Augmented Renal Clearance in Critically Ill Pediatric Patients: Does It Impact the Outcome of Pharmacotherapy?*

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Safe and effective use of medicines in critically ill pediatric patients is challenging because of limited knowledge concerning the effect of both the underlying disease state and ongoing developmental changes on both the pharmacokinetics and pharmacodynamics of even frequently used drugs (1). In this critically ill pediatric population, changes in drug distribution and organ function responsible for drug handling can be substantial, both as a consequence of the primary underlying pathophysiology and in response to clinical interventions provided in the pediatric intensive care setting.
Currently, renal dose adjustments are recommended only in patients with impaired renal function because these patients may be at risk for drug toxicity. However, particularly in adults, more recently the issue of augmented renal clearance (ARC) has received attention (2, 3). To date, there are only two papers in the literature that describe the impact of ARC on the clearance of antibiotics in pediatric patients (4, 5). With the article published in this issue of Pediatric Critical Care Medicine by Avedissian et al (6), ARC in critically ill pediatric patients is introduced as another complicating factor concerning drug dosing of children in the critical care setting. In a retrospective cohort analysis covering a large time period (2003–2016), they found 29 patients who showed ARC. As a consequence of this ARC, 23 of these children (79%) had vancomycin trough concentrations of less than 10 mg/L, whereas in 221 pediatric patients without ARC, 115 (52%) trough concentrations of less than 10 mg/L were found. Interestingly, even in the patients without ARC, more than 50% did not reach the desired trough concentration of 10 mg/L for which no clear explanation was brought up. This underscores the important need for increased attention for appropriate drug dosing in the critically ill pediatric patient irrespective of ARC! For this drug, many pharmacokinetic studies have been performed even in children, some of which propose an adjusted dosing guideline leading to predictable exposure and trough concentrations across the pediatric age range; however, as also the current study (6) shows, implementation in clinical practice remains difficult (7).
The emphasis in the adult literature has been on the impact of ARC on the use of antibacterial agents, but there is clearly a need to consider the potential impact of ARC on the majority of drugs used in the intensive care setting because even for drugs that are first metabolized by the liver or intestine, glomerular filtration rate (GFR) will ultimately determine the fate of the clearance of these metabolites (8). We need to realize that many of these metabolites are pharmacologically active such as morphine-6-glucuronide and midazolam-1-OH-glucuronide and therefore might show different duration of action whether ARC is present or not. In this respect, it is however important to mention that for these drugs in adults, also a reduction in excretion of these hydrophilic metabolites is observed implying that it is difficult to predict a priori whether these metabolites in the critically ill are excreted in an increased or decreased manner (9). In addition, in other groups among the adult population such as (morbidly) obese patients who are known for ARC, the renal excretion of, for instance, cefazolin was not found to be increased (10). As such, the clinical impact of ARC in adult or pediatric population with respect to clinical impact on adjusted doses remains to be established, particularly as also the distribution of drugs may be different in these special populations. From these results, it seems that properly designed pharmacokinetic studies using advanced statistical analysis techniques are imperative to guide dosing in special populations.

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