Antiepileptic Drugs, 5th Edition

General Principles

14

Treatment of Status Epilepticus

Brian K. Alldredge PharmD

Professor, Department of Clinical Pharmacy and Neurology, University of California, San Francisco, San Francisco, California

Generalized convulsive status epilepticus is the most life-threatening manifestation of an acute seizure episode. It is precipitated by a wide range of medical and neurologic conditions and represents the failure of normal neuronal mechanisms that limit typical convulsive seizures (1).

Population-based studies indicate that 102,000 to 152,000 cases of status epilepticus occur in the United States each year. The annual incidence is 41 to 61 per 100,000 persons and is highest during the first year of life and after the age of 60 years. The overall 30-day mortality rate after status epilepticus is 22%, with an estimated 22,200 to 42,000 deaths each year in the United States. The mortality rate in children is 3%, and is significantly lower than the 26% mortality rate in adults (2).

Historically, most clinical studies have defined status epilepticus as 30 minutes of either continuous seizures or repeated seizures without full recovery of consciousness. However, it is widely acknowledged that aggressive treatment should begin much earlier. Most secondarily generalized seizures in adults end within 2 minutes of onset (3), and in children seizures that last longer than 5 minutes are unlikely to stop spontaneously (4). Recently, an operational definition of status epilepticus as “≥5 minutes of (a) continuous seizures or (b) two or more discrete seizures between which there is incomplete recovery of consciousness” has been proposed (1,5), and has been used in one prospective study of out-of-hospital treatment (6).

Patient outcome after an episode of status epilepticus is affected by the interaction between several factors, including (a) age of the patient, (b) the etiology of acute seizures, (c) prolonged duration of seizures, and (d) concomitant physiologic disturbances (5,7).

This chapter focuses on the drug treatment of generalized convulsive status epilepticus in both hospital and non-hospital settings. Detailed discussions of the causes, clinical features, pathophysiology, and general medical management of status epilepticus are available in other reviews (5,8,9) and in a definitive text by Shorvon (10).

PRINCIPLES OF DRUG TREATMENT

The primary goal of drug treatment for status epilepticus is rapid cessation of seizures. Termination of the somatic manifestations of seizures alone is not sufficient; effective therapy must terminate both clinical and electrical seizure activity. In choosing drugs to treat status epilepticus, factors that should be considered include (a) the latency from beginning drug administration to the onset of clinical efficacy, (b) the duration of the clinical antiseizure effect, and (c) the effect of treatment on consciousness and cardiorespiratory function. Intravenous drug administration is preferred when treatment is administered by medical personnel and adequate support measures are available to manage the medical complications from ongoing seizures and their treatment.

A variety of pharmacokinetic and pharmacodynamic factors influence the clinical utility of drugs used for status epilepticus. The entry of most drugs and xenobiotics into the brain is limited by endothelial tight junctions that constitute the blood-brain barrier. Most drugs that have a rapid onset of clinical antiseizure effect are highly lipophilic compounds that reach peak brain concentrations quickly after intravenous administration. Carrier-mediated transport mechanisms also may play a role in enhancing the efficiency of brain entry, particularly for hydrophilic compounds (11). For highly lipophilic drugs such as benzodiazepines, the duration of antiseizure effect is largely affected by the rate and extent of drug movement out of brain tissue. These agents redistribute into other peripheral compartments (primarily lipoid tissues), resulting in a decline in brain and blood concentrations that is largely independent of drug elimination by the processes of metabolism and excretion. The biphasic decline in plasma drug concentration versus time for these drugs can be described by a two-compartment model (Figure 14.1). The first phase primarily represents distribution of drug from the central compartment (blood

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and brain for many lipophilic drugs) to various tissues representing a peripheral compartment. The second phase represents drug elimination by metabolism and excretion.

 

FIGURE 14.1. Simulated plasma drug concentration versus time relationships (semilogarithmic) from a two-compartment pharmacokinetic model after intravenous administration. Co is the peak concentration in plasma (or in the “central compartment”). B is the zero-order intercept of the elimination phase of the plasma concentration curve when extrapolated back to time zero. For highly lipophilic drugs, the initial phase primarily represents the distribution of drug from brain and blood to various body tissues. Note that this initial decline in plasma concentration may be sufficient to terminate clinical activity if the plasma level falls below some minimum effective concentration (MEC). The second phase represents elimination by metabolism or excretion. (Reprinted from Greenblatt DJ, Shader RI. Pharmacokinetics in clinical practice.Philadelphia: WB Saunders, 1985, with permission.)

Once the diagnosis of status epilepticus is established, appropriate antiepileptic drug treatment should begin immediately. Both experimental and clinical evidence support this approach. Meldrum and Brierley demonstrated that irreversible brain injury was more likely in freely convulsing baboons when seizures lasted longer than 80 minutes (12). Physiologic complications from prolonged seizures (e.g., hyperthermia and hypotension) potentiated this damage (12). Numerous clinical reports also support a correlation between increased duration of status epilepticus and neurologic sequelae in patients (7,13, 14, 15). Another advantage of early intervention is that status epilepticus is more likely to respond to drug treatment when therapy is initiated as soon as possible. In the lithium-pilocarpine model of status epilepticus in rats, Walton and Treiman found that diazepam was progressively less effective in terminating seizures as the duration of seizures lengthened (16). Clinical evidence in support of this observation was found in a study in which the response of status epilepticus to initial treatment (usually diazepam followed by phenytoin) declined from 80% in those patients whose treatment began within 30 minutes of the onset of seizures, to less than 40% when treatment was initiated 2 hours or longer after seizures began (14) (Figure 14.2).

