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`The New England Journal of Medicine
`
`Review Article
`
`Current Concepts
`
`S
`
`TATUS
`
` E
`
`PILEPTICUS
`
`, M.D.,
` H. L
`D
`OWENSTEIN
`ANIEL
` B
` K. A
`, P
`.D.
`HARM
`AND
`RIAN
`LLDREDGE
`
`A
`
` PATIENT in status epilepticus has contin-
`uous or rapidly repeating seizures. Although
`the danger of this pattern of seizure activity
`has been recognized since antiquity, our under-
`standing of the pathophysiology of status epilepticus
`is incomplete. The frequency of cases in the United
`States is approximately 102,000 to 152,000 per year,
`and roughly 55,000 deaths are associated with status
`epilepticus annually.
` Twelve to 30 percent of adult
`1
`patients with a new diagnosis of epilepsy first present
` This review focuses on gen-
`in status epilepticus.
`2,3
`eralized status epilepticus, which is the most com-
`mon form of the disorder.
` This is a life-threatening
`1,4
`condition that always requires prompt management.
`Our review emphasizes issues relevant to adults and
`older children; status epilepticus in younger children
`has been reviewed in detail elsewhere.
`
`5,6
`
`DEFINITIONS
`In 1981, the International League against Epilep-
`sy defined status epilepticus as a seizure that “per-
`sists for a sufficient length of time or is repeated fre-
`quently enough that recovery between attacks does
`not occur.”
` The lack of a specific duration of the
`7
`seizures has made this definition difficult to use.
`More recent publications have defined status epilep-
`ticus as seizures that persist for 20 to 30 minutes,
`which is an estimate of the duration necessary to
`cause injury to central nervous system neurons.
`4,5,8
`Practitioners recognize the need to begin therapy
`for status epilepticus well before 20 minutes have
`elapsed, so such a definition is also unsuitable as a
`guide for treatment. Since isolated tonic–clonic sei-
`zures in adults rarely last more than a few minutes,
`we advocate the use of an operational definition of
`
`From the Departments of Neurology (D.H.L., B.K.A.) and Anatomy
`(D.H.L.), School of Medicine, and the Department of Clinical Pharmacy,
`School of Pharmacy (B.K.A.), University of California, San Francisco. Ad-
`dress reprint requests to Dr. Lowenstein at the Department of Neurology,
`Box 0114, UCSF School of Medicine, 505 Parnassus Ave., San Francisco,
`CA 94143-0114.
`©1998, Massachusetts Medical Society.
`
`status epilepticus: either continuous seizures lasting
`at least five minutes or two or more discrete seizures
`between which there is incomplete recovery of con-
` This definition differs from that of se-
`sciousness.
`9,10
`rial seizures, which are two or more seizures occur-
`ring over a relatively brief period (i.e., minutes to
`many hours), but with the patient regaining con-
`sciousness between the seizures.
`
`CLINICAL FEATURES OF GENERALIZED
`STATUS EPILEPTICUS
`When first seen, patients with status epilepticus
`are unresponsive and usually have clinically obvious
`seizures, such as tonic, clonic, or tonic–clonic move-
`ments of the extremities. With time, however, the
`clinical manifestations often become subtle, and the
`diagnosis requires careful observation. Patients may
`have only small-amplitude twitching movements of
`the face, hands, or feet or nystagmoid jerking of the
` Some patients have no observable, repeti-
`eyes.
`11,12
`tive motor activity, and the detection of ongoing
`seizures requires electroencephalography.
` Electro-
`12
`graphic status epilepticus of this type may be more
`common in hospitalized, comatose patients than pre-
` Patients who have electrographic
`viously thought.
`13
`status epilepticus with little or no motor activity (in-
`cluding patients paralyzed for airway management)
`are still at risk for central nervous system injury and
`require prompt treatment. Myoclonic status epilep-
`ticus, which is usually seen in patients after pro-
`longed anoxia or other severe metabolic insults, con-
`sists of very brief, sudden movements of restricted
`parts of the body that may be triggered by external
`stimuli, such as mechanical ventilation.
