Issues
Surrounding the Management of Patients Who Present to
the ED with Subtherapeutic Phenytoin Levels and a History of Seizures
Case
Presentation
A 35 year-old otherwise healthy male with a history of a seizure disorder
since childhood presents to the emergency department with ambulance
personnel after having had a seizure. The patient was postictal upon
ambulance personnel arrival but in the emergency department he has
a normal mental status. His last seizure was approximately 2 years
ago. He ran out of his phenytoin approximately 2 weeks ago and has
not picked up the prescription that is waiting for him at a local
pharmacy. He has normal vital signs and a normal physical exam. His
serum phenytoin level is undetectable.
Key
Learning Points:
-
No
well designed study has addressed the short term rate of seizure
recurrence and the short term rate and severity of adverse events
by directly comparing any of the common contemporary dosing strategies
used to treat a patient with who presents to the emergency department
after having had a seizure with a “subtherapeutic” phenytoin level.
A serum phenytoin level > 10 mg/L can be achieved by all of the
common contemporary dosing strategies including intravenous loading,
oral loading and starting/restarting oral maintenance dosing.
-
Fewer adverse local effects (phlebitis, purple glove syndrome and
tissue necrosis) and fewer adverse systemic effects (impairment
of myocardial contractility, dysrhythmias, hypotension and cardiac
arrest) are associated with intravenous fosphenytoin administration
when compared to intravenous phenytoin administration.
- This
difference in adverse effects between parenteral phenytoin and fosphenytoin
is believed to be in part related to the fact that parenteral phenytoin
preparations contain propylene glycol (40%) and ethanol (10%) and
are adjusted to a pH of 12. Fosphenytoin which is more water soluble
does not contain these same diluents and has a more physiologic pH
of 8.6 to 9.
- Fosphenytoin
is significantly more expensive than intravenous phenytoin.
TOP
Issues
Surrounding the Management of Patients Who Present to
the ED with Subtherapeutic Phenytoin Levels and a History of Seizures
Introduction
What does the medical literature say are the options for treatment?
What is
the most effective phenytoin or fosphenytoin dosing strategy for preventing
short term seizure recurrence in a patient with a pre-existing seizure
disorder who presents to the emergency department within 24 hours
of having had a seizure without status epilepticus and who is determined
to have a “subtherapeutic” serum phenytoin level? There
is much debate among emergency physicians as to the safest, most efficient
and cost effective way to treat a patient who has had a recent seizure
and has a subtherapeutic serum phenytoin level.
Common
contemporary dosing strategies include:
1.
Administering an intravenous loading dose of phenytoin or fosphenytoin
and then starting/restarting daily oral maintenance dosing
2. Administering an oral loading dose of phenytoin and then starting/restarting
daily oral maintenance dosing
3. Starting/restarting daily oral maintenance dosing without administering
a loading dose
Emergency
physicians should understand that the most important measure of a particular
antiepileptic drug dosing strategy should be efficacy in preventing
seizure recurrence when viewed in conjunction with adverse events and
cost.
What is the relationship between a “therapeutic” serum phenytoin level
and the prevention of seizures?
Most
laboratories report a “therapeutic” serum phenytoin level between
10-20 mg/L. The term “therapeutic” serum phenytoin level is a misleading
since many patients remain seizure free at serum levels less than
10 mg/L and some patients may require a serum level greater than 20
mg/L to control their seizures. (Carter, Leppik 1983) Patients are
more likely to have adverse effects when their serum phenytoin level
rises above 20 mg/dL but many patients will experience adverse effects
at “therapeutic” levels. (Ambrosetto, Product information) Most pharmacokinetic
studies use achievement of a serum phenytoin level > 10 mg/L as
the primary outcome variable. Although achieving a serum phenytoin
level > 10 mg/L may be a measure of pharmacokinetic efficacy, a
more relevant measure of clinical efficacy should be prevention of
seizure recurrence with an acceptable adverse effects profile.
What
are the pharmacokinetic concerns as they relate to achieving a serum
phenytoin level > 10 mg/L?
A serum phenytoin level
> 10 mg/L can be achieved by any of the common contemporary dosing
strategies.