 

FIGURE 14.2. Relationship between duration of status epilepticus before administration of antiepileptic drugs and response to first-line therapy (usually, diazepam followed by phenytoin). Numbers in the bars refer to the total number of patients in each duration group. (Reprinted from Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:483-488, with permission.)

ANTIEPILEPTIC DRUG THERAPIES

Benzodiazepines

Benzodiazepines are widely preferred as initial antiepileptic drug therapy for status epilepticus because they are potent and have a rapid onset of effect. The most commonly used agents are lorazepam and diazepam (5,9,17). Clonazepam also is effective as initial therapy, although this author knows of no prospective, controlled comparisons with other benzodiazepines. The intravenous preparation of clonazepam is not available for use in the United States. Midazolam has been used as initial therapy for status epilepticus (18); however, the primary utility of this agent is related to its rapid absorption after nonintravenous routes of administration (see section on Out-of-Hospital Treatment). The antiseizure effect of these agents is related to allosteric interaction with the benzodiazepine binding site on the γ-aminobutyric

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acid, subtype A (GABAA) receptor, resulting in enhanced GABA-mediated neuronal inhibition. Pharmacokinetic features of benzodiazepines that are relevant to their use in status epilepticus are summarized in Table 14.1. The primary adverse effects of intravenous benzodiazepines are respiratory depression (3% to 11% of patients) and impaired consciousness (20% to 60%) (6,19,20). Hypotension and cardiac dysrhythmias are uncommon.

TABLE 14.1. PHARMACOKINETIC FEATURES OF BENZODIAZEPINES USED FOR STATUS EPILEPTICUS

 

Lorazepam

Diazepam

Midazolam

Clonazepam

Protein binding (%)

90

97

96

86

Distribution half-life (hr)

2-3

0.3

0.06

0.5

Primary elimination route

glucuronidation

demethylation oxidation

oxidation

nitro reduction acetylation

Elimination half-life (hr)

8-25

28-54

2-4

20-60

Active metabolites

none

N-desmethyldiazepam oxazepam

α-hydroxymidazolam

none

hr, hour.

Lorazepam has a longer distribution half-life than other benzodiazepines, indicating a slower rate of egress from blood and brain to peripheral tissues. It is this property that is likely responsible for the prolonged duration of action of lorazepam (12 to 24 hours) (5). Although lorazepam is less lipophilic than diazepam and has been shown to reach peak brain and cerebrospinal fluid concentrations more slowly than diazepam in animals (21,22), randomized, comparative studies show the two drugs to have a similar onset of clinical antiseizure effect (6,20). Two prospective, doubleblind studies have compared lorazepam 4 mg and diazepam 10 mg (both administered intravenously) as initial in-hospital treatment of status epilepticus in adults. In both studies, if the first injection was not effective, a repeat dose was given. Status epilepticus was terminated in 89% to 91% of patients given lorazepam and 76% to 84% of patients given diazepam. These differences were not statistically significant (20,23). Because lorazepam has a longer duration of action than diazepam and the two agents do not differ with regard to onset of effect and efficacy in status epilepticus, recent treatment paradigms recommend lorazepam over diazepam as initial treatment (5,17).

As discussed, diazepam is highly effective for termination of status epilepticus. However, its utility is limited by a short duration of antiseizure effect. This is related to the short residence time of the drug in brain tissue (24,25). Ramsay and colleagues studied the concentrations of diazepam in brain and plasma after intravenous administration to cats (26). As shown in Figure 14.3, peak brain and plasma concentrations of diazepam were attained within 1 minute. Thereafter, brain and plasma concentrations declined in parallel. At 45 minutes postinjection, plasma diazepam levels had declined to less than 200 ng/mL, a concentration that has been associated with clinical efficacy in status epilepticus (26). This observation is consistent with clinical reports. Peak plasma concentrations of diazepam decline by 50% within 20 minutes of intravenous administration in humans (27). Also, as much as 47% to 50% of patients treated with intravenous diazepam experience early breakthrough seizures after initial cessation of status epilepticus (28,29).

 

FIGURE 14.3. Brain concentrations (upper panel), plasma concentrations (lower panel), and brain/plasma concentration ratios (middle panel) of diazepam after intravenous administration to cats. Concentration values are means and standard deviations. (Reprinted from Ramsay RE, Hammond EJ, Perchalski RJ, et al. Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol 1979;36:535-539, with permission.)

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Phenytoin and Fosphenytoin

Phenytoin is effective for the termination of status epilepticus, but its utility as initial therapy is limited by the slow rate of drug administration and the attendant delay in attaining maximal antiseizure effect. For this reason, phenytoin most often is administered after a benzodiazepine. In this regard, phenytoin is useful for maintenance of a long-lasting antiseizure effect, and it may effectively terminate status epilepticus when a benzodiazepine fails.

