Treatment of Status Epileptic Us

8/3/2019 Treatment of Status Epileptic Us

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Treatment of status epilepticus with intravenousmedications

Status epilepticus is a medical emergency that usually requires intravenous medication.Medications are given as single IV boluses, or as IV loading doses followed by maintenancedoses, or as continuous infusions.

A. Bolus administration B. Intravenous loading C. Continuous infusions D. Loading dose calculator E. Volume of distribution calculator F. References

A. Bolus administration

Diazepam (Valium) Lorazepam (Ativan)

Diazepam

Diazepam is given IV push, at a dose of 0.2 mg/kg, at a rate of 5 mg/min.Diazepam is a benzodiazepine drug. It often suppresses respiration, and you must be prepared togive the patient artificial respiration if it does. It is highly lipid soluble, so it quickly gets intobrain, but then almost as quickly it redistributes into fat. Because of this, its duration of action isshort, approximately 10 - 20 minutes. It is useful only for stopping a seizure, not for seizureprevention.

Lorazepam

Lorazepam is given IV push, at a dose of 0.1 mg/kg, at a rate of 2 mg/min.Lorazepam is also a benzodiazepine drug, and may suppress respirations, although it is lessprone to do so than diazepam. It acts slightly more slowly than diazepam, but its effectiveduration of action is 8 to 10 hours, making it recommended as initial treatment for statusepilepticus.

B. Intravenous loading Phenytoin (Dilantin) Fosphenytoin (Cerebyx) Phenobarbital Valproic acid (Depacon)

Phenytoin
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Phenytoin is given as an IV loading dose of 18 mg/kg, dissolved in normal saline, and infused ata rate no faster than 50 mg/min. IVPhenytoin is highly effective at stopping seizures. It is water-insoluble, and supplied dissolved in40% propylene glycol/10% ethanol, pH 12. Hypotension and cardiac arrhythmias, especiallybradycardia, are common if the drug is given rapidly, so a maximum infusion rate of 50 mg/min

is recommended. Some physicians recommend cardiac monitoring during the infusion. It cannotbe dissolved in glucose-containing solutions because it precipitates. It cannot be givenintramuscularly because it crystallizes and can cause sterile abscesses. It must be given in a goodIV site, because if it infiltrates it may cause "purple glove syndrome"--necrosis and sloughing of skin.

Phenytoin has non-linear elimination kinetics because it is capable of completely saturatingthe enzyme that metabolizes it. At low concentrations, elimination follows first order kinetics(i.e., the amount metabolized is proportional to concentration), but at higher concentrationselimination follows zero-order kinetics (i.e., a fixed amount is metabolized in a given time). Aloading dose of 18 mg/kg is sufficient to saturate the metabolic enzymes, push its metabolisminto the range where zero-order kinetics occur, and give good serum level for almost a day.

If the patient already has been given some phenytoin, and more is required the dose necessaryto achieve a particular serum level can be calculated (see loading dose calculator below).

Fosphenytoin

Fosphenytoin is given as an IV loading dose of 27 mg/kg (or 18 mg/kg in "phenytoinequivalents"), dissolved in IV fluid and infused at a rate of up to 150 mg/min.Fosphenytoin is phenytoin with a phosphate group added. This gives the drug several desirablequalities compared to phenytoin: it is water-soluble, it is less prone to cause hypotension andcardiac arrhythmias, it can be given more rapidly, it does not cause "purple glove syndrome",and it can be given intramuscularly. A disadvantage is that fosphenytoin is inactive--it is only a

pro-drug for phenytoin, so phosphatases in the body must cleave the phosphate group before ithas an effect. However, phosphatases capable of catalyzing this reaction are very abundant in thebody. Because the reaction proceeds very quickly, and because fosphenytoin can be infused atthree times the rate of phenytoin, serum phenytoin levels after infusion of fosphenytoin arepractically equivalent to those attained by infusing phenytoin itself. The molecular weight of fosphenytoin is 1.5 times that of phenytoin, and one common method of dosing is as "phenytoinequivalents", that is, the weight of an equivalent amount of phenytoin.

It is important not to overdose patients with phenytoin or fosphenytoin, because phenytoin, inhigh concentrations (50 - 60 mg/dl), can promote seizures rather than reduce them.

Phenobarbital

Phenobarbital is given as an IV loading dose of 20 mg/kg dissolved in IV fluid and infused at arate not more than 100 mg/min.Phenobarbital is a second-line agent if phenytoin or fosphenytoin fails. It is highly sedating andcan depress respiration, so artificial ventilation is often required if this drug is used. It may causehypotension. Unlike phenytoin, exacerbation of seizures is not a problem with high doses, and if artificial respiration is used, serum levels of 40 - 60 can be achieved, which is occasionallynecessary for control of status epilepticus.


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Valproic Acid

Valproic acid is given as an IV loading dose of 20 mg/kg dissolved in IV fluid and infused at arate of 20 - 50 mg/min.Valproic acid is available in an IV form, but its role in the treatment of status epilepticus is not

clear at present. It is useful for administration to patients who for any reason cannot take theirusual dose of valproate by mouth, or whose serum level of valproate is low and must beincreased quickly. In general, it is well tolerated, but patients with known liver dysfunction ormitochondrial disease may not be good candidates for this drug. Cases of pancreatitis have beenreported after IV valproate.