Oral phenytoin dosing at the "appropriate" daily maintenance
dose, without a loading dose, can achieve a serum phenytoin level
> 10 mg/L in 3-7 days. (Buchanan, Gugler, Svensmark). Although
many common references recommend that adult dosing be initiated at
300 mg per day, many patients will not achieve a serum phenytoin level
> 10 mg/L at this daily dose. (Physician's Desk Reference) Two
volunteer studies showed that less than 20% of adult patients taking
300 mg per day achieved a serum level > 10 mg/L. (Buchanan, Gugler)
The reasons for this are multifactorial and include failure to dose
the medication based upon a patients weight and individual differences
in metabolism. Regardless of the initial dosing strategy employed
patients require a daily maintenance dosing to maintain their serum
level > 10 mg/L. Patients who are discharged on daily maintenance
dosing, even those that receive a loading dose, need follow-up to
make sure that they are receiving the appropriate daily maintenance
dose of phenytoin. Intravenous
loading of either phenytoin or fosphenytoin usually achieves a peak
serum phenytoin level > 10 mg/L within minutes following completion
of the infusion. (Carducci, Kugler, Leppik, Salem).
Oral loading of phenytoin as a single dose and in divided doses can
produce a serum phenytoin level > 10 mg/L in some cases within
3-10 hours and in most cases within 24 hours following the initial
ingestion. (Osborn, Ratanakorn, Record, Wildner 1973
Intramuscular loading of fosphenytoin as a single dose and in divided
dose can reliably produce serum phenytoin level > 10 mg/L in most
cases within 1-2 hours and in almost all cases within 24 hours following
injection. (Boucher, Browne 1989, Kugler, Uthman, Wilder 1996)
What
adverse effects are associated with oral, intravenous and intramuscular
dosing of phenytoin and fosphenytoin?
Irrespective
of the dosing strategy, the most common adverse effects associated
with phenytoin and fosphenytoin include ataxia, nystagmus, tremor
and somnolence. (Wilder 1996)
Fosphenytoin,
the disodium phosphate ester of phenytoin, is a parenteral phenytoin
pro-drug that is rapidly converted to phenytoin by blood and tissue
phosphatases following intravenous and intramuscular injection. (Browne,
Leppich) Many of the adverse local effects including phlebitis, purple
glove syndrome and tissue necrosis associated with intravenous and intramuscular
phenytoin, occur much less frequently when fosphenhytoin is administered
by these routes. (Comer, Marchetti, O’Brien, Kilarski) Many of the adverse
systemic effects including impairment of myocardial contractility, dysrhythmias,
hypotension and cardiac arrest associated with intravenous phenytoin
administration, have also been reported much less frequently with intravenous
fosphenytoin administration. (Earnest, Russell, York). This difference
in adverse effects between parenteral phenytoin and fosphenytoin is
believed to be in part related to the fact that parenteral phenytoin
preparations contain propylene glycol (40%) and ethanol (10%) and are
adjusted to a pH of 12. Fosphenytoin which is more water soluble does
not contain these same diluents and has a more physiologic pH of 8.6
to 9. (Browne 1996)
Although
it is difficult to make comparisons between studies with respect to
adverse events since most studies do not report adverse effects in
a standardized form and often do not evaluate for their severity,
fosphenytoin appears to have a better safety profile than intravenously
and intramucularly administered phenytoin. (Boucher, Henken, Jameson)
What
are the pharmacoeconomic concerns as they relate to phenytoin and
fosphenytoin?
The acquisition
costs of fosphenytoin are considerably more than those for either
parenteral or oral phenytoin products. In 4/2002 it costs approximately
$95.00 for 1000 mg of fosphenytoin, $5.50 for 1000 mg of parenteral
phenytoin and $5.00 for 1000 mg of oral phenytoin. (Kuffner). These
prices are consistent with those previously published. (Browne 1998)
What
is the risk of seizure recurrence in a patient who is discharged from
the emergency department?
Data on
the risk of seizure recurrence is commonly reported in years not days.
(Hauser) The baseline rate of seizure recurrence within a few days
to a few weeks of emergency department discharge for the patient population
of interest is unknown. Without knowing the background prevalence
of short-term seizure recurrence, individual studies that address
the rate of seizure short-term recurrence are difficult to interpret
and compare.
It is
difficult to make comparisons between the few studies that did report
the rate of seizure recurrence since most of these studies included
patients with many different etiologies for their seizures. The underlying
cause of seizures is likely an important variable in determining the
rate of seizure recurrence. (Cranford) Based upon the available literature
it appears that the rate of seizure recurrence following emergency
department discharge varies from 6-20%. (Cranford, Huff, Leppick,
Osborn).
