PEDIATRIC EMERGENCY MEDICINE

0031-3955/92 $0.00

+

.20

STATUS EPILEPTICUS IN CHILDREN The Acute Management Michael G. Tunik, MD, and Grace M. Young, MD

Status epilepticus (SE) is a common pediatric emergency that may result in significant morbidity and mortality. The child who experiences an episode of SE creates a frightening scenario for parents and a challenge for health care workers. Only an organized approach to the initial stabilization and management of the child in SE helps prevent unnecessary complications and death. Seizures may be classified as generalized or partial. Generalized seizures present with an altered mental status and can be associated with convulsive motor activity. Status epilepticus is prolonged seizure activity and has been defined as a single seizure or recurrent seizures lasting more than 30 minutes, during which time consciousness is not regained. Status epilepticus lasting longer than 60 minutes, despite optimal therapy, may be defined as refractory SE.20, 23, 55, 63, 69, 72, 75 Generalized tonic-clonic status epilepticus is the most common form of SE and has the highest potential for complications or death. This article provides a clinical update on generalized tonic-clonic SE in children and a practical approach to their initial stabilization and pharmacologic management. Evaluation and management of other types of SE have been reviewed elsewhere. 53, 63, 75 PATHOPHYSIOLOGY

Generalized tonic-clonic SE is the result of abnormal random discharges of a large number of central nervous system (eNS) neurons. From the Department of Pediatrics, Division of Ambulatory and Emergency Pediatrics, New York University School of Medicine; and Bellevue Hospital Center, New York, New York

PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 39' NUMBER 5· OCTOBER 1992

1007

1008

TUNIK & YOUNG

These random neuronal discharges cause abnormal repetitive motor activity. Several phases of electroencephalographic (EEG) changes occur during generalized convulsive SE. The abnormal electrical discharges are initially discrete; they then consolidate into continuous electrical discharges. Periods of electrical silence follow and intersperse with these electrical discharges. Finally, an absence of electrical activity surrounds paroxysmal epileptiform discharges. During this phase, motor activity eventually ceases. so, 82 At the cellular level in the CNS, there is an increased metabolic rate, a depletion of glucose stores, and an increase in cerebral oxygen extraction and consumption. so, 58, 59 These metabolic changes cause neuronal injury. Supplemental oxygen and glucose are critical substrates in preventing neuronal damage. Some experimental evidence in mice suggests that when seizures continue for longer than 60 minutes, the risk for neuronal injury increases despite optimal concentrations of oxygen and glucose. Therefore, seizures in children should optimally be controlled within the first 60 minutes of presentation. so, 58, 59 Clinically, an increase in sympathetic output occurs during the first 30 minutes of convulsive SE. The child presents with tachycardia, arterial hypertension, cerebral hypertension, hyperglycemia, and hyperpyrexia. Secondary metabolic acidosis also occurs. Prolonged status epilepticus lasting more than 1 hour results in hyperkalemia, hypoglycemia, hypotension, respiratory acidosis, and death. so, 59 The child in SE may experience difficulty in swallowing, pooling of secretions in the pharynx, emesis, and aspiration pneumonia. Trauma to the extremities, oropharynx, and head may result from the violent muscle contractions of the seizure. ETIOLOGY

The cause of SE in children is age dependent (Table 1). Acute CNS injury (hypoxemia, hypoglycemia, head trauma, meningitis, hyponatremia, hypocalcemia, and hypomagnesemia) frequently precipitates SE Table 1. CAUSE OF STATUS EPILEPTICUS ACCORDING TO AGE Percent of Children by Age (in years) 15

Febrile Acute CNS injury Idiopathic Chronic CNS injury Progressive encephalopathy

37 46 7 0 10

49 20 13 13 5

10 14 31 38 7

3 24 40 30 0

0 0 45 55 0

0 25 25 44 6

Total Percentage (Number of children per age group)

100% (41)

100% (55)

100% (29)

100% (30)

100% (22)

100% (16)

Cause

Data from Maytal J. Shinnar S, Moshe SL, et al: Low morbidity and mortality of status epilepticus in children. Pediatrics 83:323-331, 1989.

STATUS EPILEPTICUS IN CHILDREN

1009

in children. Intoxication by common toxins and medications also may cause seizures acutely (Table 2). Febrile SE (seizures associated with rapid elevations of temperature without other acute injury) occurs commonly in children younger than 5 years. Chronic CNS injury (previous head trauma, meningitis or stroke, hypoxic or static encephalopathy, in the absence of an intercurrent illness or injury) frequently causes SE in children older than 5 years, as does idiopathic SE (seizures that occur without fever, acute or chronic CNS injury). SE caused by progressive encephalopathies (SE associated with neurodegenerative diseases, malignancies, or neurocutaneous syndromes) is seen in all age groups. The withdrawal from anticonvulsants is also a common cause of SE that is seen in all age groups and is classified as an acute CNS injury. In a recent study of 193 children, Maytal et al55 correlated the causes of SE according to age (see Table 1). Acute CNS injury is most common in children younger than 3 years. Febrile SE is common in children younger than 5 years. Idiopathic SE and SE caused by chronic CNS injury are both more frequent in children older than 3 years. Progressive encephalopathic SE is infrequent but seen in all age groups. SE due to anticonvulsant withdrawal is relatively common and also seen in all age groups. Similar causes of SE were associated with children of comparable ages in another recent study by Phillips and Shanahan. 66

PROGNOSIS

The prognosis for any child is determined primarily by the cause of the SE. The presence of acute or chronic CNS injury significantly increases the risk of death, neurologic dysfunction, and subsequent epilepsy. In the absence of acute CNS injury, a definite risk, though small, of death remains due to the seizure activity itself. The prognosis is improved if stabilization with optimal oxygenation and glucose levels is combined with treatment directed toward the underlying cause of the SE.1, 55, 66 . The mortality associated with generalized convulsive SE has decreased. Deaths associated with an episode of convulsive SE were Table 2. SUBSTANCES THAT CAUSE SEIZURES Amphetamines Anticonvulsant overdose Belladonna alkaloids Camphor Carbon monoxide Cocaine Cyanide Cyclic antidepressants Hypoglycemic agents (insulin)

Isoniazid Lead Lidocaine Nicotine Organophosphates Phencyclidine Phenylpropanolamine Theophylline

1010

TUNIK & YOUNG

reported as 11 % in 1970 in a study by Aicardi and Chevrie/ 6% in 1989 by Phillips and Shanahan,66 and 3.6% in 1989 by Maytal et al,55 Most deaths reported by Phillips and May tal were attributed to acute CNS injury or prior progressive encephalopathy. No mortality was associated with idiopathic or febrile SE in May tal et aI's study. In Phillips and Shanahan's study of 218 children, 1 previously healthy child (0.5%) died during an episode of idiopathic SE. Improved management of SE may account for the decrease in mortality noted in these recent studies. Permanent CNS damage is associated with generalized convulsive SE in children who were previously neurologically and developmentally normal. In these children, Aicardi and Chevrie found that permanent neurologic sequelae occurred in 20% and mental retardation in 33%. Aicardi and Chevrie 1 did not associate, however, the sequelae with the cause of SE. May tal et al 55 noted that the new onset of encephalopathy or neurologic dysfunction occurred in 24% of children in SE because of acute CNS injury, 4% in idiopathic SE, and 0% in febrile SE, with an overall incidence of 9%. The new onset of epilepsy also has been associated with an episode of SE. In a study of 239 children, Aicardi and Chevrie 1 noted that 57% had recurrent seizures after an episode of SE, but they did not categorize the frequency of epilepsy according to the cause of SE. May tal et al55 described that the frequency of subsequent epilepsy differed depending on the origin of the SE. This frequency was 25% for children with idiopathic SE and 4% for children after an episode of febrile SE.55 In children with underlying neurologic abnormalities, the frequency of recurrent febrile SE after the first episode of febrile SE was 38%, whereas the frequency for neurologically normal children was only 4%.55 Refractory seizures may occur in 26% of children during an episode of SE.55 Children experiencing an episode of SE caused by acute CNS injury have an increased frequency of 46% for refractory SE, as compared with children experiencing an episode of idiopathic or febrile SE who have a subsequent frequency of refractory SE of 17% and 14%, respectively. The mortality of refractory SE depends on the cause of the seizure and ranges from 0% to 70%.42,55,68 No deaths occurred in children with refractory SE whose underlying cause was idiopathic, febrile, or chronic CNS injury.55

