P HARMACOTHERAPY IV S TATUS E PILEPTICUS Rowa’ Al Ramah 1

DEFINITION Status epilepticus (SE) is any seizure lasting longer than 30 minutes whether or not consciousness is impaired, or recurrent seizures without an intervening period of consciousness between seizures. SE is a medical emergency with significant morbidity and mortality, and aggressive treatment of seizures which last 5 minutes or more is strongly recommended. 2

TREATMENT For any tonic-clonic seizure that does not stop automatically or when doubt exists regarding the diagnosis, treatment should begin during the diagnostic workup. Normal to high blood pressure should be maintained. All patients should receive IV glucose, and thiamine (100 mg IV) should be given prior to glucose in adults. 3

Metabolic and/or respiratory acidosis should be assessed by ABG measurements to determine pH, PaO2, PaCO2, and HCO3. If pH is < 7.2, secondary to metabolic acidosis, sodium bicarbonate should be given. 4

BENZODIAZEPINES A benzodiazepine (BZ) should be administered as soon as possible if the patient is actively seizing. Generally one or two IV doses will stop seizures within 2 to 3 minutes. Diazepam, lorazepam, and midazolam are equally effective. If seizures have stopped, a longer-acting anticonvulsant should be given. 5

Diazepam is extremely lipophilic and quickly distributed into the brain, but redistributes rapidly into body fat, causing a very short duration of effect (0.25 to 0.5 hours). Therefore, a longer-acting anticonvulsant (e.g., phenytoin, phenobarbital) should be given immediately after the diazepam. The initial dose of diazepam can be repeated if the patient does not respond within 5 minutes. 6

Lorazepam is currently considered the BZ of choice. It takes longer to reach peak brain levels than diazepam but has a longer duration of action (12 to 24 hours). Patients chronically on BZs may require larger doses. The administration rate of diazepam and lorazepam should not exceed 5 and 2 mg/min, respectively, because the propylene glycol in the vehicle can cause dysrhythmia and hypotension. 7

Midazolam is water soluble and diffuses rapidly into the CNS but has a very short half- life (0.8 hours). It must be given by continuous infusion. There is increasing interest in using it buccally and intramuscularly when IV access cannot be obtained readily. With BZ administration, a brief period of cardiorespiratory depression (less than 1 minute) may occur and can necessitate assisted ventilation or require intubation, especially if BZs are used with a barbiturate. Hypotension may occur with high doses of BZs. 8

PHENYTOIN Phenytoin has a long half-life (20 to 36 hours), but it cannot be delivered fast enough to be considered a first-line agent. It takes longer to control seizures than do the BZs because it enters the brain more slowly. It causes less respiratory depression and sedation than the BZs or phenobarbital, but it is associated with administration-related cardiovascular toxicity (the vehicle is 40% propylene glycol). These administration-related problems are more likely to occur with large loading doses or in critically ill patients with marginal blood pressure. 9

Phenytoin should be diluted to ≤ 5 mg/mL in normal saline. The maximum rate of infusion is 50 mg/min in adults (25 mg/min in the elderly) and 3 mg/kg/min in children < 50 kg. Vital signs and ECG should be obtained during administration. If arrhythmias or hypotension occurs or if the QT interval widens, the rate should be slowed. Maintenance doses should be started within 12 to 24 hours of the loading dose. 10

If the patient has been on phenytoin prior to admission and the phenytoin concentration is known, this should be considered in determining a loading dose. A reduction in the loading dose is recommended for elderly patients, and a larger loading dose is required in obese patients. For seizures continuing after the initial loading dose, some practitioners have recommended an additional loading dose of 5 mg/kg (after waiting 60 minutes for response), 11

but additional phenytoin may result in toxicity and exacerbation of seizures. There is no evidence that a total loading dose > 20 mg/kg will be of benefit in these patients. Phenytoin is associated with pain and burning during infusion. Phlebitis may occur with chronic infusion, and tissue necrosis is likely on infiltration. Intramuscular administration is not recommended. 12

FOSPHENYTOIN Fosphenytoin, the water-soluble phosphate ester of phenytoin, is a phenytoin prodrug. The dose of fosphenytoin sodium is expressed as phenytoin sodium equivalents (PE). Adverse reactions include nystagmus, dizziness, and ataxia. Paresthesias and pruritus typically disappear within 5 to 10 minutes after the infusion. Continuous ECG, blood pressure, and respiratory status monitoring is recommended for all loading doses. Serum phenytoin concentrations should not be obtained for at least 2 hours after IV and 4 hours after intramuscular administration. 13

PHENOBARBITAL The Working Group on Status Epilepticus recommends that phenobarbital be given after a BZ plus phenytoin has failed. Most practitioners agree that phenobarbital is the long-acting anticonvulsant of choice in patients with hypersensitivity to the hydantoins or in those with cardiac conduction abnormalities. 14

