Dosing Recommendations for Continuous Venovenous Hemodiafiltration: DISCUSSION
For many medications, the effect on drug dosing regimens of clearance due to continuous renal replacement therapy is unknown. The risk of toxic effects because of drug accumulation due to overestimation of clearance and the risk of therapeutic failure due to underestimation of extracorporeal drug clearance are major concerns for critically ill patients undergoing such therapy. This study provides an initial dosing guide for selected medications based on studies involving patients undergoing CVVHDF with a Prismaflex dialyzer and AN69 filter. These dosing recommendations will not necessarily be applicable to other types or brands of filters, which may have different physiochemical properties and therefore different rates of drug filtration.
Current guidelines for treatment of sepsis recommend that initial empirical anti-infective therapy be administered at doses that will penetrate to the presumed septic source at adequate concentrations. The guidelines also recommend that patients receive a full loading dose. Therefore, the dose adjustments for anti-infectives during CVVHDF shown in Table 3 are based on more aggressive dosing for serious infections in patients not undergoing CVVHDF and are intended to avoid subtherapeutic concentrations.
Several assumptions were made in preparing the dosing recommendations. It was assumed that the volume of distribution was the same in critically ill patients and those who were not critically ill. This assumption may frequently be incorrect, but the variability in the magnitude of any increases in volume of distribution and rate of return to normal volume of distribution makes it impossible to accurately estimate the impact on pharmacokinetics. This assumption allowed recommendations for loading doses for selected antibiotics to ensure adequate plasma concentrations with the first dose. If the drug therapy is initiated before CVVHDF, loading doses are not necessary. Recommendations for adjustment from recommended maintenance dose schedules were based on the need to avoid accumulation of the drug or unwanted rapid clearance resulting in prolonged periods of subtherapeutic plasma concentrations. The dose recommendations for antibiotics took into consideration the pharmacodynamic parameter of concentration-dependent killing versus time-dependent killing. viagra plus
Another consideration in the use of these dosing guidelines is that many patients in the studies included in this review had severe kidney disease with minimal intrinsic kidney function. For critically ill patients with normal kidney function or mild kidney disease for whom CVVHDF is used for clearing acid or exogenous toxins, Table 1 provides the clearance of drugs strictly by the dialyzer. Depending on the degree to which the dialyzer clears the drug, clinicians can assess whether dose adjustments are necessary. If the CVVHDF process is interrupted and the downtime is anticipated to be longer than 24 h, drug doses should be adjusted according to residual kidney function. The published data do not allow assessment of the magnitude of drug clearance with poorly functioning filters, as is frequently encountered when the filter begins to clot. Clinicians should estimate the potential for drug accumulation and associated toxic effects as filter efficiency declines.
Because of the methods used, this review had several limitations. Pharmacokinetic studies that fulfilled the stated inclusion criteria were limited in number, and only a modest number of medications could be covered by this review. No unpublished studies (i.e., studies not found in the search databases) were identified. The ability to conclusively recommend doses for individual patients is limited, because the pharmacokinetic parameters were extracted from studies with limited numbers of patients and large interpatient variability. This variability extended to the characteristics of patients within studies, who had a wide range of medical conditions, reasons for admission to critical care units, concurrent medications, severity of illness, and residual kidney function. Although calculation of the mean total clearance may minimize the impact of such variability, clinicians should appreciate these limitations when extrapolating recommendations to individual patients with characteristics different from those of patients in the included studies. Furthermore, the blood flow rates and dialysate rates used in the CVVHDF process varied among the studies. It was not possible to quantify the potential impact of these variations on clearance. Table 1 provides the parameters of the renal replacement therapy in the cited studies, which clinicians may need to take into consideration if they differ from those typically encountered in their own clinical practices. canadian discount pharmacy
For the drugs listed, additional studies with larger numbers of patients might confirm the pharmacokinetic parameters previously determined. In addition, pharmacokinetic studies of other medications that meet the aforementioned criteria but are not listed here are warranted.
Despite these limitations, the dosing recommendations in Table 3 represent the most up-to-date evidence-based estimations of initial dose regimens for the listed medications for patients undergoing CVVHDF with a Prismaflex dialyzer and AN69 membrane filters. Any clinician using the dose recommendations in Table 3 should recognize that these are intended only as a guide, and the determination of dose regimens for an individual patient should involve consideration of patient- specific factors and clinical judgement. Monitoring of efficacy and toxicity is necessary.