MANAGEMENT OF STATUS EPILEPTICUS

Generalized convulsive SE is a medical emergency. The priorities for treatment are (1) Stabilization. Adequate cerebral oxygenation and glucose level should be maintained by ensuring optimal respiratory and hemodynamic function. (2) Evaluation. A history, physical and neurologic examination, and pertinent diagnostic studies should be obtained concurrent with stabilization. Reversible causes of the seizure

STATUS EPILEPTICUS IN CHILDREN

1011

should be identified. (3) Treatment. Both clinical and electrical seizure activity should be controlled within 30 to 60 minutes of presentation while treating any underlying reversible etiology. The initial pharmacologic treatment includes benzodiazepines, followed by phenytoin or phenobarbital. In refractory SEt general anesthesia should be induced. Common pitfalls in the management of SE include (1) inadequate oxygenation and ventilation during initial stabilization, (2) difficult venous access, (3) inadequate doses of anticonvulsant administered for the child, and (4) insufficient time allowed for the anticonvulsant to reach therapeutic levels in brain tissues. Table 3 summarizes the priorities in the management of SE. Stabilization

Oxygenation and Ventilation

The first priority in managing the child who presents in SE is ensuring airway patency. Positioning the child's head and suctioning any secretions usually provide a patent airway. A rigid large bore suction catheter should be available immediately. Oral or nasal airways may be used to help to maintain airway patency. Force should not be Table 3. MANAGEMENT OF STATUS EPILEPTICUS Stabilization Airway position suction Oxygenation and Ventilation supplemental 100% oxygen by face mask bag-valve-mask endotracheal intubation Circulation Monitoring pulse oximeter cardiorespiratory rljOnitor end tidal CO2 monftor Establish Presence of Status Epilepticus Observe continuous seizure activity Observe intermittent seizure activity and altered mental status Decreased level of consciousness and history of above Perform Immediate Procedures Establish vascular access intravenous access intraosseous access central venous access Obtain initial arterial blood gas and glucose Evaluation Obtain a directed history Perform a directed physical and neurological examination Obtain initial laboratory tests Treatment

1012

TUNIK & YOUNG

used to open clenched jaws during convulsive SE. Oral or nasogastric decompression of the stomach contents should be performed as early as possible to prevent emesis and secondary aspiration. If there is no history or evidence of trauma, the child may be placed in a left lateral decubitus position to help prevent aspiration of gastric contents. The next priority in stabilization is ensuring adequate oxygenation and ventilation. Supplemental oxygen at high concentrations (100%) by face mask should be administered to all patients in SE. Inadequate chest rise, poor axillary breath sounds, tachypnea, apnea, poor respiratory effort, and central cyanosis suggest inadequate oxygenation and ventilation. Poor oxygen saturation by pulse oximeter (0 2 saturation 80 mm Hg or O 2 saturation >95%). End tidal CO 2 monitoring, if available, is extremely useful and provides continuous measurements of expiratory carbon dioxide levels. To correct for inadequate oxygenation and ventilation, one should first reassess and establish airway patency. Assisted ventilation should then be initiated using a bag-valve mask. The child can usually be ventilated despite convulsive jaw closure. If high-pressure ventilation is required to obtain adequate ventilation, the mask should be held with two hands to ensure a tight seal with the face. Cricoid pressure 12 (Sellick maneuver) helps prevent stomach distention secondary to highpressure ventilation and subsequent reflux of gastric contents. If ventilation remains inadequate, the child should be intubated. Indications for endotracheal intubation include inadequate oxygenation or ventilation, increased intracranial pressure that requires treatment by controlled oxygenation and hyperventilation, and refractory SE that requires general anesthesia. Intubation of the child in convulsive SE requires muscle paralysis to prevent trauma to the oropharynx and upper airway. Successful intubation is performed using the technique of rapid sequence intubation, which has been reviewed recently. 56,91 In the child with SE who may have already received a benzodiazepine or barbiturate, the use of sedative hypnotics and analgesics may not be required. Once muscle paralysis is induced and the child intubated, the EEG and cardiorespiratory status must be closely monitored. Continued electrical seizure activity requires additional anticonvulsant intervention. Circulation and Vascular Access

Assessment and stabilization of the circulatory status follow oxygenation and ventilation. The child who presents early in convulsive SE often has adequate perfusion, tachycardia, and hypertension. With prolonged seizure activity, the child may develop hypovolemic or cardiogenic shock and should be treated initially with fluids. 12,76 Clinical signs of poor perfusion, which include thready peripheral or central pulses, delayed capillary refill time, and cool extremities, should be

STATUS EPILEPTICUS IN CHILDREN

1013

monitored closely. Cardiac rhythm and blood pressure are monitored with continuous electrocardiography and oscillometric blood pressure devices. As the presence of SE is established, vascular access must be obtained. Because most of the available and effective anticonvulsants are administered through an intravenous (IV) route, venous access is of paramount importance. Establishing IV access in the child with seizures is often difficult. In the child less than 6 years of age who is hemodynamically unstable or has been seizing for more than 30 minutes, vascular access should be obtained through an intraosseous (10) route. All fluids and medications that are given IV may be administered by 10 infusion. 36, 79, 85 Guidelines for the 10 technique are described elsewherey,76 Other routes for drug delivery include intramuscular (1M) or rectal (PR), but few drugs given 1M or PR adequately control SE. (See section on Anticonvulsants in the Treatment of Status Epilepticus.) Evaluation

During the initial stabilization, a directed history, physical, and neurologic examination (Table 4) help to identify the cause of the child's SE. The initial approach to the management of SE should be consistent regardless of the cause. Certain etiologies, however, require specific interventions to stop the seizure and prevent complications. For example, head trauma with expanding intracranial hematomas requires immediate neurosurgical drainage; certain intoxications (e.g., theophylline, isoniazid) have specific treatments; and pyridoxine deficiency in infants should be reversed with pyridoxine administration. Obtaining routine laboratory tests is controversial in the evaluation of SE. Immediate tests usually include cardiac monitoring, rapid glucose level, and pulse oximetry or arterial blood gas in any stable child. For the child in SE, electrolytes, glucose, calcium, blood urea nitrogen, Table 4. DIRECTED EVALUATION OF CONVULSIVE STATUS EPILEPTICUS History

Physical Examination

Head trauma Symptoms of meningitis Toxic exposure or ingestions Prodromal illness Seizures in the past Compliance with anticonvulsants Prior CNS infection or trauma Medications Perinatal history Neurocutaneous syndromes Development General health Other past medical history

Vital signs (HR, RR, BP) Temperature Respiratory status Circulatory status Pupils (size, symmetry, reaction to light) Evidence of increased intracranial pressure Signs of head injury Signs of other trauma Toxicologic syndromes Cholinergic syndrome Anticholinergic syndrome Sympathetic syndrome