`
`OUTCOMES AND CAUSES OF STATUS
`EPILEPTICUS
`The overall mortality rate among adults with sta-
`tus epilepticus is approximately 20 percent, and pa-
`tients who have a first episode of status epilepticus
`are at substantial risk for future episodes and the de-
` The outcome is usu-
`velopment of chronic epilepsy.
`5
`ally worse in patients with status epilepticus of long
`duration and those who have severe physiologic dis-
`turbances. However, the predominant factor affect-
`ing outcome is cause. Status epilepticus has many
`causes, which vary depending on the patient popu-
`lation. It is useful to categorize the causes according
`to acute and chronic processes, because there are dif-
`ferences between the two in management, response
`to treatment, and outcome.
`
`14-17
`Acute processes that cause status epilepticus in-
`clude metabolic disturbances (e.g., electrolyte abnor-
`
`970
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`ⴢ
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`April 2, 1998
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`AQUESTIVE EXHIBIT 1101 Page 0001
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`Downloaded from nejm.org by DEEANN JEHNING on January 15, 2020. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`CURRENT CONCEPTS
`
`malities, renal failure, and sepsis), central nervous sys-
`tem infection, stroke, head trauma, drug toxicity, and
`hypoxia. Seizures in this category are often difficult
`to control and are associated with a higher mortality,
`especially those occurring after hypoxia and in older
`patients.
` Myoclonic status epilepticus after hypoxia
`16,17
`carries an especially grave prognosis and is often not
`treated as aggressively as other forms of status epi-
`lepticus.
`
`18
`Chronic processes that cause status epilepticus in-
`clude preexisting epilepsy in which status epilepticus
`is due to breakthrough seizures or the discontinua-
`tion of antiepileptic drugs, seizures in the context of
`chronic ethanol abuse, and remote processes such as
`central nervous system tumors or strokes that lead to
`status epilepticus after a latent period that may span
`weeks to years. In general, patients with status epi-
`lepticus due to these chronic processes respond well
`to anticonvulsant treatment, and they recover from
`the acute episode of seizures.
`
`PATHOPHYSIOLOGY
`The fundamental pathophysiology of status epi-
`lepticus involves a failure of mechanisms that nor-
`mally abort an isolated seizure. This failure can arise
`from abnormally persistent, excessive excitation or
`ineffective recruitment of inhibition. The relative
`contributions of these factors are poorly understood.
`The temporal and spatial determinants of status epi-
`lepticus are also relatively unknown; experimental
`studies suggest there is induction of reverberating sei-
`zure activity between, for example, hippocampal and
`parahippocampal structures and that the seizures pro-
`gress through a sequence of distinct electrographic
`changes.
`
`19,20
`It is likely that numerous mechanisms are involved,
`depending on the underlying cause. Our best in-
`sights come from cases in which status epilepticus
`was caused by an exogenous toxin. The most nota-
`ble example involved the ingestion in 1987 of mus-
`sels contaminated with domoic acid, an analogue of
`glutamate (the principal excitatory amino acid neu-
` Some patients had pro-
`rotransmitter in the brain).
`21
`longed and profound status epilepticus.
` This occur-
`22
`rence suggests that excessive activation of excitatory
`amino acid receptors can cause prolonged seizures
`and suggests that excitatory amino acids have a caus-
`ative role in status epilepticus.
` Status epilepticus
`23
`can also be caused by penicillin and related com-
`pounds that antagonize the effects of
`-aminobu-
`g
`tyric acid (GABA), the main inhibitory neurotrans-
`mitter of the brain.
` Very recent studies suggest that
`19
`the failure of inhibition may be due in some cases to
`a shift in the functional properties of the GABA
` re-
`A
`
`ceptor that occurs as seizures become prolonged.
`24
`Status epilepticus lasting approximately 30 to 45
`minutes can cause cerebral injury, especially in lim-
`bic structures such as the hippocampus, and seizure
`
`activity itself is sufficient to damage the central nerv-
`ous system.
` This damage is partly a consequence
`25,26
`of glutamate-mediated excitotoxicity and does not
`appear to be due primarily to an excessive metabolic
`demand imposed by repetitive neuronal firing. The
`superimposition of systemic stresses such as hyper-
`thermia, hypoxia, or hypotension exacerbates the
`degree of neuronal injury in animal models of status
`epilepticus, a finding consistent with empirical ob-
`servations in humans.
