Epilrpsio, 24:330-335.

1983
Raven Pre\a. New York

Anticonvulsant Serum Levels Are Useful Only

If the Physician Appropriately Uses Them: An
Assessment of the Impact of Providing Serum
Level Data to Physicians

*Robert S. Beardsley, ?John M. Freeman, and

$Francis A. Appel

*School of Pharmacy, UniLwsity of Maryland; ?Department of Nenrology,

Johns Hopkins University; and $Department of Qiiality Assurance, Ftznklin
Square Hospital, Baltimore, Mnrylatid

Summary: The ability to measure serum levels of anticonvulsants has been a

significant advance in the treatment of epilepsy. This technique enables prac-
titioners to monitor a patient's plasma concentration, to detect potential tox-
icity, and to assess compliance with the prescribed regimen. A retrospective
study of 164 adults with epilepsy was conducted to evaluate how serum an-
ticonvulsant determinations were used by physicians in their treatment of epi-
lepsy. Results indicate that the availability of test results did not improve the
degree of seizure control, nor did it diminish patient reports of toxicity. In
179%of therapeutic decisions, prescribers did not appear to use the blood levels
appropriately in their therapeutic decision-making process. When physicians
did appropriately utilize information from serum levels, the degree of seizure
control improved significantly compared with when the prescribers did not
use this information. The cost of determining serum levels of anticonvulsants
is justified only if the information is appropriately utilized.

The ability to measure anticonvulsant
serum levels has had a major impact on the
management of seizures and on the ability
to control epilepsy. Serum levels provide
documentation of patient noncompliance, a
common cause of continued seizures; they
also give indication of drug absorption
problems, and occasionally of increased
metabolism and of drug interactions. Lev-
els may also correlate with subjective com-
plaints of toxicity. Studies have shown that
the use of information provided by the
measurements of blood levels can improve
the control of seizures (Dawson, 1971; Bor-
ofsky et al., 1972; Sherwin et al., 1973; Ea-
die, 1976).
The goal of this project was to evaluate
the hypothesis that patient outcomes will
be improved when practicing physicians are
provided with serum levels of anticonvul-

Received June 1 I , 1982; revision received December 22, 1982.

Address correspondence and reprint requests to Dr. Beardsiey at School of Pharmacy, University of Mary-
land, Baltimore, Maryland 21201.
Key words: Anticonvulsant levels-Physician prescribing-Seizures-Epilepsv.