1014

TUNIK & YOUNG

magnesium, and complete blood count with differential are recommended. Although these blood tests are frequently normal in the child who presents a brief seizure,25, 61 in children younger than 3 years, electrolyte imbalance, hypoglycemia, hypocalcemia, meningitis, acute trauma, and intoxication are frequent causes of SE.I, 55, 66 Further diagnostic tests, such as serum anticonvulsant level, lumbar puncture, toxicology screen, or electroencephalogram, should be obtained based on the child's presentation (Table 5). Treatment Overview

Status epilepticus generally responds well to an appropriately administered anticonvulsant. Infrequently, convulsive SE due to intracerebral hemorrhage, hypoxic injury, meningoencephalits, hypertensive encephalopathy, or idiopathic causes requires more intensive management with general anesthesia. 83 The goal of anticonvulsant intervention is to achieve effective therapeutic levels as quickly as possible and ideally within 30 to 60 minutes of presentation. The initial dose of an anticonvulsant for the treatment of SE should rapidly and sufficiently saturate brain tissues and suppress seizure activity. If another anticonvulsant is required acutely, it should potentiate the antiepileptic properties of the first without causing respiratory or cardiovascular compromise. Once an anticonvulsant is administered, however, the treating physician must allow for an adequate time for the anticonvulsants to reach therapeutic levels in the brain. If the child continues to have seizures for longer Table 5. TESTS AND PROCEDURES FOR THE EVALUATION OF STATUS EPILEPTICUS To Be Done In All Unresponsive Children Pulse oximetry Cardiac monitor Glucose Arterial blood gas

To Be Done For All Children in SE

To Be Considered Based on Presentation

Electrolytes Calcium Blood urea nitrogen Complete blood count Platelet count Magnesium

Anticonvulsant levels Toxicology screen (urine, blood) Carbon monoxide level Lumbar puncture (include opening pressure) Urinalysis Coagulation profile (PT/PTT) Liver function tests (SGPT) Ammonia level (serum) Cerebrospinal fluid culture Blood culture Urine culture Electroencephalogram CT or MR image scan of head Lead levellfree erythrocyte protoporphyrin Amino acid levels (serum, urine) Electrocardiogram

STATUS EPILEPTICUS IN CHILDREN

1015

than 60 minutes, control of the seizures with general anesthesia should follow. Any child treated with general anesthesia must have mechanical respiratory and pharmacologic cardiovascular support. The choice of one anticonvulsant over another is less important than a well designed, predetermined protocol that ensures rapid administration of adequate and effective doses in the emergency department. Optimally, such a plan includes the induction of general anesthesia in the critical care unit. It also should involve the pediatric neurology, anesthesiology, and critical care staff. Several protocols for managing convulsive SE have been presented previously. 19, 20, 45, 69, 75, 81 Historically, the standard treatment for SE prior to 1960 was parenteral administration of phenobarbital or paraldehyde. With its introduction in the early 1960s, IV diazepam became the first line anticonvulsant in the treatment of SE. Currently, the anticonvulsants used in the treatment of SE fall into three categories: benzodiazepines, phenytoin, and barbiturates. The major anticonvulsants are summarized in Table 6. Inhalation anesthetics and barbiturate induced coma are effective for refractory SE (Table 7). ANTICONVULSANTS IN THE TREATMENT OF STATUS EPILEPTICUS Benzodiazepines

All benzodiazepines are highly lipophilic; they cross the bloodbrain barrier readily but have short distribution half-lives. The benzodiazepines act at specific receptor sites that are part of the benzodiazepine-gamma-aminobutyric acid (GABA)-barbiturate receptor complex in the CNS.8! Therapeutically, benzodiazepines have anticonvulsant activity against generalized and focal SE; they decrease anxiety and induce sedation, hypnosis, amnesia, and muscle relaxation. Because of their short duration of action, most benzodiazepines are used in addition to other anticonvulsants, most commonly phenytoin, to prevent recurrent SE.69, 75, 80 The primary adverse effects of benzodiazepines are respiratory depression and a decreased level of consciousness. These symptoms develop especially when used concurrently with barbiturates. Occasionally, hypotension occurs, probably secondary to propylene glycol, a solvent in the IV preparations of diazepam and lorazepam. 8o A benzodiazepine receptor antagonist, flumazenil (Mazicon), was introduced for use in the United States in 1992 (see article entitled Update in Medical Toxicology in this issue). 38, 39 Although it significantly decreases benzodiazepine-induced sedation, flumazenil is only minimally effective in reversing benzodiazepine-induced depression of hypoxic ventilatory drive. Therefore, flumazenil should not be used to reverse benzodiazepine-induced respiratory depression in those in whom benzodiazepines were used to control seizures. In addition, flumazenil also can cause seizures, 10, 60, 89

Table 6. THE MAJOR ANTICONVULSANTS IN THE TREATMENT OF STATUS EPILEPTICUS Route of Administration

Dose

Diazepam

IV, 10

0.25-0.40 mg/kg MAX 10 mg/dose; may repeat q 10-15 minutes MAX 40 mg/24 hrs

Lorazepam

(PR)t IV, 10

(0.05 mg/kg PR)t 0.05-0.10 mg/kg

Midazolam

IV, 10 1M

Phenytoin

IV, 10

Phenobarbital

IV, 10, (IM)t

Phenytoin prodrugll

IV, 10, 1M

MAX 4.0 mg/dose; may repeat q 10-15 minutes 0.05-0.20 mg/kg 0.20 mg/kg 1M MAX 5 mg/dose 18-20 mg/kg initial bolus MAX 1000 mg; infusion rate must be < 0.5-1.0 mg/kg/min to a MAX rate < 50 mg/min 20-25 mg/kg initial bolus MAX 1000 mg; infusion rate must be < 100 mgl min 25 mg/kg; infusion rate must be < 75 mg/min

Onset of Action

Duration of Action

Side Effects·

Effective Serum Concentration

1-3 minutes (1-2 hours PR)t

5-15 minutes

Yes

**:j:

2-3 minutes

24-48 hours

Yes

**:j:

1.5-5.0 minutes

1-5 hours

Yes

**:j:

10-30 minutes after

12-24 hours

No§

10-20 fLg/mL

10-20 minutes IV (2-4 hours IM)t

1-3 days

Yes§

15-40 fLg/mL

5-10 minutes IV 30-35 minutes 1M

Similar to phenytoin

No§

**:j:

infusion

*Side effects include cardiorespiratory depression, central nervous depression, drug interactions. tThis route should be considered for the acute treatment of status epilepticus only when immediate intravenous access is not available. :j:Serum concentrations are not clinically useful in the acute phase of treatment. §Cardiovascular side effects occur if infused too rapidly. IIPhenytoin prodrug is not currently available for clinical use.