The usual intravenous loading dose of phenytoin is 20 mg/kg. This dosage should be reduced in the elderly (to 15 mg/kg) and in patients who have a baseline phenytoin level of 10 mg/L or more (5,9). If the initial loading dose of phenytoin is ineffective, an additional 5 to 10 mg/kg may be given. Phenytoin should be administered at a maximal rate of 50 mg/min. Peak brain concentrations are attained at the end of an intravenous infusion (30). Thus, a delay in maximal antiseizure effect of approximately 30 minutes can be expected when intravenous phenytoin is administered to an adult of average size. In a randomized comparison of four treatment regimens, Treiman and colleagues found that phenytoin 18 mg/kg was less effective than lorazepam 0.1 mg/kg as initial therapy for patients with overt (clinically evident) generalized convulsive status epilepticus (43.6% and 64.9% response rates, respectively; p = .002). Efficacy was initially assessed 20 minutes after beginning the drug infusions (31). The slower administration rate for phenytoin (mean infusion time, 33 minutes) may account for the inferior response rate.

Hypotension is a common adverse effect during intravenous infusion of phenytoin. The risk is highest in elderly patients and in those with preexisting cardiac disease, and when administration rates exceed 50 mg/min (32). Cardiac arrhythmias also may occur. Under these circumstances, slowing or stopping the infusion is recommended. Phenytoin is less likely to depress consciousness than benzodiazepines or phenobarbital.

Fosphenytoin is a phosphate ester prodrug of phenytoin with several potential advantages. Unlike parenteral phenytoin solution, fosphenytoin is water soluble (and compatible with all common intravenous solutions) and does not require a propylene glycol diluent or adjustment to alkaline pH. For these reasons, fosphenytoin causes fewer local injection site reactions and it can be administered at a faster rate than intravenous phenytoin. Conversion to phenytoin occurs with a half-life of 15 minutes and is catalyzed by nonspecific phosphatases that are ubiquitous in blood and body tissues. At recommended infusion rates, both phenytoin and fosphenytoin yield therapeutic unbound phenytoin concentrations (1 mg/mL) in blood within 10 minutes after beginning the infusion (33). Thus, the lag time in fosphenytoin conversion to phenytoin is overcome by a more rapid administration rate. In an open-label study, fosphenytoin was safe and well tolerated in the treatment of status epilepticus (34). Walton and colleagues compared fosphenytoin and phenytoin administered to nonconvulsing rats and found lower initial brain concentrations of phenytoin immediately after the end of the fosphenytoin infusion (35). The significance of this finding in humans is unknown because no studies have been conducted to compare the two drugs. Doses of fosphenytoin are expressed in terms of the milligrams of phenytoin that are yielded after cleavage of the phosphate ester bond. Thus, administering a dose of 1,000 mg phenytoin equivalents (PE) of fosphenytoin is equivalent to administration of 1,000 mg of phenytoin. The recommended dose of fosphenytoin for status epilepticus is 20 mg/kg PE and the maximal infusion rate is 150 mg/min PE. If ineffective, a supplemental dose of 5 to 10 mg/kg PE fosphenytoin may be given.

Phenobarbital

Phenobarbital has been shown to be effective as initial therapy for status epilepticus in two randomized trials. Shaner and colleagues compared phenobarbital (infusion rate, 100 mg/min) with simultaneous treatment with diazepam and phenytoin (infusion rates, 2 mg/min and 50 mg/min, respectively), and found phenobarbital-treated patients to have a shorter latency from initiation of treatment to cessation of seizures (36). In the randomized, blinded trial of Treiman et al., phenobarbital (100 mg/min) stopped overt status epilepticus in 58.2% of patients. In this study, phenobarbital was equivalent to other treatments (lorazepam, phenytoin alone, or diazepam followed by phenytoin) with regard to efficacy and safety end points (31). Loading doses of phenobarbital can cause significant depression of consciousness. Also, hypotension and respiratory depression are more common when phenobarbital is combined with a benzodiazepine (37). For these reasons, phenobarbital most often is reserved for patients who fail to respond to a benzodiazepine and phenytoin. In this setting, the recommended dose of phenobarbital is 20 mg/kg, and support measures for respiration and blood pressure should be readily available (9).

Valproate

Experience with intravenous valproate for the treatment of status epilepticus has increased despite lack of formal approval by the U.S. Food and Drug Administration and recommendation only for slow intravenous administration (20 mg/min). Loading doses of 21 to 28 mg/kg valproate given intravenously result in a mean postinfusion serum concentration of 133 mg/L (range, 64 to 204 mg/L) (38). Infusion rates of 200 mg/min in adults and 3 mg/kg/min in children are safe and well tolerated (39,40).

Open-label experience has shown valproate to be effective in both adults and children with various types of status epilepticus (i.e., generalized convulsive, partial, and generalized

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nonconvulsive status epilepticus) (41, 42, 43, 44). The circumstances of valproate use vary widely in these reports from administration as initial therapy (43) to treatment after the failure of benzodiazepines, phenytoin, and barbiturates (44). In addition, a variety of dosing regimens were used and widely variable response rates (30-83%) are reported. No controlled clinical trials have compared valproate with other therapies for status epilepticus. Thus, the preferred place of valproate in an overall approach to management is unknown. Based on available evidence, the recommended loading dose of valproate for status epilepticus in adults and children is 20 to 25 mg/kg (diluted 1:1 with D5W) administered at 3 to 6 mg/kg/min (up to 200 mg/min).

Apparent advantages of intravenous valproate include minimal effects on level of consciousness and cardiorespiratory function. Hypotension has been reported with intravenous valproate in the treatment of status epilepticus (45), but it appears to be uncommon. Sinha and Naritoku reported the successful administration of intravenous loading doses of valproate to 13 adult (primarily elderly) patients with medically refractory status epilepticus and cardiovascular instability. Most patients required vasopressive agents for blood pressure support before treatment with valproate. No significant changes in blood pressure, pulse, or vasopressor use were reported with valproate infusion rates of 6 to 100 mg/min (46).

