NEUROLOGY/ORIGINAL RESEARCH
Cost-effectiveness of Oral Phenytoin, Intravenous
Maria I. Rudis, PharmD
Daniel R. Touchette, PharmD
Stuart P. Swadron, MD
Amy P. Chiu, PharmD
Michael Orlinsky, MD
From the Department of
Pharmacy, School of Pharmacy
(Rudis, Chiu), and the
Department of Emergency
Medicine (Rudis, Swadron,
Orlinsky), Keck School of
Medicine, University of
Southern California, Los
Angeles, CA; and the
Department of Pharmacy
Practice, Oregon State
University, Portland, OR
(Touchette).
Dr. Chiu is currently affiliated
with the Department of
Pharmacy, John Muir Medical
Center, Walnut Creek, CA.
0196-0644/$30.00
Copyright © 2004 by the American
College of Emergency Physicians.
doi:10.1016/
j.annemergmed.2003.10.011
3 8 6
Phenytoin, and Intravenous Fosphenytoin in the
Emergency Department
See editorial, p. 398.
Study objective: Oral phenytoin, intravenous phenytoin, and intravenous fosphenyt-
oin are all commonly used for loading phenytoin in the emergency department (ED).
The cost-effectiveness of each was compared for patients presenting with seizures
and subtherapeutic phenytoin concentrations.
Methods: A simple decision tree was developed to determine the treatment costs
associated with each of 3 loading techniques. We determined effectiveness by com-
paring adverse event rates and by calculating the time to safe ED discharge. Time to
safe ED discharge was defined as the time at which therapeutic concentrations of
phenytoin (*10 mg/L) were achieved with an absence of any adverse events that pre-
cluded discharge. The comparative cost-effectiveness of alternatives to oral pheny-
toin was determined by combining net costs and number of adverse events, expressed
as cost per adverse events avoided. Cost-effectiveness was also determined by com-
paring the net costs of each loading technique required to achieve the time to safe
ED discharge, expressed as cost per hour of ED time saved. The outcomes and costs
were primarily derived from a prospective, randomized controlled trial, augmented by
time-motion studies and alternate-cost sources. Costs included the cost of drugs,
supplies, and personnel. Analyses were also performed in scenarios incorporating
labor costs and savings from using a lower-urgency area of the ED.
Results: The mean number of adverse events per patient for oral phenytoin, intra-
venous phenytoin, and intravenous fosphenytoin was 1.06, 1.93, and 2.13, respec-
tively. Mean time to safe ED discharge in the 3 groups was 6.4 hours, 1.7 hours, and
1.3 hours. Cost per patient was $2.83, $21.16, and $175.19, respectively, and did not
differ substantially in the Labor and Triage (lower-urgency area of ED) scenarios.
When the measure of effectiveness was adverse events, oral phenytoin dominated
intravenous phenytoin and intravenous fosphenytoin, with a lower cost and number
of adverse events. With time to safe ED discharge as the outcome measure, the
incremental cost-effectiveness ratios were $3.90 and $387.27 per hour of ED time
saved for oral phenytoin versus intravenous phenytoin and for intravenous fospheny-
toin versus intravenous phenytoin, respectively.
Conclusion: Oral phenytoin is the most cost-effective loading method in most set-
tings. Intravenous phenytoin is preferred if one is willing to pay an additional $20.65
ANNALS OF EMERGENCY MEDICINE 43:3 MARCH 2004
C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al
Capsule Summary
What is already known on this topic
The emergency department (ED) management of patients who
have suffered a seizure and have subtherapeutic serum levels of
phenytoin is common and time consuming. Fosphenytoin has
been proposed as a safer and more efficacious preparation of
phenytoin to use in these situations.
What question this study addressed
The authors analyzed the cost-effectiveness of oral phenytoin,
intravenous phenytoin, and intravenous fosphenytoin in this
scenario, accounting for a broad variety of costs.
What this study adds to our knowledge
Cost-effectiveness was determined by comparing the net costs of
each loading technique required to achieve the time to safe dis-
charge, combined with the cost per adverse event avoided. Costs
were primarily derived from a randomized controlled trial, aug-
mented by time-motion studies and alternate costing sources.
Oral phenytoin was the most cost-effective loading method in
most settings.
How this might change clinical practice
Intravenous fosphenytoin is unlikely to be cost-effective in any
setting. Intravenous phenytoin decreases time to discharge but
increases costs and adverse effects compared with oral dosing.
to $44.25 per patient and willing to have more adverse
events for a quicker average time to safe ED discharge.
It is unlikely that intravenous fosphenytoin is justifiable
in any setting.
[Ann Emerg Med. 2004;43:386-397.]
INTRODUCTION
Phenytoin remains one of the most commonly used
antiepileptic medications in the emergency department
(ED). For patients presenting to the ED with seizures
and subtherapeutic serum concentrations of phenyt-
oin, it is common practice to use a loading dose of
phenytoin with the aim of achieving therapeutic serum
phenytoin concentrations. Patients with subtherapeu-
tic phenytoin concentrations are often noncompliant
and consume significant and valuable health care
resources.1-3
Methods for loading phenytoin both orally and intra-
venously vary widely.4-7 Each loading technique has
significant disadvantages: the adverse events of intra-
venous loading, the potential delayed effectiveness of
oral phenytoin, and the expense of fosphenytoin. In
determining the most cost-effective, safe, and rapid
method of preventing seizures and achieving therapeu-
MARCH 2004 43:3 ANNALS OF EMERGENCY MEDICINE
tic concentrations (10 to 20 mg/L), published data sug-
gest that drug formulation and pharmacokinetic differ-
ences may indeed account for differences in adverse
events and clinical efficacy.8-11
There is a paucity of published data evaluating the
cost-effectiveness of various methods of phenytoin
loading in the ED.7,12-14 The existing literature has
used pharmacoeconomic modeling outside the scope of
a clinical trial,13,14 has overestimated costs attributable
to adverse events,12 or has not focused solely on the ED
patient population.13,14 Furthermore, none of these
studies has included oral loading techniques in a cost-
effectiveness analysis.7 The purpose of our study was to
determine the cost-effectiveness of 3 methods of load-
ing phenytoin in the ED. We determined effectiveness
by comparing adverse event rates and by calculating the
time to safe ED discharge. Time to safe ED discharge
was defined as the time at which therapeutic concentra-
tions of phenytoin (*10 mg/L) were achieved with an
absence of any adverse events that precluded discharge.
The comparative cost-effectiveness of alternatives to
oral phenytoin was determined by combining net costs
and number of adverse events, expressed as cost per
adverse event avoided. Cost-effectiveness was also
determined by comparing the net costs of each loading
technique required to achieve safe ED discharge, ex-
pressed as cost per hour of ED time saved. The data on
effectiveness were reported in a previous article.15 In
this article, we report on the cost-effectiveness data.
METHODS
This analysis was based on our prospective, random-
ized, clinical trial comparing oral phenytoin (n=16),
intravenous phenytoin (n=14), and intravenous fos-
phenytoin (n=15) in 45 patients admitted to the ED
after seizure. Written informed consent was obtained
from all patients. A detailed description of the clinical
trial is published elsewhere.15 In brief, patients were
enrolled in the study if they were receiving maintenance
phenytoin therapy for an existing seizure disorder and
presented to the ED with a seizure in the past 48 hours
and a serum phenytoin concentration less than 5
µg/mL. After their ED evaluation, patients were trans-
ferred to the General Clinical Research Center unit for
phenytoin loading and subsequent observation before
discharge. Patients were observed for a period of 24
hours from the time of initiation of study medication
for drug administration, pharmacokinetic sampling at
predetermined times, and observation of adverse
3 8 7
C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al
events. Oral phenytoin was administered in increments
of 400 mg every 2 hours until a dose of 20 mg/kg was
reached. Dosing for the intravenous routes was 18
mg/kg for phenytoin and 18 mg/kg phenytoin equiva-
lents for fosphenytoin. The infusion rates were initi-
ated at 50 mg/min and 150 mg/min for each drug,
respectively, and adjusted downward according to a
preset protocol. Adverse events were also managed
according to a standardized algorithmic approach
(Table 1).
To determine the cost-effectiveness, we used a sim-
ple decision tree to determine the total treatment costs
associated with each of the 3 loading techniques (Fig-
ure 1). Outcomes considered important and included in
the analysis were time to achieve therapeutic phenytoin
concentrations, incidence of adverse events, the calcu-
lated ED length of stay, and cost of care. Seizure recur-
rence was also collected in the study but was not in-
cluded in the pharmacoeconomic analysis because a
significant difference was not observed in this outcome
and none were attributed to subtherapeutic concentra-
tions. The pharmacoeconomic analysis was performed
from the perspective of the institution, a 750-bed, uni-
versity-affiliated, county hospital in an urban setting.
Sample size calculations were performed by the
General Clinical Research Center Department of Bio-
statistics at our institution. These calculations were
based on the characteristics required to conduct a cost-
effectiveness study. The pharmacoecomonic character-
istics used in the determination of sample size included
the cost of drug and other products used in the loading
process, the costs of nursing and medical personnel
time, and rates of adverse events as estimated from a
Table 1.
Adverse event treatment guidelines for intravenous phenytoin
and intravenous fosphenytoin.
Adverse Event Treatment Guideline
Arrhythmia/ataxia/ Stop intravenous infusion; restart infusion at
disorientation/ slower rate; monitor; switch to oral regimen if
dizziness/nystagmus necessary
Hypotension Administer 250 mL of normal saline solution; monitor
Pain/phlebitis Stop intravenous infusion; apply ice pack;
administer 250 mL of normal saline solution;
restart new peripheral line; switch to oral
regimen if necessary
Pruritus Restart infusion at slower rate; monitor
3 8 8
medical record review. According to the total estimated
costs for each arm, the sample size was calculated to
detect a minimum difference of 30% in cost between the
3 groups, with 80% power. A total sample size of 180,
with 60 patients per group, was conservatively chosen
on the basis of this analysis. An interim analysis was
performed after the enrollment of the first 45 patients,
at which time significant differences in costs were
found among the 3 groups.
The model was populated with data from several
sources. All of the characteristics for calculation of the
time to safe ED discharge were obtained directly from
the clinical trial data, namely, the time at which thera-
peutic concentrations were achieved, the time the
patient was free of adverse events precluding discharge,
and, in the case of the intravenous arms, the time at
which the infusion was complete.
According to the institutional perspective, costs
were defined as those incurred by the hospital only.
Cost of care and salary data were obtained from hospital
administrative databases and applied as outlined below.
The cost of care included cost of drug administration
and management of adverse events in the clinical trial.
The cost of care was estimated by applying microcost-
ing methods. The resources use for intravenous phenyt-
oin and intravenous fosphenytoin administration was
obtained through time and motion studies. The time
and motion studies were performed by randomly select-
ing 6 nurses from the ED staff and timing their perfor-
mance of starting an intravenous line, setting up the
cardiac monitor and intravenous pump for drug admin-
istration, and preparing the medication for administra-
tion. A research assistant not involved in the care of the
patient timed the procedures from the moment the
nurse initiated the first activity to the time the drug
infusion was started. To minimize the chance of intro-
ducing timing bias, 4 (66%) of the 6 timed events were
randomly selected, and the mean time per event was
calculated for purposes of estimating the cost per event.
The mean nurse salary and benefits of $0.66 per minute
was derived from a mean of 2,080 hours worked each
year at an annual salary plus benefits of $75,900. The
cost per adverse event was calculated by multiplying
the time to adverse event resolution, measured in the
clinical trial, by the nurse salary for that period. Physi-
cian time for adverse event management was similarly
estimated with time and motion studies by applying a
salary plus benefits cost of $87,377 ($0.70 per minute),
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Figure 1.
Tree structure (mathematical model) used in the decision model. The tree structure was too large to demonstrate using a single fig-
ure and has been divided up into 4 sections labeled a, b, c, and d. The 3 therapies evaluated are presented after the decision node,
indicated by a square, in section a. Each possible adverse event (eg, ataxia, disorientation) is presented on a tree branch after a
chance node, shown as a circle on the tree. The probability of the adverse event occurring is indicated by a variable beneath the
appropriate decision tree branch (eg, p_disorientation_pop for the probability of experiencing disorientation while on oral pheny-
toin). The complete tree is symmetrical beginning from the left of section a and moving to the right, through to sections b, c, and
eventually d. The costs and outcomes were entered at the payoff node, indicated by a triangle at the end of the model in section d.
An individual simulated patient can be followed through the tree by starting with the treatment choice in section a and moving
through the tree (to the right). The patient will have the potential to develop adverse events based on the probabilities indicated at
each chance node, which were derived from the observed adverse events in the clinical trial. At the end of the tree (in section d), the
total cost for that simulated patient is calculated on the basis of the drug therapy received and adverse events experienced. The
expected cost of each therapy, a weighted average of all simulated patients, was determined by multiplying through the probability
of progressing down a particular branch by the payoff for that branch, to determine the weighted cost for that branch, and then
adding all of these weighted branch costs together. PO, Oral; IV, intravenous.