STATUS EPILEPTICUS IN CHILDREN

1017

Three benzodiazepines may be given IV for the acute treatment of SE: diazepam, lorazepam, and midazolam. The differences in their pharmacokinetics influence the choice of benzodiazepine in the acute management of SE. Diazepam and lorazepam are the most widely studied benzodiazepines for the treatment of convulsive SE. 80 Diazepam (Valium) was introduced in 1961 for antianxiety and muscle relaxation, and its use in SE was first published in 1965. 80 Lorazepam (Ativan) was introduced in 1977 as a sedative-anxiolytic and found to be clinically efficacious for the management of SE in the late 1980s. 17, 29, 43,88 Midazolam (Versed) was synthesized in 1976 for use as an anesthetic induction agent; the first review of it as an anticonvulsant was published in 1985.71 Diazepam

Diazepam is highly effective in the treatment of patients with generalized convulsive SE.81 The onset of action of diazepam is within 1 to 3 minutes of IV administration because of its highly lipophilic properties. Its duration of action (5-15 minutes) is very short, however. Because diazepam is highly protein bound and has a large volume of distribution, it rapidly redistributes from brain tissues. Seizures often recur after initial control with diazepam and require an additional longer acting anticonvulsant. IV diazepam for acute SE is best titrated for clinical response. The range for the initial dose of diazepam is 0.25 to 0.40 mg/kg, with a maximum dose of 10 mg. It may be repeated every 10 to 15 minutes to a maximum of 40 mg over a 24-hour period. 22, 46, 69, 81 Lorazepam

Lorazepam readily crosses the blood-brain barrier, and its onset of action is within 2 to 3 minutes of administration, similar to diazepam. Lorazepam has a longer duration of action, however. Compared with diazepam, lorazepam is less lipophilic, less protein bound, and has a smaller volume of distribution. Lorazepam has anticonvulsant activity that lasts from several hours to 24 to 48 hours. The initial IV dose of lorazepam is 0.05 to 0.10 mglkg, with a maximum dose of 4 mg. It may be repeated every 10 to 15 minutes. Lorazepam also should be titrated for clinical response. 17, 29, 43, 69, 75, 81, 88 In comparative studies in the acute treatment of SE, lorazepam was about 89% effective and diazepam 76% effective in stopping seizure activity. When compared with phenytoin as the first anticonvulsant given, lorazepam was 79% effective and phenytoin 56% effective. Overall, both lorazepam and diazepam achieved lasting control in 79% of patients in SE without significant adverse effects. 13, 29, 80, 81 Although both diazepam and lorazepam treat seizures rapidly and effectively, lorazepam is the preferred benzodiazepine for the acute treatment of SE (Fig. 1). Lorazepam has a distinct advantage over diazepam because of its significantly longer duration of action and an

1018

TUNIK & YOUNG

equally rapid onset of action. If lorazepam is not immediately available, diazepam is the alternative. Midazo/am

Midazolam differs from lorazepam and diazepam in that its structure contains a fused imidazole ring. This ring renders midazolam stable in aqueous solutions so that a diluent such as propylene glycol is not required. Midazolam causes little local irritation as an IV or 1M injection. 71 With its lipophilic properties and extensive protein binding, midazolam readily enters into brain tissue and equilibrates quickly between plasma and the cerebrospinal fluid. It has a rapid onset of action (1.5-5.0 minutes), a high rate of elimination, and a short duration of action (1-5 hours).71 Its mechanism of action and side effects are similar to other benzodiazepines. Chemically, midazolam appears to be 1.5 to 2.0 times more potent than diazepam. 71 In mice, midazolam is a more effective anticonvulsant than either diazepam or lorazepam. 67 In humans, there are no published prospective, randomized studies comparing its efficacy with other anticonvulsants in the acute management of SE. Several case reports l8, 28, 37, 54, 67 have indicated midazolam to be an effective anticonvulsant, however. The initial IV dose is 0.05 to 0.20 mglkg, with a maximum dose of 5 mg. 18, 28, 35 Although IV midazolam has no particular advantage over diazepam or lorazepam in humans, it is clearly efficacious as an 1M anticonvulsant (see section on Intramuscular Administration of Anticonvulsants), Phenytoin Phenytoin

Phenytoin (Dilantin) is used frequently for SE. It was introduced in 1938 and its efficacy in SE was demonstrated in the late 1970s.15,9O Phenytoin inhibits the spread of electrical discharges from the epileptic foci and works best for idiopathic generalized tonic-clonic, focal, posttraumatic, and psychomotor seizures. Phenytoin works less well for absence, febrile, or SE due to alcohol withdrawal. 3, IS An IV loading dose of at least 18 to 20 mg/kg of phenytoin is effective in 70% to 90% of patients in SE.15, 83, 90 Occasionally, higher doses of up to 20 to 30 mg/kg may be required. 83 The effective serum phenytoin concentration is 10 to 20 J.Lg/mL Phenytoin's long half-life allows at least 24 hours of anticonvulsant activity. 15, 90 Peak activity of phenytoin in the brain occurs in 10 to 30 minutes. Because an IV infusion for phenytoin requires 20 minutes, however, the total time until peak activity is often 30 to 50 minutes. The drug then redistributes as a result of protein binding and fat deposition. IS Phenytoin is metabolized by hepatic microsomal enzymes. The elimination kinetics of phenytoin are complicated. At a lower concentration, the phenytoin level falls by a constant percentage (first order

.. STATUS EPILEPTICUS IN CHILDREN

1019

kinetics). At therapeutic or toxic levels, phenytoin metabolism is concentration dependent as enzyme degradation pathways become saturated. The phenytoin level decreases at a constant j-Lg/h rate (zero order kinetics). Therefore, phenytoin levels decrease more slowly at the higher therapeutic and toxic concentrations than at lower concentrations. These kinetics explain why, in the presence of a therapeutic level, small additional doses can unintentionally cause a toxic leveU,90 Proper administration of phenytoin is critical. First, phenytoin must be given in saline; it is poorly soluble in water and precipitates in dextrose-containing solutions. Second, phenytoin must be given slowly. Rapid administration most commonly results in hypotension as well as in bradycardia, cardiac conduction defects, cardiac arrhythmias, and congestive heart failure. Some of these cardiotoxic effects are probably caused by the propylene glycol solvent in the IV preparation. They occur especially in those who are already hypotensive or have preexisting cardiovascular disease. 23 , 69 Phenytoin's IV preparation also contains alcohol and is highly alkaline, which causes local irritation at the injection site. Intravenous phenytoin must be infused at a rate of less than O.S to 1.0 mg/kg/min in children and less than SO mg/min in adults. Concomitant hemodynamic monitoring during infusion is imperative. 23 ,69 To avoid complications, one should slowly infuse phenytoin by a constant infusion pump rather than by direct manual injection into the vein. One should mix the appropriate loading dose of phenytoin with normal saline to yield a phenytoin concentration of 10 mg/mL. An infusion rate of ISO mLih (2.5 mLimin) of this dilution safely delivers phenytoin at a rate of 25 mg/min for the child older than 4 years. For the younger child, the maximum rate of infusion may be decreased to 1 mglkg/min or 6 mLlkglh. For the adolescent or adult, an infusion rate of 240 mLih (4.0 mLimin) delivers phenytoin at a rate of 40 mg/min.9, 15,21,90 Phenytoin loading by oral and 1M routes is not recommended in the treatment of SE. 1M phenytoin is poorly and erratically absorbed; it also causes sterile abscesses or tissue necrosis at the injection site. 3, 23 Oral phenytoin absorption requires 6 to 14 hours, is variable, and often incomplete. 26, 70 The main advantage of phenytoin is that it does not severely depress the child's mental status. After an initial IV loading dose, transient ataxia, blurred vision, and dizziness are common initially. Nystagmus occurs at a high therapeutic or toxic level. Given its slower onset of action and requirement for slower administration, phenytoin is best given in combination with a rapidly acting benzodiazepine .23, 75, 83, 90 Phenytoin Prodrug

Phenytoin prodrug, ACC-96S3 (3-hydroxy-methyl-S-phenytoin phosphate ester), is an investigational drug that was developed in 1989 to enhance the solubility of phenytoin. Phenytoin prodrug is rapidly hydrolyzed to phenytoin by circulating phosphatase enzyme and is completely absorbed within 3 hours of administration. It is water soluble