`
`27,28
`
`MANAGEMENT
`The initial care of a patient with status epilepticus
`includes standard measures applicable to any acute
`medical emergency (Fig. 1). A few aspects of man-
`agement deserve special mention. Proper assessment
`and control of the airway and of ventilation in a pa-
`tient with ongoing convulsive seizures can be chal-
`lenging. Arterial-blood gas monitoring is especially
`useful. Many patients have a profound metabolic
`7.0) that corrects itself
`acidosis (e.g., arterial pH
`⬍
`once seizures are controlled; treatment with sodium
`bicarbonate should be reserved for the most extreme
`circumstances.
` However, arterial-blood gas val-
`14,29
`ues may also reveal respiratory acidosis or hypoxia
`that requires immediate treatment through airway
`management and supplemental oxygen.
`Despite the periods of apnea and cyanosis that oc-
`cur during the tonic or clonic phases of their seizures,
`most patients in status epilepticus breathe sufficiently
`as long as the airway remains clear. Nonetheless, pa-
`tients should receive 100 percent oxygen by nasal
`cannula or a nonrebreathing mask, and airway paten-
`cy should be maintained by an oral or nasopharyn-
`geal device while the patient remains unresponsive.
`Nasal or orotracheal intubation or bag valve-mask
`ventilation should be undertaken if there is clinical or
`laboratory evidence of respiratory compromise. If
`neuromuscular blockade is needed to facilitate intu-
`bation, the use of a short-acting drug (e.g., 0.1 mg
`of vecuronium per kilogram of body weight) will
`help the physician promptly regain the ability to de-
`termine whether seizures are present clinically.
`Hyperthermia occurs relatively frequently during
`status epilepticus (in 28 to 79 percent of patients),
`and in many cases it is primarily a manifestation of
`the seizures rather than evidence of an infection.
`14,29
`Given the damaging effects of fever in patients with
`central nervous system injury, hyperthermia should
`be treated promptly with passive cooling.
`Electroencephalographic monitoring should be
`used for any patient who has received a relatively
`long acting paralytic agent, remains unconscious af-
`ter the initial phase of antiepileptic-drug treatment,
`or requires prolonged therapy for refractory status ep-
`ilepticus (discussed below). Electroencephalography
`continues to be underused in such patients. Relatively
`simple electroencephalographic monitoring devices
`
`971
`Volume 338 Number 14
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`ⴢ
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`The New England Journal of Medicine
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`Downloaded from nejm.org by DEEANN JEHNING on January 15, 2020. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`The New England Journal of Medicine
`
`1. Assess and control airway
`2. Monitor vital signs (including temperature)
`3. Conduct pulse oximetry and monitor
`cardiac function
`4. Perform rapid blood glucose assay
`
`Start intravenous infusion
`
`Administer thiamine (100 mg)
`and glucose (50 ml of 50 percent dextrose)
`
`Start anticonvulsant therapy
`
`Take focused history and examine patient
`
`Perform laboratory studies
`
`Known seizure disorder or other illnesses?
`Trauma?
`Focal neurologic signs?
`Signs of medical illnesses (e.g., infection,
`hepatic or renal disease, substance abuse)?
`
`Complete blood count
`Serum electrolytes and
`calcium
`Arterial-blood gas
`Liver function
`Renal function
`Toxicology
`Serum antiepileptic-drug
`concentrations
`
`Undertake further workup to
`define cause
`Manage other medical problems
`
`Figure 1.
` Algorithm for the Initial Management of Status Epilepticus.
`
`are now available and will probably become common
`in emergency departments and intensive care units.
`
`PRINCIPLES OF DRUG TREATMENT
`The goal of treatment for status epilepticus is the
`prompt cessation of seizure activity. Ideally, a drug
`used in this setting would be easy to administer,
`have an immediate and long-lasting antiseizure ef-
`fect, and be free of serious effects on cardiorespira-
`tory function and the level of consciousness. Un-
`fortunately, all current therapies fall short of this
`ideal. Benzodiazepines and barbiturates depress con-
`sciousness and respiratory drive in a dose-dependent
`manner, phenytoin and fosphenytoin cause infusion-
`rate–related hypotension and cardiac dysrhythmias,
`and limits on the rate of intravenous administration
`delay the maximal antiseizure effect of phenytoin,
`fosphenytoin, and phenobarbital.
