Int J Clin Pharm
DOI 10.1007/s11096-013-9843-3
RESEARCH ARTICLE
Drug prescribing in patients with renal impairment optimized
by a computer-based, semi-automated system
Ana Such Daz Javier Saez de la Fuente Laura Esteva Ana Mara Alanon Pardo
Nelida Barrueco Concepcion Esteban Ismael Escobar Rodrguez
Received: 19 October 2012 / Accepted: 26 August 2013
 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2013
Abstract Background According to several studies,
despite of the existence of several published guidelines for
dosing adjustments based on renal function, inappropriate
prescribing is a common drug-related problem in inpatient
care. Objective We developed and implemented a system
for drug dosage adjustment integrated into the Hospital
computer provider order entry system. This system allows
pharmacists to identify patients with reduced renal func-
tion, identify medication orders that may require dosage
modifications based on renal function, and generate an alert
with a recommendation of specific dosage adjustment.
Using the Summary of Product Characteristics and two
drug databases (Micromedex 2.0 and Lexicomp), spe-
cific dosage guidelines for drugs used in patients with renal
impairment were established. Setting A 264-bed tertiary
teaching hospital. Methods We performed a quasi-experi-
mental, one-group, pretestposttest study to assess the
efficacy of this intervention program. We compared the
differences between the frequency of appropriate orders
pre- and post-test using the McNemar test. Main outcome
measures: the frequency of appropriate orders before the
recommendation (pre-test) and after the recommendation
(post-test). Results Before the intervention, the frequency
A. Such Daz (&)
J. Saez de la Fuente
N. Barrueco

C. Esteban
I. Escobar Rodrguez
Pharmacy Department, Hospital Universitario Infanta Leonor,
Gran Va del Este, 80, 28031 Madrid, Spain
e-mail: ana.such@salud.madrid.org
L. Esteva
Pharmacy Department, Hospital de Torrejon, Torrejon de Ardoz,
Spain
A. M. Alanon Pardo
Pharmacy Department, Hospital Universitario Virgen de las
Nieves, Granada, Spain
of appropriate prescribing based on renal function was
65 %. After the intervention, this frequency was 86 %
(p \ 0.001). The interventions were more frequent in the
emergency department (45 %). The program required
3045 min of pharmacist time per day. The average
number of patients reviewed daily was 28. This study
found that a computer-based, semi-automated drug-dosage
program for renal failure patients was able to reduce the
number of inappropriate orders due to renal insufficiency.
Keywords Computer-assisted drug therapy

Decision support systems
Medical order entry
systems
Medication errors
Renal insufficiency

Spain
Impact of findings on practice
A computer-based semi-automated alerts system
enables pharmacists to quickly review medication orders
written for renal failure patients. A computer-based semi-
automated alerts system improves drug prescribing in
patients with renal insufficiency, allows pharmacists to
participate more actively in patient care, and it improves
the basic clinical decision support system, avoiding over-
alerting in a cheap and easy way.
Introduction
Chronic kidney disease (CKD) is a significant and costly
worldwide health problem. According to the Spanish
Society of Nephrologys (SEN) database of patients with
kidney disease, Spain has one of the highest rates of end-
stage CKD, and this problem will increase in the coming
123

