Volume I:
First Thirty Minutes
- Section 1
  Acute Care Algorithm/ Treatment Plans/ Acronyms
- Section 2
  Universal Approach
  - CALS Universal Approach To Emergency Advanced Life Support
- Section 3
  Steps 1-6
- Section 4
  Preliminary Impression/Focused Clinical Pathways
Volume II:
Resuscitation Procedures
Volume III:
Definitive Care

Neurology 1: Status Epilepticus Portal

Introduction
Status epilepticus is an emergency associated with substantial morbidity and mortality. Between 100 000 and 200 000 cases of status epilepticus occur each year in the United States^{1, 2} with an overall mortality rate of 21% to 22%.³ In more than 50% of cases, status epilepticus is the patient's first seizure. Often, status epilepticus is not part of a seizure disorder but is a response to an acute cerebral insult. Although appropriate and timely therapy reduces the associated morbidity and mortality, the ultimate prognosis is more closely correlated with the etiology of the seizure and any other associated conditions. Prolonged seizure activity in the brain can cause irreversible neuronal damage. There appears to be a 30-minute period during which these changes may be reversible, but after longer seizures, neuronal death is likely.⁴

Definition of Status Epilepticus
There is not a single definition of status epilepticus that is accepted by all authorities. The International Classification of Epileptic Seizures defines status epilepticus as a seizure that “persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur.”^{5, 6, 7} Since this definition is rather arbitrary, many publications have defined status epilepticus as seizures that persist for 20 to 30 minutes, which is the estimated duration of seizures that will cause CNS neuronal injury.⁶ This definition, while being more specific, is not very practical as a guide for treatment. Thus a more useful operational definition of status epilepticus is: “either continuous seizures lasting at least 5 minutes or 2 or more discrete seizures between which there is incomplete recovery of consciousness.”⁶

The most common and the most dangerous type of status epilepticus is generalized convulsive status epilepticus, but status epilepticus may be exhibited as repeated partial seizures or even as a nonconvulsive seizure.

Nonconvulsive status epilepticus may be manifested by abnormal mental behavior of a variety of types such as aphasia, confusion, or coma. Most people who present with nonconvulsive status have a history of epilepsy or have manifested a more conventional epileptic feature at some point during or preceding the presentation. For example, a patient may present with a single convulsion observed at home but then remain confused for many hours. Continuing nonconvulsive status epilepticus should be suspected under such circumstances. An EEC is the diagnostic test of choice.

The term acute repetitive seizures is used for a patient with epilepsy who has many seizures, or clusters of seizures, in rapid sequence. If these are not treated promptly, these may evolve into status epilepticus.⁴

Incidence, Epidemiology, and Etiology
Over half of patients with status epilepticus have not had a previous seizure. Although the majority of patients who exhibit status epilepticus have some precipitating cause, in approximately 1/3 of cases, the status epilepticus is idiopathic and occurs without provocation in an otherwise neurologically normal person (either as part of an established seizure disorder or as a first seizure).⁵An alteration in antiepileptic drug levels or seizure threshold can precipitate an increase in patients who have been stable on antiepileptic drugs for a long time. Missed doses can result in breakthrough seizures. The liver metabolizes most antiepileptic drugs. Other prescription drugs, over-the-counter (OTC) drugs, herbal products, or the use of alcohol and tobacco can alter antiepileptic drug levels and result in seizures or toxicity.⁴ Seizure thresholds can be altered by concomitant medical illnesses, drugs (like the powerful central nervous system stimulant ephedrine found in many OTC medications), stress, loss of sleep, and other factors.⁴

Diagnostic Studies
Perform initial diagnostic studies in conjunction with initial therapeutic measures. Draw blood for CBC, glucose, sodium, calcium, magnesium, BUN, and anti-epileptic drug levels. Obtain urine and blood samples for toxicological screening. Monitor ABGs or oximetry to assure that the patient is adequately oxygenated. All patients in status epilepticus develop acidosis, but this usually resolves promptly when status terminates. Obtain pH determination if the status epilepticus lasts longer than 30 minutes or if the patient is hypotensive.