Other Therapies

Alternative therapies that have been used for in-hospital management of status epilepticus include lidocaine, paraldehyde, and chlormethiazole. Although effective, these agents have not been shown to be more efficacious or safer than the treatments discussed previously. In small case series, intravenous lidocaine 1 to 3 mg/kg (usually followed by a maintenance infusion) has been effective for terminating status epilepticus refractory to other agents (47). Some authors suggest that lidocaine may have a unique role in the treatment of status epilepticus in neonates and in patients with respiratory disease (48, 49, 50). Chlormethiazole is used in the United Kingdom, Europe, and Australia, but is not approved in the United States. The recommended dose in adults is 320 to 820 mg (40 to 100 mL of a 0.8% solution) given at a rate of 5 to 15 mL/min, followed by a continuous infusion of 0.5 to 1 mL/min titrated upward according to response (10). A continuous infusion is necessary because of the short distribution half-life. Chlormethiazole causes sedation and respiratory depression that is potentiated by benzodiazepines and barbiturates. Paraldehyde can be given by rectal and intramuscular routes for the treatment of status epilepticus. Historically, the drug has been useful for the treatment of acute alcohol-related seizures and for patients in whom intravenous access is not feasible. Its use is limited by foul odor, lack of widespread availability, and requirements for light-protected storage and use with glass syringes (10).

Refractory Status Epilepticus

Status epilepticus fails to respond to standard treatment with benzodiazepines, phenytoin, and barbiturates in 10% to 15% of patients (14). These patients are at increased risk for permanent neurologic damage and death from prolonged electrical seizure activity and from severe physiologic complications associated with both seizures and intensive drug therapies (51). Mortality rates for refractory status epilepticus range from 32% to 77% (52). Definitive therapy with high-dose midazolam, barbiturates (usually pentobarbital), or propofol usually is necessary. These therapies also should be considered for patients at earlier stages of treatment if status epilepticus has been ongoing for 60 to 90 minutes or longer. Patients should be managed in an intensive care unit during treatment because ventilatory assistance and hemodynamic support usually are required.

The optimal treatment for refractory status epilepticus has not been defined. The number of patients who have been treated with midazolam, pentobarbital, and propofol in this setting is relatively small, and no randomized, controlled comparisons of treatments have been conducted. In adults, midazolam usually is administered as a single dose of 0.2 mg/kg by slow intravenous injection, followed by a continuous infusion of 0.075 to 10 µg/kg/min (53). Midazolam is highly effective for initial control of refractory status epilepticus; however, tachyphylaxis and breakthrough seizures are detected in approximately 50% of patients during continuous electroencephalographic (EEG) monitoring (54). Escalation of the midazolam infusion rate often is necessary. With prolonged, high-dose therapy, the half-life of midazolam is significantly prolonged owing to accumulation in peripheral tissues. This may lead to unexpected delays in the return of consciousness and spontaneous respiration during gradual withdrawal of midazolam (55).

The recommended dose of propofol is 1 to 2 mg/kg, followed by a maintenance infusion of 2 to 10 mg/kg/hr. Rates of successful treatment with propofol are similar to those with high-dose midazolam (52,56). However, in one retrospective comparison, the overall mortality rate was higher in propofol-treated patients (8 of 14 patients; 57%) than in those who received midazolam (1 of 6 patients; 17%) (52). Another retrospective study of propofol for refractory status epilepticus reported a higher mortality rate with this agent (7 of 8 patients; 88%) compared with patients treated with pentobarbital (4 of 8 patients; 50%) (56). In neither study was the mortality rate with propofol significantly higher than with the comparison treatment.

Pentobarbital is highly effective for control of refractory status epilepticus. However, myocardial depression, hypotension, and delayed postinfusion respiratory recovery are limitations (51,57,58). Nonetheless, there is no clear

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evidence for significant differences between pentobarbital and other therapies with regard to overall mortality. The recommended dose of pentobarbital is 10 to 15 mg/kg administered intravenously over 1 hour, followed by a continuous infusion of 0.5 to 1 mg/kg/hr.

For all of the aforementioned therapies, dosages should be adjusted to suppression of all electrographic seizures. Intravenous fluids and vasopressive agents may be required to treat hypotension. Once seizures have been controlled for 12 to 24 hours, therapy should be gradually weaned. Continuous EEG monitoring is required during high-dose treatment and while therapy is gradually withdrawn.

OUT-OF-HOSPITAL TREATMENT

Traditionally, status epilepticus has been managed in hospitals and emergency departments using drugs administered by the intravenous route. However, status epilepticus often occurs outside of the hospital. In a review of 804 paramedic encounters for seizures over a 3-month period in San Francisco, 117 (14%) were for multiple seizures or status epilepticus (59). Given the demonstrated value of early intervention in seizure emergencies, there is interest in developing and evaluating out-of-hospital therapies to stop status epilepticus or to prevent the evolution of acute seizure events into a more prolonged seizure state.

