SE in adults and older children (>5 years
`old) to incorporate the practical considerations of patient management.
`Generalized, convulsive status epilepticus in adults and older children
`(> 5 years old) refers to 25 minutes of (a) continuous seizures or (b) two or
`more discrete seizures between which there is incomplete recovery of con-
`sciousness. This determination was based in part on a study completed
`by Theodore et allo1 that analyzed 120 generalized tonic-clonic seizures
`recorded during inpatient monitoring and reported a mean seizure dura-
`tion of 62 seconds. Because no seizures lasted more than 2 minutes, more
`prolonged seizures encourage the development of SE and the need for
`intravenous (IV) therapy. This determination excludes children less than
`5 years old because relatively little is known about typical ”single” seizures
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`TREATMENT OF STATUS EPILEPTICUS
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`349
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`in this age group. Initial febrile seizures5 and acute symptomatic seizures&
`in children can be prolonged but do not result in the same morbidity seen in
`adults with prolonged seizures. Further work, specifically in the pediatric
`population, is needed before an operational definition can be formulated
`and treatment strategies devised.
`
`CLASSIFICATION OF STATUS EPILEPTICUS
`Gastaut33 has suggested that there are as many types of SE as there are
`seizures, and there one other SE syndromes described in the literat~re.~~,"~
`Classification of SE is similar to the classification of single seizures in that
`they are both based on clinical and electroencephalogram (EEG) findings;
`however, the emergent nature of patient presentation makes this difficult.
`In an attempt to simplify the classification for emergency treatment situa-
`tions, SE has been divided into generalized convulsive SE, nonconvulsive
`SE (complex-partial SE and absence SE), and simple-partial SE.'3,'05
`Recurrent convulsions without complete recovery between seizures
`is overt generalized convulsive SE and easily recognized. On the other
`hand, there are patients who present in a comatose state with subtle con-
`vulsive features (rhythmic muscle twitches or tonic eye deviation) who
`require an EEG to demonstrate ongoing epileptiform ictal patterns. This
`has been classified as symptomatic-myoclonic SEE or nonconvulsive SE,
`but Treiman"' argues this should be called subtle generalized convulsive
`SE. Treiman describes generalized convulsive SE as a dynamic process that
`if inadequately treated can progress from overt generalized convulsive SE,
`to subtle generalized convulsive SE, and then to electrical generalized con-
`vulsive SE. Clinical changes, from discrete seizures to subtle movements
`to a profound SE-induced encephalopathy in which no motor activity can
`be processed, may occur.11o The EEG also goes through a predictable se-
`quence of changes from repetitive discrete seizures to periodic epileptiform
`discharges.lo7 Treiman"' suggested that recognition of these ictal EEG pat-
`terns, even in a patient with subtle or completely absent motor evidence
`of ongoing SE, should lead to the diagnosis of generalized convulsive SE
`and the initiation of aggressive therapy.
`The classification of subtle generalized convulsive SE continues to
`receive significant debate. Gastaut33 described "so-called myoclonic status
`epilepticus during acute or subacute brain disorders in nonepileptics."
`This SE involves myoclonic features, generally occurring in adults, and
`they are always secondary to acute or subacute encephalopathy whose
`origin is metabolic (especially anoxia), toxic, viral, or degenerative. It is
`Gastaut's opinion that this type of myoclonic syndrome should not be
`regarded as SE in the strict sense of the term but as the late myoclonic
`phase of the underlying condition. The outcome is always very severe, if not
`fatal.
`Not all physicians are convinced of this theory, and they argue that
`this type of presentation should not be classified as a form of SE or re-
`ceive aggressive treatment. Are these patients exhibiting both clinical and
`electrographic symptoms that remain after an acute diffuse cerebral injury
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`350 SMITH
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`(i.e., anoxia) with no relationship to SE? Or, are these findings end-stage
`remnants of an untreated, rapidly evolving, epileptic process (SE)? Can a
`controlled prospective study be completed showing that aggressive treat-
`ment in this population makes a difference? These are important ques-
`tions that may be difficult to answer. Patients with a history of acute clin-
`ical seizure activity or with an EEG pattern showing evolving features
`should be treated aggressively. The comatose patient with severe hypoxic
`encephalopathy, no reported seizure activity, and a nonreactive EEG pat-
`tern will often receive treatment with benzodiazepines, phenytoin, or phe-
`nobarbital, but not more aggressive treatment.
