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Reminders of Drug Effects on Laboratory Test Results

Article in Clinical Chemistry · October 2000

DOI: 10.1093/clinchem/46.9.1395 · Source: PubMed

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Clinical Chemistry 46:9
1395–1400 (2000)
Reminders of Drug Effects on Laboratory
Test Results
Marita Kailajärvi,1* Timo Takala,1 Paula Grönroos,1 Nils Tryding,2 Jorma Viikari,3
Kerttu Irjala,1 and Jari Forsström4
Drug effects on laboratory test results are difficult to
take into account without an online decision support
system. In this study, drug effects on hormone test
results were coded using a drug-laboratory effect (DLE)
code. The criteria that trigger the reminders were de-
fined. To issue reminders, it was necessary to write a
computer program linking the DLE knowledge base
with databases containing individual patient medica-
tion and laboratory test results. During the first 10
months, 11% of the results from hormone samples were
accompanied by one or more DLE reminders. The most
common drugs to trigger reminders were glucocorti-
coids, furosemide, and metoclopramide. Physicians fac-
ing the reminders completed a questionnaire on the
usefulness of the reminders. All respondents considered
them useful. In addition, DLE reminders had caused
74% of respondents to refrain from additional, usually
performed examinations. In conclusion, drug effects on
laboratory tests should always be considered when
interpreting laboratory results. An online reminder sys-
tem is useful in displaying potential drug effects along-
side test results.
© 2000 American Association for Clinical Chemistry
Drugs often alter laboratory test results; the literature
reports ⬎40 000 drug effects on laboratory tests (1 ). These
effects may cause misinterpretation of laboratory data and
lead to unnecessary further tests, missed diagnoses, and
additional costs, as pointed out in the case report below.
The vast amount of medical information, with its
varying quality and ready availability, has to date made it
1
Central Laboratory and 3 Department of Medicine, Turku University
Central Hospital, Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland.
2
Box 57, SE-29621 Åhus, Sweden.
4
Medical Informatics Research Centre in Turku (MIRCIT), Kiinamyl-
lynkatu 4 – 8, FIN-20520 Turku, Finland.
*Author for correspondence. Fax 358-2-261 3924; e-mail marita.
kailajarvi@utu.fi.
Received March 15, 2000; accepted June 15, 2000.
1395
Laboratory
Management
laborious to take drug-laboratory effects (DLEs)5 into
account in everyday patient care. The prevalence of DLEs
is not negligible: as many as 12% of patients have had
laboratory results potentially affected by drugs in a gen-
eral medical ward (2 ). The effects of drugs on laboratory
tests have been published in extensive catalogs (1, 3– 6 ),
from which data have to be sought manually with active
effort. A modern solution for bringing this knowledge to
clinical routine is computerization and automatic remind-
ers. Because physicians are already flooded with informa-
tion, it is important to remind them only of the effects
relevant for the patient in question. This requires storing
individual medications in a structured way and coding
the data on DLEs in a logical way as well as building a
reminder system that can be integrated into the laboratory
information system (LIS) and hospital information system
(7 ). Until now, there have been very few computer
applications offering automatic monitoring of DLEs (2, 8 ).
In Turku University Central Hospital, coding of drug
effects in clinical chemistry was started in 1995 when a
DLE code was developed (9 ). In November 1998, an
online reminder system built on the DLE knowledge base
became operational. The system produces reminders in
cases where patient medication may affect the results of
hormonal laboratory tests. This report describes the DLE
reminder system in detail and presents the reminders
issued during the first 10 months as well as clinicians’
attitudes toward the reminders.
Case
In April 1998, a 66-year-old man was admitted to our
hospital because of vertigo and impaired swallowing and
speech. He had a history of obstructive bronchitis, diabe-
tes, and left hemiparesis following cerebral infarction. His
medication comprised dipyridamole, glibenclamide, and
5
Nonstandard abbreviations: DLE, drug-laboratory effect; LIS, laboratory
information system; TSH, thyroid-stimulating hormone, thyrotropin; FT4, free
thyroxine; ATC, Anatomical, Therapeutic, Chemical; and ID, identification
code.