years due to the aging population and the increasing
prevalence of diabetes and hypertension [1].
The ERPHOS study, conducted in Spanish hospitals,
found a glomerular filtration rate (GFR) \60 mL/min in
28.4 % of hospitalized patients and\44 mL/min in 13.1 %
of patients. Additionally, 42 % of men and 59 % of women
older than age 80 had a GFR of \60 mL/min [2].
The National Kidney Foundation Kidney Disease Out-
comes Quality Initiative (K/DOQI) defines chronic kidney
disease as the presence of kidney damage or a reduction in
the GFR to \60 mL/min/1.73 m2 for 3 months or longer.
The K/DOQIs chronic kidney disease staging is based on
GFR [3].
The consensus of the SEN and the Community and
Family Medicine Spanish Society (SemFYC) is to use an
equation to routinely estimate GFR rather than using serum
creatinine levels alone, because the equations take into
account several clinical and demographic parameters and
are considered the best index of GFR in clinical practice.
The same consensus recommends the use of the Modifi-
cation of Diet in Renal Disease (MDRD) formula for
estimation of GFR, and the traditional Cockcroft-Gault
(CG) formula as an alternative (Table 1).
The Cockcroft-Gault formula aims to predict creatinine
clearance from knowledge of serum creatinine, age,
weight, and sex [4]. The MDRD4 formula considers serum
creatinine, age, weight, sex, and race [5, 6].
Many drugs, or their metabolites, are eliminated through
the kidney. CKD can also affect other pharmacokinetic and
pharmacodynamic processes. So modifications in the dos-
age of a variety of drugs are needed in the presence of renal
failure to avoid drug toxicity, ineffective therapy, and
increased costs [6, 7].
Drugs that require dose adjustments in patients with
renal impairment are commonly used in hospitals and can
result in adverse drug events (ADEs).
According to several studies, despite of the existence of
published guidelines for dosing adjustments based on renal
function, inappropriate dosing of renally cleared or
potentially nephrotoxic drugs is a common drug-related
problem in inpatient care [8].
Improvements in compliance with renal-dosing guide-
lines are needed to achieve good prescribing practices in
inpatients with renal impairment. Good prescribing prac-
tices in patients with renal insufficiency are defined as
orders that are appropriate by dose and frequency accord-
ing to renal dosing guidelines.
Table 1 Recommended
COCKCROFT-GAULT Creatinine clearance (mL/min) = [(140 - age years) 9 (weight kg) 9
equations for routine estimation
(0.85 if women)]/(72 9 serum creatinine mg/dL)
of GFR4 [4, 5]
MDRD-4 GFR (mL/min/1.73 m2) = 186 9 [serum creatinine (mg/dL)]-1.154 9
(age years)-0.203 9 (0.42 if women) 9 (1.212 if African American)
GFR glomerular filtration rate
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Int J Clin Pharm
Computerized provider order entry (CPOE) with clinical
decision support system (CDSS) can improve patient safety
and lower medication-related costs [9], but at present, these
systems are unevenly developed in Spain [10].
Several studies have been developed to assess the effi-
cacy of CPOE with CDSS and/or review of orders by
pharmacists for reducing prescription errors related to drug
dosage in renal insufficiency. The studies have shown
varying results [1126].
We developed and implemented a system for drug
dosage adjustment that is integrated into the Hospital
CPOE/CDSS system (excluding intensive-care units and
anaesthesiology wards) and allows pharmacists to identify
patients with reduced renal function, identify medication
orders that may require dosage modifications based on
renal function, and generate an alert with a recommenda-
tion of specific dosage adjustments (based on current
dosage guidelines).
We decided to combine automated-alert systems with
manually reviewed patient charts to avoid unnecessary
alerts and allow enhancement of the process.
Aim of the study
Our goals were to develop a semi-automated alert system
for checking doses of medications according to the
patients renal function and determine if this intervention
improves drug prescribing practices.
Method
Study site and setting
Our study was conducted in a 264-bed tertiary teaching
hospital (Hospital Universitario Infanta Leonor, Madrid).
The hospitals information system (Selene) integrates
an electronic health record (EHR) and CPOE with basic
clinical decision support system (CDSS). This basic CDSS
includes drug-allergy checking, formulary decision sup-
port, and drugdrug interaction checking. CPOE and lab-
oratory data are integrated with other applications such as
the pharmacy information management system (Farma-
tools). All inpatient orders (except ICU and anaesthesi-
ology ward orders) are entered into Selene (EHR with
CPOE).
Int J Clin Pharm
