STATUS EPILEPTICUS

PEDIATRIC CRITICAL CARE: A NEW MILLENNIUM

0031-3955/01 $15.00

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STATUS EPILEPTICUS Usama A. Hanhan, MD, Mariano R. Fiallos, MD, and James P. Orlowski, MD

Status epilepticus (SE) is a common neurologic medical emergency, affecting 65,000 to 150,000 persons in the United States each year?, It may be lifethreatening to the patient and a challenge to the treating physician. It is estimated that 1.3%to 16% of all patients with epilepsy will develop SE at some point in their lives. In some patients, it is the presenting initial seizure. Although definitions of SE have evolved, the main feature of this epileptic state is a continuous seizure lasting longer than 30 minutes or repeating convulsions lasting 30 minutes or longer without recovering consciousness between them. SE is commoner in childhood than in adulthood, and there is no clear sexual predominance. Its onset may be partial (focal) or generalized. This article focuses only on the most dramatic and dangerous type of SE generalized convulsive SE (GCSE). ORIGIN

The cause of SE varies according to the age group studied. In adults, the largest group of patients are those with an underlying seizure disorder in whom SE develops as a result of drug withdrawal or in whom alcohol use is a f a ~ t o r . ~ Other causes include acute central nervous system (CNS) injury, such as stroke, anoxic insults, tumors, and meningitis. In a group of children with SE, Aicardi and Chevrie' reported that 26% of the patients had an acute insult to the CNS or a metabolic disorder and that 21% had an underlying chronic seizure disorder or static encephalopathy. In this group of children, sudden discontinuation of antiepileptic medications and fever were the commonest precipitants. The remaining 53% had no apparent cause. Of this group of patients, however, fever was thought to have provoked the SE in half. In another study, Maytal et all3 reported that approximately one fourth of From the Division of Pediatrics, Department of Critical Care Medicine, University Community Hospital, Tampa (UAH, MRF, PO); Department of Pediatrics, NOVA Southeastem University, Ft. Lauderdale (UAH); and Department of Pediatrics, Critical Care, and Medical Ethics, University of South Florida, Tampa, Florida (JPO)

PEDIATRIC CLINICS OF NORTH AMERICA

VOLUME 48 NUMBER 3 JUNE 2001

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children with SE had fever as the precipitant event; one fourth had a previous neurologic problem; one fourth had an acute symptomatic event, such as anoxia, trauma, hemorrhage, anticonvulsant withdrawal, or CNS infection; and one fourth had no apparent cause of SE. MORTALITY AND MORBIDITY The outcome of SE varies according to the age of the patient, the underlying cause of the SE, and the duration, with the risk for complications increasing substantially if the GCSE lasts longer than 60 minutes. Some early studies3,25 suggested that the mortality rate among people with SE ranged from 6% to 30%. Death can be caused by the underlying disease or result from respiratory, cardiovascular, or metabolic complications. In addition, a significant proportion of patients recovering from SE demonstrate residual neurologic abnormalities. One reviewI3 of morbidity and mortality rates among children with SE showed neurologic complication rates of 29% among infants younger than 1 year, 11%among children ages 1 to 3 years, and 6% among children older than 3 years of age. In 30% of patients, a chronic seizure disorder developed. The mortality rate was approximately 3%. It seems that, in general, infant and younger children tend to exhibit a higher risk for neurologic sequelae, which may include mental retardation, behavioral disorders, focal motor deficits, and chronic epilepsy, than older children." This higher risk among infants may reflect the increased frequency of severe, acute neurologic insults causing SE in infants. SYSTEMIC COMPLICATIONS DURING GENERALIZED CONVULSIVE STATUS EPILEPTICUS Several systemic changes occur during tonic-clonic seizures. Some of these changes, if prolonged, can be life-threatening and undoubtedly contribute to the morbidity and mortality of patients with SE. Early recognition, appropriate intervention, and prevention of such complications are imperative during treatment of SE. Hypoxia is a common occurrence in patients with SE. It is a result of impaired ventilation, excessive salivation, tracheobronchial secretions, and increased oxygen consumption. Hypoxia is responsible for most of the complications seen in SE. Brain adenosine triphosphate is depleted to the greatest degree during seizures associated with hypoxia. In addition, brain glucose levels are reduced significantly only when prolonged seizures are accompanied by hypoxia.17 Furthermore, seizures during hypoxia result in the greatest degree of lactic acidosis, the highest brain lactate levels, and the lowest brain intracellular pH levels.z6Hypoxia, in combination with the insults of prolonged seizures and acidosis, results in impaired cardiac ventricular function, reduced cardiac output, and hypotension, further compromising neuronal and tissue cell function. Metabolic and respiratory acidosis are also common. The respiratory acidosis is the result of mechanical impairment of ventilation by the tonic-clonic activity, secretions, and increased metabolic production of carbon dioxide. The metabolic acidosis is mainly a lactic acidosis from impaired tissue oxygenation and perfusion in the face of increased metabolic needs and energy expenditure. With the onset of SE, there is massive catecholamine release and sympathetic discharge resulting in increased blood pressure, heart rate, and central venous pressure. There is also an increase in cerebral blood flow (CBF) in the range of