CNS infection is a consideration in any patient with status epilepticus, (PEDS:) especially in young children with a fever. If CNS infection is suspected on clinical grounds, perform a LP unless a contraindication is present. Contraindications may include suspected intracranial hypertension, suspected cerebral mass lesion, or obstructed CSF flow (eg, hydrocephalus). In adults (PEDS: and occasionally in children over 1 year of age), perform a CT scan before the LP (except in those cases where suspicion of CNS infection is high). If you suspect meningitis but a LP cannot be performed promptly, administer antibiotics immediately rather than delaying until a CT and a LP can be obtained.⁵ Approximately 1/5 of patients who experience status epilepticus have CSF pleocytosis with WBC counts of up to 80 cells/mm³ (so-called benign post-ictal pleocytosis).⁸ Although the presence of WBCs in CSF is usually not due to a CNS infection, treat patients with a CSF pleocytosis for suspected meningitis until the diagnosis is excluded by culture or other means.

Diagnostic studies to consider in the patient stabilization phase after the status epilepticus is controlled include EEG, brain imaging studies such as a CT scan or MRI scan, and liver function tests.

Treatment of Convulsive Status Epilepticus
Status epilepticus can result in brain damage or death and therefore must be terminated as soon as possible. The longer the status epilepticus continues, the harder it is to control the seizure with medications.⁹

Immediate Treatment Concerns
The definition of status epilepticus is controversial. Some say it cannot be diagnosed until a seizure has lasted 30 minutes. However, in practice, whenever a patient’s seizure has lasted over 5 minutes, consider anti-epileptic drug therapy.⁵

Airway and Oxygenation: Cerebral hypoxia can be a cause and a consequence of status epilepticus. Severe hypoxia potentiates hypotension-induced cerebral hypoperfusion and accelerates neuropathological damage.
1. Open the airway by positioning the head and jaw.
2. Suction the airway as needed.
3. Place an oral airway if possible.
4. Administer oxygen per nasal cannula/mask or ventilate with a BVM. If ET intubation is needed, the convulsive motor activity must first be stopped to avoid patient injury. This can be accomplished with either an anti-convulsive medication or by muscular paralysis. Note: Occasionally, neuromuscular blocking agents will need to be used to deal with the systemic effects of seizures such as fractures, acidosis, rhabdomyolosis, or hyperthermia. Neuromuscular paralysis without the administration of effective antiepileptic drug is inappropriate in patients with status epilepticus because sustained brain electrical discharges continue—even in a paralyzed patient—and cause irreversible brain damage.⁵ Therefore, the use of neuromuscular blocking agents in patients with status epilepticus mandates that continuous EEG monitoring guide the adequacy of the antiseizure drug treatment.

Glucose and Thiamine: Hypoglycemia is a rare cause of status epilepticus, but many factors result in early hyperglycemia, which promotes insulin secretion. This causes later (usually after 2 hours) secondary hypoglycemia. Therefore, all patients with status epilepticus need a prompt glucose determination or, if the glucose level is unable to be determined, glucose IV. The treatment of hypoglycemia in the adult consists of first giving thiamine 100 mg IV followed by a 50 mL IV bolus of 50% glucose. PEDS: In children, the treatment of hypoglycemia consists of the use of 25% glucose at a dose of 2 mL/kg. For neonates, use 10% glucose at a dose of 2 to 4 mL/kg.

Blood Pressure: During status epilepticus, cerebrovascular resistance falls and cerebral autoregulation is impaired, making cerebral perfusion dependent on systemic BP. Status epilepticus usually produces hypertension during the first 30 to 45 minutes, but then the BP decreases, in part due to the build-up of lactate levels, and the patient may become hypotensive. This hypotension reduces the cerebral blood flow and potentiates the brain injury from the status epilepticus. Maintain BP in normal or high normal levels during prolonged status epilepticus with the use of vasopressor agents like dopamine, if necessary.⁵

Longer Term Treatment Issues

Fluids: Since all patients with status epilepticus have some degree of cerebral edema, do not over-hydrate.
Blood Studies, Acidosis: All patients in status epilepticus develop some degree of acidosis, but this usually resolves when status is terminated. Bicarbonate therapy is rarely necessary; use only for severe acidosis with the pH < 7.15. (See preceding section, Diagnostic Studies.)
Body Temperature: The increased motor activity of status epilepticus can cause a marked rise in body temperature. Hyperpyrexia can contribute to status epilepticus brain injury and needs to be prevented.