330
 PHYSICIAN USE OF SERUM LEVEL DATA
sants and when they utilize the results of
these serum levels to alter appropriately the
medication prescribed. Accordingly, this
study was designed to assess both the im-
pact of blood level availability and the uti-
lization of the information on patient out-
comes as measured by seizure frequency,
toxicity, and compliance.
METHODS
In July 1974 the determination of anti-
convulsant serum levels became available
in a large metropolitan hospital associated
with a medical school. Prior to this the lev-
els were available only on special order and
were utilized infrequently. During the
course of this study, levels were made
available for patient care at no charge.
One hundred sixty-four adults with epi-
lepsy who were being followed in the sei-
zure clinic of the hospital served as the study
population. Criteria for selection of these
patients were that the patients had been fol-
lowed for at least 1 year before and at least
1 year after the availability of anticonvul-
sant levels, that they were being treated with
phenytoin, phenobarbital, primidone, or a
combination, and that they continued under
care for at least 1 year after the first anti-
convulsant level was measured. Informa-
tion about the degree of seizure control,
toxicity, compliance, drug therapy, and
serum levels was collected retrospectively
from the patients’ clinic and hospital rec-
ords. Four neurologists provided the con-
tinuity of care for these patients.
Two slightly different hypotheses were
tested simultaneously: (1) that blood level
information provided to physicians would
be utilized to improve physician prescribing
and patient outcomes; and (2) that patient
outcomes would be improved in cases in
which the physician utilized the informa-
tion appropriately. The first hypothesis
deals with the question of the effect of test
result availability and assumes that physi-
cians utilize the information. The second
addresses the more specific question of
331
whether o r not physicians appropriately
utilize the test results provided.
The effect of providing information was
assessed by chart review of reported tox-
icity, patient compliance, and seizure fre-
quency before and after the introduction of
blood level measurements, as well as phy-
sician prescribing patterns.
T h e “appropriate” utilization of infor-
mation about the serum levels was assessed
through a retrospective review of the phy-
sician’s drug prescribing. Prescribing deci-
sions were reviewed by a panel consisting
of board-certified neurologists, a pharma-
cist, and a research assistant to determine
whether the decision to increase, decrease,
or not change medication appeared appro-
priate in light of the serum information pro-
vided, or whether the decision was inap-
propriate in light of that information.
This analysis was based on four main fac-
tors: ( 1 ) the blood levels of all the anticon-
vulsant agents as they appeared in the lab-
oratory report; (2) the patient’s seizure fre-
quency and previous seizure history: (3) the
subjective and objective evidence of patient
toxicity; and (4) the perceived level of pa-
tient compliance. For example, if the blood
level appeared to be low and the patient
was still having seizures, not displaying any
signs of toxicity, and appeared to be taking
the medication regularly. then an increase
in drug dose would appear to be warranted.
If the physician ordered such an increase,
then the decision was recorded as being ap-
propriate. On the other hand, if the physi-
cian did not alter the therapy. the panel felt
that the decision was inappropriate in light
of the blood level information. if the panel
was uncertain about the classification of the
decision owing to unclear o r missing infor-
mation, the decision was placed in a neutral
category.
The dependent variables were degree of
seizure control, degree of toxicity, and pa-
tient compliance. All three factors were
based on physician reporting i n the pa-
tient’s chart of frequency and type of sei-
332 R . S . BEARDSLEY ET A L .
zures, type and severity of drug-related
toxicity as perceived by the physician, the
patient, or both, and physician perception
of patient compliance based on workshop
interview and, in some instances, prior
serum levels. If physicians utilized the
serum level anticonvulsant data in making
their decisions, it was expected that seizure
control should improve and that toxicity
should decrease. Patient compliance might
also improve.
Approximately 172 adult patients were
eligible to be included in the study's patient
population. However, complete records
could not be located for eight patients. Thus,
164 patients served as the study population.
Most of the patients were black (74%) and
male (55%). Their ages ranged from 17 to
71 years. Most of the patients' visits were
paid for by Medicare or Medicaid. Only 25%
of the patients were employed on a fulltime
basis. Forty-two percent of the patients
were seizure free during the 6 months prior
to their inclusion in the study.
RESULTS
Patients were seen more frequently in the
year after the introduction of blood level
measurements than they had been previ-
ously. The mean number of visits prior to
the introduction of blood level measure-
ments was 2.98. In the year following it was
4.12 (p < 0.001). However, the mean num-
ber of seizures per year was the same (4.5
before, 4.1 after). In the period after levels
became available, one-third of the patients
had fewer seizures, one-third had more sei-
zures, and one-third had the same number
of seizures as before. Thus, it would appear