1020

TUNIK & YOUNG

and does not require high alkalinity or solvents such as propylene glycol in its IV preparation. It produces no local tissue reaction when given IV or 1M. The onset of action of phenytoin prodrug is within 5 to 10 minutes of IV administration and within 30 to 35 minutes of 1M administration. The effective anticonvulsant dose appears to be 25 mg/kg IV or 1M, given at a rate of less than 75 mg/min. Although phenytoin prodrug appears to be an exciting and potent anticonvulsant for the treatment of SE, it is not yet available for clinical use. 8 , 34, 46-48, 77, 83

Barbiturates

Phenobarbital

Phenobarbital was introduced in 1912 and was the first line anticonvulsant for the treatment of SE until diazepam became available in the 1960s. Phenobarbital continues to be one of the major anticonvulsants. It has a high degree of efficacy against most seizures, especially in the treatment of febrile and neonatal SE. Phenobarbital is available for IV and 1M administration, has a relatively low toxicity, and is inexpensive. Its role in acute seizure control has been extensively reviewed.3, 23, 74 Absorption of phenobarbital is nearly complete after all routes of administration and it can be safely mixed with all IV fluids. When given IV, phenobarbital is rapidly distributed to most body tissues. Equilibration between brain and plasma occurs within 10 to 20 minutes, the time to peak activity level after an IV loading dose. 69 Phenobarbital is metabolized slowly by hepatic microsomal enzymes, and its primary metabolite, p-hydroxyphenylbarbital, is excreted in the urine. With an elimination half-life ranging from 60 to 150 hours, phenobarbital has a long duration of action, 1 to 3 days.69, 74 Effective serum phenobarbital concentration is 15 to 40 fLg/mL and requires a loading dose of 20 mg/kg (maximum dose is 1000 mg). Neonates may require a larger loading dose of 20 to 25 mg/kg. The rate of administration must be less than 100 mg/min or hypotension may result. 74--76 The main disadvantage of phenobarbital is that it significantly depresses mental status. Severe lethargy and coma are associated with serum levels of more than 60 fLg/mL. Respiratory depression and hypotension are common at these serum concentrations; these side effects occur frequently at therapeutic concentrations when given concomitantly with benzodiazepines. 23, 81

Intraosseous Administration of Anticonvulsants

Intraosseous infusion of benzodiazepines,36, 44, 52 phenobarbitaV or phenytoin85 , 87 is equally efficacious in the child who does not have immediate IV access. The doses recommended for IV administration

STATUS EPILEPTICUS IN CHILDREN

1021

are used for 10 administration with the same pharmacokinetics and toxic side effects. Intramuscular Administration of Anticonvulsants

Few anticonvulsants are available for 1M injection or are efficacious for the treatment of SE when given 1M. Midazolam (see section on Benzodiazepines) can be given safely as an 1M injection and has a rapid onset of action. 24, 54, 67 A dose of 0,20 mglkg 1M appears to be clinically efficacious in more than 90% of children in SEY These are preliminary results from a prospective study of 1M midazolam in children without immediate IV access (C.M. Young, et aI, unpublished data, 1992). Phenytoin prodrug (see section on Phenytoin) appears to be an effective anticonvulsant that can be given 1M. Still an investigational drug, phenytoin prodrug has great potential in the treatment of SE in the child without immediate vascular acess,34, 46-48, 83 Although phenobarbital may be administered 1M, the time to peak activity is 2 to 4 hours. Intramuscular phenobarbital is therefore suboptimal for the acute treatment of SE. Both diazepam and phenytoin by 1M administration have highly variable and slow absorption rates, can cause neurovascular injury, and are not recommended,2 Rectal Administration of Anticonvulsants

Rectal administration of anticonvulsants is suboptimal for the acute control of seizures because of variable absorption rates from rectal mucosa and a slower onset of action. Diazepam and valproic acid (Depakene) have been used to treat seizures in the child without immediate vascular access, however. Diazepam is absorbed well from rectal mucosa through the lower or middle hemorrhoidal veins. Several case reports have shown adequate control of SE when diazepam is given rectally. 2, 32, 40 In 96% of these children, seizure activity was controlled within 6 to 10 minutes of rectal administration. An initial dose of 0.5 mg/kg (maximum of 20 mg) appears effective. The parenteral preparation of diazepam is injected into the lower rectum using a I-mL syringe, feeding tube, or 6cm catheter advanced 4 to 6 cm.73. 84 It is unclear to what extent the volume of injected fluid, the presence of fecal mass, or the appearance of the rectal mucosa alters pharmacokinetics. 32, 40,73 In the prehospital setting, rectal diazepam may be considered for the child with seizures who has no vascular access. Valproic acid was introduced in the late 1970s for convulsive and nonconvulsive seizure disorders. 14 Although no parenteral preparation of valproic acid is available for the acute management of SE, it is currently being developed. 46 The oral preparation of valproic acid, however, has been given rectally in SK The 250 mg/mL syrup is diluted

1022

TUNIK & YOUNG

1:1 with water, and 20 to 30 mg/kg are administered as a retention enema. 69, 78, 84 The major disadvantage of valproic acid is that its absorption rate in the gastrointestinal route is slow, and its onset of action is 2 to 4 hours. Thus, several hours may lapse before control of seizures is possible. 14, 78

Other Medications

Lidocaine (Xylocaine) is reported to be effective for acute seizure control. 6, 19, 69 In Europe, it is commercially available for the treatment of SE.31, 65 A loading dose of 1.0 to 2.0 mglkg IV should yield an immediate clinical response. If the seizures stop, this should be followed by a continuous lidocaine infusion of 6 mglkglh because of its short half-life. If the seizures continue, they should be considered refractory to lidocaine and no further doses are indicated. In most reports, lidocaine was used in conjunction with phenobarbital or phenytoin. Its use has been reported primarily for neonatal SE secondary to birth asphyxia and intracranial hemorrhageY' 86 No controlled studies, however, demonstrate its clinical efficacy or mechanism of action, except for one study with three patients done in 1958. 6 Side effects include seizures as well as cardiovascular dysfunction. 6, 65, 69 The use of lidocaine is generally not recommended in the treatment of SE.46 Paraldehyde (Para) is a sedative hypnotic that has anticonvulsant activity both parenterally and rectally. Although it has been used successfully for SE when conventional measures are ineffective, its pharmacokinetic properties have not been established clearly. 19, 46, 75 Dosages for seizure control have not been well studied for the pediatric population, and levels are difficult to control. Paraldehyde has many adverse toxic effects that include tissue necrosis, sterile abscess, nerve damage, metabolic acidosis, hepatitis, renal failure, pulmonary edema, hypotension, cardiac failure, and death. In addition, it is destructive to certain plastic compounds contained in IV tubing and is labile in the presence of light and oxygen. 4, 6, 75 Although still marketed in Canada, the parenteral preparation of paraldehyde is not commercially available in the United States. 51 Most authorities no longer recommend this drug in the management of SE.4, 46 TREATMENT OF REFRACTORY STATUS EPILEPTICUS General Anesthesia

General anesthesia is recommended for SE that is refractory to conventional anticonvulsant therapy. It is induced by high-dose barbiturates or inhalation anesthesia. General anesthesia causes a state of unconsciousness, muscle relaxation, significant respiratory depression, and loss of the gag reflex. All patients receiving such treatment must

STATUS EPILEPTICUS IN CHILDREN

1023

be paralyzed, intubated, and have continuous EEG and cardiorespiratory monitoring. Equally important are the presence of a pediatric anesthesiologist and critical care staff who are familiar with the risks and complications of these agents. 19, 62, 69, 75 The goal of general anesthesia in the management of SE is conversion of the high-voltage spike and wave pattern to burst suppression of at least 30 seconds or silence on EEG. Maximal depression of cerebral metabolism results. Hypothermia (30-31°C) during induction of anesthesia further reduces metabolic demand. Once burst suppression intervals of 15 to 30 seconds or isoelectric tracing are achieved on EEG, anesthesia is maintained for at least 2 hours. If electrical status returns as anesthesia is slowly withdrawn, the EEG is again returned to burst suppression or an isoelectric tracing for several hours with general anesthesiaY' 75 Any child who remains in SE for 45 to 60 minutes despite adequate trials of effective doses of the major anticonvulsants should receive general anesthesia (Table 7 and Fig. 1).

