ROLE OF CLINICAL PHARMACIST
IN DOSE ADJUSTMENT OF RENALLY ELIMINATED DRUGS IN PATIENTS
WITH RENAL IMPAIRMENT SECONDARY TO CARDIAC PROBLEMS
Background
Acute renal failure is classified into three categories; prerenal azotemia, intrinsic
renal azotemia and post renal etiologies. Prerenal azotemia, a physiological response to
renal hypoperfusion in which the integrity of renal tissue is preserved. Intrinsic renal
azotemia (acute tubular necrosis), acute damage of renal tissue is induced by nephrotoxic
drugs or ischemia. Post renal etiologies are urologic problems (due to obstruction,
diabetes, or recurrent urinary tract infection). In all types of acute renal failure, the
potassium level is increased since it is excreted renally causing lethal cardiac arrhythmias
(1). Patients with cardiac events or problems or those undergoing heart surgery may
experience impaired renal function. This impairment is usually associated with increased
morbidity and mortality due to the decrease in cardiac output that will decrease renal
perfusion, and it is leading for worsening of those already renally impaired (2).
Patient characteristics related to increased risk of acute renal failure are
sometimes severe enough to require dialysis including aging (>65 years old), high
preoperative serum creatinine (>100 µmol/L), congestive heart failure, ejection fraction
less than 50%, extent of disease, cardiac procedure [coronary artery bypass grafting,
valve(s) or both] and cardiopulmonary bypass duration (>90 minutes) (3-5).
Effect of renal impairment on drug disposition especially for renally eliminated
drugs is due to decreased clearance, tubular secretion or reabsorption. It is important to
reduce dose of certain drugs if the serum creatinine increases by 0.6 mg/dL/day. This
indicates 25% to 30% loss of renal function. The most important factors for patients with
renal impairment include:
1) Serum albumin levels (major binding protein for many drugs such as digoxin). In case
of hypoalbuminemia (such as diabetic patients with advanced renal disease) toxic
levels are predicted also for NSAIDs as more free form of the drug is much higher.
2) Creatinine clearance that decreases with the age at a rate of 1 ml/min/year between the
ages of 30 to 60 due to the decrease in muscle and nephron mass.
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3) Volume depletion induced by some drugs such as gentamicin is a risk factor for renal
failure. Furthermore, if patients are already with intravascular volume depletion, they
will be more susceptible to toxicity, or if they undergo dialysis that places them at
increased risk of infection then the use of antibiotics is required.
4) Cardiac function, as discussed before, decreases the renal perfusion and makes patients
prone to toxicity of certain drugs such as angiotensin converting enzyme inhibitors
and NSAIDs.
5) Ideal body weight (IBW) should be calculated especially for obese patients as it is a
major determinant of volume of distribution. In patients with low body weight, the
actual body weight should be used for the estimation of clearance rather than IBW
(see methodology) (4, 6, 7, 9).
The renal function and severity of impairment are usually assessed by the following:
1) Estimating CLCr ,
2) Measuring blood urea nitrogen (BUN),
3) BUN/Creatinine ratio. The increase in both measures (BUN and BUN/Creatinine ratio)
indicates systemic hypoperfusion rather than intrinsic renal dysfunction in the absence
of conditions that enhance urea production, such as gastrointestinal bleeding,
corticosteroid therapy, or a high-protein diet (2,8). Serum creatinine levels rise only if
glomerular filtration rate (GFR) is markedly reduced and thus the equation proposed
by Cockcroft and Gault ( CLCr estimation rather than depending on SCr level only) is
frequently used in practice and correlates well with sensitive measurements of
glomerular function. In renal impairment, the dose adjustment of renally eliminated
drugs is required to prevent drug accumulation and thus avoiding of toxicity or
decreasing drug-related adverse effect and decreasing hospitalization stay and costs
(10). An important example of the effect of moderate renal impairment, digoxin
therapy was associated with more than a twofold increase in the risk of primary
cardiac arrest that offset its benefit in patients with congestive heart failure so, dose
reduction is critical in this case (11). In addition, renal replacement therapy (RRT)
may complicate therapy and leads to under- or overdosing (12).
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Having clinical pharmacist during physician rounds will decrease preventable
adverse drug events especially in intensive care unit. Adverse drug events were the sixth
leading cause of death in USA in 1994 with 10.9% of all hospital patients. A list of safe
and cost-effective medications must be identified. Most of interventions made by clinical
pharmacist are through adjustment of dose or frequency coming first and laboratory
monitoring. Pharmacists working beside the dispensing windows miss the opportunity to
analyzing patient problem and thus become less able to assist physicians in rational
prescribing. Also, on-call pharmacist may not be efficient in this regard as they are
distant from the decision-making process. Addressing medical errors is one strategy to
improve safety of medication (13) Requirements for clinical pharmacist for promotion
includes interpretation of laboratory values and pharmacokinetics (14) and this study
depends on these.