The pharmacy department has 5 staff pharmacists who
provide drug distribution services, preparation and distri-
bution of sterile and non-sterile products, outpatient ser-
vices (including outpatient counselling), and clinical
services (review of all medication orders for interactions,
allergies, duplications, and appropriate doses). Pharmacists
also participate in several hospital committees. Pharmacists
provide these services 12 h per day, 6 days per week.
All orders are reviewed for interactive validation and
approved by ward pharmacists through the EHR and the
pharmacy system.
Population and inclusion criteria
All patients older than 18 years of age who are admitted to
medical and surgical services (excluding the intensive care
unit and the anaesthesiology ward) with an estimated glo-
merular filtration rate \60 mL/min using the MDRD4
formula were included in the study. We excluded intensive
care unit and anaesthesiology ward patients because of
different and incompatible CPOE systems. Haemodialysis
patients were also excluded.
Patients could be enrolled more than once if a new
treatment was started during the study. The patients were
consecutively included in the study.
The study was open; every patient admitted to the
medical and surgical services (excluding the intensive care
unit and the anaesthesiology ward) with an estimated GFR
\60 mL/min was included.
To identify patients with a GFR \60 mL/min, the labo-
ratory results from the EHR were integrated with the
pharmacy computer system, as were orders from the CPOE.
When measured serum creatinine was available, the
laboratory service calculated the GFR with the MDRD4
formula for each patient.
We consider a patient to be in steady-state regarding
renal function when the value of the GFR was consistent
with previous GFR values or when two consecutive GFR
values in 72 h were similar. We also excluded any possible
situation that can change creatinine serum level
temporarily.
Intervention
Using the Summary of Product Characteristics and two
drug databases (Micromedex 2.0 and Lexicomp) spe-
cific-dosage guidelines for drugs used in patients with renal
impairment were established and entered into the pharmacy
computer system.
These guidelines allow the pharmacist to identify which
drugs require monitoring in patients with renal insuffi-
ciency and make dosage recommendations to the pre-
scribing physician.
Before the daily electronic order validation by the
pharmacist (6 days a week, Monday to Saturday), a list of
patients with a GFR \60 mL/min and a drug prescribed
that may require renal dose adjustment was displayed using
the pharmacy computer system.
To avoid over alerting, not all dosage modification alerts
were forwarded to the physician, and pharmacists reviewed
the electronic charts of the patients marked in the list and
recommend (if necessary) appropriate dosage-modifica-
tions to the prescribing physician through a specific note in
the EHR (Fig. 1). With this review, the pharmacist also
looked for any condition that could invalidate or change the
recommendation (i.e., patient on renal replacement, a
transitory renal failure, etc.).
The pharmacists used the progress notes function in the
EHR to give information on how to prescribe drugs in
renally impaired patients to the physicians. The pharmacist
reviewed these alerts 24 and 48 h later, and noted any
changes in the study database. A time point of 48 h was
chosen because it is the validation period of the comput-
erized medication order, and the Pharmacy Service is
closed on Sundays.
A semi-automated procedure was chosen for two rea-
sons. First, we wanted to improve the quality of the CDSS
in a cheap and easy way (our CDSS is provided by an
external enterprise). Second, we wanted to avoid over
alerting.
Three pharmacists participated in this program.
Study design and outcomes
We performed a quasi-experimental, one-group, pretest
posttest study from February to May 2011.
Our primary outcome was: evaluate the efficacy of this
computer-based intervention program on the frequency of
appropriate orders.
We measured the percentage of appropriate orders
before the recommendation (pre-test) and after the rec-
ommendation (post-test).
Our secondary outcomes were:
The frequency of appropriate and inappropriate orders
among orders that required a dosage adjustment.
The frequency of accepted recommendations: A drug
dosage recommendation was made for each inappro-
priate order detected by the semi-automated system.
The recommendations were reported to the prescriber
through specific notes in the EHR.
Accepted recommendations were defined as changes in
dose, frequency, or drug previously recommended \48 h
ago, and were included in the study database.
Partial agreements were considered as accepted recom-
mendations. Partial agreement was defined as a different
123

