Kaj Sep Nellie Mags STATUS EPILEPTICUS

SEIZURE Paroxysmal, abnormal, excessive, excessive neuronal discharge arising from the brain Capable of causing alteration in function and/or behavior

STATUS EPILEPTICUS “seizure that persists for a sufficient length of time or is repeated frequently enough to produce an enduring epileptic condition” Recurrent seizures without complete recovery of consciousness between attacks or virtually continuous seizure activity for more than 30 min with or without impairment of consciousness

Any seizure lasting more than 5 minutes or two or more discrete seizures between which there is incomplete recovery of consciousness Seizures lasting longer than 10 minutes or seizures on presentation at the ER or recurring in the ER

REFRACTORY SE Seizure that continues and fails to respond to appropriate first line drug therapy and persists for longer than 60 minutes

ETIOLOGY Genetic and birth factors (eg Anoxia) CNS Infection Head trauma Circulatory disturbances (syncope) Neoplasms Metabolic or nutritional deficiencies (Hypoxia, Hypoglycemia Eclampsia Toxic factors (Abrupt withdrawal of alcohol or drugs) Unknown causes

PATHOGENESIS Cellular ischemic changes begin to occur in 15 to 30 minutes of seizure and irreversible damage begins to occur in 90 to 120 minutes of continuous seizures Damage in SE is due to combined effects of: Hypoxia Hypotension Hyperthermia Hypoglycemia Acidosis

TREATMENT GOALS Immediate termination of seizure ABCs of life Identification and treatment of cause

SUGGESTED PROTOCOL FOR SE TIME ACTION 0 to 5 minutes Diagnose by clinically observing patient Maintain good airway. Give oxygen by nasal cannula or mask; position patient’s head for optimal airway patency; consider intubation VS, control any abnormalities, ECG monitoring IV line; draw blood for glucose level, serum chemistries, hematology studies, toxicology screen and determination of AED level

Assess oxygenation with oximetry or ABG TIME ACTION 6 to 9 minutes Assess oxygenation with oximetry or ABG If hypoglycemia is established give glucose solution Diazepam 5mg/IV – can be repeated if seizures do not stop after 5 minutes DIAZEPAM – advantage of stopping seizures in 3 minutes in a third of cases; greatest drawvack – short lived effect

TIME ACTION 10 To 20 minutes If diazepam is used to stop SE, phenytoin should be administered to prevent recurrence If seizures persist, infuse 15-20 mg/kg phenytoin very slow IV push, monitor HR Fosphenytoin is the ideal drug – long duration of action, does not impair consciousness

TIME ACTION 21 to 60 minutes - If seizures persist, give another 10mg/kg of phenytoin >60 minutes If seizures do not stop after 30mg/kg of phenytoin – phenobarbital 20 mg/kg IV or barbiturate drip (pentobarbital coma)

Treatment  Excitatory neurotransmission  Inhibitory neurotransmission

Pharmacologic Therapy First line treatment: drugs that stop SE as fast as possible within a few minutes (diazepam, lorazepam) Second line treatment: drugs that prevent recurrence of seizures and stop SE if the first line fails (phenytoin, phenobarbital, valproic acid)

Anti-epileptic Drugs Type I – blockade of Na channel Type 2 – enhancing post-synaptic GABA receptor current Type 3 – inhibition of low threshold Ca++ current Type 4 – inhibition of excitatory amino acids or neurotransmission by NMDA and non-NMDA receptor antagonism

Phenytoin : type I Antiarrhythmic Trigeminal neuralgia Migraine Status epilepticus

Phenytoin Slows the rate of recovery of voltage-activated sodium channels Blocks sustained high-frequency repetitive firing of action potentials

Phenytoin At high concentrations: Inhibits release of serotonin, norepinephrine Inhibits calcium influx Promotes uptake of dopamine

Phenytoin: Cardiovascular complications Nystagmus Diplopia & ataxia Mental changes, lethargy & dysarthria Stupor Gingival hyperplasia Hirsutism Skin rashes (purple glove syndrome) Fetal Hydantoin syndrome: craniofacial abn, nail & digit hypoplasia, MR, microcephaly Chronic use: Osteomalacia Megaloblastic anemia

Phenytoin loading dose: 15-20 mg/kg administered at a maximal rate of 50 mg/min an additional 10 mg/kg may be given because many patients may require serum levels of approximately 25 to 30 µg/mL to achieve seizure control BP and ECG monitoring

Fosphenytoin: administered at a maximal rate of 150 mg of phenytoin equivalent/min More expensive Better pharmacokinetic profile

Phenobarbital: type 2 AED Generalized tonic-clonic seizures Febrile seizure prophylaxis Status epilepticus

Phenobarbital increasing GABA-A mediated cellular inhibition Its mechanism of action is similar to benzodiazepines but involves a different isoform of the GABAA receptor

Phenobarbital At high concentration: Serious adverse effects: Suppresses high frequency repetitive firing – Na blockade Block Ca currents Blocks excitatory response induced by glutamate Serious adverse effects: half-life of more than 48 hours

Phenobarbital Repiratory depression CNS depression Severe hypotension secondary to peripheral vasodilation and decreased cardiac contractility Nystagmus Ataxia Rash Megaloblastic anemia

SE loading dose: 15-20 mg/kg by IV push Maintenance: 0.5-5mg/kg/h Monitor BP, ECG, respiratory function

Benzodiazepines GABA-A receptor agonist For status epilepticus and act as adjunctive therapy with other convulsants Sedation, development of tolerance

Benzodiazepines GABA-induced opening of chloride channels allowing intracellular chloride influx causing hyperpolarization  Inhibitory neurotransmission

Benzodiazepines Fast onset of action Highly lipid soluble, redistributed rapidly to peripheral fat stores clinical effectiveness: 20-30 minutes Diazepam, lorazepam, midazolam

Benzodiazepines CNS Depression Respiratory depression Hypotension Teratogenic – oral clefts, 1st trimester use

Diazepam: IV push 0.2mg/kg at 5mg/min with maximum dose of 20mg Lorazepam: IV push 0.1mg/kg at 2mg/min with maximum dose of 8mg Midazolam: 0.2mg/kg bolus injection followed by infusion of 0.05-0.5 mg/kg/h)

Refractory SE seizures recalcitrant to standard loading doses of anticonvulsant medications require treatment with anesthetic doses of benzodiazpines, short-acting barbiturates, or propofol

Midazolam: loading dose of 0 Midazolam: loading dose of 0.2 mg/kg and is maintained at a continuous infusion of 0.05 to 2.0 mg/kg/h Rapid and effective Favorable pharmacologic profile

Propofol: loading dose of 3 to 5 mg/kg is given slowly followed by an infusion of 1 to 15 mg/kg/h short-acting nonbarbiturate hypnotic used to induce general anesthesia GABA A agonist Rapid induction and elimination Propofol infusion syndrome: hypotension, lipidemia and metabolic acidosis

Barbiturates Pentobarbital: loading dose of 5 to 15 mg/kg over 1 hour and is maintained at an infusion dosage of 0.5 to 10.0 mg/kg/h Thiopental is given as needed in 75- to 125-mg IV boluses maintained between 1 and 5 mg/kg/h

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