No
well-designed study has compared the rate of seizure recurrence for
patients with different etiologies of seizures using any of the common
contemporary dosing strategies.
What
guidelines currently exist?
There
are no commonly distributed guidelines that specifically address the
issue of dosing strategy for preventing short term seizure recurrence
in a patient with a pre-existing seizure disorder who presents to
the emergency department within 24 hours of having had a seizure without
status epilepticus and who is determined to have a “subtherapeutic”
serum phenytoin level. This is likely due to the fact that the medical
literature does not contain enough information to answer this question.
If
no guidelines exist, what would you recommend?
Emergency
physicians who understand the pharmacokinetic, pharmacoeconomic and
adverse event profiles of phenytoin and fosphenytoin as well as the
limitations of the available medical literature are best suited to
help their patients make informed decisions regarding the different
dosing strategies.
When
I want to achieve a “therapeutic” serum phenytoin level as soon as
possible or prior to emergency department discharge I administer either
fosphenytoin or phenytoin intravenously.
Examples:
1. Patient had a prolonged seizure.
2. Patient has a recent history of multiple seizures or status epilepticus.
3. Upon emergency department discharge the patient is likely to be
in a environment/situation where another seizure carries an increased
risk of morbidity/mortality. Such environments/situations include
operating a motor vehicle or dangerous machinery, a hazardous occupational
setting, homelessness and suboptimal social situations.
4. Medicolegal concerns
I always want to minimize the risk of adverse local and systemic effects
associated with intravenous loading, so, when available, I administer
fosphenytoin.
Examples:
1. Patients who have poor intravenous access or small intravenous
catheters (children)
2. Patients are agitated.
3. There may be suboptimal supervision during dosing.
4. Medicolegal concerns.
When I want
to minimize the amount of time a patient is in the emergency department,
when cost is an especially important issue and when the indication for
phenytoin therapy is questionable, I administer oral phenytoin.
Examples:
1. Emergency department resources are at a critical level.
2.
Alcoholic patients whose seizures are likely secondary to alcohol
withdrawal.
TOP
Issues
Surrounding the Management of Patients Who Present to
the ED with Subtherapeutic Phenytoin Levels and a History of Seizures
References
1.Ambrosetto G, Tassinari CA, Baruzzi
A et al: Phenytoin encephalopathy as probable idiosyncratic reaction:
case report. Epilepsia 1977; 18:405.
2.Boucher BA, Feler CA, Dean C, et al. The safety,
tolerability and pharmacokinetics of fosphenytoin after intramuscular
and intravenous administration in neurosurgery patients. Pharmacotherapy
1996;16:638-645.
3.Browne TR, Davoudi H, Donn KH,
et al. Bioavailability of ACC-9653 (Phenytoin prodrug). Epilepsia
1989;30:S27-S32.
4.Browne TR. Intravenous phenytoin.
Cheap but not necessarily a bargain. Neurology 1998;51:942-943.
5.Buchanan RA, Kinkel AW, Goulet
JR. The metabolism of diphenylhydantoin (Dilantin) following once-daily
administration. Neurology 1972;22:126-130.
6.Carducci B, Hedges JR, Beal JC,
et al. Emergency phenytoin loading by constant intravenous infusion.
Ann Emerg Med 1984;13:1027-1032.
7.Carter CH. Use of parenteral
diphenylhydantoin (Dilantin) sodium in control of status epilepticus.
Arch Neurol Psychiatry 1958;79:136-137.
8.Comer JB: Extravasation from
intravenous phenytoin. Am J Intrav Ther Clin Nutr 1984;11:23-29.
9.Cranford RE, Leppik IE, Patrick
B, et al. Intravenous phenytoin: clinical and pharmacokinetic aspects.
Neurology 1978;28:874-880.
10.Earnest EP, Marx JA, Drury LR:
Complications of IV phenytoin for acute treatment of seizures: recommendations
for usage. JAMA 1983;6:762-765.
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DL. Phenytoin: pharmacokinetics and bioavailability. Clin Pharmacol
Ther 1976;19:135-142.
12.Hauser WA, Rich SS, Lee JRJ,
et al. Risk of recurrent seizures after two unprovoked seizures. N
Engl J Med 1998;338:429-434.
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MF, et al. Tolerance of intravenous fosphenytoin (Cerebrex) compared
with Dilantin: an overview of 3 studies. Epilepsia 1996;37(suppl 5):157
(abstract).