`
`MORBIDITY AND MORTALITY
`The overall incidence of SE is approximately 100,000 to 150,000 people
`anually and accounts for about 7% of all epilepsy case^.*^**,^^ The mortality
`of generalized convulsive SE has been estimated to be about 20% (range
`3%-35%)43, 124 with age and etiologic factors having prognostic significance.
`It occurs most frequently in the very young and elderly.", 43 Typically, out-
`come is worse when SE is of longer duration (> 1 hour),23,103 occurs in the
`elderly, or has an etiology of anoxia. Patients with an acute central ner-
`vous system injury, (i.e., head injury, rapidly growing brain tumor, anoxic
`encephalopathy, stroke, central nervous system infection, and toxicity) are
`usually more difficult to contr01.5~
`Chronic processes may also lead to status epilepticus, but patients
`with SE and these etiologies tend to respond better to antiepileptic ther-
`apy, and the patient is much more likely to return to baseline functioning.
`Chronic processes may include patients with preexisting epilepsy (acute
`exacerbation and antiepileptic drug reduction), alcohol withdrawal, and
`remote focal epileptogenic lesions (tumor, stroke, and posttraumatic in-
`jury). As with most conditions, children show more resilience and have a
`lower mortality rate.39
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`PREHOSPITAL TREATMENT
`The major variable of SE that can be altered with rapid and effective
`treatment is its duration. Historically, the start of effective treatment has
`occurred in the emergency department (ED), but often this is too late. In
`the VA randomized study, Treiman et al1IZ reported the median duration
`of SE prior to initiation of treatment was 2.8 hours for 384 patients with
`overt generalized convulsive SE and 5.8 hours for 134 patients with subtle
`SE. Jordanq8 completed a retrospective review of 30 patients with SE who
`presented to the ED. Treatment access time was determined from the onset
`of SE to arrival of the emergency medical team (EMT) (treatment access
`time l), transit time from the amval of EMT to delivery in the ED (treatment
`access time 21, and arrival in the ED to initiation of treatment according to
`the hospital's SE protocol (treatment access time3). The average duration of
`treatment access time 1 was 30 minutes (range 15-140 minutes), treatment
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`TREATMENT OF STATUS EPILEPTICUS 351
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`access time 2 was 20 minutes (range 10-40 minutes), and treatment access
`time 3 was 35 minutes (range 15-83 minutes). The cumulative delay in this
`group of patients, from the onset of SE outside the hospital to the initiation
`of a treatment protocol, averaged 85 minutes (maximum 6.5 hours).
`In an attempt to provide earlier intervention in SE, paramedics have
`become involved in the delivery of first-line antiepileptic drug treatment, in
`addition to stabilizing the patient. Because benzodiazepines stop seizures
`most rapidly regardless of the etiology,79 they are considered first-line treat-
`ment for SE before arrival in the hospital and in the emergency room.
`
`TREATMENT
`Benzodiazepines
`Benzodiazepines, as antiepileptic drugs, include diazepam, cloraze-
`pate, oxazepam, lorazepam, clonazepam, nitrazepam, and clobazam.44 Pro-
`bable pharmacologic actions include benzodiazepine-receptor-mediated
`enhancement of gamma-aminobutyric acid mediated transmission and, at
`higher doses, limited, sustained repetitive neuronal firingg The role of
`cations.lo6,'0 T: The author will focus on the agents available in the United
`benzodiaze ines in acute seizures has been addressed in multiple publi-
`States (diazepam, lorazepam, and midazolam) that have been used out-
`side the hospital setting. Oral diazepam and lorazepam, and sublingual
`lorazepam, have been successfully used to treat acute episodes, but treat-
`ment is delayed by slow absorption. Placement of medication in the oral
`cavity during a generalized convulsive SE is also not recommended.84 Intra-
`venous administration is the preferable route of delivery but may be limited
`by an inability to obtain intravenous or intraosseous access. Rectal, intra-
`muscular, and intranasal routes are alternatives in some circumstances.
`
`Diazepam
`Diazepam is available in tablet, intravenous, and rectal gel forms.
`Naquet et alR and Gastaut et a13* were the first to document the use of
`intravenous diazepam in the treatment of SE. The efficacy of intravenous
`diazepam is known from experience in the ED but use in the prehospital
`setting is less documented. Earlier studies of prehospital treatment of chil-
`dren with SE led to some recommendations against the use of intravenous
`diazepam because of a high risk of intubation-related complications.@'
`The
`use of parenteral diazepam solution administered rectally to children first
`occurred in 1975.' Subsequent work by Knudsen5' showed that rectal di-
`azepam was effective in aborting seizures and preventing febrile seizures.
