Role of clinical pharmacist in dose adjustment of renally eliminated drugs in
patients with renal impairment secondary to cardiac problems: a study conducted
in Prince Sultan Cardiac Center
Objectives
To set a percentage of the incidence of renal impairment in hospitalized patient with
cardiac problems or undergoing cardiac procedure, assessment of the role of clinical
pharmacists in monitoring renal function and suggesting appropriate dosing, the direct
cost impact of the clinical intervention done by the clinical pharmacist and indirect
reduction of preventable adverse events.
Background
Acute renal failure 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 induced by nephrotoxic drugs or
ischemia. Post renal etiologies, It is a urologic problem (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 and causing lethal cardiac arrhythmias.[1]
Patients with cardiac events or problems or those undergoing heart surgery may
experience impaired renal function that is associated with increased morbidity and
mortality due to the decrease in cardiac out put that will decrease renal perfusion. And it
is a leading for worsening of those already renally impaired.[2]
Patient characteristics that are related to increase risk of acute renal failure that
sometimes severe enough to require dialysis includes aging ( >65 years old), high serum
creatinine preoperative( >100 UMOL/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, 4, 5]
Patient characteristics that are related to increase risk of acute renal failure that
sometimes severe enough to require dialysis includes: aging ( >65 years old), high serum
creatinine preoperative( >100 UMOL/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, 4, 5]
Effect of renal impairment on drug disposition especially for renally eliminated drugs by
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 ( as the creatine, the precursor of creatinine, endogenously
produced by the liver and stored as a source of high energy phosphate for skeletal muscle
and during muscle metabolism, creatine phosphate cleaved with the release of creatinine
into the blood. Thus factors such as liver function and muscle mass, as well renal
function since the creatinine is cleared by both filtration and active tubular secretion, and
serum level increases as renal function decreases a Scr from 0.9 to 1.2 mg/dl considered
normal). Factors important to be identified for dosing in patients with renal impairment
includes: serum albumin levels as it is the major binding protein for many drugs such as
digoxin so, 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, 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, volume
depletion induced by some drugs such as gentamicin is a risk factor for renal failure and
if patients whose already with intravascular volume depletion this will make patients
more susceptible to toxicity or if patient under go dialysis that places him at increased
risk of infection and thus using antibiotics, cardiac function as discussed before that
decreases the renal perfusion and subject patients to toxicity such as angiotensin
converting enzyme inhibitors and NSAIDs, body weight specifically ideal body weight
should be calculated especially for obese patients as it is a major determinants of volume
of distribution and those with low body weight the actual body weight should be used in
estimation of clearance rather than IBW ( table 1).[ 4, 6, 7, 9]
Table 1 Equations for calculating ideal body weight and creatinine clearance from
Cockcroft and Gault.
Ideal body weight (IBW)
Male : IBW (Kg)= 50 + (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 in ml/min= [(140 – age in years) * IBW in kg] / [ 72 * serum creatinine in mg/dl]
Addressing renal function and severity of impairment not only by estimating CLcr but
also by measuring blood urea nitrogen ( BUN) and BUN/Creatinine ratio. Estimated
CLcr is the sole index in patients with stable heart failure since this measure more stable
than BUN and BUN/Creatinine ratio. This is true where the renal function parameters
change within hours or days while BUN and BUN/Creatinine ratio fluctuate widely
during heart failure decompensation however the increase in both measures (BUN and
BUN/Creatinine ratio) indicates systemic hypoperfusion rather than intrinsic renal
dysfunction in the absence of conditions that enhances urea production, such as
gastrointestinal bleeding, corticosteroid therapy, or a high-protein diet, elevations in
blood urea nitrogen level are often due to a decrease in glomerular filtration rate.
