Status Epilepticus D. Franzon, MD

Definition & Background Status epilepticus (SE) presents in a multitude of forms, dependent on etiology and patient age (myoclonic, tonic, subtle, tonic-clonic, absence, complex partial etc.). Generalized, tonic-clonic SE is the most common form of SE and the most likely to require intervention and management in the PICU. Status epilepticus is generally defined as a single or multiple seizures lasting greater than 30 minutes. If appropriate therapy is delayed, SE can cause permanent neurologic sequela or death, so you should assume that any child who presents actively convulsing is in status epilepticus. As the duration of SE increases, the potential for spontaneous cessation decreases, control with medications becomes more challenging, and the morbidity and mortality increases. Treatment for most seizures needs to be instituted after > 5 minutes of seizure activity. Etiologies of Status Epilepticus ETIOLOGIES

PERCENTAGE

Fever

36%

Medication change

20%

Other – trauma, vascular, infection, tumor, drugs

15%

Unknown

9%

Metabolic

8%

Congenital

7%

Anoxic injury

5%

Some of the more common drugs known to cause seizures include: • • • • • •

Penicillins Isoniazid Metronidazole Antihistamines Narcotics Ketamine

• • • • • •

Halothane Enflurane Tricyclic antidepressants Antipsychotics Phencyclidine Cocaine

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Physiologic consequences of prolonged seizures
Phases of SE: • Hyperdynamic phase: During the initial phase of SE, the increased cerebral metabolic requirements (CMRO2) are met by a massive catecholamine / autonomic discharge which increase the cerebral blood flow (CBF). Hypertension, tachycardia also occur secondary to the catecholamine discharge. • Exhaustion phase: With persistent seizures, catecholamine depletion occurs leading to hypotension and decreased CBF. Neuronal damage now ensues due to tissue hypoxia particularly in the face of ongoing demand from continued seizures.
Respiratory effects: • Hypoxia and hypercarbia are frequently noted during SE due to many causes. The chest wall maybe rigid due to muscle spasm or the patient is unable to manage oral secretions. The brain is also in a hypermetabolic state and therefore has increased O2 consumption and CO2 production. • Neurogenic pulmonary edema is a rare complication of SE. A marked increase in pulmonary vascular pressure is the presumed etiology.
Hyperpyrexia may develop during protracted SE thus exacerbating the mismatch of cerebral metabolic requirement and substrate delivery. Therefore, fevers should be treated aggressively with antipyretics and external cooling.
Metabolic derangements: • Acidosis: Poor tissue oxygenation in conjunction with increased energy expenditure secondary to tonic-clonic activity leads to a lactic acidosis. Respiratory acidosis may occur for reasons noted above. • Glucose abnormalities: Initially, hyperglycemia occurs due to the catecholamine surge. Once the exhaustion phase sets in, blood sugars drop. This hypoglycemia is detrimental to the brain since glucose is the only metabolite the CNS can use. In peripheral tissue hypoglycemia causes anaerobic metabolism. • Rhabdomyolysis: Patients with protracted tonic-clonic activity can have extensive muscle breakdown leading to hyperkalemia and myoglobinuria. These metabolic derangements should be recognized and treated aggressively.
Laboratory changes: elevation of white blood cells (WBCs); the stress response causes a demargination of intra-vascular WBCs causing a leukocytosis. In 15% of children, this leukocytosis can also be reflected in CSF.

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Time-related complications of Status Epilepticus Parameter

Early (< 30min)

Late (>30 min)

Complications

Blood pressure

Increase

Decrease

Hypotension

Arterial oxygen

Decrease

Decrease

Hypoxia

Arterial CO2

Increase

Increase

Increased ICP

Serum pH

Decrease

Decrease

Acidosis

Temperature

Increase by 1°

Increase by 2°

Increased CMRO2

Autonomic activity

Increase

Increase

Arrhythmias

Lung fluids

Increase

Increase

Edema

Serum K+

Increase or Nl.