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200% to 7oo%.15 This increase in CBF is presumably compensatory for the increased metabolic needs of the brain. As the seizure persists, however, blood pressure tends to decrease, often to hypotensive levels. CBF also is reduced, although it remains higher than normal levels. As seizure activity continues, the brain metabolic rate remains high. The observed increase in CBF, however, is incapable of supplying adequate substrate and oxygen to meet the increased cerebral metabolic demands. Furthermore, animal studies9suggest that, although cerebral oxygen delivery seemed to be adequate to meet metabolic demands during the initial seizure, prolonged seizures were not accompanied by an increase in oxygen delivery and therefore compromised cortical oxygenation. Intracranial pressure also increases early in SE and remains elevated throughout prolonged seizures. Brain edema becomes a risk because cerebral demands exceed supply, especially in the presence of hypoxia, acidosis, hypotension, and a nonautoregulated cerebral vascular bed. Cerebral herniation has been observed in animal studies.15 Serum glucose levels also change during prolonged seizures. Within the first few minutes of a seizure and as a result of the massive adrenergic discharge, blood glucose levels increase and may remain elevated for 15 to 40 minutes. Prolonged seizures often are accompanied by hypoglycemia, however. In patients with uncontrolled seizures, generalized muscular contractions are responsible for an increase in body temperature and even hyperpyrexia. Prolonged seizure activity also results in hyperkalemia; increased muscle enzymes, especially creatinine phosphokinase; and myoglobinuria caused by rhabdomyolysis. In combination with hypotension and severe metabolic acidosis, myoglobinuria may compromise renal function, resulting in acute renal failure. Peripheral blood leukocytosis is another common finding, occurring in 50% to 60% of patients: even in the absence of infection, potentially resulting in some diagnostic confusion. Also, minimal cerebrospinal fluid pleocytosis, which also can complicate the differential diagnosis by suggesting meningitis or encephalitis as a cause of the SE, has been observed in 10% to 15% of patients.'j PATHOPHYSIOLOGY OF STATUS EPILEPTICUS

The basic pathophysiology of SE involves failure of the mechanisms that normally prevent isolated seizures. This failure can OCCLU when the stimuli producing seizures are overwhelming and excessive or when the intrinsic mechanisms that inhibit or terminate seizures are ineffective. Excitatory neurotransmitters that have a major role in SE include glutamate, aspartate, and acetylcholine, and the dominant inhibitory neurotransmitter is gamma-aminobutyric Neuronal inhibitory mechanisms include the calcium ion (Ca+z)-dependentpotassium ion (K+) current and the blockage of N-methyl-d-aspartate (NMDA) channels by magnesium ions (MgZ+).The NMDA-linked channels seem to be particularly important in the pathogenesis of neuronal damage in SE.lZWhen these neuronal cells are depolarized, the Mg2+ blocking the channel diffuses outward, allowing sodium ions (Na2+)and Caz+to flood the cell, resulting in a cascade of Ca +rmediated cytotoxic events, leading to neuronal injury, cell lysis, and cell death. The destruction triggered in this manner may be reversible if SE is terminated within the first hour. Evidence also shows that heat-shock protein (72 kDa, HSP-72) is induced in some neurons in SE and that it may have a neuroprotective role.23Although prolonged seizures may be sufficient to cause neuronal cell injury, the superimposition of hypoxia, hypotension, acidosis, and hyperpyrexia exacerbate the degree of damage to the CNS.