`Drug treatment for status epilepticus should be
`started without delay after the diagnosis has been es-
`tablished. This approach is supported by the correla-
`
`tion between the duration of status epilepticus and
`the extent of neurologic morbidity and by experi-
`mental and clinical observations that status epilepti-
`cus of longer duration is less responsive to drug ther-
`apy than that of shorter duration. For example, in a
`review of status epilepticus in San Francisco in the
`1980s, we found that seizures were stopped by first-
`line therapy (usually diazepam followed by phenyto-
`in) in 80 percent of patients when treatment was be-
`gun within 30 minutes of the onset of the seizures.
`16
`In contrast, the response rate was less than 40 percent
`when treatment was begun two hours or more after
`the onset of the seizures. In rats, status epilepticus be-
`comes progressively less responsive to treatment with
`diazepam as electrographic seizures continue.
`
`30
`Figure 2 is a suggested algorithm for the treat-
`ment of status epilepticus in adults and older chil-
`dren. The choice of drugs and the recommended
`sequence of administration are based on the rapid on-
`set and extended duration of the effect of lorazepam
`and the presumed value of an additional long-acting
`
`972
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`April 2, 1998
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`AQUESTIVE EXHIBIT 1101 Page 0003
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`The New England Journal of Medicine
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`Downloaded from nejm.org by DEEANN JEHNING on January 15, 2020. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`CURRENT CONCEPTS
`
`1.
`
`Lorazepam
`(0.1 mg/kg IV at 2 mg/min)
`
`Additional emergency drug therapy may not be required if seizures
`stop and the cause of status epilepticus is rapidly corrected.
`
`Seizures continuing
`
`2.
`
`Phenytoin (20 mg/kg IV at 50 mg/min) or
`fosphenytoin (20 mg/kg PE IV at 150 mg/min)
`
`Seizures continuing
`
`3.
`
`Phenytoin or fosphenytoin
`(additional 5 – 10 mg/kg or 5 – 10 mg/kg PE)
`
`Seizures continuing
`
`4.
`
`Phenobarbital
`(20 mg/kg IV at 50 – 75 mg/min)
`
`Proceed immediately to anesthesia with midazolam or
`propofol if the patient develops status epilepticus while in
`the intensive care unit, has severe systemic disturbances
`(e.g., extreme hyperthermia), or has seizures that have
`continued for more than 60 to 90 minutes.
`
`Seizures continuing
`
`5.
`
`Phenobarbital
`(additional 5 – 10 mg/kg)
`
`Seizures continuing
`
`6.
`
`Anesthesia with midazolam
`or propofol
`
`0
`
`10
`
`20
`
`30
`
`40
`Time (minutes)
`
`50
`
`60
`
`70
`
`80
`
`Figure 2.
` Antiepileptic-Drug Therapy for Status Epilepticus.
`IV denotes intravenous, and PE phenytoin equivalents. The horizontal bars indicate the approximate duration of drug infusions.
`
`drug, such as phenytoin or fosphenytoin. In a recent
`prospective, blinded clinical trial comparing loraz-
`epam alone, phenytoin alone, diazepam with pheny-
`toin, and phenobarbital alone for the treatment of
`generalized status epilepticus, the treatments were
`equally effective, except that lorazepam alone was
`superior to phenytoin alone when seizures were as-
`sessed 20 minutes after administration of the drug
`began.
` Lorazepam followed by phenytoin (i.e., the
`31
`medication sequence shown in Fig. 2) is currently
`the treatment preferred by many neurologists and
`epileptologists, but it was not studied in this trial.
`Nonetheless, the results of the study suggest that
`
`treatment with lorazepam alone may be sufficient
`and may obviate the need for intravenous phenytoin
`or fosphenytoin loading when status epilepticus is
`caused by a rapidly reversible process (e.g., the ef-
`fects of subtherapeutic antiepileptic-drug concentra-
`tions or metabolic derangement).
`PHARMACOLOGIC THERAPY
`Benzodiazepines
`Benzodiazepines (diazepam, lorazepam, midazo-
`lam, and clonazepam) are potent, fast-acting antisei-
`zure drugs, and they (particularly diazepam and
`lorazepam) are therefore preferred as initial therapy.