`It stopped seizures in 96% of patients if given within 15 minutes of seizure
`onset but in only 57% of patients if given later. Rectal diazepam is the most
`commonly used medication given before admission to the hospital. The
`rectal route of administration is not, however, always acceptable or conve-
`nient. Many teachers, parents, and caregivers are reluctant to administer
`rectal medication for fear of sexual abuse allegations?O
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`SMITH
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`Because of issues of overall efficacy and potential complications of
`prehospital treatment, studies were undertaken to compare intravenous
`by Dieckmann' ? compared
`and rectal diaze am re arations for early SE. An initial study completed
`p p the effectiveness and safety of rectal and in-
`travenous diazepam in 36 children in status epilepticus. Rectal and intra-
`venous diazepam were initially effective in terminating status epilepticus
`in 81% and 100% of children, respectively; however, seizures recurred in
`only 30.8% of the children treated with rectal diazepam, as opposed to
`60% treated with intravenous diazepam. Two patients treated with intra-
`venous diazepam required intubation prior to arrival in the ED because of
`respiratory depression, while none in the rectal diazepam group required
`prehospital intubation. This study did not include a comparison group of
`children who did not receive prehospital therapy for SE.
`Using a retrospective case-control study design, Alldredge et a1' com-
`pared the clinical course of children with SE who received prehospital
`diazepam therapy (either by rectal or intravenous administration) with
`a group of children who received only standard ED antiepileptic drug
`therapy. Prehospital diazepam therapy was associated with SE of shorter
`duration (32 minutes versus 60 minutes) and a reduced likelihood of re-
`current seizures in the ED (58% versus 85%). There were no significant
`differences between rectal and intravenous diazepam therapy with regard
`to SE duration, intubation, or recurrent seizures in the ED.
`The benefits unique to rectal diazepam compared with oral or intra-
`venous preparations include desirable pharmacokinetics, improved safety,
`and ease of admini~tration.~~ Various preparations have been available
`throughout the world, and most clinicians have used an intravenous so-
`lution drawn into a syringe and given either directly or through a rectal
`tube. Because of the inconvenience of having to accurately measure the
`preparation prior to administration, a diazepam rectal gel (Diastat) was
`formulated, which is now available in 5,10,15, and 20 mg preparations.
`
`Lorazepam
`Lorazepam is considered the drug of choice in the emergency room
`but has had limited use by paramedics in the field. Lorazepam has been
`compared with diazepam in multi le clinical trials and is considered by
`many as the drug of choice for SE.'DB1"7 Leppik et a156 compared lorazepam
`and diazepam in a double-blind study for treatment of SE. With the initial
`injection of lorazepam 4 mg intravenous or diazepam 10 mg intravenous,
`status epilepticus was stopped in 78% and 58% of patients, respectively.
`After a second injection, these numbers improved to 84% and 76%, respec-
`tively. Although diazepam enters the brain rapidly and somewhat faster
`than lorazepam, this does not significantly alter the speed of clinical effect.
`Because of rapid and extensive redistribution of diazepam to peripheral
`fat stores, the duration of clinical effectiveness with diazepam is only 20 to
`30 minutes. Lorazepam has a different volume of distribution of the free
`drug; therefore, its clinical effectiveness can last for several hours. A
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`TREATMENT OF STATUS EPILEPTICUS 353
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`previous study completed by Levy and Kra1158 suggested that the use of
`lorazepam for SE might be safer, in that only one out of 53 patients expe-
`rienced respiratory depression with intravenous lorazepam as compared
`with eight of 33 treated with intravenous diazepam. The frequency of en-
`dotracheal intubation during SE in children who received lorazepam was
`significantly lower (27%) compared with those who received diazepam
`(73%), when either agent was given alone or combined with phenyt~in.'~
`Also, when given intravenously for SE, lorazepam causes fewer side effects
`than diazepam.28
`Only one formal clinical study comparing intravenous lorazepam
`(2 mg) and diazepam (5 mg) in a prehospital setting has been under-
`taken. Lowenstein et al" designed a prospective, randomized, double-
`blind placebo-controlled trial administered by paramedics in the San
`Francisco area. This trial included adults with prolonged (>5 minutes)
`or repetitive generalized convulsive seizures. The primary outcome mea-
`sure was cessation of SE by the time of ED arrival, and the secondary
`outcome measure was prehospital complications. Of 205 patients enrolled,
`39 of 66 (55%) responded to lorazepam therapy, 29 of 68 (43%) responded
`to diazepam therapy, and 15 of 71 (21%) responded to placebo therapy.