Inhalation Anesthetics Isoflurane

Isoflurane produces a dose-related reduction in cortical electrical activity. It appears to decrease cerebral oxygen consumption and metabolic rate without a significant increase in cerebral blood flow. Isoflurane has minimal organ toxicity; its hemodynamic effects include minimal negative inotropic effects, myocardial depression, and peripheral vasodilation. 33, 41, 42, 57 It induces EEG suppression at concentrations of 0.5% to 1.5%, which are not ordinarily associated with hemodynamic effects. 33 Elimination of isoflurane is rapid and almost completely via the lungs. 41 , 42 Isoflurane is titrated for clinical response. Several series have demonstrated that isoflurane adequately stops seizure activity at conTable 7. CONTROL OF REFRACTORY STATUS EPILEPTIC US

Barbiturate Coma

Inhalation Anesthetics Hypothermia

Anesthetic Agent

Initial Dose

Pentobarbital

5 mg/kg IV bolus

Thiopental

30 mg/kg IV bolus

Phenobarbital

5-20 mg/kg IV bolus repeat q30-60 min 0.5%-3.0%

Isoflurane

Maintenance Infusion

-3-5 mg/kg/h continuous infusion 5 mg/kg/h continuous infusion

Goal: Administer agents until EEG burst suppression or silence, then slowly withdraw. Preferred setting: (1) pediatric critical care unit, (2) continuous hemodynamic monitoring, (3) continuous EEG monitoring, and (4) use agents with which the staff has experience.

1024

TUNIK & YOUNG

centrations of 0.5% to 3.0%. The hemodynamic effects of isoflurane were generally well tolerated at these concentrations. 41, 42, 57 Halothane

Halothane has been the recommended inhalation anesthetic agent for SE.19, 62 There are no published clinical series or experimental models to support its use, however. The doses of halothane required for EEG suppression also cause unacceptable hemodynamic side effects: systemic vasodilation and negative inotropy. In addition, it can be hepatotoxic. 42 Barbiturate-induced Coma

Barbiturates used to induce coma include pentobarbital,49, 68 thiopental,64 and phenobarbital. 16 These agents act as global CNS depressants with GABA-receptor agonist properties similar to the benzodiazepines. Short-acting barbiturates require continuous IV infusion and are titrated for clinical response. The long-acting barbiturate, phenobarbital, is relatively safe, inexpensive, and clinically efficacious. The major disadvantage to the use of high-dose barbiturates is that hypotension is common, and after prolonged administration, withdrawal seizures may occur, Pentobarbital

Pentobarbital is a short-acting barbiturate, introduced in 1983 for induction of barbiturate coma in SE.49 Lockman49 showed that seizures were controlled by 8 mg/kg of pentobarbital given as an IV bolus followed by a continuous infusion of 3 mg/kg/h for 3 days. Rashkin et al68 followed a similar protocol that was also effective: 5 mglkg IV bolus and 25 to 50 mg every 2 to 5 minutes until EEG suppression, followed by 5 mg/kg/h continuous infusion for 12 to 24 hours, and weaned at the rate of 1 mg/kg/h every 6 hours. SE was controlled within 1 hour of induction of coma. Although mortality remained high (77%), the children who died had SE associated with metabolic and structural lesions. o8 As with other barbiturates, pentobarbital's toxicities include pulmonary edema, generalized edema, intestinal ileus, and cardiorespiratory arrest. 49, 68 Thiopental

Thiopental (Pentothal) is also a short-acting barbiturate. Orlowski et al64 administered a loading dose of thiopental of 30 mg/kg over 1 hour, followed with continuous infusion of 5 mg/kg/h, and increased the rate up to 10 to 20 mglkg/h as needed to achieve optimal EEG suppression. Optimal thiopental levels were 250 to 400 j-Lg/mL. Concurrently, hypothermia was used to maintain a core body temperature of 30 to 31°C and dopamine to maintain blood pressure and cardiac

s d t r e l e -

ki 1 d

STATUS EPILEPTICUS IN CHILDREN

1025

output. Burst suppression was maintained for 48 to 72 hours and the child was slowly rewarmed at the rate of 1°C every 3 to 4 hours. 64 Phenobarbital

Phenobarbital is a long-acting barbiturate. Crawford et aP6 administered 15 to 20 mglkg IV boluses of phenobarbital every 30 to 60 minutes until cessation of clinical seizures or EEG burst suppression. Phenobarbital levels in the range of 60 j.Lg/mL (range 30-120 j.Lg/mL) successfully achieved seizure control. 16 AN APPROACH TO THE TREATMENT OF STATUS EPILEPTICUS

The management of seizures in any child begins with the following: administration of supplemental (100%) oxygen; stabilization of ventilation and oxygenation; establishment of the presence of SE; and establishment of vascular access (Fig. 1). The initial drug used to treat convulsive SE should be a benzodiazepine, which has a rapid onset of action. Lorazepam is the preferred benzodiazepine; it has a prolonged duration of action and may obviate the immediate need for additional anticonvulsants. If diazepam is chosen, a longer acting anticonvulsant should follow. The choice of additional anticonvulsants depends on the cause of the seizures and the age of the child. Phenytoin is preferred because it has a minimal effect on the level of consciousness. Phenobarbital is considered for the treatment of febrile seizures, neonatal SE, or the child allergic to phenytoin. If the child does not have immediate venous access, midazolam may be administered IM while attempts to obtain vascular access continue. If this child has continued seizure activity for longer than 30 minutes and is under 6 years of age, IO administration of anticonvulsants is appropriate. If the IO route is not possible, diazepam PR and phenobarbital 1M are suboptimal choices. For refractory SE, the induction of general anesthesia is warranted (Table 7). Isoflurane and pentobarbital have demonstrated excellent clinical efficacy in the control of SE. Both anesthetics suppress seizure activity at concentrations that produce few adverse hemodynamic effects. All children requiring general anesthesia should be treated in the critical care setting, with continuous hemodynamic and EEG monitoring.