`
`973
`Volume 338 Number 14
`AQUESTIVE EXHIBIT 1101 Page 0004
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`ⴢ
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`The New England Journal of Medicine
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`Downloaded from nejm.org by DEEANN JEHNING on January 15, 2020. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`The New England Journal of Medicine
`
`Their primary pharmacologic actions are probably
`related to a benzodiazepine-receptor–mediated en-
`hancement of GABAergic transmission. At higher
`concentrations, benzodiazepines also limit sustained
`repetitive neuronal firing in a manner similar to that
`of carbamazepine and phenytoin, and this effect may
`be relevant to their mechanism of action in status
`epilepticus.
`
`32
`Lorazepam is less lipid-soluble than diazepam, and
`in animals, brain and cerebrospinal fluid concentra-
`tions of lorazepam rise at a slower rate than those of
` However, a
`diazepam after intravenous injection.
`33,34
`double-blind, randomized comparison of intravenous
`diazepam (10 to 20 mg) and lorazepam (4 to 8 mg)
`in patients with status epilepticus found both drugs
`to be equally fast-acting; the median time to the end
`of seizures was two minutes for diazepam and three
`minutes for lorazepam.
` Both drugs were equally
`15
`effective in controlling generalized convulsive, ab-
`sence, and partial status epilepticus (response rates,
`79 percent for diazepam and 89 percent for loraz-
`epam). Despite their equivalence as initial therapies,
`lorazepam has a longer duration of antiseizure effect
`(12 to 24 hours) than diazepam (15 to 30 minutes),
`and it is this property that has made lorazepam pref-
`erable to diazepam for the treatment of status epilep-
`ticus.
` Adverse effects of intravenous benzodiazepines
`4
`include respiratory depression (in 3 to 10 percent of
`2 percent), and impaired
`patients), hypotension (in
`⬍
`consciousness (in 20 to 60 percent).
`
`15,35,36
`
`Phenytoin and Fosphenytoin
`Phenytoin is useful for maintaining a prolonged
`antiseizure effect after rapid termination of seizures
`with a benzodiazepine, as an initial therapy for ter-
`minating status epilepticus, or when benzodiaz-
`epines fail. The recommended starting dose is 20
`mg per kilogram administered intravenously at a
`maximal rate of 50 mg per minute. The common
`practice of giving a standard loading dose of 1000
`mg of phenytoin (14.3 mg per kilogram for a pa-
`tient weighing 70 kg) provides inadequate therapy
`for many adults.
` As much as 30 mg per kilogram
`37
`may be required to stop seizures in some patients.
`37
`This dose may be reduced in patients known to have
`a serum phenytoin concentration of more than 10
`mg per liter at the onset of status epilepticus. How-
`ever, therapy should not be delayed to measure se-
`rum drug concentrations.
`Brain concentrations of phenytoin are nearly max-
`imal at the end of an intravenous infusion.
` Thus, it
`38
`may take 20 to 25 minutes for phenytoin to attain
`its maximal effect when a typical loading dose is giv-
`en to an adult.
` When phenytoin is administered at
`39
`the maximal recommended rate of 50 mg per
`minute, hypotension occurs in 28 to 50 percent of
`patients, and cardiac arrhythmias (bradycardia and
` These adverse
`ectopic beats) occur in 2 percent.
`39,40
`
`974
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`ⴢ
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`April 2, 1998
`
`effects are more common in patients over 50 years
`old and those with preexisting cardiac disease. Car-
`diovascular complications of intravenous phenytoin,
`which are due to the phenytoin itself and to the pro-
`pylene glycol diluent, can be mitigated by slowing or
`stopping the infusion.
`
`40
`Fosphenytoin, a new water-soluble prodrug of
`phenytoin, is converted to phenytoin (half-life, 15
`minutes) by nonspecific phosphatases. Doses of fos-
`phenytoin are expressed as phenytoin equivalents,
`which are the amounts of phenytoin released from
`the prodrug in the presence of phosphatases. Fos-
`phenytoin can be administered at phenytoin-equiva-
`lent rates of up to 150 mg per minute, since it is not
`formulated with propylene glycol. Therapeutic se-
`1 mg per liter
`rum concentrations of phenytoin (
`⭓
`unbound) are attained within 10 minutes when fos-
`phenytoin or phenytoin is administered at maximal
`infusion rates. Thus, fosphenytoin and phenytoin are
`likely to have a similar time to the onset of an effect
` No clinically sig-
`in controlling status epilepticus.