`The physicians' conclusion was that paramedics can administer benzo-
`diazepines in a safe and effective manner out-of-hospital in adults, and
`intravenous lorazepam was superior to diazepam; a potential limitation is
`the need for refrigeration, which may limit its use outside the hospital.40
`Rectal lorazepam has not been studied as extensively as rectal di-
`azepam. Most of the studies have been performed with children in part be-
`cause of the uncomfortable (physical and social) route of delivery in adults.
`Rectal lorazepam has a slower onset of action compared with diazepam.37
`In the pediatric study comparing rectal and intravenous delivery of di-
`azepam and lorazepam, there were minimal differences in the mean time
`to seizure cessation for both drugs with both types of administration. Those
`receiving diazepam, however, were much more likely to require additional
`drugs for seizure
`Lorazepam is also used by the sublingual route for rapid effect, be-
`cause any form of therapy through the buccal cavity bypasses the liver
`and avoids first-pass elimination. Yager and Seshia'26 reported absorption
`of sublingual lorazepam within 20 seconds and subsequent control of serial
`seizures in 8 of 10 children within 15 minutes. A concentrated oral solution
`of lorazepam has been described by Schroeder et a F for the management
`of hospitalized pediatric patients with epilepsy.
`
`Midazolam
`Midazolam is an imadazobenzodiazepine drug, which stands out in
`comparison with the other benzodiazepines because it is water-soluble
`and can be administered intramuscularly (IM). When injected, the ben-
`zodiazepine ring closes at physiologic pH and the substance becomes
`lipid-soluble allowing rapid cerebral penetrati0n.9~ Both diazepam and
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`lorazepam may be administered IM but this is not recommended treatment
`because of slower, more erratic absorption and increased local discomfort.
`Since its introduction as an agent with antiepileptic effects, midazolam has
`been used in the prehospital setting for status epilepticus via intravenous,
`intramuscular, intranasal, rectal, and buccal routes.
`Intramuscular midazolam is very effective in stopping seizure activity
`within 5 to 10 minutes’04 with no significant adverse effects. A prospec-
`tive, randomized study, including 24 children requiring acute treatment
`for seizures upon arrival in the ED, compared the effectiveness of in-
`tramuscular midazolam and intravenous diazepam. There was approxi-
`mately a 4-minute difference in both the times for drug administration
`and seizure cessation in favor of Ih4 mida~olam.’~ There have been no pre-
`hospital studies completed using IM midazolam and experience is limited
`to case rep0rts.5~ Intravenous access in the prehospital setting can be diffi-
`cult in certain patients who are seizing, especially children, the elderly, or
`obese patients. Intramuscular midazolam treatment may be an easier, safer,
`more predictable and effective treatment option than either diazepam or
`lorazepam treatment by the rectal or IM routes.’04
`Scott et als9 were the first physicians to show that buccal/sublingual
`midazolam could be rapidly absorbed, with a cerebral effect seen on EEG
`in ten normal subjects, within 5 to 10 minutes. The physicians subsequently
`performed a study in a residential center with children and young people
`with severe epilepsy who had continuous seizures of more than 5 minutes.
`The patients either received sublingual/buccal midazolam (10 mg) or rec-
`tal diazepam (10 mg). For administration, midazolam (2 mL; 10 mg) was
`drawn into a 2-mL syringe, the student’s lips were parted, and the drug
`was squirted around the buccal mucosa. Midazolam stopped 30 of 40 (75%)
`seizures in 14 students, whereas diazepam stopped 23 of 39 (59%) seizures
`in 14 patients. Buccal midazolam appeared to have some distinct advan-
`tages over rectal diazepam, but Holmes” suggested some caution be used
`in extrapolating these results for the standard treatment of SE.