The contribution of clinical pharmacy services is difficult to be measured but for
sure it is beneficial since it covers prescription monitoring, reduction in length of hospital
stays and incidence of adverse drug reactions and in total cost (15). A 6-Month creatinine
clearance dosing adjustment program conducted in Albany Medical Center Hospital,
USA in 1995 resulted in a total cost avoidance of $11,702.08 (16). Six clinical
pharmacists at Barnes-Jewish Hospital (1200-bed teaching hospital) recorded all
interventions done for 30 days and extrapolated an annual savings of $394,000 (95%
confidence interval, $46,000-$742,000) (17). A review of the economic benefit of clinical
pharmacy services through 59 articles published between 1996 to 2000 performed by
Center for Pharmacoeconomics Research and Department of Pharmacy Practice,
University of Illinois at Chicago, USA, estimated that $45.6 billion in direct health care
costs would be avoided even when this kind of service led to 4-fold increase in fee
association. For every dollar invested in clinical pharmacy services, $4 in benefit is
expected provided that this kind of service has positive financial benefits (18).
Through clinical observation, patients with cardiac problems were in high risk to
develop renal impairment. In this study we are interested in assessing the role of clinical
pharmacist in dosage adjustment in these patients and the cost impact of such a service.
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Objectives
This study will be conducted to:
1. Determine the incidence of renal impairment in hospitalized patient with cardiac
problems or undergoing cardiac procedure.
2. Assess the role of clinical pharmacists in monitoring renal function and
suggestion of an appropriate dosage regimen.
3. Evaluate the direct cost impact of the clinical intervention instituted by the
clinical pharmacist and the indirect reduction of preventable adverse events.
Methodology:
The study will be conducted at Prince Sultan Cardiac Center in Riyadh, Kingdom
of Saudi Arabia, 160 full-capacity beds instituted for hospitalized patients with cardiac
problems or scheduled procedures and also serve outpatient and emergency clinics. This
prospective, observational and interventional study will be conducted from June to
August 2004 five days a week. A list of drugs comprises: ceftazidime, cefuroxime,
ciprofloxacin, digoxin, gentamicin, meropenem, piperacillin/tazopactam (tazosin),
ranitidine, vancomycin will be monitored. The list was selected based on three major
factors: these drugs are mainly eliminated via the kidneys, safety concern in using them
and their high acquisition cost.
Patients and Interventions
The clinical pharmacist will identify patients receiving these drugs on daily basis,
review their demographic data and assess laboratory findings. The appropriate dosing
adjustment will be recommended according to renal function. Some of these drugs may
require monitoring the serum level for appropriate dosing, culture sensitivity and MIC90
but parallel to the degree of renal impairment, recommendation of dosing depends in
information approved by Pharmacy and Therapeutic Committee, Drug Information
Handbook 11th edition from lexi-comp’s, and MICROMEDEX®. The documentation of
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whether the recommendation has been accepted or not, or any reevaluated dose according
to renal function will be considered as a new intervention.
Cost avoidance will be determined by calculating the difference between the costs
of the original and adjusted regimens. Drug administration devices, pharmacist time in
monitoring, nursing administration, pharmacy preparation, if any, will not be included in
these calculations. Cost incurred due to recommendation to increase dose will be
included in the calculation. Clinical outcome will not be assessed, but it is believed that if
the given dose is comparable to that in someone with normal renal function there will be
an optimal effect without adverse events. In the design and study calculation, the suitable
pharmacoeconomic principles will be implemented (19-21).
Inclusion Criteria
Only the following patients will be included in the study:
1) Adult hospitalized patient with cardiac problems or undergoing cardiac procedure.
2) Patients older than 18 years of age.
Exclusion Criteria
The following patients will be excluded from the study:
1) Female patients who are pregnant during the study period.
2) Patients not receiving any of the study medications.
Data Collection
The clinical pharmacist will monitor all hospitalized patients above 18 years old on one
or more of the following drugs: ceftazidem, cefuroxime, ciprofloxacin, digoxin,
gentamicin, meropenem, piperacillin/tazopactam (tazosin), ranitidine and vancomycin,
follow them up for 8 weeks 5 days per week. Their demographic data will be reviewed
[age, sex, weight, height, body mass index (BMI) (kg/m2)]. Scr, BUN, BUN: Scr and if
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other important laboratory findings such as electrolytes (potassium) will be recorded.