G

CONCLUSION

nre ac

The morbidity and mortality after an episode of generalized convulsive SE has improved with optimal seizure management; prognosis

1026

TUNIK & YOUNG

I Stabilization I (oxygen, suction, airway management)

~

Presence of Status Epilepticus (continuous seizure activity)

yes

, - - - - - - - - 1 Venous Access Established no Perform Intraosseous - - - - - - - . \ Cannulation or Consider

Mldazolam 1M Diazepam PR Phenobarbital 1M

duration of seizure longer than 60 minutes

Treatment of Refractory Status Epilepticus FIgure 1. An approach to the treatment of seizures.

reflects the severity of underlying neurologic disease that precipitated the seizures. Febrile and idiopathic SE have low associated mortality if optimally managed. Acute eNS injury is still associated with significant mortality. The use of 10 access and 1M administration of effective drugs may circumvent current vascular access problems in children with SE. Midazolam and phenytoin prodrug appear to be such drugs. An organized approach with appropriate stabilization and therapy improves outcome. Despite the literature supporting an aggressive organized approach to generalized tonic-clonic SE, many pediatric residency programs still have incomplete guidelines for its management. 7, 30 References

J, Chevrie JJ: Convulsive status epilepticus in infants and children: A study of 239 cases. Epilepsia 11:187-197, 1970 2. Albano A, Reisdorff EJ, Wiegenstein JG: Rectal diazepam in pediatric status epilepticus. Am J Emerg Med 70:168-172, 1989 1. Aicardi

STATUS EPILEPTICUS IN CHILDREN

1027

3. Berman PH: Management of seizure disorders with anticonvulsant drugs: Current concepts. Pediatr CIin North Am 23:443-456, 1976 4. Bostrom B: Paraldehyde toxicity during treatment of status epilepticus. Am J Dis Child 136:414-415, 1982 5. Brickman KR, Rega P, Guinesi M: A comparative study of intraosseous versus peripheral intravenous infusion of diazepam and phenobarbital in dogs. Ann Emerg Med 16:1141-1144, 1987 6. Browne TR: Paraldehyde, chlormethiazole, and lidocaine for treatment of status epilepticus. In Delgado-Escueta AV, Wasterlain CG, Treiman DM, et al (eds): Status Epilepticus. Advances in Neurology. New York, Raven Press, 1983, pp 509-517 7. Browne TR: The pharmacokinetics of agents used to treat status epilepticus. Neurology 40 (suppl 2):2~32, 1990 8. Browne TR, Davoudi H, Donn KH, et al: Bioavailability of ACC-9653 (phenytoin prodrug). Epilepsia 30(suppl 2):527-32, 1989 9. Carducci B, Hedges JR, Bear JC, et al: Emergency phenytoin loading by constant intravenous infusion. Ann Emerg Med 13:1027-1031, 1984 10. Carter AS, Bell GO, Coady T, et al: Speed of reversal of midazolam-induced respiratory depression by flumazenil: A study in patients undergoing upper GI endoscopy. Acta Anesthesiol Scand 34(suppl 92):5~, 1990 II. Chamberlain JM, Altieri MA, Futterman C et al: Intramuscular midazolam for the treatment of status epilepticus in children [abstract]. Pediatr Emerg Care 6:224, 1990 12. Chameides L: Textbook of Pediatric Advanced Life Support. Dallas, American Heart Association, 1988 13. Chiulli DA, Terndrup TE, Kanter RK: The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus. J Emerg Med 9:13-17, 1991 14. Committee on Drugs: Valproic acid: Benefits and risks. Pediatrics 70:316-319, 1982 15. Cranford RE, Leppik IE, Patrick B, et al: Intravenous phenytoin in acute treatment of seizures. Neurology 29:1474--1479, 1979 16. Crawford TO, Mitchell WG, Fishman LS, et al: Very-high-dose phenobarbital for refractory status epilepticus in children. Neurology 38:1035-1040, 1988 17. Crawford TO, Mitchell WG, Snodgrass SR: Lorazepam in childhood status epilepticus and serial seizures: Effectiveness and tachyphylaxis. Neurology 37:190-195, 1987 18. Crisp CB, Gannon R, Knauft F: Continuous infusion of midazolam hydrochloride to control status epilepticus. CIin Pharm 7:322-324, 1988 19. Delgado-Escueta AV, Wasterlain C Treiman DM, et al: Management of status epilepticus. N Engl J Med 306:1337-1340, 1982 20. Delgado-Escueta A V, Wasterlain C, Treiman DM, et al: Status epilepticus: Summary. In Delgado-Escueta AV, Wasterlain CG, Treiman DM, et al (eds): Status Epilepticus. Advances in Neurology. New York, Raven Press, 1983, pp 537-541 2l. Donovan PI, Cline 0: Phenytoin administration by constant intravenous infusion: Selective rates of administration. Ann Emerg Med 20:139-142, 1991 22. Drugs for Epilepsy. Med Lett Drugs Ther 31:1-4, 1989 23. Dunn DW: Status epilepticus in infancy and childhood. Neurol CIin 8:647-657, 1990 24. Egli M, Albani C: Relief of status epilepticus after 1M administration of the new short-acting benzodiazepine midazolam [abstract 137]. Presented at the 12th World Congress of Neurology, Kyoto, Japan, September 20-25, 1981 25. Eisner RF, Turnbull TL, Howes OS, et al: Efficacy of a "standard" seizure workup in the emergency department. Ann Emerg Med 15:33-39, 1986 26. Evens RP, Fraser DG, Ludden TM, et al: Phenytoin toxicity and blood levels after a large oral dose. Am J Hosp Pharm 37:232-235, 1980 27. Freeman JM: Status epilepticus: It's not what we've been taught [editorial]. Pediatrics 83:444--445, 1989 28. Galvin GM, Jelinek GA: Midazolam: An effective intravenous agent for seizure control. Arch Emerg Med 4:169-172, 1987 29. Giang DW, McBride MC: Lorazepam versus diazepam for the treatment of status epilepticus. Pediatr Neurol 4:35~361, 1988 30. Gushurst CA, Lewis JM: Pediatric residency guidelines for management of status epilepticus. Pediatr Emerg Care 3:71-74, 1987

I

1028

TUNIK & YOUNG

31. Hellstrom-Westas L, Westgren U, Rosen IS, et a1: Lidocaine for treatment of severe seizures in newborn infants. I. Clinical effects and cerebral electrical activity monitoring. Acta Paediatr Scand 77:79-84, 1988 32. Hoppu K, Santavuori P: Diazepam rectal solution for home treatment of acute seizures in children. Acta Paediatr Scand 70:369-372, 1981 33. Ito BM, Sato 5, Kufta CV, et a1: Effect of isoflurane and enflurane on the electrocorticogram of epileptic patients. Neurology 38:924-928, 1988 34. Jamerson BD, Donn KH, Dukes GE, et al: Absolute bioavailability of phenytoin after 3-phosphoryloxymethyl phenytoin disodium (ACC-9653) administration to humans. Epilepsia 31:592-597, 1990 35. Jawad 5, Oxley J, Wilson J, et al: A pharmacodynamic evaluation of midazolam as an antiepileptic compound. J Neurol Neurosurg Psychiatry 49:1050-1054, 1986 36. Jim KF, Lathers CM, Farris VL, et al: Suppression of pentylenetetrazol-elicited seizure activity by intraosseous lorazepam in pigs. Epilepsia 30:480-486, 1989 37. Kaneko 5, Kurahashi K, Fujita 5, et al: Potentiation of GABA by midazolam and its therapeutic effect against status epilepticus. Folia Psychiatrica et Neurologica Japanica 37:307-310, 1983 38. Karavokiros KA, Tsipis GB: Flumazenil: A benzodiazepine antagonist. DICP 24:976981, 1990 39. Klotz U, Kanto J: Pharmacokinetics and clinical use of flumazenil (Ro15-1788). Clin Pharmacokinet 14:1-12, 1988 40. Knudsen FU: Plasma diazepam in infants after rectal administration in solution and by suppository. Acta Paediatr Scand 66:563-567, 1977 41. Koike WA, Snider MT, Young RS, et al: Prolonged low flow isoflurane anesthesia for status epilepticus. Anesthesiology 62:653--656, 1985 42. Koike WA, Young RSK, Davis P, et al: Isoflurane for refractory status epilepticus: A clinical series. Anesthesiology 71:653--659, 1989 43. Lacey DJ, Singer WD, Horwitz SJ, et al: Lorazepam therapy of status epilepticus in children and adolescents. J Pediatr 108:771-774, 1986 44. Lathers CM, Jim KF, Spivey WH: A comparison of intraosseous and intravenous routes of administration for anti seizure agents. Epilepsia 30:472-479, 1989 45. Leppik IE: Status epilepticus. Neurol Clin 4:633--643, 1986 46. Leppik IE: Status epilepticus: The next decade. Neurology 40(suppl 2):4-9, 1990 47. Leppik IE, Boucher R, Wilder BJ, et al: Phenytoin prodrug: Preclinical and clinical studies. Epilepsia 30(suppl 2):522-26, 1989 48. Leppik IE, Boucher BA, Wilder BJ, et al: Pharmacokinetics and safety of a phenytoin prodrug given IV or 1M in patients. Neurology 40:456-460, 1990 49. Lockman LA: Treatment of status epilepticus in children. Neurology 40(suppl 2):4346, 1990 50. Lothman E: The biochemical basis and pathophysiology of status epilepticus. Neurology 40(suppl 2):13-23, 1990 51. McEnvoy GK: American Hospital Formulary Service, Drug Information 91. Bethesda, American Society of Hospital Pharmacists, Inc., 1991, pp 1376-1377 52. McNamara RM, Spivey WH, Unger HD, et al: Emergency applications of intraosseous infusion. J Emerg Med 5:97-101, 1987 53. Manning DJ, Rosenbloom L: Non-convulsive status epilepticus. Arch Dis Child 62:3740, 1987 54. Mayhue FE: 1M midazolam for status epilepticus in the emergency department. Ann Emerg Med 17:643-645, 1988 55. Maytal J, Shinnar 5, Moshe SL, et al: Low morbidity and mortality of status epilepticus in children. Pediatrics 83:323-331, 1989 56. Medina F: Rapid sequence induction/intubation in the pediatric emergency department. International Pediatrics 4:24-29, 1989 57. Meeke RI, Soifer BE, Gelb AW: Isoflurane for the management of status epilepticus. DICP 23:579-581, 1989 58. Meldrum BS, Brierley JB: Prolonged epileptic seizures in primates. Arch Neurol 28:10-17, 1973 59. Meldrum BS, Horton RW: Physiology of status epilepticus in primates. Arch Neural 28:1-9, 1973