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MANAGEMENT

The main goals of the treatment of SE are to (1) maintain adequate vital functions with prevention of systemic complications, (2) terminate the seizure activity safely and quickly while minimizing treatment-related morbidity, and (3) evaluate and treat any underlying causes. The management of patients with SE requires prompt intervention. As with any other acute medical emergency, the initial goals of therapy are maintenance of adequate airway, breathing, and circulation, with particular attention to preventing hypoxia. Accordingly, the first step in management, before attempting to stop the seizures, is providing adequate oxygenation. The patient should be positioned to avoid aspiration and physical injury. Airway patency may be maintained by a plastic oral airway device or a nasopharyngeal device, if tolerated. Tongue blades or other foreign metal objects in the mouth should be avoided because they can cause severe oral injury. Oxygen should be administered by a nasal cannula or a nonrebreathing mask. Patients with SE are continuously at risk for respiratory failure and inadequate ventilation, and many of the drugs used to terminate seizures are respiratory depressants. Therefore, the treating physician continuously and repeatedly must assess adequacy of oxygenation and ventilation and be prepared to intervene and intubate the patient at any time if there is any clinical or laboratory indication of respiratory insufficiency or if the SE becomes refractory to the standard therapy. If intubation becomes necessary, the rapid-sequence technique should be used. Some patients with SE require muscle relaxants to facilitate mechanical ventilation. In these patients, clinical seizure activity no longer can be used to guide and titrate anticonvulsant therapy, and continuous EEG monitoring should be considered. Maintenance of airway, breathing, and circulation is assessed best by direct physical examination, vital signs, and monitoring of the electrocardiogram (ECG) and pulse oximetry. The next steps in management are to establish a secure intravenous catheter for obtaining blood samples for laboratory studies and to administer intravenous fluids and anticonvulsant drugs. The patient should have a rapid determination of the blood glucose level at the bedside. Other initial laboratory studies should include serum chemistries and electrolytes, blood gases, pH level, calcium and magnesium levels, and a complete blood cell count. In addition, blood samples for toxicology screens, liver function, blood cultures, and anticonvulsant levels should be collected and some blood kept for additional testing if indicated later. Several crucial laboratory studies can be performed at the bedside using point-of-care (POC) testing systems, including measurement of blood gases, electrolytes, calcium, and glucose, which enables the treating physician to treat and correct any abnormalities promptly. If hypoglycemia is found or suspected, 2 mL/kg of 25%dextrose solution should be administered. Maintenance intravenous fluids should be started next, unless the patient clearly is dehydrated. Metabolic acidosis is common among patients with SE, and it usually resolves after seizure control has been achieved. If however, the patient is in shock or hypotensive, intravenous fluid resuscitation and pressor therapy should be administered. Intravenous bicarbonate therapy rarely is necessary. The initial stabilization phase of patients with SE usually is accomplished within the first 10 minutes after presentation to the emergency department. Specific anticonvulsant therapy then is initiated. Although the definition of SE incorporates a 30-minute duration, which is useful for research and publications, it can be misleading in terms of treatment

