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 (Valium)
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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 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
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 (Dilantin)
-
Fosphenytoin (Cerebyx)
-
Phenobarbital
-
Valproic acid (Depacon)
Phenytoin
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
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
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 (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 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
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.
Propofol
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).
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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).
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 |
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