Prehospital Therapy

Recently, many emergency medical services (EMS) systems have adopted the practice of paramedic administration of benzodiazepines for out-of-hospital status epilepticus. Diazepam is the drug of choice in most EMS systems, and patients usually are transported to an emergency department for further evaluation and treatment. Despite the intuitive appeal of this approach, the equipment and consultant resources available to paramedics in the field differ significantly from those in hospitals. This may affect the management of status epilepticus, related physiologic complications, and adverse effects from medical treatment in a way that alters the balance between efficacy and safety (60,61).

The value of paramedic treatment for out-of-hospital status epilepticus was studied in a randomized, doubleblind clinical trial (6). Adults with repeated or continuous seizures for more than 5 minutes were treated with either lorazepam 2 mg, diazepam 5 mg, or placebo by slow intravenous injection. An identical dose was given if seizures persisted. Patients received active antiepileptic drug therapy at the discretion of the treating physician when they arrived at a hospital. The primary outcome variable was termination of status epilepticus by the time the patient arrived at an emergency department. Response rates were 59.1% for lorazepam, 42.6% for diazepam, and 21.1% for placebo. With adjustment for covariates (cause of status epilepticus, time interval from status epilepticus onset to study treatment, and time interval from treatment to emergency department arrival), lorazepam and diazepam were more effective than placebo. The trend favoring lorazepam over diazepam did not reach statistical significance. Out-of-hospital respiratory or circulatory complications occurred in 10.6% of lorazepam-treated patients, 10.3% in the diazepam group, and 22.5% in the placebo group (p = .08). The rates of cardiorespiratory complications that persisted to the time of emergency department arrival were approximately 50% of those in the field, suggesting that paramedics effectively managed these conditions. The three treatment groups did not differ with regard to neurologic outcome or mortality rates. A practical issue regarding the use of lorazepam in this setting is that the drug is heat labile and requires frequent restocking or refrigerated storage on ambulances in warm climates (62).

Despite the demonstrated value of paramedic drug treatment with benzodiazepines for out-of-hospital status epilepticus, many patients in the aforementioned trial did not respond to treatment. Intensive medical care was required in 73% of patients who continued in status epilepticus until emergency department arrival, and in 32% of those whose seizures ended. Thus, further study is required to identify more effective drugs or treatment regimens for this condition. Experience with the management of children with out-of-hospital status epilepticus is limited. Paramedic administration of intravenous or rectal diazepam significantly shortens the total duration of status epilepticus (63). However, one small case series of children treated with intravenous diazepam by paramedics found an unacceptably high rate of respiratory depression and intubationrelated complications (64).

Alternate Routes of Drug Administration

Drugs and drug products available for administration by nonintravenous routes also are available for the out-of-hospital management of patients with seizure emergencies. Benzodiazepine antiseizure agents are most useful in this regard because they are potent, can be administered in small volumes, and are rapidly absorbed when the appropriate drug/route combination is chosen. Agents that are effective after transmucosal administration can be given by family members and caregivers after these individuals are properly trained. These therapies also may be considered by medical and paramedical personnel as treatment options for patients in whom venous access is unavailable. Throughout the following discussion, it should be kept in mind that none of these treatments is approved for the treatment of status epilepticus and that most published experience is in patients with prolonged or repetitive seizures who have not met defined criteria for status epilepticus.

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Rectal Administration

Diazepam is rapidly and reliably absorbed after rectal administration. Bioavailability is 80% to 100% and peak drug concentration are attained within 30 minutes of rectal administration of the parenteral solution to children (65, 66, 67). A gel formulation of diazepam (Diastat) also is available for rectal use, and it has the advantages of improved retention characteristics and availability in premeasured doses in an applicator with a flexible plastic tip. Rectal diazepam has been reported to be effective for acute repetitive seizures, prolonged seizures, and status epilepticus (68, 69, 70, 71). Clinical effect is evident approximately 15 minutes after administration. The recommended dose of diazepam for rectal administration is 0.5 mg/kg for children younger than 6 years of age, 0.3 mg/kg for children 6 to 12 years of age, and 0.2 mg/kg for patients 12 years of age or older. Somnolence, ataxia, and incoordination occur occasionally after treatment. Respiratory depression is rare even when recommended doses are exceeded (67,72). Lorazepam and midazolam are not recommended for rectal administration because of unreliable absorption (73,74).

Intranasal Administration

Intranasal administration of midazolam for acute seizures has gained popularity, particularly for children. The nasal mucosa is highly vascularized, which aids in drug absorption. However, the volume of drug that can be administered without being swallowed is small, approximately 0.5 mL per nostril. Peak concentrations of midazolam occur within 12 minutes after administration to children, and the estimated bioavailability is 55% (75). Oral bioavailability is 15% to 27%; therefore, drug that is swallowed will likely contribute little to the clinical effect (73). When administered to 20 children with prolonged generalized seizures, intranasal midazolam was effective in all patients within 5 minutes (76). Adolescents and adults have been effectively treated despite the large volume of medication required (77). A recent randomized comparison of intravenous diazepam and intranasal midazolam for prolonged febrile seizures in children demonstrated potential advantages for midazolam. The mean time from arrival at the hospital to cessation of seizures was shorter in patients treated with midazolam (6.1 minutes; 95% confidence interval, 6.3 to 6.7 minutes) than in patients treated with intravenous diazepam (8.0 minutes; 95% confidence interval, 7.9 to 8.3 minutes) (78). The recommended dose of intranasal midazolam is 0.2 mg/kg, with half the dose administered in each nostril. The parenteral solution should be used, but it can cause local irritation and tastes bitter (75).