STATUS EPILEPTICUS IN CHILDREN

1029

60. Mora CT, Torjman M, White PF: Effects of diazepam and flumazenil on sedation and hypoxic ventilatory response. Anesth Analg 68:473-478, 1989 61. Nypaver MM, Reynolds SL, Tanz RR, et al: Emergency department laboratory evaluation of children with seizures: Dogma or dilemma? Pediatr Emerg Care 8:1316, 1992 62. Opitz A, Marshall M, Degen R, et al: General anesthesia in patients with epilepsy and status epilepticus. In Delgado-Escueta AV, Wasterlain CG, Treiman DM, et al (eds): Status Epilepticus. Advances in Neurology. New York, Raven Press, 1983, pp 531-535 63. Oppenheimer EY, Rosman NP: Seizures and seizure-like states in the child: An approach to emergency medicine. Emerg Med Clin North Am 1:125-140, 1983 64. Orlowski JP, Erenberg G, Lueders H, et al: Hypothermia and barbiturate coma for refractory status epilepticus. Crit Care Med 12:367-372, 1984 65. Pascual I, Sedano MI, Polo JM, et al: Intravenous lidocaine for status epilepticus. Epilepsia 29:584-589, 1988 66. Phillips SA, Shanahan RJ: Etiology and mortality of status epilepticus in children: A recent update. Arch Neurol 46:74-76, 1989 67. Raines A, Henderson TR, Swinyard EA, et al: Comparison of midazolam and diazepam by the intramuscular route for the control of seizures in a mouse model of status epilepticus. Epilepsia 31:313-317, 1970 68. Rashkin Me, Youngs e, Penovich P: Pentobarbital treatment of refractory status epilepticus. Neurology 37:500--503, 1987 69. Rawal K, D'Souza BJ: Status epilepticus. Crit Care Clin 1:339-353, 1985 70. Record KE, Rapp RP, Young AB, et al: Oral phenytoin loading in adults: Rapid achievement of therapeutic plasma levels. Ann Neurol 5:268--270, 1979 71. Reves JG, Fragen RI, Vinik HR, et al: Midazolam: Pharmacology and uses. Anesthesiology 62:310--324, 1985 72. Rothner AD, Erenberg G: Status epilepticus. Pediatr Clin North Am 27:593-602, 1980 73. Seigler RS: The administration of rectal diazepam for acute management of seizures. J Emerg Med 8:155-159, 1990 74. Shaner DM, McCurdy SA, Herring MO, et al: Treatment of status epilepticus: A prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurol 38:202-207, 1988 75. Shields WD: Status epilepticus. Pediatr Clin North Am 36:383-393, 1989 76. Silverman BK: Advanced Pediatric Life Support. Elk Grove Village, IL, American Academy of Pediatrics, 1989 77. Smith RD, Brown BS, Maher RW, et al: Pharmacology of ACC-9653 (phenytoin prodrug). Epilepsia 30(suppl 2):Sl5-21, 1989 78. Snead Oe, Miles MV: Treatment of status epilepticus in children with rectal sodium valproate. J Pediatr 106:323-325, 1985 79. Spivy WH, Unger HD, Lathers CM, et al: Intraosseous diazepam suppression of pentylenetetrazole-induced eleptogenic activity in pigs. Ann Emerg Med 16:156-159, 1987 80. Treiman DM: Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus. Epilepsia 30(suppl 2):54-510, 1989 81. Treiman DM: The role of benzodiazepines in the management of status epilepticus. Neurology 40(suppl 2):32-42, 1990 82. Treiman DW, Walton NY, Wickboldt e, et al: Predictable sequence of EEG changes during generalized convulsive status epilepticus in man and three experimental models of status epilepticus in the rat. Neurology 34:244-245, 1987 83. Uthman BM, Wilder BJ: Emergency management of seizures: An overview. Epilepsia 30(suppl 2):533-537, 1989 84. van Hoogdalem EJ, de Boer AG, Breimer DD: Pharmacokinetics of rectal drug administration, part 1. Clin Pharmacokinet 21:11-26, 1991 85. Vinsel PI, Moore GP, O'Hair KC: Comparison of intra osseous versus intravenous loading of phenytoin in pigs and effect on bone marrow. Am J Emerg Med 8:181183, 1990 86. Wallin A, Nergardh A, Hynning PA: Lidocaine treatment of neonatal convulsions: A therapeutic dilemma. Eur J Clin Pharmacol 36:583-586, 1989

1030

TUNIK & YOUNG

87. Walsh-Kelly CM, Berens RJ, Glaeser PW, et al: Intraosseous infusion of phenytoin. Am J Emerg Med 4:523-524, 1986 88. Walton NY, Treiman DM: Lorazepam treatment of experimental status epilepticus in the rat: Relevance to clinical practice. Neurology 4:990-994, 1990 89. Weinbrum A, Geller E: The respiratory effects of reversing midazolam sedation with flumazenil in the presence or absence of narcotics. Acta Anesthesiol Scand 34(suppl 92):64-69, 1990 90. 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 Neurol 1:511-518, 1977 91. Yamamoto LG, Yim GK, Britten AG: Rapid sequence anesthesia induction for emergency intubation. Pediatr Emerg Care 6:200-211, 1990

Address reprint requests to Michael G. Tunik, MD Pediatric Emergency Services Room 1 South 6 Bellevue Hospital Center First Avenue and 27th Street New York, NY 10016