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decisions. According to the Working Group on Status Epilepticus of the Epilepsy Foundation of America, patients with seizures lasting more than 10 minutes should be treated. Most self-limiting generalized convulsions stop within 3 minutes, and almost all stop by 5 minutes from onset.*O Furthermore, early therapy is far more effective than is delayed therapy, so the longer the seizures persist, the more difficult they are to stop. Therefore, patients seizing for 10 minutes should be treated on the assumption that they are in SE. Several drugs are effective in the treatment of SE. The timing, route, and adequacy of dosages of the medications used are probably more important than is the choice of drugs in determining success of therapy. Although the use of a single drug of sufficient dosage always is preferred, often, more than one agent is needed to achieve all of the therapeutic goals. The treating physician must be familiar with the various medications used and their possible side effects, including respiratory and cardiovascular depression, and be prepared to manage these side effects. If possible, the drugs should be administered intravenously. Intramuscular injections should be avoided because they may produce uncertain blood levels. If intravenous access cannot be achieved in a timely manner, other emergency alternatives exist for treating patients with SE. In critical situations, some anticonvulsant drugs, including diazepam, valproate, thiopental, and paraldehyde can be administered per rectum, and adequate drug levels can be obtained. In one study,18buccal midazolam was found to be as effective as rectally administered diazepam in the acute treatment of seizures. Probably the best emergency alternative to intravenous access in patients with critical, prolonged SE is the intraosseous route. Benzodiazepines, barbiturates, and phenytoin are effective when administered by the intraosseous route. Furthermore, intravenous fluids and pressors can be administered by the intraosseous route to resuscitate the patient until a secured intravenous access is obtained. The goals of anticonvulsant therapy in SE are to achieve cessation of clinical and electrical seizure activity and prevent its recurrence. The most commonly used drugs for the initial treatment of SE include lorazepam, diazepam, phenytoin, and phenobarbital. Other drugs that have been used to treat SE and prolonged seizures include midazolam, fosphenytoin, intravenous valproic acid, and propofol. Advantages and disadvantages, doses, onset of action, rate of administration, and possible side effects of these agents are outlined in the following paragraphs and in Tables 1 and 2 . When a drug is selected to be used, sufficient time must be allowed for the drug to act before more of the same medication or another medication is used. If a single agent does not control the seizures, a second drug may be needed. If the combined effects of several drugs do not achieve cessation of seizures, alternative, aggressive treatment, including high-dose phenobarbital, thiopental, or intravenous or general anesthesia to induce electrocerebral silence, should be considered. In such patients with refractory SE, other contributing causes, such as an unrecognized metabolic disorder or toxin, must be considered.

Benzodiazepines The benzodiazepines are effective, highly potent, and rapidly acting antiepileptic agents. They also are administered easily and are effective in controlling generalized and partial seizures and therefore often are preferred as initial therapy for SE.

20 mg/kg

15-20 mg PE/kg

20 mg/kg

Phenytoin

Fosphenytoin

Phenobarbital

Rate of Infusion

2 mg/kg/min (max, 30 mg/min)

1 mg/kg/min (max, 50 mg/min) 3 mg/kg/min (max, 150 mg/min)

0.5-2 mg/min

2 mg/min

1000 mg/dt

1500 m g / d t

1500 m g / d t

4 mg

10 mg*

~

Maximum Single Dose

*May require less of initial dose if seizure terminates before completing the dose. tMonitor drug levels. IV = intravenous; N/S = normal saline; BP = blood pressure; ECG = electrocardiogram.

0.05-0.1 mg/kg

Lorazep am

Initial IV Dose

0.3 mg/kg

Diazepam

Drug

Remarks

Sedation, apnea, respiratory depression, hypotension; must be followed by phenytoin loading Same side effects as diazepam; may repeat after 5-7 min if needed Cardiovascular collapse with rapid IV infusion; arrhythmias, hypotension; mix only with N/S Require BP and ECG monitoring; same side effects as phenytoin, less risk for hypotension and phlebitis; limited pharmacokinetic data in children Hypotension and respiratory depression, especially if used after benzodiazepines

Table 1. ANTIEPILEPTIC DRUGS USED IN THE MANAGEMENT OF STATUS EPILEPTICUS IN CHILDREN

IV = intravenous; EEG

= electroencephalography.