Buccal Administration

In healthy volunteers, midazolam is 75% bioavailable after buccal administration, and peak plasma concentrations occur within 30 minutes (79). The pharmacodynamic effect of midazolam appears even more quickly. Scott and colleagues reported changes in the 8- to 30-Hz frequencies on the EEG within 5 to 10 minutes after buccal administration of midazolam to nonepileptic subjects (80). The clinical efficacy of buccal administration of the parenteral midazolam solution also has been demonstrated. In a nonblinded, randomized comparison in 42 patients, buccal midazolam stopped prolonged seizures in 75% of episodes, compared with a 59% response with rectal diazepam (p = .16) (81). The recommended dose of buccal midazolam is 0.2 mg/kg. Treatment is administered by parting the lips of the patient and squirting the solution between the cheek and gingiva. This route is advantageous over intranasal administration because the volume of drug need not be restricted. However, studies comparing the two routes have not been conducted. Both intranasal and buccal administration have advantages over rectal treatment with regard to ease of access and greater social acceptability.

Intramuscular Administration

Of the benzodiazepines available for intramuscular administration, midazolam is absorbed most rapidly. Peak plasma concentrations occur within 30 minutes and bioavailability is 90% (82). Suppression of interictal spikes in people with epilepsy is evident within 5 minutes of intramuscular administration (83).

In open-label use, intramuscular midazolam is effective for terminating status epilepticus in adults and children (84, 85, 86). Chamberlain and colleagues randomly assigned children with status epilepticus to intramuscular midazolam or intravenous diazepam and found both treatments to be equally effective for terminating seizures within 10 minutes of administration (overall, 92% response) (86). When the two treatments were compared with regard to time from patient arrival in the emergency department to cessation of seizures, midazolam was superior to diazepam (7.8 versus 11.2 minutes, respectively; p = .047) (86). Respiratory depression after intramuscular midazolam is rare, but has been reported (87). The recommended dose of intramuscular midazolam is 0.2 mg/kg.

SUMMARY

Status epilepticus is a neurologic emergency that requires prompt recognition and aggressive drug treatment. An organized, systematic approach to drug selection and administration results in more rapid control of seizures (88). Figure 14.4 gives a recommended approach to drug treatment. A comparable sequence of treatment and dosages may be used for status epilepticus in children. However, drug administration rates should be appropriately

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adjusted (89). When status epilepticus occurs outside of the hospital, several treatment options are available. Paramedic administration of intravenous lorazepam and diazepam has been shown to be safe and effective in adults. For out-of-hospital status epilepticus, this treatment approach is preferred. When emergency medical services are not available, transmucosal drug administration may be considered. Rectal diazepam, buccal midazolam, and intranasal midazolam have been reported to be effective in a variety of acute seizure conditions. However, experience with these therapies for the treatment of status epilepticus is limited.

 

FIGURE 14.4. Antiepileptic drug therapy for status epilepticus in adults. Horizontal bars indicate approximate duration of drug infusions. Doses (mg/kg) are appropriate for children; however, infusion rates should be adjusted as follows: lorazepam 0.5 to 2 mg/min; phenytoin 1 mg/kg/min; fosphenytoin 3 mg/kg/min; phenobarbital 2 mg/kg/min. The maximal infusion rates recommended in adults should not be exceeded (89). (Reprinted from Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970-976, with permission.)

REFERENCES

  1. Lowenstein DH, Bleck T, Macdonald RL. It's time to revise the definition of status epilepticus. Epilepsia1999;40:120-122.
  2. DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology1996;46:1029-1035.
  3. Theodore WH, Porter RJ, Albert P, et al. The secondarily generalized tonic-clonic seizure: a videotape analysis. Neurology1994; 44:1403-1407.
  4. Shinnar S, Berg AT, Moshe SL, et al. How long do new-onset seizures in children last? Ann Neurol2001;49:659-664.