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C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al
which was derived from salary information of the cur-
rent mix of attending physicians and residents employed
in our ED. Because oral phenytoin requires minimal
preparation time and its adverse events are typically
transient and do not require additional supplies or
physicans’ orders, only nursing time was included in
the analysis.
For the base case (Base), physician and nursing time
for drug preparation and adverse event management
were omitted. The base case is likely the most accurate
for our ED because the number of personnel is unlikely
to be influenced by phenytoin loading strategy. The per-
sonnel costs to the institution remain constant, regard-
less of the time required to treat individual patients
because seizure patients do not compose a large portion
of the ED population. As a result, only direct medical
variable costs were included in the Base analysis.
To apply our results to different practice settings and
different beliefs on how to value employee contribu-
tion, an alternative “Labor” analysis was developed.
This Labor analysis takes into account the cost associ-
ated with physician and nursing time for drug adminis-
tration and adverse event management. In this analysis,
time saved by treating patients with medications that
were either faster to administer or resulted in fewer
adverse events allowed clinicians to focus on other
duties that would be cost-saving to the institution,
completely offsetting their salaries. The true costs to
any health care system associated with treating post-
seizure patients lies somewhere between the 2 extremes
of the Base and this Labor analysis.
A second alternative, “Triage” (lower-urgency area of
ED) analysis, was developed to examine the costs and
effect of treating patients receiving oral phenytoin in a
triage or minor care area, rather than having them
assigned to a monitored bed. Because cardiac and intra-
venous infusion monitoring is not necessary when oral
phenytoin is used, this method may be useful in a very
busy ED by freeing a monitored bed, which would also
allow the hospital to charge for having treated an addi-
tional patient in this setting. In this analysis, the Base
costs were used to estimate the costs of drug adminis-
tration and adverse events (ie, direct medical variable
costs were used). However, the reimbursement associ-
ated with a county hospital visit ($300) was subtracted
from the cost to allow for the increase in efficiency from
having a free emergency bed for another patient.
For all 3 scenarios (Base, Labor, and Triage), we
reported the costs and outcomes separately. The costs
and outcomes were then combined to create the follow-
ing incremental cost-effectiveness ratios: cost per
3 9 0
adverse event avoided and cost per ED hour saved. The
incremental cost-effectiveness ratios were estimated
with the following equation:
(C1 – C2)/(E2 – E1)
where C1 and C2 are the costs of the 2 therapies being
compared and E1 and E2 are either the number of
adverse events or estimated ED length of stay.
Sensitivity analyses are performed because there is
always uncertainty in decision analysis. This uncer-
tainty results from several sources. First, because the
clinical and administrative research studies used in
decision models sample from a larger population, there
is variability around the mean values derived from these
samples. Another source of variability is present in
decision models because the studies and database infor-
mation incorporated in the analysis differ in enrollment
criteria, treatment administration, and study setting.
Combining different studies and data from other sources
into a single estimate of cost-effectiveness carries with
it a considerable degree of uncertainty that must be
addressed. A third source of uncertainty comes from the
application of studies from a clinical trial to that of clin-
ical practice. The decision analysis provides only single-
point estimates (mean cost, mean effectiveness, and
mean cost-effectiveness) without any measure of the
variance or uncertainty associated with it.
Sensitivity analyses are a collection of methods
designed to provide insight into the effects of this uncer-
tainty on the results of the model. Sensitivity analyses
were performed to ensure that our results are applicable
throughout a wide range of variability and costs in dif-
ferent practice environments. In our analysis, we used 2
methods of sensitivity analysis to the decision model to
characterize this uncertainty: one-way sensitivity analy-
sis and Monte Carlo simulation. One-way sensitivity
analysis is a procedure in which each variable in the
model is varied, one at a time, between 2 extreme but
believable values. The model results are then recalcu-
lated with the new inputs and recorded. The process is
repeated for all the variables in the model. Variables that
result in a change in the preferred treatment option or
that result in a substantial impact on the costs, effective-
ness, or cost-effectiveness estimates are reported. One-
way sensitivity analyses alter only a single model input
at a time and inform readers of which variables are most
important in the model but do not provide information
on the overall uncertainty associated with the model.
We also used a second approach, Monte Carlo simu-
lation, which is a method of varying some or all of the
decision model variables simultaneously to assess the
overall variability in the model.16,17 With this method,
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C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al