that the availability of blood levels per se
had little effect on overall seizure control.
There was also little effect on reported tox-
icity.
Comments about patient compliance were
recorded on only -20% of the visits during
the 2-year study period. During the year be-
fore blood levels were available, patients
were noted to be compliant on 23% of the
TABLE 1. Number of decisions appropriate
or inappropriate in light of' blood levels
Where change in
Total dosage advisable
Decision n % n %
Appropriate 311 10 174 72
Neutral 89 20 28 I1
Inappropriate 45 10 41 17
Total 4.51" 100 243 I00
" Two hundred eight decisions in patients who were
seizure free and nontoxic, with no change in medica-
tion required.
recordings. During the following year, pa-
tients were thought to be cornpliant on 32%
of the recordings (p < 0.02). Thus, knowl-
edge that their blood levels were being
monitored may have had some effect on pa-
tient compliance.
During the year after introduction of blood
level measurements, prescribers made more
changes in therapy than in the previous year
(p < 0.001); however, the mean daily dose
of each medication was the same for both
years.
Thus, the introduction of blood level data
resulted in an increased number of office
visits and changes in medication, and pos-
sibly a slight increase in compliance, but
had no effect on seizure control or reported
toxicity.
The second hypothesis tested was that
patient outcomes would improve when the
physician appropriately utilized informa-
tion derived from the blood level data. Re-
sults were based on the prescriber's deci-
sion following the availability of blood level
information. A total of 451 prescribing de-
cisions involving the 164 patients were ex-
amined during this analysis. Using the pre-
viously discussed review process, 317 of the
4.51 decisions were judged to be appropriate
in light of the blood level information,
whereas 45 appeared t o be inappropriate
(Table 1). An additional 89 decisions were
assigned to the neutral category, since the
review panel was uncertain about the judg-
 PHYSICIAN USE OF SERUM LEVEL DATA
TABLE 2. Degree of seizure control v e i w s
type of decision in patients who were not
free of seizures
Decision
Appropriate Inappropriate
-
Degree of control" n % n <%,
Improved 88 51 2 5
Same 53 30 26
Worse 33 19 13
Total decisionsb 174 100 41
" Based on number of seizures
'x = 29. df = 2. p < 0.001.
ment because of unclear or missing infor-
mation or because the panel might have
made a different decision, but did not think
that the decision made was clearly appro-
priate. Of the 451 decisions evaluated, 208
were in patients who were seizure free and
for whom no decision to change medication
had to be made. If these are eliminated and
only decisions concerning patients who
either continued to have seizures or were
toxic are included, then of these 243 deci-
sions 174 (72%) were thought to be appro-
priate and 41 (17%) were thought to be in-
appropriate. Twenty-eight decisions were
neutral.
The relationship between the physicians'
decisions and the degree of seizure control
was analyzed further. The degree of seizure
control was noted during the patient's first
clinic visit after the physician had the drug
information available and had made a de-
cision either to change or not to change the
drug regimen. The degree of seizure control
was defined as the change in number of sei-
zures reported between clinic visits. Those
reporting fewer seizures were placed in the
improved category; those having more sei-
zures were categorized as having worse
control.
Table 2 displays the degree of seizure
control compared with the type of decision
the physician made. Patients who were sei-
zure free before the levels were available
were eliminated, since no decision had to
be made. Of those patients who were con-
333
TABLE 3 . Degree of control versus type of
change in decision
Type of change
lnappropriate to Appropriate to
Control appropriate inappropriate
Improved 20 I
Same 5 12
63 Worse 0 9
32
Total" 25 22
I00
" x? = 29.25, df = 2, p < 0.001.
tinuing to have seizures, 5 1% improved fol-
lowing a decision that was deemed appro-
priate on the basis of blood level informa-
tion, whereas 30% remained the same and
19% had more seizures. On the other hand,
following an inappropriate decision, only 5%
of patients had fewer seizures and 32% of
patients had more seizures (p < 0.001).
The degree of control and the change in
physician decision over time were further
correlated. Cases were identified in which
a physician had changed a decision from
one previously deemed inappropriate in light
of the serum level data to a decision at the
next visit that was thought to be appropri-
ate. Alternatively, some physicians changed
from a decision deemed appropriate to one
thought to be inappropriate. The degree of
seizure control was noted after each of these
decision changes. Twenty cases were iden-
tified in which the patient's seizure control
improved after the decision was changed
from inappropriate to appropriate, whereas
only one case improved when the decision
was altered from appropriate to inappro-
priate (Table 3). On the other hand, nine
situations were identified in which a patient
had more seizures after the physician
switched from an appropriate to an inap-
propriate decision (p < 0.001).
Analysis of the effects of the appropri-
ateness or inappropriateness of the deci-
sions showed that the reported toxicity was
not significantly influenced by the type of
decision made. Similarly, there was no re-
334 R . S . BEARDSLEY ET A L .