Fig. 1 Note in the EHR (Explanations/translations). Note: Phar-
macy Service: Estimated glomerular filtration rate by MDRD4 of
18.11 mL/min/1.73 m2 (Cr = 2.7 mg/dL). For creatinine clearance
\20 mL/min and nosocomial pneumonia, a dose adjustment of
dose adjustment according to any other published guideline
for dosing adjustments based on renal function.
For example, piperacillin-tazobactams Spanish package
insert recommend a different dose adjustment (the dose rec-
ommended in patients with a creatinine clearance of
2040 mL/min is 4/0.5 g every 8 h) than the Micromedex 2.0
database, (for all indications except nosocomial pneumonia and
ClCr of 2040 mL/min, the dose recommended is 2/0.25 g
every 6 h, for nosocomial pneumonia is 3/0.75 g every 6 h).
Description of alert type: Each recommendation was
categorized as a dose, frequency, dose and frequency,
drug change or discontinuation, and therapeutic drug
monitoring alert.
Drugs most frequently involved in recommendations.
Medical wards most frequently involved in
recommendations.
Statistical analysis
To show a difference in the frequency of appropriate orders
of 10 %, with alpha of 0.05 and beta of 0.1 (power of
123
Int J Clin Pharm
piperaciline/tazobactam to 2/0.25 g every 6 h is recommended. We
advised that if the renal function improves, reviewing pre-adjusted
dose drugs is necessary. Thank you. For further information, please
contact Pharmacy Service: 418470
90 %), we calculated a sample of 211 cases (drug orders)
assuming a frequency of appropriate orders of 50 %.
Because the frequency of inappropriate orders reported
in other hospital-based studies ranges from 67 % [15] to
15 % [16], we assumed a frequency of 50 %, which gives
the largest sample size.
Results are expressed as mean values with a 95 %
confidence interval, proportions, or median, as appropriate.
We assessed the effectiveness of the intervention pro-
gram by comparing the differences between the frequen-
cies of appropriate orders pre- and post-test using the
McNemar test. Statistical significance was established at
p \ 0.05. All tests were performed with the SPSS v.15
software for Windows (SPSS Inc., Chicago, IL, USA).
The McNemar test was chosen to assess whether there is
a pre-post difference within a single group, and because
responses were correlated within each patient from the pre-
test to the post-test.
We developed a secondary analysis without the cases
in which the patient was discharged before the acceptance
of the recommendation could be evaluated (early
discharges).
Int J Clin Pharm
Results
A total of 171 patients were included in the study (42.7 %
male). The mean age was 76.4 years (95 %CI 74.478.5).
The mean value of serum creatinine concentration was
2.2 mg/dL (95 % CI 2.12.4).
The mean value of GFR estimated by MDRD4 was
31.3 mL/min/1.73 m2 (95 % CI 29.433.1).
A total of 286 drug orders were reviewed in 171
patients. Of those, 35 % prompted a dosage adjustment
recommendation in 44 % of patients. Physicians accepted
60 % of these recommendations.
The frequency of appropriate prescribing based on renal
function was 65 % before the intervention. After the inter-
vention, this frequency was 86 % (p \ 0.001) (Table 2).
The distribution of alert type is summarized in Fig. 2.
Drugs most frequently involved were levofloxacin
(19 % of the interventions), dexketoprofen (13 %), and
metformin (9 %) (Table 3).
The interventions were more frequent in the emergency
department (45 %), followed by internal medicine (22 %),
and traumatology (8 %) (Table 4).
In the secondary analysis, we excluded the cases in
which the patient was discharged before being able to