Increase

Hyperkalemia

Serum CPK

Normal

Increase

Rhabdomyolysis ARF

Cerebral blood flow

Increase 900%

Increase 200%

Bleed

CMRO2

Increase 300%

Increase 300%

Ischemia

+

K – potassium, CMRO2 – cerebral metabolic oxygen consumption

Treatment of status epilepticus
ABCs: • Avoid hypoxia. Provide oxygen via simple facemask or nasal cannula. • An oral airway may be helpful but difficult to place in a seizing patient. A nasal trumpet can be a good alternative. Simple repositioning or jaw thrust will often reposition the tongue and improve air exchange. • If poor respiratory effort is noted, begin bag-valve mask ventilation and consider intubation. Recognize that any paralytic agent used during intubation does not control the CNS epileptiform discharge even though the tonic-clonic activity is not apparent. Some indications for intubation in a SE patient include: o Difficulty maintaining airway o Unable to tolerate oral secretions o Ineffective respirations o Hypoxia o Hypercarbia o Unequal pupils or CNS pathology o Status that persists >30 min despite appropriate anticonvulsants

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Venous Access: • Obtain IV/IO access. Some antiepileptics can be given IM or rectally but an IV is imperative. • Seizing patients will often be hypertensive but do not require any treatment; the hypertension will resolve once the seizures are controlled. However, in some conditions the hypertension may be the cause of the seizure (i.e. post-streptococcal glomerulonephritis, certain meds or toxic ingestion, etc.). In those settings, slow stepwise decrease in blood pressure with a continuous infusion anti-hypertensive agent is indicated. • If the patient is noted to be hypotensive, begin volume resuscitation with 20cc/Kg NS.
Labs: Labs that must be acquired in seizing patients are: • Na, Ca, Mg, PO4 • Glucose • CBC • Liver function tests • Ammonia • Anticonvulsant levels • Toxicology screen • Lumbar puncture (consider after head CT if sns/sxs of increased ICP) • A finger-stick blood glucose check is of vital importance particularly in the neonatal and infant population as hypoglycemia can precipitate seizures and is readily treated. • Hyponatremia and hypocalcemia are also easily identified and readily treated causes of seizures.
Diagnostics • Defer an LP in unstable patients, but do not delay antibiotic/antiviral therapy if indicated. • A CT scan is indicated for focal seizures or deficit, history of trauma, or in patients with a bleeding diathesis. A non-contrast CT can be used to evaluate for mass lesions – intracranial hemorrhage, tumor – or for hydrocephalus. Infectious etiologies such as meningitis, encephalitis, cysticercosis or abscess are typically contrast enhancing. • EEG is indicated in all patients with SE and can be utilized in several ways: o Standard: a one time study or “snapshot” to evaluate for epileptiform activity or foci in a patient whose seizure has stopped. o Continuous: Utilized in the ICU for patients with difficult to control seizures, in burst suppression, or concern for subclinical seizures. o Video: Can be used in conjunction with standard or continuous EEG and is useful for seizures that are difficult to characterize (i.e. abnormal tone or movement that cannot be clearly diagnosed as seizure activity).

