You only find what you look for: the importance of high creatinine clearance in the critically ill.
Typically, acute elevations in serum creatinine are interpreted as renal dysfunction, particularly in concert with oliguria, and suggest a reduced glomerular filtration rate (GFR). The need to reduce the dose of many drugs in this setting to avoid toxicity is generally accepted, although may not be uniformly applied. Dose adjustment of renally eliminated drugs with a narrow therapeutic index, including aminoglycoside antibiotics and digoxin, are especially important. Hence, a raised serum creatinine commonly triggers the clinician to decrease the dose of renally eliminated drugs.
In general, a 'normal' serum creatinine concentration is assumed to equate to normal renal function especially when urine outputs are greater than 0.5 ml/kg/h. In this setting, little attention is paid to modifying drug dosages from those routinely recommended by the manufacturer. However, this interpretation of renal function may not always be correct. In the elderly or malnourished, where protein stores or intake may be low, a 'normal' serum creatinine may be associated with significant renal impairment. Similarly, a 'normal' serum creatinine at the end of pregnancy may imply some renal dysfunction. In these circumstances, drug dosage adjustment should be considered.
To further complicate the interpretation, a 'normal' serum creatinine concentration may represent higher than anticipated GFRs. In this setting, reconsideration of standard dosing regimens to include more frequent or higher doses of renally cleared drugs will be necessary. Currently this phenomenon is poorly described and increasing drug doses in response to higher clearances is seldom considered. However, in order to maintain therapeutic concentrations, an increase in dose or frequency may be clinically appropriate.
There are an increasing number of publications describing 'supranormal' creatinine clearances in subsets of critically ill patients. The corresponding potential for increased renal drug clearance and sub-therapeutic dosing is high (1). However, until recently, little data was available to describe the incidence or the characteristics of those patients most at risk. A paper by Fuster-Lluch and co-workers in the August 2008 edition of Anaesthesia and Intensive Care (2) has furthered awareness of this very important, but largely underappreciated topic.
Fuster-Lluch and co-workers report an incidence of glomerular hyperfiltration (defined as a urinary creatinine clearance >120 ml/min/1.73m (2)) of 17.9% on the first morning of admission to the intensive care unit (2). While the use of GFRs to stage the severity of chronic kidney disease (3) has become widespread practice, an accepted definition of glomerular hyperfiltration is still debated. The definition and categorisation system as proposed by SunderPlassmann (4) requires validation, and a GFR less than 120 ml/min/1.73[m.sup.2] may still represent an elevation from baseline, particularly in the elderly. Such a change may significantly impact upon the anticipated value, and a relative rather than an absolute figure may better represent augmented clearances in the individual patient. In such patients, dose adjustments made on the basis of age-related predictions of GFR would be inappropriate.
The cohort identified with 'glomerular hyperfiltration' on admission were primarily either postoperative or multi-trauma patients (2). In such a setting, a high cardiac output contributing to an elevated renal blood flow is likely due to the effects of volume loading, use of vasoactive agents, and the underlying systemic inflammatory response syndrome (5,6). Animal data has confirmed this in the setting of experimental sepsis (7). Although neither cardiac output nor the dose of vasoactive medications were provided by Fuster-Lluch and colleagues, diastolic blood pressure was higher in the hyperfiltration group (2). Although the impact of noradrenaline on renal blood flow has been debated in the literature (8-11), recent experimental animal data demonstrates that noradrenaline acts to increase renal blood flow (12), particularly in states of generalised vasodilation (13).
Further research is clearly needed in this area to better define the pathophysiological mechanisms and identify those sub-groups more likely to develop augmented renal clearance (ARC).
The most accurate, routinely available clinical method of determining renal function is still debated. Although most commonly used, isolated serum creatinine values within the normal range are insensitive indicators of GFR in the intensive care unit (14). Age, gender, race, state of hydration, muscle mass, metabolic state and muscle injury can all influence the serum creatinine value. In addition, equations used to estimate GFR in ambulatory or ward patients (such as the Modification of Diet in Renal Disease equation (15)) are not accurate in the critically ill (14,16).
Measured urinary creatinine clearance remains the most widely used surrogate for GFR, although it will tend to over-estimate the true value at lower filtration rates (17). Eight, 12 and 24 hour timed collections have been used (18-20), although a two-hour collection may be just as accurate (21,22). Given the dynamic nature of critical illness, controversy exists over the most useful time for specimen collection and intra-individual variability may be substantial. More frequent measurement may be necessary in the critically ill, particularly in tailoring drug dosing. With these considerations in mind, we believe urinary creatinine clearances should be routinely measured where there is doubt about the GFR, particularly with the recognition of a cohort of patients with ARC.
Using the [beta]-lactam group of antibiotics as an illustration, the implications of elevated creatinine clearances can be better appreciated. These agents demonstrate time-dependent killing, such that the time for which the drug concentration remains above the minimum inhibitory concentration (MIC) for bacterial growth (T >MIC), is the best predictor of antibiotic efficacy (23). Therefore, in the absence of any post-antibiotic effect for a given agent, schedules should aim to maintain the serum concentration of [beta]-lactams above the MIC for 90 to 100% of the dosing interval (24).
Previously, Lipman and colleagues have demonstrated increased [beta]-lactam clearance in a cohort of septic patients without organ dysfunction, leading to sub-therapeutic levels for significant periods of the dosing interval (25,26). Increased drug elimination can be directly correlated with creatinine clearance (27) and similar results have been reported by separate investigators (28-32). As a consequence, failing to identify patients with elevated creatinine clearances and the use of standard dosing regimens may lead to sub-therapeutic [beta]-lactam concentrations, promoting treatment failure or the selection of drug resistant mutants (33).
In summary, a raised serum creatinine concentration, in the absence of acute muscle injury, will commonly signify decreased glomerular filtration and should trigger a consideration for dose-reduction of renally excreted drugs. A 'normal' serum creatinine concentration may also represent renal dysfunction, such as in pregnancy or debilitated states. However, a 'normal' serum value may also be observed in the presence of ARC, a phenomenon likely to occur with high cardiac output states. This results in an elevated creatinine clearance, and unless considered as a part of routine clinical practice, is likely to remain unrecognised. You only find what you look for.
Commonly provided therapeutic interventions in the intensive care unit and the underlying hyperdynamic state are likely to be the key determinants. The implications in terms of enhanced drug elimination are significant, and as this has largely been neglected in the clinical arena, more frequent estimations of creatinine clearance and therapeutic drug monitoring are warranted. Dosage adjustment can then be considered. Further research should now focus on identifying the predictors of elevated creatinine clearance in the critically ill, the validation of bedside tests to allow more frequent measurement and adjustment of dosing regimens in this setting.
We would like to acknowledge the support of the National Health and Medical Research Council Australia in the preparation of this manuscript (NHMRC Project Grant 519702).
A. UDY J. A. ROBERTS R. J. BOOTS J. LIPMAN
University of Queensland Burns Trauma Critical Care Research Centre Department of Intensive Care Medicine Royal Brisbane and Women's Hospital Herston, Queensland
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|Author:||Udy, A.; Roberts, J.A.; Boots, R.J.; Lipman, J.|
|Publication:||Anaesthesia and Intensive Care|
|Date:||Jan 1, 2009|
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