Treatment of status epilepticus with intravenous medications

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 maintenance doses, 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 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 to give the patient artificial respiration if it does. It is highly lipid soluble, so it quickly gets into brain, but then almost as quickly it redistributes into fat. Because of this, its duration of action is short, approximately 10 - 20 minutes. It is useful only for stopping a seizure, not for seizure prevention.


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 less prone to do so than diazepam. It acts slightly more slowly than diazepam, but its effective duration of action is 8 to 10 hours, making it recommended as initial treatment for status epilepticus.

B. Intravenous loading


Phenytoin is given as an IV loading dose of 18 mg/kg, dissolved in normal saline, and infused at a rate no faster than 50 mg/min. IV
Phenytoin is highly effective at stopping seizures. It is water-insoluble, and supplied dissolved in 40% propylene glycol/10% ethanol, pH 12. Hypotension and cardiac arrhythmias, especially bradycardia, 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 cannot be dissolved in glucose-containing solutions because it precipitates. It cannot be given intramuscularly because it crystallizes and can cause sterile abscesses. It must be given in a good IV 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 saturating the enzyme that metabolizes it. At low concentrations, elimination follows first order kinetics (i.e., the amount metabolized is proportional to concentration), but at higher concentrations elimination follows zero-order kinetics (i.e., a fixed amount is metabolized in a given time). A loading dose of 18 mg/kg is sufficient to saturate the metabolic enzymes, push its metabolism into 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 necessary to achieve a particular serum level can be calculated (see loading dose calculator below).


Fosphenytoin is given as an IV loading dose of 27 mg/kg (or 18 mg/kg in "phenytoin equivalents"), 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 desirable qualities compared to phenytoin: it is water-soluble, it is less prone to cause hypotension and cardiac 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 it has an effect. However, phosphatases capable of catalyzing this reaction are very abundant in the body.  Because the reaction proceeds very quickly, and because fosphenytoin can be infused at three times the rate of phenytoin, serum phenytoin levels after infusion of fosphenytoin are practically 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 "phenytoin equivalents", that is, the weight of an equivalent amount of phenytoin.
    It is important not to overdose patients with phenytoin or fosphenytoin, because phenytoin, in high concentrations (50 - 60 mg/dl), can promote seizures rather than reduce them.


Phenobarbital is given as an IV loading dose of 20 mg/kg dissolved in IV fluid and infused at a rate not more than 100 mg/min.
Phenobarbital is a second-line agent if phenytoin or fosphenytoin fails. It is highly sedating and can depress respiration, so artificial ventilation is often required if this drug is used. It may cause hypotension. 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 occasionally necessary for control of status epilepticus.

Valproic Acid

Valproic acid is given as an IV loading dose of 20 mg/kg dissolved in IV fluid and infused at a rate 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 their usual dose of valproate by mouth, or whose serum level of valproate is low and must be increased quickly. In general, it is well tolerated, but patients with known liver dysfunction or mitochondrial disease may not be good candidates for this drug. Cases of pancreatitis have been reported after IV valproate.

C. Continuous infusions


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 a continuous drug infusion for status epilepticus, but it is absolutely necessary if pentobarbital is used. The drug infusion rate is titrated to produced a burst suppression pattern on EEG. Given enough pentobarbital, all detectable EEG activity can be suppressed, but this amount of cerebral suppression 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 is given as a 200 microgram/kg bolus, followed by 0.75 - 10 micrograms/kg/min continuous 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 with pentobarbital. 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 200 microgams/kg followed by a 10 microgram/kg/hr infusion for one hour. Continuous EEG monitoring, with titration of dose to suppression of electrographic seizures is recommended.


One recommended propofol regimen [Stecker et al. 1998] is to initiate continuous EEG monitoring, then give an initial bolus of 1 mg/kg over 5 min. If the EEG shows burst suppression, then initiate a continuous infusion. If EEG seizures are still evident, then give another bolus. Start a continuous infusion at 2-4 mg/kg/h and titrate up to 15 mg/kg/h while monitoring for burst suppression and seizures. Like barbiturates, propofol has a tendency to cause hypotension, and artificial ventilation will be required. In some cases, it is thought that propofol 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 few advantages over pentobarbital.

D. Loading dose calculator

The purpose of a loading dose is to quickly bring the patient's serum concentration of drug up to a desired level. If a drug distributes equally into the entire body mass, the loading dose is simply the desired concentration times the patient's mass. However, drugs distribute in the body to varying 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), and
Vd 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.........
Volume of distribution (L/kg)........
LOADING DOSE (milligrams)............

Open this form as a separate page

E. Volume of distribution calculator

The values for volume of distribution published by different authorities vary widely. At best they are only average values and your patient may have a Vd very different from the average. It may be helpful for you to determine a drug's Vd for a particular person. A simple calculation of Vd can be done if a serum concentration of the drug is measured immediately after drug infusion and distribution. The computed Vd will be falsely high if drug is metabolized during a slow infusion, 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), and
D is the loading dose of drug (mg).

Initial serum concentration (mg/L)...
Peak serum concentration (mg/L)......
Weight pounds kilos ............
Loading dose (milligrams)............

F. References

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

Parent JM, Lowenstein DH (1994) Treatment of refractory generalized status epilepticus with continuous 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 intravenous valproic acid. J Neurol. 249: 484-5.

Last revised 7/23/2003
M. Steven Evans [ mail | home page ]