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  1. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med1998;338:970-976.
  2. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med2001;345:631-637.
  3. Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia1994;35:27-34.
  4. Treiman DM. Therapy of status epilepticus in adults and children. Curr Opin Neurol2001;14:203-210.
  5. Working Group on Status Epilepticus. Treatment of convulsive status epilepticus: recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA1993; 270:854-859.
  6. Shorvon S. Status epilepticus: its clinical features and treatment in children and adults.Cambridge: Cambridge University Press, 1994.
  7. Naora K, Shen DD. Mechanism of valproic acid uptake by isolated rat brain microvessels. Epilepsy Res1995;22:97-106.
  8. Meldrum BS, Brierley JB. Prolonged epileptic seizures in primates. Arch Neurol1973;28:10-17.
  9. Rowan AJ, Scott DF. Major status epilepticus: a series of 42 patients. Acta Neurol Scand1970;46:573-584.
  10. Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology1993;43:483-488.
  11. Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med1980;1980: 657-666.
  12. Walton NY, Treiman DM. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp Neurol1988:267-275.
  13. Walker MC. The epidemiology and management of status epilepticus. Curr Opin Neurol1998;11:149-154.
  14. Galvin GM, Jelineck GA. Midazolam: an effective intravenous agent for seizure control. Arch Emerg Med1987;4:169-172.
  15. George KA, Dundee JW. Relative amnestic actions of diazepam, flunitrazepam and lorazepam in man. Br J Clin Pharmacol1977; 4:45-50.
  16. Leppik IE, Derivan AT, Homan RW, et al. Double-blind study of lorazepam in status epilepticus. JAMA1983;249:1452-1454.
  17. Arendt RM, Greenblatt DJ, deJong RH, et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther1983; 227:98-106.
  18. Walton NY, Treiman DM. Lorazepam treatment of experimental status epilepticus in the rat: relevance to clinical practice. Neurology1990;40:990-994.
  19. Andermann F, Cendes F, Reiher J, et al. A prospective doubleblind study of the effects of intravenously administered lorazepam and diazepam in the treatment of status epilepticus. Epilepsia1992;33[Suppl 2]:3.
  20. Greenblatt DJ, Divoll M. Diazepam versus lorazepam: relationship of drug distribution to duration of clinical action. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, et al., eds. Status epilepticus: mechanisms of brain damage and treatment,vol 34. New York: Raven Press, 1983:487-491.
  21. Browne TR. The pharmacokinetics of agents used to treat status epilepticus. Neurology1990;40[Suppl 2]:28-32.
  22. Ramsay RE, Hammond EJ, Perchalski RJ, et al. Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol1979;36: 535-539.
  23. Booker HE, Celesia CG. Serum concentrations of diazepam with epilepsy. Arch Neurol1973;29:191-194.
  24. Naquet CF, Tutton JC, Smith BH. First attempt at treatment of experimental status epilepticus in animals and spontaneous status epilepticus in man with diazepam (Valium).Electroencephalogr Clin Neurophysiol1965;18:427.
  25. Bell DS. Dangers of treatment of status epilepticus with diazepam. BMJ1969;1:159-161.
  26. Wilder BJ, Ramsay RE, Willmore LJ, et al. Efficacy of intravenous phenytoin in the treatment of status epilepticus: kinetics of central nervous system penetration. Ann Neurol1977;1: 511-518.
  27. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med1998;339:792-798.
  28. Cranford RE, Leppik IE, Patrick B, et al. Intravenous phenytoin: clinical and pharmacokinetic aspects. Neurology1978;28: 874-880.
  29. Kugler AR, Knapp LE, Eldon MA. Attainment of therapeutic phenytoin concentrations following administration of loading doses of fosphenytoin: a metaanalysis. Neurology1996;46 [Suppl]:A176.
  30. Fischer JH, Allen FH, Runge J, et al. Fosphenytoin (Cerebyx) in status epilepticus: safety, tolerance, and pharmacokinetics. Epilepsia1996;37[Suppl 5]:202.
  31. Walton NY, Uthman BM, El Yafi K, et al. Phenytoin penetration into brain after administration of phenytoin or fosphenytoin. Epilepsia1999;40:153-156.
  32. Shaner DM, McCurdy SA, Herring MO, et al. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology1988;38:202-207.
  33. Goldberg MA, McIntyre HB. Barbiturates in the treatment of status epilepticus. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, et al., eds. Status epilepticus: mechanisms of brain damage and treatment.New York: Raven Press, 1983:499-503.
  34. Venkataraman V, Wheless JW. Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients. Epilepsy Res1999;35:147-153.
  35. Yu KTT, Mills SM, Thompson NM. Safety and efficacy of intravenous valproate loading in pediatric status epilepticus and acute repetitive seizures. Epilepsia2001;42[Suppl 7]:188-189.
  36. Limdi N, Faught E. The safety of rapid valproic acid infusion. Epilepsia2000;41:1342-1345.
  37. Price DJ. Intravenous valproate: experience in neurosurgery. In: Chadwick D, ed. Fourth international symposium on sodium valproate and epilepsy.Jersey, UK: Royal Society of Medicine Services, 1989:197-203.
  38. Naritoku DK, Sinha S. Outcome of status epilepticus treated with intravenous valproate. Neurology2001;56[Suppl 3]: A235-A236.
  39. Giroud M, Gras D, Escousse A, et al. Use of injectible valproic acid in status epilepticus: a pilot study. Drug Invest1993;5: 154-159.
  40. Uberall MA, Trollmann R, Wunsiedler U, et al. Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology2000;54:2188-2189.
  41. White JR, Santos CS. Intravenous valproate associated with significant hypotension in the treatment of status epilepticus. J Child Neurol1999;14:822-823.
  42. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology2000;55: 722-724.
  43. Walker IA, Slovis CM. Lidocaine in the treatment of status epilepticus. Acad Emerg Med1997;4:918-922.
  44. Pascual J, Cuidad J, Berciano J. Role of lidocaine (lignocaine) in managing status epilepticus. J Neurol Neurosurg Psychiatry1992; 55:49-51.
  45. Hellstrom-Westas L, Westgren U, Rosén I, et al. Lidocaine for treatment of severe seizures in newborn infants: I. clinical effects and cerebral activity monitoring. Acta Paediatr Scand1988; 77:79-84.