The ideal body weight (IBW) will be estimated. If the actual body weight is less than the
IBW, then the actual will be used in calculation of CLcr using Cockcroft and Gault
equation (table 1). A CLcr  50 ml/min will be considered normal, less than 50 or on
dialysis will be included in the study taking into consideration the type of the dialysis.
Incidence of renal impairment among all screened patients will be calculated. Severity of
heart events, underlying disease (such as IDDM), ejection fraction and cardiac output,
procedure type [CABG, valve(s) or both, number and duration], and pharmacotherapy
(digoxin, diuretics, etc), diagnosis for which the target drugs being prescribed will be
recorded. Routine daily review of drug order sheet, suggestion of an appropriate dosing
regimen in case of under- or overdosing either by dose and/or interval adjustment will be
carried out. A dosage adjustment depends on renal function estimated by CLcr, serum
level of some drugs, culture sensitivity when applicable taking into consideration MIC90,
type of dialysis and filtrate pore size. Action(s) taken by physicians will be recorded
either agree, disagree or if change but with modification then these information will be
used in the analysis. Then calculation of cost avoidance and extrapolation of the results to
one year will be performed.
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Table 1 Equations for calculating ideal body weight and creatinine clearance
Ideal body weight (IBW)
Male : IBW (Kg)= 50.0 + (2.3 * height in inches over 5 ft)
Female: IBW (Kg)= 45.5 + (2.3 * height in inches over 5 ft)
Creatinine clearance using Cockcroft and Gault equation ( CLCr )
CLcr (males) 
For Males:
Where,
CLCr
[140  Age] W
72 Scr
is the creatinine clearance in ml/min, age in years, W is the ideal body
weight (IBW) in kg and
For Females:
SCr
is the serum creatinine in mg/dl.
CLCr (females)  0.85  CLCr (males)
Statistical Analysis
Variables will be coded individually, and data will be analyzed using the Statistical
Package for Social Sciences (SPSS) version 12.0 for Windows (SPSS Inc., Chicago,
Illinois). Homogeneity of test groups will be determined using repeated measures
analysis of variance (ANOVA) for continuous data, and chi-square with and/or without
Yates' correction for continuity and Kruskal-Wallis tests for discrete data. The analysis
will include frequencies of discrete variables and codescriptives. Results will be analyzed
and, depending on the type of data, appropriate statistical tests will be used for
comparisons. For data that are not normally distributed, either the Wilcoxon rank sum or
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Mann-Whitney U test will be used. The chi-square and Fisher exact tests might also be
used to assess the differences in case of discrete variables. Agreements between
physician’s and pharmacist’s assessments will be evaluated using the Kendall tau rank
correlation and Spearman rho test. Additional analyses (eg, analysis of variance and
Kruskal-Wallis tests) will be used when appropriate. Normality of continuous variables
will be ascertained using Shapiro-Wilks test, Kolmogorov-Smirnov goodness-of-fit test,
Anderson-Darling test or probit analysis. If the question of data normality arises (based
on one of the previous tests), log-transformed data will be used followed by a parametric
test. Otherwise, a nonparametric alternative will be used. Statistical significance will be
defined as p≤ 0.05. ADAPT II package of programs (University of Southern California,
USA) will be used in the simulation of serum/plasma levels for certain drugs if necessary.
References
1. Gottlieb S. Clinical Correlates Acute Renal Failure. Medscape Med Students 2(1),
2000.
2. Maxwell AP, Ong HY, Nicholls DP. Influence of progressive renal dysfunction in
chronic heart failure. Eur J Heart Failure 2002; 4:125–130.
3. Grayson AD, Khater M, Jackson M, and Fox MA. Valvular Heart Operation Is an
Independent Risk Factor for Acute Renal Failure. Ann Thorac Surg 2003; 75:1829 –
35.
4. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Independent
Association between Acute Renal Failure and Mortality following Cardiac Surgery.
Am J Med. 1998; 104:343–348.
5.
Stewart S, Blue L, Capewell S, Horowitz JD, McMurray JJ. Poles apart, but are they
the same? A comparative study of Australian and Scottish patients with chronic heart
failure. Eur J Heart Failure 2001; 3: 249-255.
6. Bakris GL, Talbert R. Drug dosing in patients with renal insufficiency. A simplified
approach. Postgrad Med. 1993 Dec; 94(8): 153-6, 159-60, 163-4.