`Nasal administration of midazolam has been used as a sedativeI8 and
`preinduction agenP by anesthesiologists in the past. ORegan et a176 sub-
`sequently demonstrated decreases in interictal epileptiform activity with
`intranasal midazolam administration. Two cases of SE terminated with
`the administration of intranasal midazolam, while IV access was being
`attempted were subsequently documented.50 Lahat et a1% completed a
`3-month study in which all children who presented to the pediatric ED
`with generalized motor seizures of at least 10 minutes received midazo-
`lam solution (5 mg/mL) at a dose of 0.2 mg/kg dropped into both nostrils.
`Twenty children participated in the study and seizure control was achieved
`in all but one case in which IV diazepam was also ineffective. The mean
`time until seizure control was 3.5 minutes despite a mean seizure duration
`of 17 minutes prior to drug administration. In a commentary by Wallace,”’
`the author noted that children who have seizures when febrile, frequently
`have an upper respiratory tract infection. Nasal secretions can dilute the
`midazolam solution and make it more difficult for this agent to have con-
`tact with the absorbing surface. Further studies of intranasal midazolam
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`TREATMENT OF STATUS EPILEPTICUS
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`in the treatment of SE are needed, especially in children with respiratory
`infections.
`
`Propofol
`Propofol (Z,&diisopropylphenol) is a rapidly acting, highly lipid-
`soluble anesthetic used in the induction of general anesthesia. Propofol has
`a short duration of action, barbiturate- and benzodiazepine-like effects on
`the GABA-A receptor, and can suppress central nervous system metabolic
`activity." The initial case report of inpatient treatment of SE with propofol
`infusion was in 1988,'= and the first study of prehospital use of propofol
`was from Helsinki in 1995.53 A prehospital treatment protocol for convul-
`sive SE using IV diazepam (520 mg) already existed; this was followed
`by general anesthesia induced with thiopental sodium or propofol. Eight
`consecutive adult patients with SE were treated by a physician-manned
`mobile intensive care unit in 1994. The physicians administered propo-
`fol boluses of 30 mg every 30 seconds in patients who continued to seize
`despite adequate doses of IV diazepam. All patients required intubation
`and mechanical ventilation because of hypoxia or inefficient ventilation.
`All patients stopped convulsing with propofol administration. Only one
`patient required intensive care unit admission.
`An approach to the initial treatment of SE in the prehospital setting
`is shown in Figure 1. Mdazolam has significant potential but has limited
`practical experience in the community. More aggressive options, including
`propofol, will have to be reserved for communities in which emergency
`medical services are equipped to provide cardio pneumatic support and
`direct physician input. Unfortunately, in many communities, more basic
`concerns such as delayed response time and limited funding need to be
`addressed before these changes can be considered.
`
`EMERGENCY DEPARTMENT INPATIENT TREATMENT
`VA Status Epilepticus Cooperative Study Group
`The main objective in the treatment of SE is to abort seizures and
`treat the condition."O How physicians approach the neurologic emergency
`of SE (Table 1) has not changed dramatically, but the initial evaluation
`continues to be paramount in determining appropriate intervention. Deci-
`sions made concerning drug selection (first-line therapy) have been based
`on past experience. Phenobarbital, phenytoin, diazepam plus phenytoin,
`and lorazepam were all advocated for the initial treatment of generalized
`convulsive SE. There were few controlled studies using these agents for
`direct comparison. A five-year randomized, double-blind, multicenter trial
`comparing these four intravenous regimens was undertaken by the VA
`Status Epilepticus Cooperative Study Group and the results were pub-
`lished in 1998."*
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`Emergency Medical Services*
`Intravenous benzodiazepine
`lorazepam 0.1 rng/kg or diazepam 0.1-0 3 mgkg
`or
`(if unable to obtain venous access)
`
`. Intramuscular midazolarn 0.15-0.30 rnglkg
`. Intravenous propofol. 30 mg with
`
`repeated boluses (30 mg) every 30 s’
`
`and / or 6 Fosphenytoin (IM, IV)$
`
`356
`
`SMITH
`
`Caregiver I family
`Rectal diazepam
`- intravenous solution 0.2-0.6 rng/kg
`or
`-rectal gel 0.2-0.5 rnglkg
`
`w
`
`Figure 1. Prehospital treatment of status epilepticus. *Emergency medical service options
`may be limited by availability of the medications and the need for Advanced Cardiac Life Sup-
`port (ACLS) certification. + Previous reported experience with prehospital propofol administra-
`tion includes physician supervision. toption to be considered, no reported prehospital expe-
`rience. §No prehospital trials or experience reported in the United States. IM-intramuscular;
`IV-intravenous. Data from Kuisma M, Roine RO: Propofol in prehospital treatment of con-
`vulsive status epilepticus. Epilepsia 36:1241-1243, 1995; Runge JW, Allen FH: Emergency
`treatment of status epilepticus. Neurology 46(suppl 1):S2O-S23, 1996; and Scott RC, Besag
`FM, Neville BG: Buccal midazolam and rectal diazepam for treatment of prolonged seizures
`in childhood and adolescence: A randomized trial. Lancet 353:623-626, 1999.