Drug Therapy in Status Epilepticus

General Approach to Drug Therapy: Successful treatment of status epilepticus requires a clear plan of treatment with prompt administration of adequate doses of effective drugs. (See ACUTE CARE PORTALS Status Epilepticus Treatment Plan.) Due to the sedating drugs used to treat the seizure or due to the seizure itself, watch for and actively treat hypoventilation and/or apnea with assisted ventilation. The main categories of drugs traditionally used to treat status epilepticus are benzodiazepines, phenytoin (or fosphenytoin), barbiturates, or propofol.¹

If possible, give all medications via IV to patients with status epilepticus. If an adequate IV or IO line cannot be quickly established, rapid termination of seizures can be accomplished by administering diazepam (Valium) or lorazepam (Ativan) rectally or giving midazolam (Versed) by nasal or buccal route.^{10, 11} Fosphenytoin (Cerebyx) may also be given IM.

Benzodiazepines: The first-line treatment for status epilepticus is benzodiazepines because these drugs can rapidly control seizures.¹² Do not use benzodiazepines alone in the treatment of status epilepticus, since there is a high risk of recurrent seizures after the sole use of these drugs. Benzodiazepines are used only for patients who are actively convulsing and in conjunction with or followed by phenytoin loading. Lorazepam, diazepam, and midazolam are the commonly used benzodiazepines and all increase chloride conductance in the central nervous system (CNS) GABA receptors and thus decrease neuronal excitability.¹³

All three of the above benzodiazepines may cause respiratory depression and hypotension as well as impair consciousness. The onset of action of diazepam IV (1 to 3 minutes) is faster than lorazepam IV (6 to 10 minutes); however, many epileptologists prefer lorazepam because of its longer duration of antiepileptic action.^* (Lorazepam's antiepileptic half-life is 14 hours versus 30 minutes for diazepam.) On the other hand, diazepam has a longer half-life for sedative effect. Leppik¹⁶ compared the efficacy of IV diazepam and lorazepam in the initial treatment of status epilepticus and found no significant clinical difference. But studies by Appleton^17,18 suggested that lorazepam was more effective than diazepam and had fewer side effects and less respiratory depression. Due to the pharmacokinetic differences between diazepam and lorazepam, the working group on status epilepticus states that lorazepam is theoretically preferable.⁵ Diazepam has a higher lipid solubility than lorazepam and thus more rapidly crosses the blood-brain barrier than lorazepam. The effect of diazepam upon seizure activity can be seen as early as 10 to 20 seconds after IV or IO administration¹⁹ with CNS levels reaching half of their maximum level in 3 minutes.¹⁹ But due to the rapid redistribution of the drug into adipose tissue, the anticonvulsant effect may last no longer than 20 minutes.¹⁹ Lorazepam, on the other hand, may take as long as 2 minutes to reach effective seizure control but its duration of action is 4 to 6 hours due to less redistribution into the adipose tissue as opposed to diazepam.19 While midazolam has a very rapid onset of action after IV administration, it has a very short half life in the CNS and thus has a very short period of anti-seizure activity. An advantage of midazolam over diazepam and lorazepam is that its use is associated with fewer cardiovascular side effects and use of a continuous infusion for seizure control has been thoroughly investigated.¹ The administration of midazolam by intranasal (IN) or buccal routes have been found to be useful in the termination of seizures when IV or IO access is not available.^11,20 A pooled study by McMullan¹⁰demonstrated that IM- or IN-administered midazolam was as effective as diazepam IV and that buccal midazolam was superior to rectal diazepam in controlling seizures. Of note is that few studies on the use of midazolam for control of status epilepticus in children have been conducted and it is not approved for this use in the United States.¹⁹