`41
`nificant differences between the hypotensive or ad-
`verse cardiac effects of phenytoin loading and those
`of fosphenytoin loading have been reported, al-
`though infusion-site reactions (phlebitis and soft-tis-
`sue damage) are less common with fosphenytoin.
`
`Phenobarbital
`In a small, randomized study, phenobarbital was
`as effective as the combination of diazepam and
`phenytoin for the treatment of status epilepticus.
`42
`However, the depressant effects of phenobarbital on
`respiratory drive, level of consciousness, and blood
`pressure may complicate management, especially when
`phenobarbital is administered after a benzodiaz-
` For these reasons, phenobarbital (20 mg per
`epine.
`43
`kilogram at a rate of 50 to 75 mg per minute) is rec-
`ommended only when benzodiazepines and pheny-
`toin fail. Respiratory and blood-pressure support
`must be immediately available.
`
`Other Therapies
`Intravenous valproic acid, recently marketed in
`the United States as an alternative to oral therapy,
`appears to stop some types of status epilepticus.
`44
`However, further experience is needed before this
`therapy can be recommended. Lidocaine, chlor-
`methiazole (outside the United States), and paralde-
`hyde (the availability of which is limited in the Unit-
`ed States) have been used successfully to terminate
`status epilepticus.
` Each has substantial toxicity, and
`45
`they offer little or no advantage over the therapies
`previously discussed.
`
`Treatment of Refractory Status Epilepticus
`Status epilepticus that does not respond to a benzo-
`diazepine, phenytoin, or phenobarbital is considered
`refractory and requires more aggressive treatment.
`
`AQUESTIVE EXHIBIT 1101 Page 0005
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`Downloaded from nejm.org by DEEANN JEHNING on January 15, 2020. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`CURRENT CONCEPTS
`
`Continuous intravenous infusions with anesthetic
`doses of midazolam, propofol, or barbiturates are
`the most useful treatments. A team approach to pa-
`tient care, including the participation of an experi-
`enced neurologist and an intensivist, is often useful
`because of the need for higher-level neurologic and
`cardiovascular monitoring and ventilatory support.
`The use of midazolam (0.2 mg per kilogram ad-
`ministered by slow intravenous bolus injection, fol-
`lowed by 0.75 to 10
`g per kilogram per minute)
`m
`or propofol administered intravenously (1 to 2 mg
`per kilogram, followed by 2 to 10 mg per kilogram
`per hour) to induce anesthesia for the treatment of
`refractory status epilepticus (Table 1) has become
`very popular in recent years. Both drugs have the
`substantial advantage over barbiturates of rapid
`clearance, and midazolam has less pronounced hy-
` The infusion is typically main-
`potensive effects.
`46-49
`tained for 12 to 24 hours and is then withdrawn
`gradually while the patient is observed for clinical or
`electrographic evidence of seizure recurrence. If sei-
`zures continue, the therapy should be resumed for
`progressively longer periods, as needed. Midazolam
`may be associated with tachyphylaxis, leading to the
`need for exceedingly high doses. Seizures have been
`observed during the induction of anesthesia with
`propofol and emergence from it, but the importance
`of these proconvulsant effects in the management of
`status epilepticus is unknown.
`Thiopental and pentobarbital are potent antisei-
`zure drugs that have potential, though unproved,
`cerebral protective effects in the management of sta-
`tus epilepticus. In adequate doses these drugs will al-
`most always control seizures, but severe hypotension
`requiring pressor therapy limits their safety.
` We
`5,50
`therefore prefer to reserve anesthesia with barbitu-
`rates for patients in whom midazolam or propofol
`fails. Thiopental has pharmacokinetic disadvantages,
`including saturable metabolism, an active metabolite
`(pentobarbital), and the fact that it accumulates in
`lipoid tissues during prolonged infusions, with re-
`sultant delays in postinfusion recovery.