the distributions associated with model variables, usu-
ally obtained from a clinical trial or other database, are
entered into a computer program. For a single Monte
Carlo simulation run, the program uses the entered dis-
tributions to randomly select values for each variable
and calculates the model results. This process is re-
peated a predetermined number of times, and the re-
sults are used to demonstrate the model variability.
All of the sensitivity analyses presented in this study
were performed on all 3 scenarios. One-way sensitivity
analysis was performed on all variables included in the
model. Adverse event rates and time to safe ED discharge
were varied by their 95% confidence intervals (CIs),
whereas cost inputs were varied by 50% to 200% of their
Base values. In additional one-way sensitivity analyses,
adverse event costs were treated as a single variable and
varied by 50% to 200% of their Base values. We chose this
arbitrary range because these values should incorporate
the vast majority of believable values for costs.
As mentioned previously, a Monte Carlo simulation
was also conducted for each scenario. Adverse event
rates and calculated time to safe ED discharge were
altered according to distributions from the clinical trial,
and the results were plotted on a cost-effectiveness
plane. Labor, drug, and supply costs were held con-
stant. For example, the incidence of an adverse event
was allowed to vary according to the binomial distribu-
tion from the clinical trial in which the estimate was
obtained. The results of the Monte Carlo simulations
were used to construct acceptability curves. Accepta-
bility curves characterize the proportion of time one
option is cost-effective for various thresholds of what is
considered cost-effective, called a ceiling ratio. Accepta-
bility curves use the concept of net benefits to reorgan-
ize the incremental cost-effectiveness ratio according to
the following equation:
NMB1 – NMB2 = h × (E1 – E2) – (C1 – C2)
where NMB1 and NMB2 are the net benefits of therapies
1 and 2, respectively, E1 and E2 are the effects, C1 and C2
are the costs, and h is the ceiling ratio. Rearranging the
cost-effectiveness equation in this way overcomes many
of the methodologic difficulties of estimating CIs sur-
rounding a ratio and is therefore becoming a preferred
method of handling uncertainty in cost-effectiveness
analyses. This method has been described in greater
detail by Briggs and Fenn18 and Briggs et al.19 All calcu-

Table 2.
Model inputs and range tested in one-way sensitivity analyses.

