"In Through the Out Door": Led Zeppelin and Drug Administration in Continuous Renal Replacement Therapy.

Unauthorized reproduction of this article is prohibited Pediatric Critical Care Medicine www.pccmjournal. org 373 Vancomycin remains as an integral part of the antimicrobial arsenal used in the intensive care environment both as empiric and targeted therapies. For the antibiotic to be effective, the dosing must achieve appropriate levels for antimicrobial activity, that is the minimum inhibitory concentration (MIC) specific to that organism. For vancomycin, the necessary levels are not the peak or maximum concentration but instead the levels described by the area under the concentration-time curve (AUC) for 24 hours (AUC 0–24 ) relative to the MIC (AUC 0–24 :MIC) (1–4). Current adult vancomycin dosing guidelines support targeting an AUC 0–24 , which is at least 400 times that of the MIC to treat Staphylococcus aureus infections; however, the pediatric guidelines acknowledge that further study may be required to confirm this finding (1, 5). Achieving the AUC:MIC target in pediatric patients may require higher dosing regimens, which puts the patient at risk of the ototoxicity and nephrotoxicity of higher peak concentrations (6). Although one group has studied higher intermittent dosing regimens than those currently recommended (4), another method of achieving the target concentrations is to provide vancomycin in continuous infusion rather than intermittent dosing. This approach makes sense for a drug efficacy measured by AUC rather than peak levels; yet, there is limited literature supporting this as a superior approach (7, 8). In this issue of Pediatric Critical Care Medicine, Cies et al (9) report the results from a retrospective study of 11 pediatric patients receiving vancomycin concurrently with continuous renal replacement therapy (CRRT). Vancomycin was administered as an IV loading dose of 15–20 mg/kg and then included in the dialysate and/or filter replacement fluid (FRF) at a concentration of 18–30 mg/L. Vancomycin blood concentrations were reported 8 hours after the initial load and then every 24 hours with a goal patient serum concentration of 15–30 mg/L. The study was small, and most patients received the drug for only 2–3 days; therefore, there were a varying number of blood trough levels presented for each patient. Nonetheless, from these limited data, the authors found that a mean CRRT concentration of 26.5 ± 5 mg/L was associated with a patient mean concentration of 22.3 ± 3.3 mg/L. Although dialysate and ultrafiltrate are usually the drug “exit” in CRRT, these authors described a relatively novel way of drug administration by adding vancomycin to dialysate and/or FRF. Although going “In Through the Out Door” was coined by Zeppelin (10) in 1979, antibiotic administration in dialysate was described in peritoneal dialysis (PD) at least as far back as the mid-1960s (11). Indeed, antibiotic administration via dialysate is the preferred route of administration to treat PD-associated peritonitis (12), and Cies et al (9) have previously reported a similar approach with acyclovir during CRRT (13). In theory, the proposed method would work, and from the limited drug level data available, it seems the authors were able to achieve the target serum concentration of 15–30 mg/L. As drug is removed by nonrenal or residual renal means and serum concentrations drop, vancomycin should cross the dialyzer (with dialysis therapy) and bring serum concentrations up to the dialysate vancomycin concentration. In convection mode, a similar continuous exposure occurs and serum concentrations should never exceed that of the infusing FRF. The main advantage we see is that “therapeutic” serum concentrations could be maintained despite changes to the effluent rate chosen by the team. The question at hand for the reader is whether this method is superior or preferential to a traditional IV administration, either by intermittent or continuous infusion. The addition of any substance to commercially preprepared solutions for CRRT carries the risk of multiple system errors. An incorrect amount added to the solution will be very effectively delivered by CRRT with the potential for significant alterations in drug levels in a short period of time depending on the magnitude of the error (14). This remains a constant threat in CRRT and is not specific to the methodology reported by Cies et al (9) as it exists with the routine addition of electrolytes to dialysate solutions. The development of a new drug administration modality (antibiotic infusion via CRRT dialysate or FRF) provides further system error threat. Antibiotic administration by atypical routes can mean that “normal” systems with all of their checks and balances are bypassed, which can be a significant safety threat. We *See also p. e138.