Benzodiazepine Dosing for the Treatment of Status Epilepticus

Lorazepam²¹

PEDS: Neonate: Lorazepam IV needs to be used with caution in neonates due to the potential toxic effects of the benzyl alcohol contained in IV lorazepam. The dose in neonates is 0.05 mg/kg given IV or IO over 2 to 5 minutes. This dose may be repeated in 10 to 15 minutes if the seizures continue.
Infants and children: Dose = 0.05 to 0.1 mg/kg slowly IV or IO over 2 to 5 minutes with a maximum single dose of 4 mg. A second IV or IO dose of 0.05 mg/kg may be given if needed 10 to 15 minutes later.
Adolescents: Dose = 0.07 mg/kg slowly IV or IO over 2 to 5 minutes with a maximal single dose of 4 mg. A second dose of the same size may be repeated 10 to 15 minutes later.
Adults: Dose = 4 mg slowly IV or IO over 2 to 5 minutes. Repeat dose of 4 mg IV or IO in 10 to 15 minutes may be given to a maximum of 8 mg over 12 hours.

Diazepam (Valium)²¹

PEDS: Infants and children (ages >30 days to <5 years): 0.05 to 0.3 mg/kg dose IV or IO given over 3 to 5 minutes. This may be repeated every 15 to 30 minutes up to a cumulative dose of 5 mg.
Children >5 years of age: 0.05 to 0.3 mg/kg/dose given IV or IO over 3 to 5 minutes. This may be repeated every 15 to 30 minutes up to a cumulative dose of 10 mg.
Adults: 5 to 10 mg IV slowly per dose. This may be repeated every 15 to 30 minutes up to a total of 30 mg in 8 hours.

Midazolam (Versed)

PEDS: Infants and children: 0.05 to 0.1 mg/kg IV or IO to maximum of 5 mg²² or 0.2 to 0.5 mg/kg to maximum of 10 mg by buccal route^10,19 or
0.1 to 0.2 mg/kg IM to a maximum of 10 mg^19,22
Adults: 0.1 to 0.2 mg/kg IV or IO to a maximum of 10 mg bolus, followed by continuous infusion at rates of 0.75 to 10 µg/kg per minute.¹

Phenytoin: To control status epilepticus with phenytoin IV takes longer than with diazepam or lorazepam. Standard loading dose is 18 to 20 mg/kg for adults (15 mg/kg in geriatric patients.) PEDS: The standard loading dose for children > 5 years is 15 to 20 mg/kg. Give phenytoin IV at a rate not to exceed 50 mg/min in adults or PEDS: 1 mg/kg/min (< 50 kg). Phenytoin may precipitate cardiac arrhythmias, especially for patients with cardiac conduction abnormalities. If possible, attach the patient to an ECG monitor and observe during phenytoin IV administration. If the QT interval widens or arrhythmias develop, slow the infusion rate. Phenytoin may also cause hypotension, especially in geriatric or seriously ill patients. Monitor BP carefully during phenytoin infusion, and if hypotension develops, slow or stop the infusion. If the seizure stops during the infusion, slow the rate of infusion to reduce the risk of complications. Sedation and respiratory depression occur occasionally with phenytoin infusions. Doses of phenytoin > 30 mg/kg are contraindicated because higher doses provoke seizure activity. Careful maintenance of a patent IV is essential to prevent the infiltration of phenytoin into the tissues with the development of a purple glove syndrome.

Fosphenytoin (Cerebyx) (Vol III—NEU4 Phenytoin and Fosphenytoin): This is an aqueous prodrug to phenytoin that is converted to phenytoin in vivo with a conversion half-life of 8 minutes. Fosphenytoin is becoming the preferred method of administering IV phenytoin loading dose or bolus dose due to its greater safety and ease of use in this setting. Fosphenytion may be infused at a more rapid rate (up to 3 times as rapidly) than phenytoin and may be administered IM if IV access is a problem.