evaluate the acceptance of the recommendation (15 cases,
5.2 %). In this analysis, the frequencies of appropriate
orders before and after intervention were 68.6 vs. 90.77 %
(p \ 0.001). A total of 70.6 % of the interventions were
accepted.
The program required 3045 min of pharmacist time per
day. The average number of patients reviewed (listed in the
automatic record) daily was 28.
Discussion
The frequency of appropriate prescribing detected prior to
intervention was 65 %, and after the intervention was 86 %.
This represents a 60 % increase over the pre-test frequency
of appropriate orders in patients with renal impairment.
Reported inappropriate frequencies in other hospital-based
studies ranged from 15, 19.9, 22.5, and 23, to 67 % [1113,
15, 16]. These great differences can be explained by differ-
ences in guideline compliance among institutions, inconsis-
tent definitions of CKD, the type of drugs evaluated, and
differences between dosage guidelines used. In any case, they
point to a need to evaluate the situation in each institution.
In our case, the frequency of appropriate prescribing was
65 % before the intervention. This corresponds to 35 % of
inappropriate prescribing.
It can be considered consistent with that identified in
previous studies and demonstrates the need for interven-
tions that improve the renal dosing of medications.
Table 2 Contigency table for the primary result number of appro-
priate orders before and after the recommendation) (McNemar test)
Appropriate orders Appropriate orders after the Row
before the recommendation (post-test) total
recommendation
(pre-test) Yes No
Yes 186 0 186
No 60 40 100
Colum total 246 40 286
Fig. 2 Type of alert. Examples: Dose change: Initial dose of
piperaciline/tazobactam: 4/0.5 g every 6 h. For creatinine clearance
\20 mL/min and nosocomial pneumonia, a dose adjustment of
piperaciline/tazobactam to 2/0.25 g every 6 h is recommended.
Dosage interval change: Initial interval of meropenem 1 g: every
8 h. For creatinine clearance between 26 and 50 mL/min, a dosage
interval change to every 12 h is recommended. Dose and frequency
change: Initial dose of amoxicillin/clavulanic acid: 1 g/200 mg every
8 h. For creatinine clearance between 10 and 30 mL/min, a dose and
frequency change to 500/50 mg every 12 h is recommended.
Therapeutic drug-monitoring: in theses cases, the results delivered
by the hospital laboratory confirmed the wrong dose
We found several kinds of intervention programs stud-
ied in the available literature from manual reviews to a
completely-automated alert system with varying results.
We chose a mixed system that combines an automated alert
system with manual review of patient charts to avoid
unnecessary alerts and allow enhancement of the process.
According to the results, this program improved renal
dosing guideline compliance in our institution.
The frequency of accepted recommendations found was
60 % in the primary analysis and 70.6 % in the secondary
analysis (without early discharges).
This frequency in other hospital-based studies was
41.8 % [18], 52 % [13], 87.7 % [17], and 88 % [12]. Our
results are similar to those found by Montanes-Pauls et al.
(63.5 %) and Nightingale et al. (65 %) however, their
populations were significantly different. Montanes-Pauls
et al. [26] developed their study in 3 long-term care
facilities, and the creatinine clearance threshold selected
was 30 mL/min. The Nightingale et al. [21] study was
performed on a specific renal service, so the patient and
practitioner profiles were very different.
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 Int J Clin Pharm