14.Huff JS, Morris DL, Kothari
RU, et al. Emergency department management of patients with seizures:a
multicenter study. Acad Emerg Med 2001;8:622-628.
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KR, et al. Venous irritation related to intravenous administration
of phenytoin versus fosphenytoin. Pharmacotherapy 1994;14:47-52.
16.Kilarski DJ, Buchanan C, Von
Behren L. Soft-tissue damage associated with intravenous phenytoin.
N Engl J Med 1984;311:1186-1187.
17.Kuffner EK: personal communication
with hospital pharmacy 10/2001.
18.Kugler AR, Knappp LE, Eldon
MA. Rapid attainment of therapeutic phenytoin concentrations following
administration of loading doses of fosphenytoin: a meta-analysis.
Neurology 1996;46:A176.
19.Leppik IE, Patrick BK, Cranford
RE. Treatment of acute seizures and status epilepticus with intravenous
phenytoin. Adv Neurol 1983;34:447-451.
20.Marchetti A, Magar R, Fisher
J, et al. A pharmacoeconomic evaluation of intravenous fosphenytoin
(Cerebyx) versus phenytoin (Dilantin) in hospital emergency departments.
Clin Ther 1996;18:953-966.
21.O’Brien TJ, Cascino GD, So EL,
et al. Incidence and clinical consequence of the purple glove syndrome
in patients receiving intravenous phenytoin. Neurology 1998;51:1034-1039.
22.Osborn HH, Zisfein J, Sparano
R. Single-dose oral phenytoin loading. Ann Emerg Med 1987;16:407-412.
23.Product Information: Dilantin
Ň phenytoin. Parke-Davis.
24.Rantanakorn D, Kaojarern S,
Phuapradit P, et al. Single oral loading dose of phenytoin: a pharmacokinetics
study. J Neurolo Sci 1997;147:89-92.
25.Record KE, Rapp RP, Young B,
et al. Oral phenytoin loading in adults: rapid achievement of therapeutic
plasma levels. Ann Neurol 1979;5:268-270.
26.Russell MA, Bousvaros G: Fatal
results from diphenylhydantoin administered intravenously. JAMA 1968;206:2118-2119.
27.Salem RB, Wilder BJ, Yost RI,
et al. Rapid infusion of phenytoin sodium loading dose. Am J Hosp
Pharm 1981;38:354-357.
28.Svensmark O, Schiller PJ, Buchthal
F. 5-5-Diphenylhydantoin (Dilantin) blood levels after oral or intravenous
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29.Uthman BM, Wilder BJ, Ramsay
RE. Intramuscular use of fosphenytoin: an overview. Neurology 1996;46:S24-S28.
30.Wilder BJ, Serrano EE, Ramsey
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TOP
Issues
Surrounding the Management of Patients Who Present to
the ED with Subtherapeutic Phenytoin Levels and a History of Seizures
Questions
1. What is the incidence
of recurrent seizures within 24 hours in patients discharged from
the ED?
a. 10%
b. 20%
c. 50%
d. unknown
2. What side effect
of intravenous phenytoin is avoided completely when fosphenytoin is
used?
a. Cardiac
arrhythmia
b. Hypotension
c. Ataxia
d. Purple glove syndrome
3. What is the quickest
way to attain a therapeutic phenytoin level?
a. IM fosphenytoin
b. IV phenytoin
c. IV fosphenytoin
d. B & C are both correct
4. What is the cheapest
loading strategy for phyentoin?
a. Oral
loading with phenytoin.
b. IM fosphenytoin
c. IV fosphenytoin
d. IV phenytoin
5. Which of the following
is true?
a. The therapeutic levels
of 10-20 is the goal for all patients.
b. Seizure control is the goal regardless of serum levels.
c. All patients need a level of at least 10 mg/L for seizure control.
d. Levels are overutilized and mean little.
1. Answer d.
The rate of seizure recurrence in discharged ED patients is unknown.
2. Answer d.
Purple glove syndrome is avoided with fosphenytoin administration.
Cardiac side effects may be less common but still occur.
3. Answer c.
Intravenous fosphenytoin, because it may be more rapidly administered,
will give higher levels more quickly.
4. Answer a.
Oral loading with phenytoin is the least expensive strategy.
5. Answer b.
Seizure control is the goal, not an arbitrary level.
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