The dosing of fosphenytoin is expressed as phenytoin equivalents (or PEs).
Loading Dose: Adults (< 65 years): 18 to 20 mg PE/kg IV. Geriatric: (> 65 years) 15 mg PE/kg IV. PEDS: (age 5 years or older) 15 to 20 mg PE/kg IV. IV maintenance dose: 4 to 6 mg PE/kg/day (given once per day). Equivalent doses may be given IM if there is no IV access. For the IM route, therapeutic plasma levels are achieved in 30 minutes (peak levels at 2 hours). Therefore, if given IM, administer fosphenytion at the same time as lorazepam or diazepam. Fosphenytion may have a role in prehospital care as an IM medication if transport time to an emergency department is 30 minutes or longer. Oral Maintenance Dose: See Vol III—NEU4 Phenytoin and Fosphenytoin Loading

Note:

Fosphenytoin is relatively expensive, but IV phenytoin can cause cardiovascular collapse and severe tissue necrosis so its risks may outweigh its cost savings. Therefore, fosphenytoin should be considered for IV therapy.

Checking routine phenytoin levels after an IV load is usually not necessary unless the patient continues to seize. Then, a level of phenytoin can be helpful during the process of treating status epilepticus in an attempt to maximize the blood levels. In these situations, wait 2 hours after IV loading dose or 4 hours after IM loading dose to check the phenytoin levels. Pharmacokinetic research has established that a full load of phenytoin (18 to 20 mg/kg in adults) yields a therapeutic level (1 to 2 µg/mL-free) 24 hours after the load. Therefore, if all is going well, order the first phenytoin level 5 half-lives after starting a maintenance dose to see if the prescribed maintenance dose (usually start with 5 mg/kg/day) is correct.²³

Valproic Acid
The use of valproic acid IV has been increasingly used in the treatment of status epilepticus. While only approved by the FDA to be infused slowly at the maximum rate of up to 20 mg/minute, evidence suggests that infusion rates of up to 6 mg/kg per minute in doses up to 30 mg/kg is safe in adults and does not result in adverse BP or HR effects.²⁴

PEDS: Special Considerations in Pediatric Patients Including Rectal Dosing

Treat pediatric patients with status epilepticus with the same drugs as adults. However, these patients generally tolerate more rapid IV drug administration than adult patients do. Although IV drug administration is always the route of choice for treating status epilepticus, IV access can be difficult in a small, convulsing child. If IV access is not feasible in a convulsing child, rectal administration of a benzodiazepine is a reasonable compromise.

Diazepam is absorbed rapidly and reliably when a solution (not a suppository) is administered rectally, reaching maximal drug levels within 10 minutes after rectal instillation. The rectal dose of diazepam is 0.2 to 0.5 mg/kg depending on age (to a maximum of 20 mg). For patients 2 to 5 years, use 0.5 mg/kg; for patients 6 to 11 years, use 0.3 mg/kg; and for patients 12 years or older, use 0.2 mg/kg.²¹ Use an injectable solution (undiluted) and administer via a 1 cc insulin syringe inserted 4 to 5 cm into the rectal vault. Diastat is a form of diazepam prepared for rectal administration. Diastat does not have to be refrigerated and has a long shelf-life. Diastat is available in 2.5, 5, and 10 mg delivery systems for pediatric patients (and in 20 mg delivery systems for adults). Because diastat is provided in these fixed unit doses, the prescribed dose is obtained by rounding upward to the next available dose.²¹

Diazepam Intensol (a liquid form made to be given into the cheek pouch) is available, is rapidly absorbed, and has a long room-temperature shelf-life. Lorazepam Intensol, a liquid form made to be given into the cheek pouch, is also available and is rapidly absorbed, but must be refrigerated.⁴

If lorazepam cannot be given IV due to lack of vascular access, the best route of administration is rectally. Rectal administration of lorazepam has not been studied extensively, but use of the IV dose and IV formulation of lorazepam may be administered rectally.

Buccal or intranasal (IN) midazolam has been shown to be as effective as diazepam IV and buccal midazolam has been shown to be more effective than rectal diazepam.¹⁰

Fosphenytoin may be administered IM to children ages 5 years or older in the same loading dose as the pediatric IV dose (15 to 20 mg PE /kg). Administer at the same time as rectal benzodiazepine (diazepam or lorazepam.