1396 Kailajärvi et al.: Online Reminders of DLEs

inhalations of salbutamol and beclomethasone. A com- decreasing, transient decreasing, no effect, transient
puted tomographic scan with and without contrast me- increasing, slightly increasing, increasing effect, or con-
dium enhancement did not visualize cerebral infarction. tradictory data on the effect)
However, as the symptoms progressed, intravenous hep- • Level of documentation (effect has been studied with
arin was started on the day after admission. healthy volunteers and sometimes with patient popula-
Three days after hospitalization, the patient was tachy- tions as well, or with patient populations, or effect is
cardic (pulse rate, 110/min) and mildly exophthalmic. assumed or widely known, or effect has not yet been
Previously, he had had no signs suggesting hyperthyroid- well documented)
ism. The patient’s serum thyroid-stimulating hormone • Sex of patient (effect is probably valid in males and
(TSH) was 5.4 mIU/L (reference interval, 0.4 – 4.5 mIU/L), females, only males, or only females)
his free thyroxine (FT4) was ⬎83 pmol/L (reference • Age of patient (effect is probably valid in adults and
interval, 9.6 –17.1 pmol/L), and his free triiodothyronine children, only in adults, or only in children)
was 19.0 pmol/L (reference interval, 4.3–7.5 pmol/L). A • Onset of effect after starting the medication (unknown,
TSH stimulation test did not confirm thyroidal hyperthy- in 1 day, in 1 week, or in 1 month)
roidism (TSH, 6.5 mIU/L at 0 min, 22.0 mIU/L at 20 min, • Duration of effect after stopping the medication (un-
and 18 mIU/L at 60 min), but rather the laboratory results known, at maximum 1 week, at maximum 1 month, or
seemed to suggest either thyroid hormone resistance or ⬎1 month)
pituitary hyperthyroidism. Magnetic resonance imaging • Clinical significance of effect (major clinical signifi-
of the brain was partly unsuccessful because the patient cance, moderate clinical significance, no clinical signif-
was claustrophobic. The patient was discharged 15 days icance, clinical significance with high doses, or clinical
after admission with almost regained speech and swal- significance in rare cases)
lowing.
In addition, there is a field for a free additional text
After discharge, the patient’s serum TSH was 5.5
comment for the reminder, if needed. Each code is accom-
mIU/L, similar to the earlier concentration, but his FT4
panied by a list of most relevant references of the effect.
was now within the reference interval, i.e., 17 pmol/L.
During a pilot study (11 ), during which reminders
His medication at the time of the first sampling was now
were not forwarded to the wards, it was noted that some
checked. It was concluded that intravenous heparin had
reminders were unnecessary, bringing no new informa-
most probably caused the increase in FT4 during hospi-
tion for clinicians. These included reminders of the de-
talization (10 ). The reminder system described below had
sired therapeutic effects of drugs, e.g., the decreasing
not been implemented at that time. The drug-affected
effect of bromocriptine on serum prolactin (12 ). There-
result had thus caused expensive additional examinations
fore, in Turku University Central Hospital, an option to
(magnetic resonance imaging, repeated laboratory tests,
disregard reminders of such DLEs was included in the
consultations).
system. In addition to this “Link to LIS on/off switch”,
another restriction was added: If a patient is taking a
Materials and Methods
medication with a desired effect on the laboratory test in
We first collected data on drug effects on hormone tests
question (e.g., thyroxine or carbimazole, which affect TSH
from catalogs and individual publications. Because some
older publications classify effects that have since been
found to be analytical as biological, all information was
carefully evaluated. A doctor working in the field of
clinical chemistry then brought together the results of
different studies and coded the effects using the DLE code
(9 ). Another doctor then checked the coding. Collabora-
tion with Nils Tryding, who has studied and evaluated
the literature concerning drug effects for nearly 30 years
and collected ⬃7000 references (5 ), substantially en-
hanced the coding and brought about some changes to the
code that further focused the reminders.
The DLE code consists of nine features that describe
the following aspects of the DLEs:

• Nature of effect (analytical effect, biological effect, or

unknown mechanism)
• Route of administration (effect is probably valid with all
“systemic”, parenteral, or oral administration, or with
drugs absorbed from the mouth, and so forth) Fig. 1. Model of a laboratory result report.
• Direction and strength of effect (decreasing, slightly S-PRL, serum prolactin.