Treatment Option
Variable Oral Phenytoin Intravenous Phenytoin Intravenous Fosphenytoin

Adverse event rates, % (range tested)

Ataxia 25.0 (6.8–59.5) 14.3 (1.8–42.4) 0.0 (0.0–21.8)
Disorientation 12.5 (1.6–38.3) 14.3 (1.8–42.4) 13.3 (1.7–40.4)
Dizziness/headache 37.5 (15.2–64.5) 28.6 (8.4–58.1) 40.0 (16.3–67.7)
Hypotension NA 14.3 (1.8–42.4) 6.7 (0.2–32.0)
Pruritus NA NA 80.0 (51.9–95.7)
Nausea/vomiting 12.5 (1.6–38.3) 0.0 (0.0–23.2) 26.7 (7.8–55.1)
Nystagmus 18.8 (4.0–45.7) 42.9 (17.7–71.2) 20.0 (4.3–48.1)
Phlebitis NA 78.6 (49.2–95.4) 20.0 (4.3–48.1)
Tachycardia NA 0.0 (0.0–23.2) 6.7 (0.2–32.0)
Differential costs* (range)
Administering drug, labor costs excluded (Base) $2.83 ($1.41–5.66)† $19.28 ($9.64–38.56)‡ $175.19 ($87.59–350.38)§
Administering drug, labor costs included (scenario 1) $2.83 ($1.41–5.66)† $31.06 ($15.53–62.12)‡ $186.97 ($93.48–373.94)§
Mean time to safe ED discharge, h±SDll 6.4±2.2 1.7±0.8 1.3±1.0
NA, Not applicable (adverse event would not be expected to occur in this group [attributable to diluent or drug-specific property]).
*Differential costs are those costs that occur for at least 1 of the therapies and not for another. Costs that are similar between all 3 therapies were excluded from this analysis to

maintain the model’s simplicity.

†The drug and supply costs of administering oral phenytoin include the cost of the drug ($2.83). There were no differential labor costs involved.
‡The drug and supply costs of administering intravenous phenytoin include the cost of the drug ($6.35), bag of normal saline solution ($0.66), and other supplies such as needles,

syringes, gauze, and bandages ($12.93). The labor costs included drug preparation for infusion ($1.98), starting an intravenous line ($3.30), priming the intravenous pump ($3.30), and
preparing the cardiac monitor ($2.54).
§
The drug and supply costs of administering intravenous fosphenytoin include the cost of the drug ($162.26), bag of normal saline solution ($0.66), and other supplies such as nee-
dles, syringes, gauze, and bandages ($12.93). The labor costs included drug preparation for infusion ($1.98), starting an intravenous line ($3.30), priming the intravenous pump ($3.30),
and preparing the cardiac monitor ($2.54).
llNot tested in one-way sensitivity analyses. Time to safe ED discharge for oral phenytoin was statistically different from that with intravenous phenytoin and intravenous fospheny-

toin (P<.001).

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C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al

lations were performed with DATA Professional Release

Table 3.
Time to adverse event resolution with range tested in one-
2 (TreeAge Software Inc., Williamstown, MA).
way sensitivity analyses and mean calculated costs associ-
ated with treating the adverse event (labor included).
R E S U LT S

Mean Adverse Event Costs The model structure that was used is shown in Figure 1.
for the Labor Scenario†‡ The estimates that were used to populate the model are
Time to Adverse shown in Tables 2 and 3. The adverse event rates, total
Event Resolution, Oral Intravenous Intravenous
Adverse Event Min (Range)* Phenytoin Phenytoin Fosphenytoin
number of adverse events, and time to safe ED discharge
for each of the therapies, estimated from the clinical
Ataxia 35.0 (25.0–45.0) $26.60 $28.10 $28.10 trial, are shown in Tables 2, 3, and 4. Seizures occurred
Disorientation 58.5 (12.6–104.4) $42.11 $42.11 $42.11
Dizziness/ 63.4 (3.4–123.4) $45.34 $45.34 $45.34
in 5 patients during the study; however, none was a
headache result of the loading process. In 4 patients, seizures
Hypotension 7.5 (2.5–12.5) NA $9.95 $9.95 occurred several hours after the attainment of thera-
Pruritus 18.3 (7.5–29.0) NA NA $14.18
Nausea/vomiting 18.5 (5.0–32.0) $15.58 $17.21 $17.21 peutic phenytoin concentrations, and in 1 patient, a
Nystagmus 45.9 (20.2–71.6) $33.79 $35.29 $35.29 seizure occurred after enrollment but before the initia-
Phlebitis 19.9 (11.6–28.2) NA $19.21 $19.21
Tachycardia 5.0 (0.0–100.0)‡ NA $6.80 $6.80 tion of the study protocol.
NA, Not applicable (adverse event would not be expected to occur in this group The results of the Base scenario (Table 4), a scenario
[attributable to diluents or a drug-specific property]). in which labor costs were not included, showed that oral
*Mean time to adverse event resolution obtained from clinical study. Range calculated

from 95% CIs in the study.

phenytoin was the least expensive option, costing $2.83
†Adverse event costs included monitoring of the adverse event by a nurse for the
per patient. Intravenously administered phenytoin was
entire period of the event at an average salary of $0.66 per minute, physician time
involved in evaluating the adverse event as derived from a time and motion study (3 to
the next least costly option, at $23.48 per patient, fol-
5 minutes per adverse event) at an average salary of $0.70 per minute, and drug and lowed by intravenous fosphenytoin at $176.79 per
supply costs for managing an adverse event ($0.00 to $3.98 per adverse event). patient, for an incremental cost difference compared
‡Adverse event occurred in only 1 patient; therefore, a range for the time to adverse

event resolution for use in the sensitivity analyses could not be determined from 95% with oral phenytoin of $20.65 and $173.96, respectively.
CIs and is arbitrary. The Labor scenario (Table 4) included the labor costs
associated with drug administration and adverse event

Table 4.
Predicted incremental cost-effectiveness of oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin (model results).