1-3

Propofol 2-10 mg/kg/h

1 pg/kg/min

0.15

Midazolam

Maintenance Infusion

0.5-5.0 mg/kg/h

Initial IV Dose (mgkg)

Pentobarbital

Drug

Table 2. DRUGS USED IN THE MANAGEMENT OF REFRACTORY STATUS EPILEPTICUS

Increase as needed every 15 min; respiratory depression; fewer hemodynamic adverse effects than pentobarbital Rapid infusion can cause apnea; fewer hemodynamic adverse effects than pentobarbital; quick recovery time

(EW

Significant respiratory and hemodynamic adverse effects; titrate drip to seizure control or burst suppression

Remarks

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Diazepam Diazepam is highly lipid soluble and appears in the brain as quickly as 1 minute after injection, with a median time to terminate a seizure of 2 minutes. Its antiepileptic effect, however, lasts only 20 to 30 minutes. In children, the initial dose is 0.3 mg/kg intravenously over 2 minutes (maximum, 10 mg). Because of its short antiepileptic effect, if diazepam is used to treat SE, a longer-acting agent, such as phenytoin, fosphenytoin, or phenobarbital, must be administered. Diazepam administered per rectum (0.5 mg/kg) is valuable in premonitory SE when intravenous access or intravenous injections are unavailable. Lorazepam Lorazepam is less lipid soluble than is diazepam, but it is almost as fast as diazepam in controlling seizures, with a median time to end a seizure of 3 minutes. Unlike diazepam, lorazepam has a long antiepileptic effect (12-24 h), giving lorazepam an important advantage over diazepam as initial therapy for SE. If seizures are controlled with lorazepam, it becomes less imperative to use additional long-acting drugs immediately, such as phenytoin or phenobarbital, to maintain seizure control. The dose in children is 0.1 mg/kg intravenously (maximum, 4 mg). It is infused over 1 or 2 minutes and may be repeated in 5 to 7 minutes, if needed. Like diazepam, its likelihood of effectiveness decreases if multiple dosages have been unsuccessful. Adverse effects of benzodiazepines include respiratory depression, apnea, and hypotension. Phenytoin and Fosphenytoin

Phenytoin is an efficacious, long-acting agent that has been used widely for more than 20 years in the treatment of acute and chronic seizures in children. The drug is administered at a dose of 20 mg/kg, infused slowly at a rate not to exceed 1 mg/kg/min in children or 50 mg/min in adolescents. Its antiepileptic effect may be delayed for 10 to 30 minutes, which usually necessitates the prior use of a rapid-acting agent, such as diazepam or lorazepam. Side effects include hypotension and arrhythmias, partly related to the propylene glycol diluent. These side effects are uncommon in children and can be minimized by slowing the infusion rate. Fosphenytoin is a new, water-soluble phosphate ester of phenytoin that rapidly is converted to phenytoin by nonspecific serum phosphatases. In contrast to phenytoin, fosphenytoin can be administered intramuscularly with rapid and complete absorption. The dose of fosphenytoin is expressed in phenytoin equivalents (PEs) and is 15 to 20 mg/kg of PE/kg, infused at a rate of no more than 3 mg/kg/min, not to exceed 150 mg/min, which is threefold the maximum rate for phenytoin. Although it can be infused faster than phenytoin, it is likely that phenytoin and fosphenytoin have similar time to antiepileptic effect. Phlebitis and soft tissue damage are less common with fosphenytoin, but its primary disadvantage is cost. Fosphenytoin can cost as much as 20-fold more than phenytoin. Phenobarbital

Phenobarbital is a potent, long-acting antiepileptic agent that has been used for many years in the treatment of seizures. It is a depressant drug and can lead