 Clinical Chemistry 46, No. 9, 2000
Fig. 2. The DLE browser for accessing the DLE knowledge base.
PRL, prolactin.
or FT4), all reminders of drug effects for that analyte are
disregarded automatically. The therapeutic drugs are
defined for each laboratory test in a laboratory database.
The function of the DLE reminder system is to issue
individual reminders, i.e., the system reminds when the
patient actually is taking a medication potentially affect-
ing the tests requested. To achieve this, the reminder
system links the DLE knowledge base with the databases
of laboratory test results and individual medications (7 ).
Nurses routinely store individual medications using trade
names listed in a separate database, making available
clear printouts with precise data of medication. The
medication database includes the Anatomical, Therapeu-
tic, Chemical (ATC) codes (WHO Collaborating Centre for
Drug Statistics Methodology, Oslo, Norway), which de-
scribe the generic names of drugs. The ATC codes are also
used in the DLE knowledge base. Laboratory tests are
coded using national codes [laboratory test identification
codes (IDs)] in both the test result database and the DLE
1397
knowledge base. In all databases, patients are identified
by their social security numbers (patient IDs). Conse-
quently, with the patient ID, the computer program is able
to retrieve relevant patient medication from the medica-
tion database. Using the laboratory test IDs and ATC
codes of the patient’s drugs, it then runs a query in the
DLE knowledge base to find the DLE codes for drug
effects. If all conditions for a DLE reminder are fulfilled as
described below, the system generates a brief structured
description of the possible DLE, e.g., “Haloperidol may
have increased prolactin value”. The reminder appears
alongside the laboratory test result in both the LIS, which
is used by wards, and in paper printouts (Fig. 1). To date,
a laboratory physician has checked the reminders before
forwarding them with results to clinicians. Clinicians can
obtain additional information on the reminders by open-
ing the DLE knowledge base, which is accessible on the
hospital Intranet (Fig. 2).
The conditions that trigger reminders were defined as
1398 Kailajärvi et al.: Online Reminders of DLEs

follows: the clinical significance of the effect must be at

Table 1. DLE reminders issued during the study period.a
least moderate; the effect must be well documented in the
No. of results with
Laboratory test DLE reminders/No. Drugs that caused DLE literature; the route of administration and administration
(serum/plasma) of tests taken reminders (n) dates must match the route, onset of the effect and
duration of the effect fields in the code; and the patient’s
Aldosterone 3/23 Enoxaparin (2) sex and age must match those in the code. In addition, as
Hydrochlorothiazide (1) described above, the “Link to LIS switch” must be “on”,
Androstenedione 0/0
and the patient must not have therapeutic medication that
Corticotropin 0/87
affects the test in question in the desired manner.
Cortisol 1/448 Nifedipine (1)
The DLE reminders were given, when appropriate,
Dehydroepiandrosterone
sulfate 0/1 with the laboratory analytes listed in Table 1. They were
Estradiol 0/13 issued to all wards (inpatient settings) and outpatient
Follicle-stimulating 1/33 Dexamethasone (1) clinics that store patient medications in the medication
hormone database (nine internal medicine wards, three neurology
Growth hormone 0/16 wards, three oncology wards, three obstetrics and gyne-
Luteinizing hormone 1/43 Dexamethasone (1) cology wards, three pulmonary disease wards, one pedi-
Parathyroid hormone 106/357 Furosemide (94) atric neurology ward, two ophthalmologic diseases
Diltiazem (23)
Isoniazid (2)
wards, and one rehabilitation ward as well as nephrology
Dopamine (1) and pediatric neurology outpatient clinics). The tests
Progesterone 0/0 usually are requested and interpreted by trainee resident
Prolactin 6/54 Dexamethasone (3) physicians in the wards and by experienced specialist
Amitriptyline (2) physicians at the outpatient clinics.
