Page 1762 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 125: Critical Care Pharmacology 1231

tubules. Only 1.8 L of urine is produced from the 190 L per 24 hours of Confounding factors include requirement of a steady-state serum creati-
daily glomerular filtrate (130 mL/min × 1440 minutes), because water and nine value (SCr ), estimation of ideal body weight, the empiricism of the
ss
most solutes are predominantly reabsorbed (eg, the fractional excretion of age and gender estimates used in development of the formula, 30-32 and the
sodium in a stable subject is 1%, thus 99% of filtered sodium is reabsorbed). effects of some medications on tubular creatinine secretion. It is particu-
33
Glomerular filtration of plasma constituents is primarily limited by larly difficult to account accurately for the effects on the estimated GFR
size (≤50,000 Da), water solubility, plasma protein binding (only free calculation of diminished muscle mass (and thus creatinine generation)
drug is filtered), and volume of distribution (extensively tissue-bound in the elderly, or in patients with cirrhosis, spinal cord injury, cachexia, or
4,6
substances are less likely to be renally excreted). Some drugs also other causes of muscle wasting. This limitation of Scr is regardless of which
undergo significant renal tubular secretion or reabsorption (passive equation is used and cannot be overcome by an adjustment of the equa-
or active). Passive reabsorption of weak acids or bases from the renal tion. Nevertheless, a rough estimate of the current GFR is obtained and
34
tubular lumen may be influenced by urinary alkalization or acidifica- should be used to guide dosing calculations. 35-37 The Modification of Diet
tion, respectively. Active tubular secretion by proximal tubular cationic in Renal Disease (MDRD) equation offers another method to approximate
or anionic pumps may be subject to competitive inhibition, resulting in GFR; the equation is found to be more accurate than the Cockcroft-Gault
decreased renal clearance and prolonged plasma half-life of the lower equation and takes into account more clinical factors, such as serum albu-
affinity substance. For example, probenecid inhibits tubular penicillin min and blood urea nitrogen, that likely reflect the patient’s clinical status
secretion, prolonging penicillin elimination half-life. Similarly, trim- more accurately, but is much more complicated to use. Web sites are
38
ethoprim and cimetidine inhibit renal tubular creatinine secretion, available (such as www.nephron.com) to facilitate the use of the MDRD
reducing creatinine clearance and elevating serum creatinine, without equation. The MDRD equation has been shown to overestimate measured
affecting actual GFR (see below). GFR in those values >60mL/min per 1.73m . The CKD- Epidemiology
2
The plasma clearance of creatinine (creatinine clearance; CrCl) pro- Collaboration (CKD-EPI) equation was recently developed specifically
vides a close approximation of GFR, because creatinine is produced from to overcome this limitation. It is more accurate than the MDRD study
muscle at a constant rate and freely filtered (it has a molecular weight equation, particularly at higher levels of GFR. Estimating equations are
39
of 113 Da, is water soluble, and is not protein bound). The amount of on average more accurate than measured creatinine clearance, given the
creatinine filtered (the product of the GFR and the plasma creatinine, errors in urine collection. Another interesting and accurate approach uses
20
PCr) is (theoretically) equal to the amount of creatinine excreted during measured aminoglycoside clearance, which occurs entirely by glomerular
the same period (the product of the urine creatinine concentration UCr, filtration, as a surrogate measurement of GFR. 40
and the urine flow rate V); thus, GFR = (UCr × V)/PCr. Measurement Following GFR estimation, dosage is usually adjusted based on pub-
of CrCl requires a timed urine collection to quantify the urinary excre- lished criteria for the agent in question. These maintenance dose adjust-
tion rate and a midpoint plasma creatinine sample (PCr). CrCl normally ments for renal insufficiency are made as follows: 41-44
slightly overestimates GFR because some plasma creatinine is also
secreted by renal tubules, augmenting the measured clearance value Patient’s Estimated GFR/Normal GFR × 100 = Dose Adjustment, %
beyond that due to filtration. This effect is magnified with the develop- (ie, percentage increase in interval or percentage decrease in dose).
ment of progressive glomerular disease, as hypersecretion of creatinine The dosing interval may be increased (interval extension), the size of
by remnant tubules accounts for an increasing fraction of declining individual doses decreased (dose reduction), or a combination of both
serial CrCl values. In critically ill patients, collection of a urine sample approaches may sometimes be necessary.