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7. Hu KT, Matayoshi A, Stevenson FT. Calculation of the estimated creatinine clearance
in avoiding drug dosing errors in the older patient. Am J Med Sci. 2001 Sep; 322(3):
133-6.
8.
Aronson D, Mittleman MA, Burger AJ. Elevated Blood Urea Nitrogen Level as a
Predictor of Mortality in Patients Admitted for Decompensated Heart Failure. Am J
Med. 2004; 116:466–473.
9. Luke DR, Halstenson CE, Opsahl JA, Matzke GR. Validity of creatinine clearance
estimates in the assessment of renal function. Clin Pharmacol Ther. 1990 Nov; 48(5):
503-8.
10. Schneider V, Henschel V, Tadjalli-Mehr K, Mansmann U, and Haefeli WE. Impact of
serum creatinine measurement error on dose adjustment in renal failure. Clin
Pharmacol Ther 2003; 74:458-67.
11. Rea TD, Siscovick DS, Psaty BM, Pearce RM, Raghunathan TE, Whitsel EA, Cobb
LA, Weinmann S, Anderson GD, Arbogast P, Ling D. Digoxin therapy and the risk of
primary cardiac arrest in patients with congestive heart failure Effect of mild–
moderate renal impairment. J Clin Epi 2003; 56:646–650.
12. Bugge JF. Influence of renal replacement therapy on pharmacokinetics in critically ill
patients. Best Practice & Research Clinical Anaesthesiology 2004; 18(1): 175-187.
13. Kucukarslan SN, Peters M, Mlynarek M, Naziger DA. Pharmacists on Rounding
Teams Reduce Preventable Adverse Events in Hospital General Medicine Units. Arch
Intern Med. 2003; 163:2014-2018.
14. American college of clinical pharmacy. Rewards and advancements for clinical
pharmacy practitioners. Pharmacotherapy, 1995; 15(1): 99-105.
15. Bowden J, Catell R, and Wright J. Benchmarking clinical pharmacy services;
developing the standards. The pharmaceut j. 2001 July 14; 267:60-1.
16. Preston SL, Briceland LL, Lomaestro BM, Lesar TS, Bailie GR, Drusano GL. Dosing
adjustment of 10 antimicrobials for patients with renal impairment. Ann
Pharmacother. 1995 Dec; 29(12): 1202-7.
17. McMullin ST, Hennenfent JA, Ritchie DJ, Huey WY, Lonergan TP, Schaiff RA,
Tonn ME, Bailey TC. A prospective, randomized trial to assess the cost impact of
pharmacist-initiated interventions. Arch Intern Med. 1999 Oct 25; 159(19): 2306-9.
18. Schumock GT, Butler MG, Meek PD, Vermeulen LC, Arondekar BV, Bauman JL.
Evidence of the economic benefit of clinical pharmacy services: 1996-2000.
Pharmacotherapy, 2003 Jan, 23(1): 113-32.
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19. Lyles A. Standards and Certification to Recognize Pharmacoeconomics as a
Profession. Clin The 2003; 2004-6.
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Dose recommendation
DRUG
Ceftazidime¹
Cefuroxime²
Ciprofloxacin³
Digoxin4
Gentamicin5
Meropenem6
Piperacillin/
tazopactam
(tazosin) 7
Ranitidine8
Vancomycin9
CLcr (ml/min)
31-50
16-30
6-15
<5
Hemodialysis
Peritoneal dialysis
Continuous
hemofiltration
Injection:
>20
10-20
<10
Oral:
>50
49-30
29-10
<10
Hemodialysis
Peritoneal dialysis
Continuous
hemofiltration
i.v.
>60
31-60
</=30
Oral
30-50
5-29
Extended-release tablet
Hemodialysis; oral
Peritoneal dialysis; oral
>50
10-50
<10
Dialysis
>50
10-50
<10
Hemodialysis
Hemofiltration
26-50
10-25
<10
Hemodialysis
Hemofiltration
20-40
<20
Hemodialysis
Peritoneal dialysis
<50
Hemodialysis
Peritoneal dialysis
Hemofiltration
>65
40-65
20-39
10-19
Hemodialysis
Peritoneal dialysis
Hemofiltration
DOSING RECOMMENDATION
1g q12H
1g q24H
500mg q24H
500mg q48H
1g loading dose followed by 1g after each cession
1 g loading dose followed by 500 milligrams every 24 hours
When incorporated in the dialysis fluid, it may be administered at a concentration of
250 mg for 2 L of dialysis fluid.