Moclobemide (2) To evaluate the system, the physicians facing DLE
Estrogens (1)
Haloperidol (1) reminders in the department of internal medicine were
Metoclopramide (1) asked to fill out a questionnaire about their views on the
Renin 13/24 Furosemide (5) reminders. The physicians were asked whether they had
Nifedipine (5) agreed with the reminders on a scale from 1 (never) to 5
Metoprolol (4)
Felodipine (2) (always), whether they considered the reminders useful
Hydroclorothiazide (2) (1 ⫽ not useful, 2 ⫽ slightly useful, 3 ⫽ useful, 4 ⫽ very
Propranolol (2) useful, 5 ⫽ extremely useful), and whether the reminders
Clonidine (1) sometimes made further examinations unnecessary, e.g.,
Diltiazem (1)
Spironolactone (1) radiological examinations otherwise performed because
Sex hormone-binding 0/0 of similar laboratory test results (1 ⫽ never, 5 ⫽ all
globulin reminders).
Testosterone 4/22 Moclobemide (2) The DLE reminders issued between December 1, 1998,
Diazepam (1) and September 30, 1999, and the results of the question-
Digoxin (1)
Finasteride (1) naire are presented below.
TSH 228/1826 Glucocorticoids (116)
Metoclopramide (39) Results
Propranolol (25) The DLE reminders issued during the study period and
Haloperidol (23)
Valproic acid (17)
the number of each hormone test taken in the participat-
Amiodarone (13) ing wards and outpatient clinics are presented in Table 1.
Heparin (7) Overall, DLE reminders were issued for 10.7% of the
Prazosin (4) hormone tests taken. Most DLE reminders, 55%, con-
Lithium (3)
Interferon-␣ (2) cerned drug effects on serum TSH, 26% on parathyroid
Morphine (2) hormone, and 12% on FT4. In relative amounts, DLE
Dopamine (1) reminders were most often attached to serum renin (54%
FT4 49/870 Propranolol (12) of the renin results had one or more DLE reminders),
Amiodarone (8)
Valproic acid (8)
parathyroid hormone (30%), and testosterone (18%). The
Rifampicin (7) five most common drugs that caused DLE reminders
Heparin (5) were glucocorticoids (121 reminders), furosemide (99 re-
Phenytoin (5) minders), metoclopramide (40 reminders), propranolol
Carbamazepine (4)
Primidone (2) (39 reminders), and valproic acid (25 reminders).
Triiodothyronine, free 0/28 We looked further into the reminders accompanying
Total 412/3845 (10.7%) serum TSH and FT4 results. There were 26 cases (9% of
a
TSH and FT4 reminders) in which the reminder clearly
A test result may be accompanied by more than one DLE reminder.
aided in the interpretation of the hormonal results;
 Clinical Chemistry 46, No. 9, 2000
changes around lower or upper reference limits in partic-
ular were clarified by reminding of a drug effect. For
example, there were cases where FT4 was within the
reference interval but a glucocorticoid had decreased the
TSH result to below the reference range although the
patients were euthyroid. In addition, some clinically or
subclinically hypothyroid patients with increased TSH
results had low-normal FT4 that probably had been in-
creased by a drug, e.g., valproic acid.
The questionnaire was returned by 23 physicians, 15
who were specialists in internal medicine and 8 who were
trainee resident physicians. The answers between the
groups were similar. Fifteen of the physicians (65%)
always or often agreed with the reminders, 6 (26%)
sometimes agreed, and 2 (9%) seldom agreed. No one
always disagreed with the reminders. All respondents
considered the reminders useful to at least some extent (at
least 3 on the scale); two respondents (9%) considered the
reminders extremely useful. According to eight respon-
dents (35%), half or more of the reminders made further
examinations unnecessary. Nine respondents (39%) had
rarely and three (13%) had never refrained from other
examinations because of DLE reminders.
Discussion
The online DLE reminder system is a novel decision
support system for clinicians. It brings knowledge of
DLEs from difficult-to-reach catalogs and publications to
everyday practice and thus saves time. It is also probable
that automatic reminders decrease the need for further
examinations and thus save money. This effect is, how-
ever, difficult to study, and therefore, exact figures cannot
be given.
In our experience, clinicians are not well aware of all
potential drug effects related to hormones. Therefore, we
have reason to believe that reminders have some impact
on clinical decision making. It would be useful to study
this impact, although evaluation in medical informatics is
complex because of the intersection of medicine and
healthcare delivery, evaluation methodology, and com-
puter-based information systems, as described by Fried-
man and Wyatt (13 ). In the present study, some of the
physicians facing DLE reminders completed a question-
naire on the usefulness of the reminders. The feedback
was positive. All respondents considered the reminders
useful to at least some extent. Seventy-four percent of the
respondents had sometimes refrained from further exam-
inations because of a DLE reminder. Because the two
participating outpatient clinics were small, trainee resi-
dent physicians working on wards received most of the
DLE reminders. In our teaching hospital, the DLE remind-
ers contribute to the education of residents in different
disciplines.