Outcome Scenario Oral Phenytoin Intravenous Phenytoin Intravenous Fosphenytoin

No. of adverse events per person All 1.06 1.93 2.13

Time to safe ED discharge All 6.4 1.7 1.3
Total cost, $ Base (labor costs excluded) 2.83 23.48 176.79
Total cost, $ Labor (labor costs included) 40.06 84.31 238.67
Total cost, $ Triage (labor costs excluded; oral –297.17* 23.48 176.79
phenytoin patients treated in triage)
Cost per adverse event avoided All Dominates† Dominated by oral Dominated by oral phenytoin
phenytoin
Cost per hour of ED time saved Base (labor costs excluded) Least costly $4.39 Compared with oral $383.28 Compared with intra-
alternative phenytoin venous phenytoin; $34.11
compared with oral phenytoin
Scenario 1: Labor (labor costs included) Least costly $9.41 Compared with oral $385.90 Compared with intra-
alternative phenytoin venous phenytoin; $38.94
compared with oral phenytoin
Scenario 2: Triage (labor costs excluded; Least costly $81.46 Compared with oral $383.28 Compared with intra-
oral phenytoin patients treated in triage) alternative phenytoin venous phenytoin; $105.07
compared with oral phenytoin
*
In the triage case, oral phenytoin would be expected to generate a revenue for the institution. The cost of giving oral phenytoin was estimated at $2.83, whereas the ability to admit
another patient to an ED bed would generate a $300 charge, the estimated opportunity cost of treating patients in a monitored ED bed.
†
A therapy dominates another therapy when it is more effective and less costly.

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C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al
management. In this scenario, oral phenytoin remained
the least costly option, with an expected cost of $40.06
per patient. Intravenous phenytoin cost $84.31 per
patient and an incremental cost of $44.25 compared
with oral phenytoin. Intravenous fosphenytoin was
again the most expensive agent in this analysis, with an
expected mean cost of $238.67 per patient and a differ-
ence of $198.61 compared with oral phenytoin.
The Triage scenario (Table 4) examined the cost dif-
ferences associated with providing oral phenytoin in a
triage or urgent care area. In this scenario, oral pheny-
toin resulted in a “cost-savings” to the system of $297.17,
whereas intravenous phenytoin and fosphenytoin cost
$23.48 and $176.79, with differences of $321.05 and
$473.96, respectively.
Combining costs and adverse events rate in the Base
scenario revealed that oral phenytoin was cheaper and
caused less morbidity in the Base and both scenario
analyses, dominating the other 2 therapies (Table 4).
Likewise, intravenous fosphenytoin was dominated by
intravenous phenytoin, although the differences in the
total number of adverse events for these 2 therapies
were not statistically significant in the original study.
Combining costs and time to safe ED discharge
resulted in incremental gains in effectiveness as the cost
of the regimen increased. For the Base scenario, intra-
venous phenytoin had an incremental cost-effective-
ness of $4.39 per hour of ED time saved compared with
oral phenytoin. Intravenous fosphenytoin had an incre-
mental cost-effectiveness of $383.28 per hour of ED
time saved compared with intravenous phenytoin.
Compared with that of oral phenytoin, the incremental
cost-effectiveness of intravenous fosphenytoin was
$34.11 per hour of ED time saved.
In the Labor scenario, the incremental cost-effective-
ness of intravenous phenytoin compared with oral
phenytoin was $9.41 per hour of ED time saved. The
incremental cost-effectiveness of intravenous fos-
phenytoin compared with intravenous phenytoin was
$385.90 per hour of ED time saved and compared with
oral phenytoin was $38.94 per hour of ED time saved.
In the Triage scenario, the incremental cost-effective-
ness of intravenous phenytoin compared with oral
phenytoin was $81.46 per hour of ED time saved. The
incremental cost-effectiveness estimates of intravenous
fosphenytoin compared with intravenous phenytoin
and oral phenytoin were $383.28 and $105.07 per hour
of ED time saved, respectively.
The impact of each model input on costs was exam-
ined by using one-way sensitivity analyses. The sensi-
MARCH 2004 43:3 ANNALS OF EMERGENCY MEDICINE
tivity analyses were performed on all model inputs,
including adverse events rate estimates from the clini-
cal trial, adverse event treatment and drug administra-
tion cost inputs, and time and salary inputs from the
time and motion study. No single input resulted in a
change in the preferred agent. Oral phenytoin always
remained the least costly option, followed by intra-
venous phenytoin and then intravenous fosphenytoin.
The effectiveness measure of the adverse event rate
was not examined with one-way sensitivity analyses,
because it was obtained directly from the clinical trial.
In the clinical trial, there was a statistically significant
difference in the total number of adverse events be-
tween oral phenytoin (17 adverse events in 16 patients)
and the 2 intravenous regimens (intravenous phenyt-
oin: 27 adverse events in 14 patients; intravenous fos-
phenytoin: 32 adverse events in 15 patients) in favor of
the oral regimen (Table 2). No significant differences in
the total number of adverse events were seen between
intravenous phenytoin and intravenous fosphenytoin.
With respect to calculated time to safe ED discharge,
there was no difference observed between intravenous
phenytoin (1.7 hours) and intravenous fosphenytoin
(1.3 hours). However, there was a significantly reduced
time to safe ED discharge when either of the 2 intra-
venous regimens was compared with oral phenytoin (6.4
hours; difference 4.7 hours versus intravenous phenyt-
oin and 5.1 hours versus intravenous fosphenytoin).
Because oral phenytoin dominated the decision model
when costs and adverse events rate were considered, the
Monte Carlo simulations and acceptability curves did
not provide much additional insight into this measure of
the cost-effectiveness and these results are not shown.
The results of the Monte Carlo simulations are shown for
the comparison of costs and time to safe ED discharge.
In the Monte Carlo simulations, there was no dis-
cernable overlap in the cost estimates, regardless of the
scenario (Base, Labor, or Triage). However, there was
considerable overlap in the effectiveness measure: time
to safe ED discharge. The results of the Base and Labor
scenario Monte Carlo simulations are shown on a cost
versus effectiveness graph in Figure 2.
For our analysis, the ceiling ratio for each hour of ED
time saved was the main outcome of interest and consti-
tutes the x axis of the acceptability curves. For the Base
scenario (Figure 3), a ceiling ratio of less than $2 per hour
of ED time saved results in oral phenytoin being the pre-
ferred therapy more than 95% of the time. When the ceil-
ing ratio is between $2 and $14 per hour of ED time saved,
either oral phenytoin or intravenous phenytoin may be
3 9 3
C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al