`
`The study demonstrated that all of the four treatment arms (lorazepam
`0.1 mg/kg; diazepam 0.15 mg/kg, followed by phenytoin 18 mg/kg;
`phenytoin 18 mg/kg; and phenobarbital 15 mg/kg) studied were effica-
`cious in treating overt SE. Treatment was considered successful when all
`motor and electrographic seizure activity ceased within 20 minutes after
`the beginning of the drug infusion and there was no return of seizure
`activity during the next 40 minutes. Success rates in overt generalized con-
`vulsive SE were highest with lorazepam (64.9%), followed by phenobarbi-
`tal (58.2%), diazepam and phenytoin (55.8%), and phenytoin (43.6%). In a
`pairwise comparison, the only significant difference was the effectiveness
`of lorazepam when compared with phenytoin. In the group with a diagno-
`sis of subtle generalized convulsive SE, no significant differences among
`the treatments were detected. The 20-minute time interval requirement for
`seizure cessation was thought by some physicians to be a disadvantage
`with phenytoin because of the mandatory slow infusion rate. The length
`of infusion was 33.0 f 20.1 minutes for phenytoin, significantly longer than
`the 4.7 f 7.2 minutes for lorazepam.
`Important differences in the response to therapy and outcome were
`also noted between the overt and subtle generalized convulsive SE groups.
`The median duration of status epilepticus in the overt generalized con-
`vulsive SE group at the time of enrollment was 2.8 hours and in the
`
`AQUESTIVE EXHIBIT 1108 Page 0010
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`TREATMENT OF STATUS EPILEPnCUS
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`357
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`Table 1. EMERGENCY DEPARTMENT/INPATIENT MANAGEMENT
`OF STATUS EPILEPTICUS
`StabilizatiodDiagnosis
`ABCs (Airway, Breathing, Circulation) of life support
`Assess and control airway, consider intubation (C-spine precautions)
`Pulse oximetry (consider ABGs), low-flow oxygen (nasal cannula or a
`nonrebreathing mask)
`Nasal or orotracheal intubation or bag valve-mask if respiratory compromise; if
`neuromuscular blockade is needed, use a short-acting drug (e.g., 0.1 mg/kg
`vecuronium)
`Monitor vital signs (including temperature), if elevated provide passive cooling,
`antipyretics
`Briefly observe patient to confirm diagnosis (continued seizure activity or one additional
`seizure)
`Obtain available history
`Perform neurologic and physical examination
`Identify and correct metabolic abnormalities
`Blood tests for antiepileptic drug levels, glucose, calcium, magnesium, electrolytes,
`complete blood count with differential, renal function (blood urea nitrogen,
`creatinine), hepatic enzymes, toxicology screen
`Start an intravenous line with normal saline (intraosseous line in young child if IV access
`not obtained)
`Initial treatment
`If hypoglycemia confirmed or if blood glucose determination unavailable
`Adults-100 mg thiamine, 50 mL of 50% glucose
`Pediatric-2 mL/kg or 25% glucose; pyridoxine 100-200 mg IV push (< 18 months
`old)
`Initiate antiepileptic drug therapy (see Fig. 2)
`Additional studies
`CT scan of the brain-if
`intracranial hypertension, cerebral mass lesion, or obstruction of
`CSF is suspected; CT scan should be performed before lumbar puncture
`LP-if
`central nervous system infection is a major consideration; should be deferred until
`seizures are stopped and patient is hemodynamically stable; prompt antibiotic or
`antiviral therapy should be instituted before LP
`CSF = cerebrospinal fluid; CT = computer tomography; LP = lumbar puncture; IV =
`intravenous.
`
`subtle generalized convulsive SE group, 5.8 hours. The first drug treatment
`was successful in only 14.9% of patients with subtle generalized convul-
`sive SE compared with 55.5% of patients in the overt generalized con-
`vulsive