Table 3 Number of interventions by drug

Number of interventions
1 2 4 Between 8 and 16

Drug Voriconazole Tramadol hydrochloride Imipenem monohydrate/cilastatin sodium Piperacillin/tazobactam

Tranexamic acid Ciprofloxacin Hydrochlorothiazide Meropenem
Gemfibrozil Ceftazidime Enoxaparin sodium Amoxicillin and clavulanic acid
Gabapentin Cefepime Digoxin Metformin
Clarithromycin Abacavir/Lamivudine Colchicin Dexketoprofen trometamol
Cefotaxime Levofloxacin
Cefazolin
Atenolol

Table 4 Recommendations by
Number of recommendations
medical ward
\4 8 22 45

Medical Ward Cardiology Traumatology Internal Emergency

Medicine Department
Hematology
General and
Digestive Surgery
Oncology
Urology
Gastroenterology
Otorhinolaryngology
Nephrology
Pneumonology
Neurology

Our study results may be attributed to several factors.
First, the way we communicated the recommendations
was written alerts and not oral. In our institution the pro-
gress notes can be read by any health care worker, not only
physicians.
Some authors have pointed out that making recom-
mendations part of the permanent medical record com-
promises confidentiality between the pharmacist and the
physician and can be a source of alert noncompliance [17].
Second, although a pharmacist reviewed the electronic
charts to avoid unnecessary or incorrect recommendations,
physicians could reject them because of a compelling
indication for the medication despite the risk.
And third, in some cases there was an accumulation of
notes and alerts and physicians could have unintentionally
rejected the recommendations.
As in other studies, the J group, according to ATC
classification, was the most frequently involved in recom-
mendations (56 %) (Fig. 3). This result is similar to other
studies such as Peterson et al. (66 %), Sellier et al.
(54.5 %), and A lvarez Arroyo et al. (60 %) [12, 13, 18].
The emergency department was the most frequently
involved (45 %), followed by internal medicine, (22 %).
These results reflect the importance of the intervention
since the emergency department is the first contact patients
have with the institution.
Limitations
Our study has several limitations. The intervention was
conducted in only one hospital, but with CPOE and phar-
macy software fairly widespread in our region.
eGFR was calculated with the MDRD4 formula, which
is imprecise for some cases (elderly patients, for example),
and does not accurately reflect renal function in non steady-
state conditions.
Also, the CG equation is the equation most commonly
used in consensus-based medication dosing guidelines for
patients with CKD, and some studies have reported dif-
ferences in drug dosages between the CG and the MDRD
equation [27]. On other hand, another study found a high
concordance frequency in drug dosage between these

123
Int J Clin Pharm
Fig. 3 Interventions by ATC group
equations [28]. Currently, there is not a consensus on
whether or not to use the MDRD equation to determine
drug dosages, although the NKDEP (National Kidney
Disease Educational Program) recommends both equations
to estimate renal function for dose adjustment [29].
We performed a quasi-experimental study design (pre-
post intervention study) because it was not logistically
feasible to conduct a randomized controlled trial, which
reduces spurious causality and bias to reach strong
conclusions.
We performed an open study because the hospital
doesnt allow keeping any doctor out of an intervention. It
is a small hospital with high rotation of doctors between
wards.
The pharmacists involved in the interventions were
involved in the data analysis, so this might introduce bias
to the study.
We selected a primary outcome based on the analysis of
number of orders instead of patients because, in our
experience, physicians do not give the same importance to
all drugs in renal insufficiency.
In patients with several drugs prescribed, some drugs are
adjusted and others are not. Number of orders is not the
best data set, but we wanted to assess the prescribing pat-
terns for renal impairment in our institution.
We do not know if some of the alerts were uninten-
tionally rejected. It is possible that some of the recom-
mendations were rejected without a clinical cause.
We assessed the impact of the program as the frequency
of accepted recommendations rather than patient-outcome
measures, but this is an important area for future study.
To our knowledge, only two studies assessed clinical
outcomes. They demonstrated the programs efficacy with
different clinical outcomes [16, 25].
Chertow et al. found significantly shorter length of stay
(adjusted for age, sex, and diagnosis-related group weight)
during the interventions period. In the Rind et al. study, the
intervention resulted in a decrease of relative risk of serious
renal impairment, although they excluded patients with
pre-existing moderate or severe renal insufficiency.
Another important issue is the efficiency of this kind of
program. As far as we know, only two studies have eval-
uated the cost of these programs, and they found con-
tradicting results [12, 16].
Further research is needed to elucidate these points.
Conclusion
This study found that a computer-based, semi-automated
drug-dosage program for renal-failure patients was able to
reduce the number of inappropriate orders due to renal
insufficiency.
In a considerable number of patients, the presence of
renal dysfunction is not considered in medication pre-
scribing, and that this kind of intervention may result in a
substantial reduction of inappropriate drug orders, and
consequently, may prevent adverse drug reactions.
Acknowledgments We thank Federico Tutau PharmD PhD, for his
help in the initial design of the system. We also thank the hospital
informatics department for its contribution to the design and imple-
mentation of the program.
Funding This study was supported in part by the research grant
Salud, Prevencion y Medio Ambiente y Seguros, from Fundacion
MAPFRE.
Conflicts of interest None.
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