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to sedation and respiratory difficulties, especially when administered after a benzodiazepine. For these reasons, it usually is considered second to phenytoin as a long-acting agent and usually is recommended only when benzodiazepines and phenytoin are ineffective. The dose is 20 mg/kg, infused at a rate not to exceed 30 mg/min. Respiratory and hemodynamic support should be available immediately during and after the infusion. Some investigators4have found that using increased doses of phenobarbital, at increments of 10 mg/kg every 30 minutes, was successful in controlling ongoing seizures and achieving high blood levels of 70 to 370 kg/mL without the need for intubation. Furthermore, this treatment commonly avoids the need for therapy with multiple agents. One randomized, double-blind, clinical trialz1 comparing phenobarbital alone, phenytoin alone, diazepam followed by phenytoin, and lorazepam alone showed that all the treatments were equally effective, except that lorazepam alone was more effective than was phenytoin alone, and that, although lorazepam was no more efficacious than was phenobarbital or the combination of diazepam and phenytoin, it was easier to use. This study suggests that treatment with lorazepam alone as the first-line drug may be the preferred treatment in many cases. REFRACTORY STATUS EPILEPTICUS

Most cases of SE can be treated successfully with first-line medications (e.g., diazepam, lorazepam, phenytoin, and phenobarbital); however, a few patients continue to have persistent seizure activity for longer than 60 minutes despite adequate doses of first-line medications. Such patients are considered to be in refractory SE (RSE), and escalation of therapy with the administration of a barbiturate or nonbarbiturate anesthetic agent then is recommended, with the therapeutic endpoint of achieving seizure control, electrocerebral silence, or both. The optimal management of such patients remains unclear, and large, controlled studies comparing the various agents are lacking. All patients in refractory SE must be managed in a pediatric intensive care unit, with aggressive monitoring of their hemodynamic and respiratory status and continuous EEG monitoring. The most commonly used agent for treating RSE is intravenous pentobarbital, a short-acting barbiturate with a rapid onset of action, given as a bolus of 5 to 15 mg/kg followed by an infusion of 0.5 to 5.0 mg/kg/h. Although effective in terminating seizures and inducing a burst suppression pattern on EEG, pentobarbital administration commonly is associated with significant hypotension, myocardial depression, and low cardiac output. It is a potent respiratory depressant, and these patients usually are intubated and mechanically ventilated before initiation of therapy with this drug and often require indwelling catheters to monitor central venous and arterial pressures. Inotropic agents usually are needed to support the blood pressure and cardiac output. Other side effects include pulmonary edema, ileus, and delayed neurologic recovery. Because of these disadvantages, alternative agents in the treatment of RSE have been sought. Large, controlled, comparative studies of the various agents still are needed. Some of these medications are discussed here. The recommendations for their use are largely dependent on anecdotal case reports and small, uncontrolled studies. MIDAZOLAM

Midazolam is a water-soluble imidazole benzodiazepine with a short elimination half-life of 1.5 to 3.5 hours. Commonly used as a sedative hypnotic and

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anesthetic agent, midazolam possesses potent antiepileptic effects. It can be administered by the intravenous, intranasal, oral, rectal, or intramuscular routes. At physiologic pH, it becomes extremely lipophilic, with a rapid onset of action. Its action, however, is short-lived, necessitating continuous intravenous infusion after the initial bolus dose to maintain the desired effects. Its effectiveness in the treatment of RSE has been documented in several reports.8,lo,l6 The initial bolus dose of 0.15 mg/kg is followed by continuous intravenous infusion of 1 pg/kg/min, with increasing increments of 1 pg/kg/ min every 15 minutes until seizure control has been achieved. In one study,’6 midazolam was found to be successful in terminating RSE in 24 out of 24 children, with an average time to seizure control of 47 minutes (range, 15.0 min4.5 h) and a mean infusion rate of 2.3 pg/kg/min (range, 1-18 pg/kg/ min). Similar findings also have been reported in an additional 20 children.1° More important, midazolam was well tolerated by all patients in these studies with no clinically significant cardiovascular changes, which is a major advantage over traditional pentobarbital-induced coma. Nevertheless, clinical experience with midazolam in the treatment of RSE is limited. Furthermore, some interesting questions have been raised, including: Why would midazolam successfully terminate SE when diazepam or lorazepam has failed to do Does midazolam possess unique or additional antiepileptic activity compared with other benzodiazepines? Would it be a suitable first-line drug? Whether midazolam can be a suitable first-line agent in the treatment of acute seizures and SE is unclear. Its potent antiepileptic effect, relative safety record, and ease of administration by various routes clearly makes midazolam a potentially important and useful drug in the treatment of SE inside and outside of the hospital. Clearly, its optimal dosing, safety, and clinical usefulness in various settings need further evaluation.