` Pentobarbi-
`5
`tal (10 to 15 mg per kilogram administered intrave-
`nously over a period of one hour, followed by a dose
`of 0.5 to 1 mg per kilogram per hour) is highly ef-
`fective, but cardiovascular toxicity is occasionally
`life-threatening and postinfusion weakness may de-
`
`lay weaning from ventilatory support.
`37,47
`
`OUT-OF-HOSPITAL TREATMENT
`Status epilepticus frequently occurs outside the
`hospital in situations in which treatment with intra-
`venous medications is not feasible or in which there
`are inadequate resources to manage the potential
`complications of intravenous therapy. Rectal and in-
`tramuscular routes of drug administration may be
`useful in these settings. Intramuscular midazolam is
`rapidly absorbed (mean time to peak serum concen-
`
` P
`
`
` T
`
` R
` S
`
`T
` 1.
`ROTOCOL
`FOR
`THE
`REATMENT
`OF
`EFRACTORY
`TATUS
`ABLE
`E
`
` E
` M
`
` P
`.
`PILEPTICUS
`WITH
`ITHER
`IDAZOLAM
`OR
`ROPOFOL
`
`1. Intubate and ventilate patient; admit to intensive care unit.
`2. Place electroencephalographic monitor.
`3. Place arterial catheter and central catheters if indicated.
`4. Administer either midazolam at a loading dose of 0.2 mg per kilogram
`(slow intravenous bolus), then at a dose of 0.75 to 10
`g per kilogram
`m
`per minute; or propofol at a dose of 1 to 2 mg per kilogram intravenous-
`ly, followed by a dose of 2 to 10 mg per kilogram per hour. Adjust main-
`tenance dose on the basis of electroencephalographic-monitoring results.
`Continue electroencephalographic monitoring throughout therapy —
`i.e., check hourly once patient achieves a stable response to the selected
`drug. Primary end point for therapy is suppression of electroencephalo-
`graphic spikes. If blood pressure is adequate, secondary end point is
`burst-suppression pattern with short intervals between bursts (i.e.,
`1 second).
`⬍
`5. Continue maintenance doses of phenytoin and phenobarbital; track con-
`centrations to determine optimal doses.
`6. Use intravenous fluids and low-dose dopamine to treat hypotension. If
`necessary, add low-dose dobutamine. Decrease dosage of midazolam or
`propofol if there are any signs of cardiovascular compromise.
`7. Taper infusion at 12 hours to observe for further seizure activity. If sei-
`zures recur, reinstate infusion in intervals of at least 12 hours.
`
`tration, 25 minutes), and limited experience in both
`children and adults suggests that serial seizures and
`status epilepticus are usually terminated within 10
` The usual dosage is
`minutes of administration.
`51-53
`0.15 to 0.3 mg per kilogram. Rectal administration
`of a parenteral solution of 0.5 mg of diazepam per
`kilogram (maximal dose, 20 mg) is approximately
`80 percent effective in controlling prolonged sei-
`zures in children, usually within 15 minutes.
` A gel
`54
`formulation of diazepam in a prefilled syringe for
`rectal administration (Diastat, Athena Neurosciences,
`South San Francisco, Calif.) has recently become
`available in the United States for the treatment of
`seizure clusters in children and adults. Rectal ad-
`ministration of diazepam gel may be useful for
`out-of-hospital management of status epilepticus.
`However, the onset of the antiseizure effect of the
`gel formulation requires further study.
`
`55
`In many emergency-medical-service systems, in-
`travenous benzodiazepine therapy is administered by
`paramedics to patients with status epilepticus, with
`the presumption that initiating therapy before pa-
`tients arrive at the emergency department will im-
`prove outcomes. Retrospective studies in adults and
`children suggest that prehospital therapy shortens the
`duration of status epilepticus and simplifies subse-
`quent management in the emergency department.
`56,57
`Nonetheless, this approach has not been studied
`prospectively, and the relative risks and benefits re-
`main unknown.
`
`Supported by a grant (R01 31403) from the National Institutes of
`Health.
`
`975
`Volume 338 Number 14
`AQUESTIVE EXHIBIT 1101 Page 0006
`
`ⴢ
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org by DEEANN JEHNING on January 15, 2020. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`

`

`The New England Journal of Medicine
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