Approximately 40% to 50% of filtered urea is normally reabsorbed, predominantly by the
proximal tubules, where it is linked to the reabsorption of sodium and water. This process
is passive, being driven by the increase in sodium level and water reabsorption. Thus,
the increase in sodium reabsorption in heart failure ( due to the activation of renninangiotensin-aldosterone system RAAS). Also, the increased catecholamine production,
elevated endothelin levels that has vasoconstrictive effect contribute to renal arteriolar
vasoconstriction. The result is reduction in renal perfusion with increased sodium and
water reabsorption ) produces a parallel increase in urea reabsorption. Vasopressin which
is elevated in heart failure, upon binding to V2 receptors in the inner medullary collecting
ducts, increases urea permeability through activation of urea transporters, thus enabling
urea to diffuse into the inner medullary interstitium. These neurohormonal effects are
exacerbated by diuretic induced intravascular volume depletion, which leads to renal
hypoperfusion. The net result is reduced urea excretion and an elevation in blood urea
nitrogen level that is not solely due to the fall in glomerular filtration rate and therefore
not associated with a proportional rise in serum creatinine level [2, 8], in another word
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 avoidance
of toxicity or decrease drug-related adverse effect, decrease 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]
Renal replacement therapy (RRT) may complicate therapy and leads to under- or
overdosing. For drugs that is mainly eliminated renally it is expected to be removed by
RRT and dose adjustment in this case is often required, only unbound drug (the free
form) is cleared and the bound fraction tends to be decreased in critically ill patients as
the albumin levels often be low in those patients. A large volume of distribution Vd ( ≥
1L/kg) indicates that the drug is highly tissue bound and tend not to be cleared but in
critically ill patients there is increase in capillary permeability, fluid shifts, and third
space losses resulting large extravasation, interstitial accumulation, and these changes
may increase Vd. There is re-distribution of the drug from tissue to plasma during RRT
and thus total amount of drug removal will be more if the RRT is continuous rather than
intermittent.[12]
Having clinical pharmacist during physician rounds will decrease preventable adverse
drug events especially in intensive care unit , a list of medications that because of its
safety and cost must be closely evaluated. Most of interventions made by clinical
pharmacist are through dosage or frequency coming first and others including laboratory
monitoring. Pharmacist working beside the dispensing windows miss the opportunity of
analysing patient problem and thus become less able to assist the physician with
prescribing. Also, pharmacist on call may not be sufficient as they are distance from the
decision-making process. Addressing medical error is one strategy to improve safety of
medication.[13]
A 6-Month creatinine clearance dosing adjustment program done in 1995 resulted in total
cost avoidance of $ 11 702.08.[17]
Method
Study will be conducted in Prince Sultan Cardiac Center, list of drugs identified as
renally eliminated with high acquisition or according to safety issue and includes:
ceftazidem, cefuroxime, ciprofloxacin, digoxin, gentamicin, meropenem,
piperacillin/tazopactam (tazosin), ranitidine, vancomycin. The clinical pharmacist will
identify patients receiving these drugs on a daily basis, review demographic data and
assess laboratory findings then appropriate dosing adjustment will be recommended
according to renal function, some of these drugs will require monitoring levels for dosing
but parallel to the degree of renal impairment, recommendation of dosing depends in
information approved from pharmacy and therapeutic committee and drug information
hand book 11th edition from lexi-comp’s, after that documentation of weather the
recommendation has been accepted or rejected, any reevaluated dose according to renal
function will be considered new intervention, cost avoidance will be determined simply
by subtracting the cost of the adjusted regimen from that of the original one. Drug
administration devices, pharmacist time in monitoring, nursing administration, pharmacy
preparation if any will not be included in calculating cost avoidance. Cost incurred due to
recommendation to increase dose will be included in calculation. Clinical efficacy will
not be assessed but it is believed if dose giving in comparable to someone with normal
renal function there will be optimal effect without adverse events. In some of the study
design and calculations took from other works and pharmacoeconomic issues.[14, 15, 16,
17, 18]
References
1. Scott Gottlieb. Medscape Med Students 2(1), 2000. Clinical Correlates Acute Renal
Failure.
2. A. Peter Maxwell , Hean Y. Ong , D. Paul Nicholls. The European Journal of Heart
Failure 4 (2002) 125–130. Influence of progressive renal dysfunction in chronic heart
failure
3. Antony D. Grayson, Magdy Khater, FRCA, Mark Jackson, PhD, and Mark A. Fox,
FRCA. Ann Thorac Surg 2003;75:1829 –35. Valvular Heart Operation Is an
Independent Risk Factor for Acute Renal Failure.