INTRAVENOUS PROPOFOL

Propofol is a highly effective, intravenous, nonbarbiturate, anesthetic agent originally approved for rapid induction and maintenance of anesthesia. In addition to its anesthetic, hypnotic, and sedative effects, propofol also has anticonvulsant properties. It is highly lipid soluble with a rapid onset of action and quick recovery time. Its efficacy in the treatment of RSE has been demonstrated in several case reports and few small studies.2 It usually is administered in an intravenous bolus of 1 to 3 mg/kg followed by a continuous infusion of 2 to 10 mg/kg/h. Cessation of seizure activity or inducement of burst suppression occurs within seconds after administration. Adverse effects include bradycardia, apnea, hypotension with rapid infusion, and hypertriglyceridemia after prolonged use. The cardiovascular adverse effects are significantly fewer than those observed with pentobarbital coma. Despite its anticonvulsant properties, propofol causes seizures in some anesthetic situations. In addition, a few cases of unexplained metabolic acidosis in children receiving propofol infusions have been reported, although no definite causal link to propofol has been established in these cases. The rapid onset of action, ease of titration, brief time to recovery and fewer cardiovascular adverse effects of propofol make it a potentially useful drug in treating RSE, and it deserves further evaluation.

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INTRAVENOUS VALPROIC ACID Valproic acid is one of the primary antiepileptic agents, with a broad range of efficacy in partial and generalized seizures in children. An intravenous formulation has become available in the United States and is indicated as a short-term replacement when oral medications cannot be administered to patients already receiving valproic acid treatment for their seizures. The drug is also useful in patients requiring rapid attainment of therapeutic valproic acid levels because of inadequate seizure control. The recommended dose is 15 to 20 mg/kg intravenously. The efficacy of valproic acid in treating RSE has been reported in 41 children who failed to respond to first-line anticonvulsants (diazepam, 0.2 mg/kg; phenobarbital, 20 mg/kg; and phenytoin, 20 mg/kg).22 A loading dose of 20 to 40 mg/kgZ2was used (diluted 1:l with normal saline or 5% dextrose in water) administered over 1 to 5 minutes (repeated after 10-15 min if necessary), followed by an intravenous infusion of 5 mg/kg/h. The overall success rate was 78%. Approximately 66% of the patients responded immediately (within 6 minutes) after the initial bolus. Success rate varied according to the type of SE and the loading dose used, with the highest success rate (90%) in patients with generalized tonic-clonic SE and a loading dose of 30 to 40 mg/kg. The drug was well tolerated with no systemic or local side effects. In another case report,” however, significant hypotension was believed to be associated with intravenous valproic acid when given to a child in SE. Although intravenous valproic acid has not been approved yet by the US Food and Drug Administration for treating SE, its wide spectrum of anticonvulsant activity, less sedating effect, and relatively good cardiovascular safety profile make it a potentially useful adjunct or alternative for the treatment of refractory generalized SE. Clinical trials are limited, however, and further evaluation of its optimum dosing, use, and safety record in various clinical settings is unclear. SUMMARY Status epilepticus is a serious medical emergency that requires prompt and appropriate intervention. Maintenance of adequate vital function with attention to airway, breathing, and circulation; prevention of systemic complications; and rapid termination of seizures must be coupled with investigating and treating any underlying cause. In most patients with SE, the use of adequate dosages of first-line antiepileptic agents allows for the successful and rapid termination of SE and avoidance of potential neurologic complications. Refractory SE requires more aggressive treatment, often the use of intravenous anesthetic agents and intense monitoring, and therefore must be managed in a pediatric intensive care unit with a multidisciplinary approach. Large, controlled, multicenter, comparative studies are needed urgently to clarify better the optimal management of these patients.