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Anticonvulsants: The most important aspect of controlling SE is to initiate antiepileptic therapy early. As administration is delayed, the dose required to control the seizures will increase. The choice of anticonvulsants should combine a rapid acting drug (Table 1) to immediately control the seizures and a long acting drug (Table 2) to prevent recurrence. Persistent SE If a patient persists with seizures despite appropriate treatment, then the patient requires a PICU admission and must be placed in a “pentobarb coma.” CNS electrical quiescence is accomplished by continuous infusion of any of the following medications. • Pentobarbital (most frequently used): 1-3 mg/kg/hr after bolus 10 mg/kg • Midazolam: 1 - 10 mcg/kg/min after bolus 0.15 mg/kg • Propofol 20-70mcg/kg/min—infusions>24h Normal physiologic activity is also suppressed along with seizure activity while in pentobarb coma necessitating: • Intubation: since the respiratory drive is also suppressed • CVC placement: for delivery of the continuous infusion anti-epileptics. These medications often cause hypotension, and patients also require inotropes such as epinephrine. Hypotension must be treated aggressively to assure adequate cerebral perfusion pressure, particularly at a time of high CNS demand. • Continuous EEG: “Burst suppression” is the specific electric pattern noted on EEG once the patient is in a pentobarb coma. Electrical activity is only noted every 15-20 seconds (once per screen). The patient must be started on long-acting antiepileptics while in a pentobarb coma and assure the levels are therapeutic. Once the patient is in burst suppression for 24 – 48 hours, the coma is gradually lifted as the EEG is monitored for seizure activity. Non - convulsive SE Up to 20% of children with SE have non-convulsive SE after tonic-clonic activity. If a child does not begin to respond to painful stimuli within 20 - 30 minutes after tonic - clonic SE, suspect non - convulsive SE. Acquire an urgent EEG Non - convulsive status epilepticus deserves special consideration because these patients typically have no tonic-clonic activity and do not appear in acute distress. The patients often are less responsive or have a slightly depressed mental status. They are often on multiple anti-epileptics already; some of the systemic derangements are therefore less evident and treatment may occur at a slower pace. Input from neurology is imperative for these patients.

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0.1 mg/kg IV over 1-2 min

0.1mg/kg IV or IM

Bolus: 2mg/kg Infusion: 20-100mcg/kg/min

Lorazepam (Ativan)

Midazolam (Versed)

Propofol (not usually first line drug)

• • •

•

Very effective in acutely controlling seizures Decreases ICP & CMRO2

• •

• •

•

May be given IM Rapid onset

Anticonvulsant effects last 6-12 hours Less respiratory depression than diazepam

• •

•

• •

•

•

TABLE 1 - Rapid acting anticonvulsants: Repeat every 5-10 minutes if SE persists Advantage Drug Dosing • Rapid onset due to high lipid solubility Diazepam 0.2 mg/kg IV over 1-2 min (Valium)

Status Epilepticus

Not recommended for prolonged periods in pediatric patients Hypotension Respiratory depression Very short acting

Short acting: 1-2 hours Hypotension

Low lipid solubility, thus action delayed by 2 minutes or longer

6

Disadvantage Rapid loss of anticonvulsant effects due to rapid redistribution Hypotension Respiratory depression

Loading dose: 20 mg/kg IV over 5 min

Loading dose: 20 mg/kg IV over 20 min

Fosphenytoin: phenytoin equivalent

Phenobarbital

Keppra Loading dose: 10 mg/kg (Levetiracetam) IV

Loading dose: 20 mg/kg IV over 20 min

Phenytoin (Dilantin)

TABLE 2 - Long acting anticonvulsants Drug Dosing

•

•

• •

•

Different mechanism of action, so may be effective in SE refractory to first line meds

Often very effective

Onset in 5-10 minutes Less toxic to peripheral veins and extravasation better tolerated

Advantage Cheap

• • • •

• •

•

• • • • • •

•

Onset 15-30min Greater depression of mental status making neuro exam difficult Hypotension Respiratory depression Stevens-Johnson Dosing adjustments required for patients in renal failure

Disadvantage Extravasation causes severe tissue injury Onset at 10-30 minutes Hypotension Arrhythmias Stevens-Johnson Hypotension Arrhythmias, but less likely than phenytoin Stevens-Johnson

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Other 90% of phenytoin / fosphenytoin is protein bound in the serum & the free form has the anticonvulsant effects. Therapeutic Dilantin levels: • Total phenytoin: 10 20 mcg/ml • Free phenytoin: 0.8 1.6 mcg/ml Therefore the free phenytoin level varies as serum protein levels change. Dilantin toxicity is more likely to occur in patients with an albumin level < 2 g/dL.

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