Valproic acid is also well absorbed rectally following an initial liquid dose of 20 mg/kg. However, the response to rectal Valproic acid is too slow to be useful for convulsive status epilepticus (though it can be useful for absence status); thus, diazepam is preferred when rectal administration is necessary.⁵

PEDS: Status Epilepticus in the Neonate⁴:

The diagnosis of seizure activity in the neonate is often difficult because the signs are frequently very subtle. The seizures may be manifested by apnea, random eye movement, sucking activity, stretching, yawning, or bicycling. These seizures are unlike the events seen in older patients due to the lack of myelin and dendritic connections in the neonate. Nevertheless, these seizures are often associated with serious CNS disturbances and can result in neuronal damage.

A standard loading dose of 20 to 25 mg/kg of phenobarbital IV has been found to be effective and necessary to obtain therapeutic concentrations.⁴ The primary side effects of Phenobarbital are substantial sedation, hypotension, and occasionally hypopnea or apnea.

If the phenobarbital is not effective in stopping the seizure activity, it may be followed by a fosphenytoin dose of 20 mg/kg IV. Fosphenytoin does not cause venous sclerosis and is well tolerated. Diazepam 0.3 to 0.5 mg/kg IV of lorazepam 0.1 mg/kg IV are often effective.

Refractory Status Epilepticus

If visible seizures continue after adequate doses of benzodiazepines and fosphenytoin have been given, the patient is in refractory status epilepticus. If the patient is not recovering consciousness, even if there are visible seizures, non-convulsive status epilepticus or subtle status epilepticus must be considered and EEG should be obtained. In either case, consult a neurologist and consider the need for an imaging study (MRI or CT) of the brain and a lumbar puncture.

Phenobarbital has been shown to be effective for the treatment of status epilepticus, but has a significant depressant effect on respiratory drive, level of consciousness, and blood pressure, especially if administered after a benzodiazepine.⁶ Thus, use of phenobarbital in older children and adults is recommended only if benzodiazepine and phenytoin therapy has failed, there is not another good alternative for treatment, and blood pressure and respiratory support is immediately available. The usual dose of phenobarbital is 20 mg/kg at a rate of 50 to 75 mg/minute IV.⁶

In the past, pentobarbital coma was widely used for refractory status epilepticus, but more recently propofol (Diprivan) and midazolam have been shown to have some advantage.⁴

For pentobarbital, a loading dose of 6 to 15 mg/kg is given over 1 hour while monitoring the EEG. Follow the loading dose with IV maintenance doses of 1 to 2 mg/kg/hour. This is usually effective to stop epileptic activity or suppress the seizure activity on the EEG but cardiovascular toxicity may be life-threatening and weaning from the ventilator may be very difficult. Pentobarbital coma may be required for many days.^{4, 6}

Propofol loading dose is 1 mg/kg IV as a slow IV bolus over 5 minutes, followed by a second bolus of 1 mg/kg if needed. The maintenance dose is 2 to 4 mg/kg/hour but may be adjusted up to as much as 15 mg/kg/hour using EEG monitoring to attain suppression of spikes on the EEG.⁴

Midazolam (Versed) may be used as a slow IV bolus of 0.2 mg/kg followed by continuous infusion of 0.75 to 10 µg/kg/minute.⁶ Midazolam appears to be the most potent of the benzodiazepines, but it has a shorter anti-epileptic half-life than lorazepam.⁴

Once coma with propofol, midazolam, or pentobarbital has been initiated, the EEG should be frequently monitored and further neurologic consultation obtained. Vital signs must be monitored continuously. Hypotension is common, especially with the use of pentobarbital-induced coma, and vasopressors (dopamine or dobutamine) are frequently needed. Adequate airway management and ventilation support are mandatory.

Stabilization and Transport
Any patient considered for transport should have a secure airway, good IV access, and vital signs that are as stable as possible.

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Neurology 1: Status Epilepticus Portal

References

Edition 13-October 2011