References 1. Aicardi J, Chevrie JJ: Convulsive status epilepticus in infants and children. Epilepsia 111187-197, 1970 2. Brown LA, Levin GM: Role of propofol in refractory status epilepticus. Ann Pharmacother 32:1053-1059,1998

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3. Celesia GG: Prognosis in convulsive status epilepticus. Adv Neurol 34:55, 1983 4. Crawford TO, Mitchell WG, Fishman LS, et a1 Very high dose phenobarbital for refractory status epilepticus in children. Neurology 38:1035, 1988 5. DeLorenzo RJ, Pellock JM, Towne AR, et al: Epidemiology of status epilepticus. J Clin Neurophysiol 12:31&325, 1995 6. D m DW Status epilepticus in children: Etiology, clinical features, and outcome. J Child Neurol 3:167, 1988 7. Hauser WA Status Epilepticus: Epidemiologic considerations. Neurology 4O(suppl 2):9-13, 1990 8. Igartua J, Silver P, Maytal J, et al: Midazolam coma for refractory status epilepticus in children. Crit Care Med 271982-1985, 1999 9. Kreisman NR, LaManna JC, Rosenthal M, et a1 Oxidative metabolic responses with recurrent seizures in rat cerebral cortex: Role of systemic factors. Brain Res 218:175, 1981 10. La1 Koul R, Raj Aithala G, Chacko A, et a1 Continuous midazolam infusion as treatment of status epilepticus. Arch Dis Child 76445448, 1997 11. Lombroso CT: Prognosis in neonatal seizures. Adv Neurol 34101, 1983 12. Lothman E: The biochemical basis and pathophysiology of status epilepticus. Neurology 4O(suppl2):333, 1990 13. Maytal J, Shinnar S, Moshe SL, et al: Low morbidity and mortality of status epilepticus in children. Pediatrics 83:323-331, 1989 14. Maytal J: The management of status epilepticus in children. Childs Hosp Q 3255263. 1992 15. Meldrum BS, Brierly J B Prolonged epileptic seizures in primates. Arch Neurol 28:10, 1973 16. Rivera R, Segnini M, Baltodano A, et a 1 Midazolam in the treatment of status epilepticus in children. Crit Care Med 21:991-994, 1993 17. Sapolsky RM, Stein BA Status epilepticus: Induced hippocampal damage is modulated by glucose availability. Neurosci Lett 97157,1989 18. Scott RC, Besag FM, Neville BG: Buccal midazolam and rectal diazapam for treatment of prolonged seizures in childhood and adolescence: A randomized trial. Lancet. 353:623-626, 1999 19. Tasker RC: Emergency treatment of acute seizures and status epilepticus. Arch Dis Child 79:78-83, 1998 20. Theodore W, Porter R, et al: The secondarily generalized tonic-clonic seizures: A videotape analysis. Neurology 41:1403-1407, 1994 21. Treiman DM, Meyers PD, Walton NY, et al: A comparison of four treatments for generalized convulsive status epilepticus: N Engl J Med 339:792-798, 1998 22. Uberall MA, Trollmann R, Wunsiedler U, et al: Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology 54:218&2189,2000 23. Wasterlain CG, Fujikasw DG, Penix L, et a1 Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 34(supp1 1):37, 1993 24. White JR, Santos CS: Intravenous valproate associated with significant hypotension in the treatment of status epilepticus. J Child Neurol 14:822-823, 1999 25. Yager Jy Cheang M, Seshia SS: Sfatus epilepticus in children. Can J Neurol Sci 15:402, 1988 26. Young RS, Briggs RW, Yagel SK, et al: 31P Nuclear magnetic resonance study of the effect of hypoxemia on neonatal status epilepticus. Pediatr Res 20:581, 1986

Address rqrint requests to Usama A. Hanhan, MD Pediatric Intensive Care Unit University Community Hospital 3100 E. Flecher Avenue Tampa, FL 33613