lationship between the type of decision and priately utilized the information provided to
patient compliance. them, the degree of seizure control could
have been improved significantly.
CONCLUSION In addition to the clinical ramifications of
The purpose of this study was twofold: not utilizing this information, there are eco-
(1) to assess the impact of providing infor- nomic concerns as well: the cost of each
mation about the serum levels of anticon- anticonvulsant level analysis is between $25
vulsants on physician prescribing and on and $35. Such cost is reasonable if physi-
seizure control, and (2) to measure the ef- cians are able to use the results to improve
fect of physician utilization of the infor- seizure control and decrease toxicity. How-
mation on seizure control. ever, this expense is clearly not justified if
Retrospective review of material re- physicians d o not utilize the information
corded in seizure clinic charts has many pit- appropriately.
falls. All material may not be recorded in a This study reviewed records for the pe-
systematic fashion; the rationale for a de- riod shortly after anticonvulsant blood lev-
cision may not be documented; reports of els became available. It is possible that
compliance o r patient reports of toxicity greater familiarity with the use of the levels
may not be substantiated. However, such would result in fewer inappropriate deci-
a review ha5 a major advantage. The study sions. However, this study emphasizes that
does not alter care as it is actually deliv- the mere availability of results is not suffi-
ered, eliminating the Hawthorne effect, cient to ensure that these results will be
which may have biased other studies. Those properly utilized. Continued education of
studies show what can be done when blood physicians in their meaning and their use is
levels of anticonvulsants are available; this necessary for patients t o benefit by im-
study analyzes what actually was done, even proved seizure control.
in an academic setting.
This study shows that the availability of Acknowledgment: This study was funded by
anticonvulsant serum level results per se did grant no. IR03 HS 03918-01 from the National
Center f o r Health Services Research, OASH.
not improve the degree of seizure control
or diminish the level of patient toxicity. As REFERENCES
would be expected, seizure control im- Borofsky LG, Louis S, Kutt H. Roginsky M. Diphen-
proves only when the physician utilizes the ylhydantoin. I Pediutr 1972;81:995-1002.
results in conjunction with information Dawson KP. Value of blood phenytoin in management
of childhood epilepsy. Arcl7 Dis Child 1971:46:
about seizure control, toxicity, and patient 386-8.
compliance and appropriately alters his Eadie MJ. Plasma level monitoring of anticonvulsants.
prescribing. When this is done, physicians Clin Phurmicokinet 1976:1 :52-66.
Sherwin AL. Robb JP, Lecther M. Improved control
in practice can improve seizure control sim- of epilepsy by monitoring plasma ethosuximide.
ilar to that seen in controlled studies (Sher- Arch Neurol 1973:28: 178-81.
win et al., 1973). However, even among this
group of academically based neurologists, RESUMEN
17% of the decisions were thought to be La posibilidad de medir 10s niveles skricos de anti-
inappropriate. convulsivantes ha demostrado ser un avance signifi-
cativo en el tratamiento de la epilepsia. Esta tecnica
This could explain why there were no sig- permite al clinico monitorizar la concentracion plas-
nificant differences in seizure control, tox- matica de 10s pacientes para detectar la potencial tox-
icity, o r prescribing between the year prior icidad y verificar el cumplimiento del regimen pres-
crito. Para evaluar como las determinaciones sericas
to the availability of anticonvulsant blood de anticonvulsivos han sido utilizadas por 10s medicos
levels and the year after those levels be- en el tratamiento de la epilepsia se ha realizado u n
came available. Had the physicians appro- estudio retrospectivo de 164 adultos con epilepsia. Los
 PHYSICIAN U S E OF SERUM LEVEL DATA
resultados indican que la disponibilidad de 10s resul-
tados no mejoro el grado de control de 10s ataques ni
disminuyo las quejas de toxicidad. En el l7%, de las
decisiones terapeuticas, 10s medicos no parecen haber
usado 10s niveles sericos de modo apropiado en su
proceso de tomar decisiones terapeuticas. Cuando 10s
medicos utilizan correctamente esta informacion el
grado de control de 10s ataques mejora significativa-
mente compariindolo con la falta de utilizacion de estos
datos. El coste derivado de la determinacion de estos
niveles sericos solo estii justificado si la informacion
es utilizada apropiadamente.
(A. Portera Sanchez, Mudrid)
ZUSAMMENFASSUNG
Die Moglichkeit, die Serumspiegel der Antikonvul-
siva zu bestirnmen, bedeutet einen deutlichen Fort-
schritt in der Behandlung der Epilepsie. Diese Technik
befahigt Praktiker die Plasmakonzentrationen der Pa-
tienten zu uberwachen, die moglichen toxischen Er-
335
scheinungen zu entdecken und die Mitarbeit der Pa-
tienten zu bestirnrnen. Eine retrospektive Unter-
suchung an 164 Erwachsenen mit Epilepsie wurde rnit
dern Ziel durchgefiihrt, zu erkennen, wie die Serum-
bestimmungen der Antikonvulsiva von den Arzten in
ihrer Behandlung der Epilepsie berucksichtigt werden.
Die Ergebnisse lassen erkennen, daB die Verfiigbarkeit
der Testergebnisse das AusrnaB der Anfallskontrolle
weder verbessert noch die Berichte der Patienten uber
toxische Erscheinungen vermindert hat. In 17% der
therapeutischen Entscheidungen schien der verord-
nende Arzt die Blutspiegel nicht angemessen in seinen
therapeutischen Entscheidungen zu berucksichtigen.
Immer dann, wenn die Arzte die Information aus den
Serumspiegeln angernessen verwendeten, verbesserte
sich das AusmaR der Anfallskontrolle signifikant ge-
genuber den Entscheidungen ohne Beniitzung der In-
formation. Die Kosten der Bestimrnung der Serum-
spiegel der Antikonvulsiva sind nur berechtigt, wenn
die Information angemessen beriicksichtigt wird.
(D. Scheffner, Heidelberg)