preferred, depending on patient- or institution-specific
details. Beyond $14 per hour of ED time saved, intra-
venous phenytoin is preferred in more than 95% of all tri-
als. Within the ceiling ratio range that we have shown,
fosphenytoin did not become a preferred therapy. When
the ceiling ratio was $100 per hour of ED time saved, fos-
phenytoin was preferred in 1.6% of the trials.
A similar pattern develops for the Labor scenario,
although there is more uncertainty associated with this
model. Oral phenytoin is preferred in 95% of the trials or
greater, up to a ceiling ratio value of approximately $1 per
hour of ED time saved. Intravenous phenytoin becomes
preferred more than 95% of the time beyond $30 per hour
of ED time saved. The results are shown in Figure 3.
The Triage scenario (results not shown) favors oral
phenytoin more than the previous 2 scenarios. Oral
phenytoin is preferred more than 95% of the time, up to
a ceiling ratio of $34 per hour of ED time saved. Neither
intravenous phenytoin nor intravenous fosphenytoin
achieve preference greater than 95% of the time within
the ceiling ratio range shown on the graph.
L I M I TAT I O N S
There are several limitations to our study. The first is that
we could not adequately quantify the incremental cost-
effectiveness of each therapy in preventing a seizure
because the clinical study was not designed to detect dif-
ferences in seizure rates. Given that we observed no
seizures in patients with subtherapeutic concentrations,
a large sample size would likely be needed. We are
unaware of any other published studies that compare the
relative seizure rates among the 3 loading techniques.
Second, not factored into the triage scenario is the
calculation of the incremental cost of a seizure in triage
versus a seizure in the monitored area. This incremental
cost is essentially the cost of transferring the patient
into the monitored area. However, we believe that this
cost is negligible.
The third limitation is the fact that the “time to safe
ED discharge” number does not take into account other
inefficiencies and administrative duties associated with
a normal ED encounter. Given the inherent inefficien-
cies of a large and busy ED, issues such as creating the
patient’s medical record, waiting time for room assign-
ment and physician evaluation, and drug administra-
tion and reevaluation before discharge all may take a
much longer time. In fact, in a recent quality assurance
project, we found that the average time from patient
presentation to the triage area to the start of phenytoin
loading was more than 8 hours (n=27). By this measure,
had all patients been treated before the availability of a
bed in the monitored area, they may have been ready for
discharge at the point at which they would otherwise
only be starting the loading process.
DISCUSSION
Our cost-effectiveness analysis determined effective-
ness by examining adverse events and time to safe ED

Figure 2.
Base case and Labor case cost-
effectiveness plane. This figure
shows the results of the Monte
Carlo simulation on a cost-effec-
tiveness plane, giving an esti-
mate of the variability in the
model. Each dot represents one
of the Monte Carlo runs. There
is little or no overlap between
the costs of therapy. However,
there is considerable overlap
between intravenous phenytoin
and intravenous fosphenytoin in
time to safe ED discharge.