For greater benefit, some modifications to the system
have been suggested. For example, reminders should be
accompanied by a mention of the magnitude of the
possible effect. This has been considered but, for the
1399
moment, not implemented because the magnitude often is
affected by the dose of the drug, which at present is not in
a standard format. Another suggestion was to send a
reminder of the effects when tests are requested. This
would be most useful when a physician enters requests,
which is not, however, customary in our hospital at
present. It must also be emphasized that many drugs that
cause DLE reminders are commonly prescribed, e.g.,
antihypertensives and antiepileptics, and thus often are
capable of disturbing interpretation of laboratory test
results.
Until now, it has been very difficult to recognize DLEs
in everyday practice without an automatic reminder sys-
tem. In 1987, the IFCC tackled this problem and put
forward recommendations made by an expert panel (14 ).
The panel concluded that databases are needed to obtain
reliable information of drug effects on laboratory tests in
a practical form. According to the recommendations, the
information should be available interactively via data
terminals, and it should be possible to integrate informa-
tion from databases into local computers and into routine
hospital work. In addition, such databases should be able
to exchange information with other systems and have the
potential to expand. It also should be possible to modify
the databases without altering existing programs. The
DLE reminder system meets these recommendations. The
data included in the DLE knowledge base have been
critically examined, which is also required by the IFCC
recommendations. In addition, each DLE code is accom-
panied by relevant references for further information.
The present study suggests that as many as 10% of
hormone test results may be affected by medication. With
the reminder system, the drug effects cannot be disre-
garded. Most of the reminders concerned thyroid labora-
tory tests (54% concerned serum TSH and 10% FT4),
which reflects the common use of thyroid tests. In this
study, serum TSH and serum FT4 seemed to be affected
by drugs in 12% and 6% of the tests taken, respectively. In
our pilot study (11 ), there were relatively more reminders
for these hormones. The reason for the reduction seen in
the present study was that acetylsalicylic acid adminis-
tered in small doses was noted not to affect these thyroid
determinations. Thus, the reminders of its effects on
serum TSH and FT4 were switched off. This example
demonstrates the importance of testing applications in a
real clinical environment.
The DLE codes have now been completed for the most
important hormones and proteins. Coding of the DLEs
was started with hormones because many common drugs
have a considerable effect on hormonal laboratory results.
Furthermore, serum hormone tests often refer to a specific
diagnosis instead of a symptom and are not consistently
included in the safety tests required before new drugs are
introduced. DLE coding and the reminder system will
next be extended to cover, e.g., serum glycosylated hemo-
globin and lipids. The DLE knowledge base is updated
and/or extended two to four times a year. Experts in
1400 Kailajärvi et al.: Online Reminders of DLEs
clinical chemistry are invited to present new codes or
modifications to the existing ones. Familiarity with the
structure of the code is not needed because the effects are
described in plain language both in the reminder system
and in the DLE knowledge base. The structure of the code
enables rapid translation of the effects from English into
other languages.
To build an online reminder system, some program-
ming is needed inside the LIS. If introduction of new
programs is likely to cause technical problems, it is
possible to consult the DLE knowledge base indepen-
dently outside the LIS. In the future, it will be possible to
query the DLE knowledge base for DLEs over the Internet
from any hospital or laboratory. A query can be sent using
standard TCP/IP and HL-7. The DLE server will answer
the query in just seconds. An Internet query requires less
programming inside the LIS. In addition, it allows the use
of the latest version of the DLE knowledge base. There are
no confidentiality problems because queries show no
patient identification.
In conclusion, drug effects on laboratory test results
should always be considered when interpreting labora-
tory results. This can be facilitated by automatic decision
support systems such as our online reminder system.
We gratefully acknowledge the financial support of the
Academy of Finland as well as the technical support of
Mylab Oy, (Tampere, Finland), which provided the com-
puter program needed for DLE reminders.
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