To avoid overdosing, estimated lean body mass should be used in obese patients. Peak brain concentrations occur 12 to 60 minutes after IV dosing. On average, seizures are controlled within minutes of the loading dose. If the initial loading dose does not stop the seizures within 20 to 30 minutes, an additional 10- to 20-mg/kg dose may be given. If seizures continue, a third 10-mg/kg load may be given. 15

There is no maximum dose beyond which further doses are likely to be ineffective. Once seizures are controlled, the maintenance dose should be started within 12 to 24 hours. The risk of apnea and hypopnea can be more profound in patients already treated with BZs. If significant hypotension develops, the infusion should be slowed or stopped. 16

REFRACTORY GENERALIZED CONVULSIVE STATUS EPILEPTICUS When adequate doses of a BZ, phenytoin, and phenobarbital have failed, the condition is termed refractory. Failure to aggressively treat early increases the likelihood of non response. A meta-analysis showed that among patients refractory to GCSE, pentobarbital had a 92% response rate, compared to midazolam (80%) and propofol (73%). Breakthrough seizures were least common with pentobarbital (12%, compared with propofol [15%] and midazolam [51%]). Hypotension was more common with midazolam. 17

Benzodiazepines Midazolam has been suggested by some practitioners as the first-line treatment for refractory GCSE. Most patients respond within 1 hour, but the infusion rate should be increased every 15 minutes in those who do not. Tachyphylaxis can develop, and dosing should be guided by EEG response. Once seizures are terminated, dosages can be decreased by 1 mcg/kg/min every 2 hours. 18

Successful discontinuation is enhanced by maintaining serum phenytoin concentrations above 20 mg/L and phenobarbital concentrations above 40 mg/L. Hypotension, poikilothermia, and respiratory depression can occur and may require supportive therapies. Refractory GCSE has also been treated with large-dose continuous infusion lorazepam. Lorazepam contains propylene glycol, which can accumulate and cause marked osmolar gap, metabolic acidosis, and renal toxicity. 19

Medically Induced Coma If there is inadequate response to high doses of midazolam, anesthetizing is recommended. Intubation and respiratory support are mandatory during barbiturate coma, and continuous monitoring of vital signs is essential. A short-acting barbiturate (e.g., pentobarbital or thiopental) is generally preferred. 20

Pentobarbital should be initiated with a loading dose. Serum concentrations of 30 to 40 mg/L are necessary to induce an isoelectric EEG. If hypotension occurs, the rate of administration should be slowed or dopamine should be administered. The loading dose should be followed immediately by an infusion, increasing gradually until there is burst suppression on the EEG or adverse effects occur. Twelve hours after a burst suppression pattern is obtained, the rate of pentobarbital infusion should be titrated downward every 2 to 4 hours to determine if GCSE is in remission. 21

Valproate The manufacturer recommends that IV valproate be given no faster than 3 mg/ kg/min. Some have suggested that the maintenance infusion rate should be adjusted as follows: (1) if no metabolic enzyme inducers are present, the continuous infusion rate is 1 mg/kg/hour; (2) if one or more inducers are present (e.g., phenobarbital, phenytoin), the rate is 2 mg/kg/hour; and (3) if inducers and pentobarbital coma are present, the rate is 4 mg/kg/hour. There are no reports of respiratory depression; hemodynamic instability is rare, but vital signs should be monitored closely during the loading dose. 22

Propofol Propofol is very lipid soluble, has a large volume of distribution, and has a rapid onset of action. It has comparable efficacy to midazolam for refractory GCSE. It has been associated with metabolic acidosis, hemodynamic instability, and bradyarrhythmias that are refractory to treatment. An adult dose can provide more than 1,000 cal/day as lipid and cost over $800/day. 23

O THER A GENTS Topiramate tablets can be crushed & dissolved in a small amount of water. Response tends to be delayed hours to days. It may induce metabolic acidosis & kidney stones. Levetiracetam is not hepatically metabolized & is minimally protein bound. 24

Lidocaine Lidocaine is not recommended unless other agents have failed. It has a rapid onset of action. Fasciculations, visual disturbances, and tinnitus may occur at serum concentrations between 6 and 8 mg/L. Seizures and obtundation may develop when serum concentrations exceed 8 mg/L. 25

EVALUATION OF THERAPEUTIC OUTCOMES An EEG is a key tool that allows practitioners to determine when abnormal electrical activity has been aborted and may assist in determining which anticonvulsant was effective. Vital signs must be monitored during the infusion. The infusion site must be assessed for any evidence of infiltration before and during administration of phenytoin. 26

و اخر دعوانا ان الحمد لله رب العالمين 27