C. Continuous infusions

Pentobarbital (Nembutal) 50 mg/ml (supplied as sodium salt) Midazolam (Versed) 1 or 5 mg free base / ml (supplied as hydrochloride) injectable

solution

Propofol (Diprivan) 10 mg/ml injectable solution

Pentobarbital

Pentobarbital is given as a 5 mg/kg loading dose, then 1 - 3 mg/kg/hr continuous infusion.Pentobarbital is a strong respiratory depressant, and artificial ventilation is mandatory.Continuous electroencephalographic (EEG) monitoring is advisable in any patient who needs acontinuous drug infusion for status epilepticus, but it is absolutely necessary if pentobarbital isused. The drug infusion rate is titrated to produced a burst suppression pattern on EEG. Givenenough pentobarbital, all detectable EEG activity can be suppressed, but this amount of cerebralsuppression is excessive. Hypotension is common and pressors are often needed. Seizures can

essentially always be suppressed with this drug, but they may recur on tapering the infusion rate.An infusion may be needed for several days.

Midazolam

Midazolam is given as a 200 microgram/kg bolus, followed by 0.75 - 10 micrograms/kg/mincontinuous infusion.Midazolam is a water soluble benzodiazepine. It is highly sedating and a respiratory depressant,so artificial ventilation is required. Hypotension may occur, but is less common than withpentobarbital. Midazolam infusion may need to be prolonged for days [Kumar and Bleck,1992Parent and Lowenstein, 1994] Overall, it is very well tolerated by patients. Some authorities

recommend initiating treatment for status epilepticus with a midazolam bolus of 200microgams/kg followed by a 10 microgram/kg/hr infusion for one hour. Continuous EEGmonitoring, with titration of dose to suppression of electrographic seizures is recommended.

Propofol

One recommended propofol regimen [Stecker et al. 1998] is to initiate continuous EEGmonitoring, then give an initial bolus of 1 mg/kg over 5 min. If the EEG shows burst


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suppression, then initiate a continuous infusion. If EEG seizures are still evident, then giveanother bolus. Start a continuous infusion at 2-4 mg/kg/h and titrate up to 15 mg/kg/h whilemonitoring for burst suppression and seizures. Like barbiturates, propofol has a tendency tocause hypotension, and artificial ventilation will be required. In some cases, it is thought thatpropofol has a pro- rather than anticonvulsant effect. Continuous EEG monitoring, with titration

of dose to suppression of electrographic seizures is recommended. Overall, it seems to have fewadvantages over pentobarbital.

D. Loading dose calculator

The purpose of a loading dose is to quickly bring the patient's serum concentration of drug up toa desired level. If a drug distributes equally into the entire body mass, the loading dose is simplythe desired concentration times the patient's mass. However, drugs distribute in the body tovarying extents. The amount of the body mass that the drug distributes into is reflected in its"apparent volume of distribution" (Vd). A Vd of 1.0 indicates that the drug distributes into the

entire body mass, but all intravenous anticonvulsants have a Vd less than 1.0.

The loading dose can be calculated as:

D = C * W * Vd , where

C is the desired change in serum concentration (mg/L)W is the patient's weight (kg), andVd is the estimated volume of distribution for the drug (L/kg).

Current serum concentration (mg/L)... Desired serum concentration (mg/L)...

Weight pounds kilos ............

Volume of distribution for.........fosphenytoin (0.64)

Volume of distribution (L/kg)........

LOADING DOSE (milligrams)............

CLEAR FORM

Open this form as a separate page

E. Volume of distribution calculator

The values for volume of distribution published by differentauthorities vary widely. At best they are only average values and your
http://www.msevans.com/epilepsy/loadingdose.htmlhttp://www.msevans.com/epilepsy/loadingdose.html


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patient may have a Vd very different from the average. It may behelpful for you to determine a drug's Vd for a particular person. Asimple calculation of Vd can be done if a serum concentration of thedrug is measured immediately after drug infusion and distribution. Thecomputed Vd will be falsely high if drug is metabolized during a slowinfusion, which will cause a spuriously low value for the peak

concentration.

Volume of distribution for a drug can be calculated as:

Vd = D / (C * W) , where

C is the observed change in serum concentration (mg/L)W is the patient's weight (kg), andD is the loading dose of drug (mg).

Initial serum concentration (mg/L)...

Peak serum concentration (mg/L)......

Weight pounds kilos ............

Loading dose (milligrams)............

VOLUME OF DISTRIBUTION (L/kg)........

CLEAR FORM

F. References

Kumar A, Bleck TP (1992) intravenous midazolam for the treatment ofrefractory status epilepticus. Crit. Care Med. 20: 483-488.

Parent JM, Lowenstein DH (1994) Treatment of refractory generalized status epilepticus withcontinuous infusion of midazolam. Neurology 44: 1837-1840.

Stecker MM, Kramer TH, Raps EC, O'Meeghan RO, Dulaney E, Skaar DJ (1998) Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 39:18-26.

Grosse P, Rusch L, Schmitz B (2002) Pancreatitis complicating treatment with intravenousvalproic acid. J Neurol. 249: 484-5.


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Last revised 7/23/2003M. Steven Evans [ mail | home page ]
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Treatment of Status Epileptic Us

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