P.168

 

  1. Hellstrom-Westas L, Svenningsen NW, Westgren U, et al. Lidocaine for treatment of severe seizures in newborn infants: II. blood concentrations of lidocaine and metabolites during intravenous infusion. Acta Paediatr Scand1992;81:35-39.
  2. Bleck TP. Advances in the management of refractory status epilepticus. Crit Care Med1993;21:955-957.
  3. Prasad A, Worrall BB, Bertram EH, et al. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia2001;42:380-386.
  4. Parent JP, Lowenstein DH. Treatment of refractory generalized status epilepticus with continuous infusion of midazolam. Neurology1994;44:1837-1840.
  5. Claassen J, Hirsch LJ, Emerson RG, et al. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology2001;57:1036-1042.
  6. Naritoku DK, Sinha S. Prolongation of midazolam half-life after sustained infusion for status epilepticus. Neurology2000;54: 1366-1368.
  7. Stecker MM, Kramer TH, Raps EC, et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia1998;39:18-26.
  8. Yaffe K, Lowenstein DH. Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus. Neurology1993;43:895-900.
  9. Osorio I, Reed RC. Treatment of refractory generalized tonic-clonic status epilepticus with pentobarbital anesthesia after high-dose phenytoin. Epilepsia1989;30:464-471.
  10. Alldredge BK, Corry MD, Allen F, et al. Identification and management of out-of-hospital seizures by paramedics. Epilepsia1998;39[Suppl 6]:70.
  11. Lowenstein DH, Alldredge BK, Allen F, et al. The prehospital treatment of status epilepticus (PHTSE) study: design and methodology. Control Clin Trials2001;22:290-309.
  12. Valenzuela TD, Copass MK. Clinical research on out-of-hospital emergency care. N Engl J Med2001;345:689-690.
  13. Gottwald MD, Akers LC, Liu P-K, et al. Prehospital stability of diazepam and lorazepam. Am J Emerg Med1999;17:333-337.
  14. Alldredge BK, Wall DB, Ferriero DM. Effect of prehospital treatment on the outcome of status epilepticus in children. Pediatr Neurol1995;12:213-216.
  15. Shaner SA, Shanahan RJ. Intravenous diazepam administration by paramedics in the treatment of status epilepticus in children. Ann Neurol1989;26:472-473.
  16. Moolenaar F, Bakker S, Visser J, et al. Biopharmaceutics of rectal administration of drugs in man: IX. comparative biopharmaceutics of diazepam after single rectal, oral, intramuscular and intravenous administration in man. Int J Pharmaceut1980;5:127-137.
  17. Dulac O, Aicardi J, Rey E, et al. Blood levels of diazepam after single rectal administration in infants and children. J Pediatr1978;93:109-141.
  18. Knudsen FU. Plasma diazepam in infants after rectal administration in solution and by suppository. Acta Paediatr Scand1977;66:563-567.
  19. Dreifuss FE, Rosman NP, Cloyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med1998;338:1869-1875.
  20. Hoppu K, Santavuori P. Diazepam rectal solution for home treatment of acute seizures in children. Acta Paediatr Scand1981; 70:369-372.
  21. Lombroso CT. Intermittent home treatment of status and clusters of seizures. Epilepsia1989;30[Suppl 2]:S11-S14.
  22. Kriel RL, Cloyd JC, Hadsall RS, et al. Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis. Pediatr Neurol1991;7:13-17.
  23. Brown L, Bergen DC, Kotagal P, et al. Safety of Diastat when given at larger-than-recommended doses for acute repetitive seizures. Neurology2001;56:1112.
  24. Payne K, Mattheyse FJ, Liebenberg D, et al. The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol1989;37:267-272.
  25. Dooley JM, Tibbles JAR, Rumney PG, et al. Rectal lorazepam in the treatment of acute seizures in childhood. Ann Neurol1985; 18:412-413.
  26. Rey E, Delaunay L, Pons G, et al. Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration. Eur J Clin Pharmacol1991;41:355-357.
  27. Lahat E, Goldman M, Barr J, et al. Intranasal midazolam for childhood seizures. Lancet1998;352:620.
  28. Scheepers M, Scheepers B, Clarke M, et al. Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy? Seizure2000;9:417-422.
  29. Lahat E, Goldman M, Barr J, et al. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ2000; 321:83-86.
  30. Schwagmeier R, Alincic S, Striebel HW. Midazolam pharmacokinetics following intravenous and buccal administration. Br J Clin Pharmacol1998;46:203-206.
  31. Scott RC, Besag FMC, Boyd SG, et al. Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics. Epilepsia1998;39:290-294.
  32. Scott RC, Besage FMC, Neville BGR. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet1999;353:623-626.
  33. Bell DM, Richards G, Dhillon S, et al. A comparative pharmacokinetic study of intravenous and intramuscular midazolam in patients with epilepsy. Epilepsy Res1991;10:183-190.
  34. Jawad S, Oxley J, Wilson J, et al. A pharmacodynamic evaluation of midazolam as an antiepileptic compound. J Neurol Neurosurg Psychiatry1986;49:1050-1054.
  35. Mayhue FE. IM midazolam for status epilepticus in the emergency department. Ann Emerg Med1988;17:643-645.
  36. Egli M, Albani C. Relief of status epilepticus after i.m. administration of the new short-acting benzodiazepine midazolam (Dormicum). In: 12th World Congress of Neurology, Kyoto, Japan, September 20-25, 1981.Amsterdam: Excerpta Medica, 1981, 44.
  37. Chamberlain JM, Altieri MA, Futterman C, et al. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care1997;13:92-94.
  38. Taylor JW, Simon KB. Possible intramuscular midazolam-associated cardiorespiratory arrest and death. DICP Ann Pharmacother1990;24:695-697.
  39. Gilbert KL. Evaluation of an algorithm for treatment of status epilepticus in adult patients undergoing video/EEG monitoring. J Neurosci Nurs2000;32:101-107.
  40. Hanhan UA, Fiallos MR, Orlowski JP. Status epilepticus. Pediatr Clin North Am2001;48:683-694.