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C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al
discharge. Time to safe ED discharge was, in turn, deter-
mined by the time to a therapeutic level and absence of
any adverse events that required ED care. We performed
the cost-effectiveness analysis from the perspective of a
health care system and, more specifically, from the per-
spective of a county health care system. As such, our
costs may not reflect the actual costs in other systems.
However, the Base analysis was robust to sensitivity
analyses on costs, indicating that although the esti-
mates of expected costs and cost-effectiveness may dif-
fer under different settings, the choice of preferred
Figure 3.
Acceptability curve for the Base scenario (cost of labor
excluded). The ceiling ratio in this graph refers to the maxi-
mum cost that the institution is prepared to pay to invest to
discharge a patient one hour earlier from the ED. The pro-
portion of trials from the Monte Carlo simulation in which
intravenous phenytoin is the preferred agent over oral phe-
nytoin is plotted against the ceiling ratio. Intravenous
phenytoin rapidly becomes the preferred agent as the ceiling
ratio changes from $2 (where oral phenytoin is preferred
>95% of the time) to $18 (where intravenous phenytoin is
preferred >95% of the time). Intravenous fosphenytoin does
not become a favorable therapy within this ceiling ratio
range. In the Labor scenario (cost of labor included), oral
phenytoin is the preferred drug in >95% of the trials to an
approximate ceiling ratio of $4 per hour of ED time saved.
Intravenous phenytoin is preferred >95% when the willing-
ness to pay is $46 per hour of ED time saved. Intravenous
fosphenytoin does not become a favorable therapy within this
ceiling ratio. A similar pattern was observed in the Triage
scenario (results not shown). For all 3 scenarios (Base,
Labor, and Triage), oral phenytoin was the preferred agent if
the institution was less interested in investing money to dis-
charge patients quicker from the ED, which may be appropri-
ate for many patients. In certain circumstances or for certain
patients, it may be more desirable to pay a greater amount to
discharge patients from the ED earlier. In these situations,
intravenous phenytoin would likely be the preferable therapy.
100
90
80
Preferred option
70
Proportion of trials
PO Phenytoin Base case
60
IV Phenytoin Base case
50
IV Fosphenytoin Base case
40
PO Phenytoin Labor case
30
IV Phenytoin Labor case
20
IV Fosphenytoin Labor case
10
0 were overestimated. The authors assigned a length of
0 20 40 60 80 100
Ceiling ratio
(cost per h of ED time)
MARCH 2004 43:3 ANNALS OF EMERGENCY MEDICINE
agent is not greatly affected. We chose not to do the
analysis from a societal perspective, a common recom-
mendation in pharmacoeconomic guidelines.20,21
Societal costs would be extremely difficult to obtain in
this study setting and would add little information for
our intended audience: those within a health care sys-
tem charged with selecting agents for use in the ED.
We deliberately chose our scenarios to represent cur-
rent costing practices. Our base scenario, by exclusion
of labor costs, reflects current pharmacoeconomic
methods. Labor costs were excluded regardless of
which therapy was administered. Thus, there is no cost
benefit to the institution for using a medication that is
easier to administer or has fewer adverse events. The
recently renewed interest in employee productivity as a
component of cost-of-illness analyses led us to develop
the Labor analysis in our study.22 Theoretically, these
time savings could be applied to other work that would
benefit the institution, possibly generating revenue to
offset the labor costs. In our Triage analysis, we exam-
ined the impact of using a lower-urgency area of the ED
for oral loading, allowing for even further improvement
in resource use.
Our cost-effectiveness study extends the findings
from other published data comparing the pharma-
coeconomics of phenytoin and fosphenytoin in the ED
by including an oral arm and by performing advanced
sensitivity analyses.7,12-14 Three studies have been per-
formed with adult patients.7,12,13 An additional study
performed in a pediatric population will not be dis-
cussed in this article.14 Two studies in adult patients
suggested that fosphenytoin was more cost-effective
than phenytoin for use in the ED,12,13 whereas the
other concluded that intravenous phenytoin was more
cost-effective.7
The incidence of adverse events in our study was
lower than that reported by Marchetti et al12 and
Armstrong et al13 and higher than that documented by
Touchette and Rhoney.7 In addition, the rate of adverse
events in the intravenous fosphenytoin group was
higher than was reported previously. Differences may
have occurred as a result of variations in study method-
ologies. Marchetti et al12 used clinical results from one
multicenter trial and abstracted financial data from a
different institution.12 The rate of adverse events to
intravenous phenytoin was high in this study, and the
costs attributed to the management of adverse events
time to resolution of these adverse events according to a
survey rather than quantifying real time to resolution.
They also assumed that all adverse events resulted in a
3 9 5
C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al
prolongation of length of stay in the ED. In clinical
practice, most adverse events caused by intravenous
phenytoin are usually managed during the intravenous
infusion and do not result in an increased length of stay
in the ED.23 In addition, the attempted blinding in this
study may have been unsuccessful because of the
higher infusion rate of fosphenytoin, potentially caus-
ing a bias against documentation of adverse events to
fosphenytoin. Furthermore, the investigators used
average fixed and variable costs to calculate the cost of
care for ED treatment instead of using only variable or
marginal costs of care, as is recommended.24 Our
results, together with those of Touchette and Rhoney,7
demonstrate the effect of using variable costs on the
final decision of the analysis.
In their analysis, Armstrong et al13 used a question-
naire administered to nurses from critical care, emer-
gency, and neurology services in 3 local hospitals to
obtain effectiveness data, frequency of adverse events,
and methods of treating the reactions, which may have
resulted in an overestimation of rate of adverse events
and may have unduly affected the analysis because
expert opinion overestimates time and costs of manag-
ing adverse events.25,26 In our study, we quantified the
actual time required for clinical care and management
of adverse events by performing a time-motion study,
which is a preferred costing method.24
In contrast to the 2 aforementioned studies, that of
Touchette and Rhoney7 found a lower rate of adverse
events. Again, this difference may be explained by dif-
ferences in the methods of quantifying adverse events.
Our study used an initial infusion rate of 50 mg/min,
with downward adjustment for adverse events accord-
ing to a standardized algorithmic approach. The study
on which Touchette and Rhoney based their analysis
initiated infusion rates at 20 mg/min.23 That study
quantified the rate of adverse events through retrospec-
tive medical record review and was not designed to
evaluate delayed adverse events.23 In our study, the
presence of adverse events was assessed not only during
the infusion but also at predetermined intervals there-
after for a 24-hour period by specialized nurses in a
research unit. This method may have overestimated the
rate of adverse events requiring intervention and,
hence, may have overestimated costs. Despite these dif-
ferences, our conclusion that phenytoin is more cost-
effective for intravenous loading is the same.7
Our pharmacoeconomic analysis suggests that oral
phenytoin is the least expensive method of loading
phenytoin and results in the fewest number of adverse
3 9 6
events. However, if rapid discharge from the ED is
desired, it may be preferable to use intravenous phenytoin
at an estimated additional average cost of $20.65 (Base) or
$44.25 (Labor) and with an estimated mean time savings
of 4.7 hours per patient. Several patient factors, such as
occupation, income, previous adverse events with pheny-
toin loading in the ED, and frequency of seizures are likely
to influence their preference of loading technique. For
patients who are not employed, the inconvenience of
remaining longer in the ED for oral loading may be minor
compared with the discomfort of adverse events associ-
ated with intravenous loading. For the patient who expe-
riences frequent or severe seizures when subtherapeutic,
an intravenous route may be preferable.
Cost-effectiveness analyses typically focus on gener-
alizable outcomes such as years of life saved or quality-
adjusted life-years saved. We did not expect to see dif-
ferences in quality of life between the 3 methods of
phenytoin administration and are unaware of any stud-
ies demonstrating such differences. Therefore, we eval-