1-2g q24-48H
750mg – 1.5g q8H
750mg q12H
750mg q24H
250-500mg q8H
250-500mg q12H
250-500mg q24H
250-500mg q48H
Further dose of cefuroxime sodium or cefuroxime axetil at the end of dialysis.
Injection of 750mg-1.5g q24H
Oral 250-500 q12H
750mg q12H
400mg q8H
400mg q12H
400mg q24H
250-500mg q12H
250-500mg q24H
No adjustment required
250-500mg q24H after dialysis
250-500 mg q24H after dialysis
Normal dose
25-75% q36H
10-25% q48H
10-25% q48H
60-90% of dose q8-12H
30-70% q12H
20-30% q24-48H
1-1.7mg/kg at the end of each dialysis or 2/3 dose supplement after hemodialysis
30-70% of dose q12H
1g q12H
500mg q12H
500mg q24H
Additional dose of the drug following hemodialysis procedures is recommended
1g q12H to avoid underdosing
2.25g q6H (nosocomial pneumonia 3.375g q6H)
2.25g q8H (nosocomial pneumonia 3.375g q8H)
2.25g q12H (nosocomial pneumonia 2.25g q8H)+0.75g supplement dose after dialysis
Same as in hemodialysis
Oral; 150mg q24H or 75mg q12H
i.v; 50mg q18-24H
75-150 mg q12-24H dose coincides with the end of hemodialysis
75-150mg q24H
q24H
Q8H
Q12H
Q24H
Q48H
500 mg q48-96H
500 q48-96H
500 q24-48H
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¹ Prod Info Ceptaz(R), 2002; Prod Info Fortaz(R), 2002; Prod Info Fortaz(R), 2003;
Cotterill, 1995.
² Prod Info Zinacef(R), 2001; Konishi et al, 1993; Bennett et al, 1994; Cotterill, 1995
³ Shas et al, 1996; Prod Info Cipro(R), 2002; Prod Info Cipro(R) XR, 2003; Singlas et al,
1987.
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Since even a small degree of renal failure will decrease the volume of distribution of
digoxin, adjustments in loading dose should be made. The volume of distribution may
be roughly estimated using a linear equation: Vd = 4.5 +(0.028 x Ccr) (creatinine
clearance), Dose = Cp (desired serum level) x Vd (Paulson & Welling, 1976);
Maintenance doses should replace daily digoxin loss as based upon daily excretion
rates (Jelliffe, 1968); Maintenance dose = Peak body stores (i.e. loading dose) x % daily
loss/100; Where: % daily loss = 14 + Ccr (mL/min)/5; If patients are switched from
intravenous to oral dosing, the bioavailability of the dosage forms must be considered
(Prod Info Lanoxin(R), 2000); Since cardiac glycosides are highly tissue bound,
additional doses following dialysis do not appear to be necessary (Bennett et al, 1987;
Iisalo, 1977; Ackerman et al, 1967); Potassium removal with resultant hypokalemia
which predisposes to digitalis toxicity is a significant consideration in the patient on
dialysis who is receiving digoxin. Many centers use a modest (2 to 3 mEq/L)
concentration of potassium in the dialysate for such patients, and report less difficulty
in dialyzing digitalized patients.
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Monitoring serum drug concentrations are recommended to ensure patient safety and
treatment efficacy; To adjust the interval between doses, multiply the serum creatinine
(milligrams/100 milliliters (mg/mL)) by 8; If treating serous infections, it may be
recommended to dose more frequently (ie, every 8 hours) at a lower dose. To adjust the
dose, divide the standard dose (1 mg/kg) by the serum creatinine; Prod Info
Garamycin(R), 2000; Bennett et al, 1994; Ernest & Cutler, 1992.
6
Prod Info Merrem(R), 2000; Chimata et al, 1993; Christensson et al, 1992; Leroy et al,
1992; Giles et al, 2000; Tegeder et al, 1999; Meyer et al, 1999.
7
Prod Info Zosyn(R), 2003; Sorgel & Kinzig, 1993.
8
Prod Info Zantac(R), 2000; McFadyen et al, 1983; Comstock et al, 1988; Sica et al,
1987; Cavagna et al, 1987; Gladziwa et al, 1988.
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Dose (milligrams/kilogram/24 hours) = 0.227 X creatinine clearance + 5.67 (where
creatinine clearance is standardized to milliliters/minute/70 kilograms); always follow
serum level; Rodvold et al, 1988; Bennett et al, 1994.
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