4. Glenn M. Chertow, MPH, Elliott M. Levy, Karl E. Hammermeister, Frederick
Grover, Jennifer Daley. Am J Med. 1998;104:343–348. Independent Association
between Acute Renal Failure and Mortality following Cardiac Surgery.
5. Simon Stewart, Lynda Blue, Simon Capewell, John D. Horowitz, John J. McMurray.
European Journal of Heart Failure 3 (2001) 249-255. Poles apart, but are they the
same? A comparative study of Australian and Scottish patients with chronic heart
failure.
6. Bakris GL, Talbert R. Postgrad Med. 1993 Dec;94(8):153-6, 159-60, 163-4. Drug
dosing in patients with renal insufficiency. A simplified approach.
7. Hu KT, Matayoshi A, Stevenson FT. Am J Med Sci. 2001 Sep;322(3):133-6.
Calculation of the estimated creatinine clearance in avoiding drug dosing errors in the
older patient.
8. Doron Aronson, Murray A. Mittleman, DrPH, Andrew J. Burger. Am J Med.
2004;116:466–473. Elevated Blood Urea Nitrogen Level as a Predictor of Mortality
in Patients Admitted for Decompensated Heart Failure.
9. Luke DR, Halstenson CE, Opsahl JA, Matzke GR. Clin Pharmacol Ther. 1990
Nov;48(5):503-8. Validity of creatinine clearance estimates in the assessment of renal
function.
10. Verena Schneider, Volkmar Henschel, Keyvan Tadjalli-Mehr, Ulrich Mansmann, and
Walter E. Haefeli. Clin Pharmacol Ther 2003;74:458-67. Impact of serum creatinine
measurement error on dose adjustment in renal failure.
11. Thomas D. Rea, David S. Siscovick, Bruce M. Psaty, Rachel M. Pearce, Trivellore E.
Raghunathan, Eric A. Whitsel, Leonard A. Cobb, Sheila Weinmann, Gail D.
Anderson, Patrick Arbogast, Danyu Ling. Journal of Clinical Epidemiology 56 (2003)
646–650. Digoxin therapy and the risk of primary cardiac arrest in patients with
congestive heart failure Effect of mild–moderate renal impairment.
12. Jan Frederik Bugge. Best Practice & Research Clinical Anaesthesiology Vol. 18, No.
1, pp. 175–187, 2004. Influence of renal replacement therapy on pharmacokinetics in
critically ill patients.
13. Suzan. N. Kucukarslan, Michael Peters, Mark Mlynarek, Daniel A. Naziger. Arch
Intern Med. 2003;163:2014-2018. Pharmacists on Rounding Teams Reduce
Preventable Adverse Events in Hospital General Medicine Units.
14. Alan Lyles. CLINICAL THERAPEUTICS (2003) 1004-6. Standards and
Certification to Recognize Pharmacoeconomics as a Profession
15. C. Daniel Mullins, and Shelby OgUvie. CLINICAL THERAPEUTICS/VOL. 20, NO.
6, pp. 1194-202, 1998. Emerging Standardization in Pharmacoeconomics.
16. Jon Clouse. J Allergy Clin Immunol 2002;109:S511-4. Establishing value in managed
care: Cost-effectiveness or budgetary impact?.
17. Preston SL, Briceland LL, Lomaestro BM, Lesar TS, Bailie GR, Drusano GL. Ann
Pharmacother. 1995 Dec;29(12):1202-7. Dosing adjustment of 10 antimicrobials for
patients with renal impairment.
18. McMullin ST, Hennenfent JA, Ritchie DJ, Huey WY, Lonergan TP, Schaiff RA,
Tonn ME, Bailey TC. Arch Intern Med. 1999 Oct 25;159(19):2306-9. A prospective,
randomized trial to assess the cost impact of pharmacist-initiated interventions.