uated the 3 regimens by using 2 outcome measures of
incremental cost-effectiveness: cost per adverse events
avoided and cost per hour of ED time saved. With the
cost per adverse event avoided measure, oral phenytoin
dominated both intravenous methods of administra-
tion. Intravenous phenytoin also resulted in fewer
adverse events and a lower cost compared with intra-
venous fosphenytoin. Only one identified study, by
Armstrong et al,13 estimated the cost-effectiveness of
phenytoin by using cost per adverse event avoided. This
study estimated that intravenous fosphenytoin use
resulted in an incremental cost-effectiveness of $96.91
per adverse event avoided. Other studies have neither
found differences in adverse events rates, making incre-
mental analysis impractical,7 nor performed incremen-
tal analysis.12 One limitation of using these nongener-
alizable outcomes is that an institution’s consideration
of what is cost-effective for a reduction in adverse events
or early discharge from the ED has not been quantified.
We attempted to overcome this limitation by using
acceptability curves.18,19,27 The acceptability curves
demonstrate the likelihood that one therapy is preferred
over another at various levels of cost-effectiveness.
Decisionmakers within institutions can plot their own
beliefs of what is considered cost-effective on this graph
and determine the optimal therapy and certainty with
which it is preferred. However, there are several caveats
to acceptability curves. First, the institution may not
know or be able to ascertain their beliefs on what is con-
sidered cost-effective (ie, the ceiling ratio) for early ED
ANNALS OF EMERGENCY MEDICINE 43:3 MARCH 2004
C O S T - E F F E C T I V E N E S S O F P H E N Y T O I N L O A D I N G Rudis et al
discharge. Second, the ceiling ratio for ED time saved
may actually vary considerably among institutions,
depending on the institutions’ workload, finances, and
other factors. In an ED with a high workload, the ceiling
ratio may be significantly higher for ED time saved. It
may also be higher in a competitive market, where time
to ED discharge may be a measure of work efficiency
and a marketing tool to the public.
As a result of our study, we now recommend in our ED
that oral phenytoin loading be considered in cases in which
patients do not otherwise require monitoring. In many
cases, the oral phenytoin loading process can be performed
in triage, freeing monitored beds for other patients. With
respect to fosphenytoin, we continue to restrict its use to
status epilepticus or cases in which the time required to
load must be kept to the absolute minimum (eg, patient
going immediately to the operating room).
In summary, our study demonstrated that oral
phenytoin is the most cost-effective method of loading
phenytoin in the ED in most circumstances. Intra-
venous phenytoin is preferred if one is willing to pay
and willing to have more adverse events because of a
quicker time to safe ED discharge. It is unlikely that
intravenous fosphenytoin use is justifiable in any set-
ting. The additional cost of ED time saved by using the
faster intravenous routes would cost an additional
$4.39 per hour and $383.28 per hour for intravenous
phenytoin and intravenous fosphenytoin, respectively.
We are indebted to the faculty, nurses, and residents of the Depart-
ment of Emergency Medicine at Los Angeles County+University of
Southern California Medical Center and the staff of the General
Clinical Research Center; to Gregory Garcia, MD, Christian
Zimmerman, MD, and John Murray, MD, who helped with patient
recruitment and data collection; and to Jorge Avila who provided
quality assurance data discussed in the manuscript.
Author contributions: MIR, DRT, SPS, APC, and MO collaborated on
all aspects of the study, from the initial hypotheses through the phar-
macoeconomic analysis and the preparation of the manuscript. APC
was also involved in carrying out the time-motion component of the
study. DRT carried out the modeling for the cost-effectiveness anal-
ysis and performed the statistics. MIR takes responsibility for the
paper as a whole.
Received for publication January 9, 2003. Revisions received June 27,
2003, and October 2, 2003. Accepted for publication October 8, 2003.
Presented as an abstract at the American College of Emergency
Physicians Research Forum, October 2002, Seattle, WA.
Supported by grants from the National Institutes of Health General
Clinical Research Center (grant M01 RR-43), the University of
Southern California Health Research Association, the University of
MARCH 2004 43:3 ANNALS OF EMERGENCY MEDICINE
Southern California Medical Faculty Women’s Association Fund,
and the University of Southern California School of Pharmacy Drug
Development Research Center.
Address for reprints: Maria I. Rudis, PharmD, Department of
Pharmacy, University of Southern California School of Pharmacy,
1985 Zonal Avenue, PSC 700, Los Angeles, CA 90033; 323-442-1437,
fax 323-442-1681; E-mail rudis@usc.edu.
REFERENCES
1. Krumholz A, Grufferman S, Orr ST, et al. Seizures and seizure care in an emer-
gency department. Epilepsia. 1989;30:175-181.
2. Brokaw J, Olson L, Fullerton L, et al. Repeated ambulance use by patients with
acute alcohol intoxication, seizure disorder, and respiratory illness. Am J Emerg Med.
1998;16:141-144.
3. Simonson HC, Pelberg AL. Unnecessary emergency transport and care of grand
mal seizures. Am J Med Qual. 1993;8:53-55.
4. Osborn HH, Zisfein J, Sparano R. Single-dose oral phenytoin loading. Ann Emerg
Med. 1987;16:407-412.
5. Dela Cruz FG, Kanter MZ, Fischer JH, et al. Efficacy of individualized phenytoin
sodium loading doses administered by intravenous infusion. Clin Pharm. 1988;7:219-224.
6. Johnson J, Wrenn K. Inappropriate fosphenytoin use in the ED. Am J Emerg Med.
2001;19:293-294.
7. Touchette DR, Rhoney DH. Cost-minimization analysis of phenytoin and fosphenyt-
oin in the emergency department. Pharmacotherapy. 2000;20:908-916.
8. Meyer MC, Straughn AB. Biopharmaceutical factors in seizure control and drug
toxicity. Am J Hosp Pharm. 1993;50(12 Suppl 5):S17-22.
9. Fierro LS, Savulich DH, Benezra DA. Safety of fosphenytoin sodium. Am J Health
Syst Pharm. 1996;53:2707-2712.
10. Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute
treatment of seizures. Recommendations for usage. JAMA 1983;249:762-765.
11. Bourgeois BF. Pharmacokinetic properties of current antiepileptic drugs: what
improvements are needed? Neurology. 2000;55:S11-16.
12. Marchetti A, Magar R, Fischer J, et al. A pharmacoeconomic evaluation of intra-
venous fosphenytoin (Cerebyx) versus intravenous phenytoin (Dilantin) in hospital
emergency departments. Clin Ther. 1996;18:953-966.
13. Armstrong EP, Sauer KA, Downey MJ. Phenytoin and fosphenytoin: a model of cost
and clinical outcomes. Pharmacotherapy. 1999;19:844-853.
14. Graves N. Pharmacoeconomic considerations in treatment options for acute
seizures. J Child Neurol. 1998;13(Suppl 1):S27-29.
15. Swadron SP, Rudis MI, Aziman K, et al. A comparison of phenytoin-loading tech-
niques in the emergency department. Acad Emerg Med. 2004;11:244-252.
16. Doubilet P, Begg CB, Weinstein MC, et al. Probabilistic sensitivity analysis using
Monte Carlo simulation: a practical approach. Med Decis Making. 1985;5:157-177.
17. Critchfield GC, Willard KE. Probabilistic analysis of decision trees using Monte
Carlo simulation. Med Decis Making. 1986;6:85-92.
18. Briggs A, Fenn P. Confidence intervals or surfaces? Uncertainty on the cost-effec-
tiveness plane. Health Econ. 1998;7:723-740.
19. Briggs AH, O’Brien BJ, Blackhouse G. Thinking outside the box: recent advances in
the analysis and presentation of uncertainty in cost-effectiveness studies. Annu Rev
Public Health. 2002;23:377-401.
20. Siegel JE, Weinstein MC, Russell LB, et al. Recommendations for reporting cost-
effectiveness analyses: Panel on Cost-Effectiveness in Health and Medicine. JAMA.
1996;276:1339-1341.
21. Hjelmgren J, Berggren F, Andersson F. Health economic guidelines: similarities,
differences and some implications. Value Health. 2001;4:225-250.
22. Osterhaus JT, Gutterman DL, Plachetka JR. Healthcare resource and lost labour
costs of migraine headache in the US. Pharmacoeconomics. 1992;2:67-76.
23. Coplin WM, Rhoney DH, Rebuck JA, et al. Randomized evaluation of adverse
events and length-of-stay with routine emergency department use of phenytoin or fos-
phenytoin. Neurol Res. 2002;24:842-848.
24. Weinstein MC, Siegel JE, Gold MR, et al. Recommendations of the Panel on Cost-
effectiveness in Health and Medicine. JAMA. 1996;276:1253-1258.
25. Evans C. The use of consensus methods and expert panels in pharmacoeconomic
studies; practical applications and methodological shortcomings. Pharmacoeconomics.
1997;12(2 pt 1):121-129.
26. Evans C, Crawford B. Expert judgement in pharmacoeconomic studies: guidance
and future use. Pharmacoeconomics. 2000;17:545-553.
27. Willan AR, O’Brien BJ, Leyva RA. Cost-effectiveness analysis when the WTA is
greater than the WTP. Stat Med. 2001;20:3251-3259.
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