27
during a period of stable renal function with a steady plasma creatinine For the interval extension method, the usual size dose is given, but the
value may not be possible; short (0.5- to 4-hour) collections have been intervals between individual doses are lengthened. This method is useful
used in an attempt to overcome this problem. However, this method is for drugs characterized by long plasma half-lives in the presence of renal
of limited clinical value because of frequent urine collection errors, ana- impairment and a wide therapeutic range. This approach is convenient
lytical interference with the serum or urine creatinine assay as the result but results in large plasma concentration fluctuations between peak and
of concomitant diseases, and drug therapies and the associated delay in trough levels; in drugs with a low therapeutic index, toxic or subthera-
20
the reporting of results. Inulin clearance more closely approximates peutic levels may result. For example, aminoglycosides are ideally suited
GFR, but is impractical for clinical use, since determination requires to such a dosing strategy: The peak plasma concentration correlates with
inulin infusion, and the assay is difficult to perform. Other clearance therapeutic efficacy, but trough levels must be monitored and kept low
techniques are equally impractical for routine clinical use, and more to minimize toxicity.
complex devices measuring real-time changes in renal function are not Alternatively, in drugs with a low therapeutic index, and those
widely available for clinical applications at this time. 28 for which a constant level is preferred, the size of individual doses is
In patients with stable renal function, it is appropriate to use serum reduced. This achieves a more constant plasma concentration, with less
creatinine values and demographic data in equations to calculate esti- peak-trough fluctuation; however, increased toxicity because of higher
mated GFR (eGFR). These equations have a number of limitations, but average trough levels may result. For example, antiseizure drugs must be
in critically ill patients it is most important to emphasize that calcula- dose adjusted in this fashion.
tions with these equations assume steady-state conditions, in which In the presence of renal insufficiency, hepatic metabolism accounts
renal function is not rapidly changing. This scenario is frequently for the bulk of nonrenal elimination of drugs that are normally renally
not applicable to critically ill patients, in whom serum creatinine is excreted. Hepatic biotransformation of some drugs is altered in patients
frequently increasing or decreasing; both conditions invalidate eGFR with renal insufficiency. Available evidence suggests that CKD may
calculations with standard equations. In contrast, the use of equations lead to alterations in nonrenal clearance of many medications as the
to estimate GFR is very valuable in patients with stable, apparently nor- result of alterations in the activities of uptake and efflux transporters as
mal renal function and chronic kidney disease (CKD). The steady-state well as cytochrome P450. However in contrast, studies on the impact
45
serum creatinine concentration is commonly applied to the Cockcroft- of AKI on drug metabolism show it is delayed in onset or minimal in
Gault formula to estimate GFR, without urinary collection, because of the majority of studies and some specific studies have yielded some
the relationship between patient age and weight (muscle mass), serum unexpected results. Normally, about 30% of vancomycin is cleared
20
creatinine value, and CrCl. For males: by nonrenal routes (approximately 40 mL/min). Nonrenal vancomycin
29
clearance is decreased to 6 mL/min in patients with chronic renal fail-
CrCl(mL/min) = (140 - Age)(Weight in kg)
72 × SCr ure on maintenance dialysis. The elimination pattern in acute kidney
ss injury (AKI) is more complex. Nonrenal elimination is approximately
For females multiply the above value by 0.85. halved early in the course of AKI (16 to 17 mL/min), and decreases to

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