Higher Renal Replacement Therapy Dose Delivery Influences on Drug Therapy

Higher doses of renal replacement therapy have profound effects on pharmacotherapy, yet little research has been conducted in this area. High-volume renal replacement therapies influence both the pharmacokinetic and the pharmacodynamic profiles of all drugs administered to these critically ill patients. Intermittent high-dose “hybrid” hemodialysis therapies remove drugs to a much different degree than standard thrice-weekly hemodialysis, yet pharmacokinetic studies have not been performed in patients receiving these therapies. High-volume continuous renal replacement therapies offer dosing challenges not seen with standard low-dose therapies. This article describes the pharmacokinetic and pharmacodynamic issues presented by high-volume renal replacement therapies. Given the importance that pharmacotherapy has on optimal patient outcomes, a better understanding of the influence that high-volume renal replacement therapy has on drugs is essential if these high volume therapies are to be used successfully in the intensive care unit.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75000/1/j.1525-1594.2003.07283.x.pd

We Underdose Antibiotics in Patients on CRRT

Appropriate antibiotic dosing in critically ill, infected, patients receiving continuous renal replacement therapy (CRRT) is crucial to improve patient outcomes. Severe sepsis and septic shock result in changes in pharmacokinetic parameters, including increased volume of distribution, hypoalbuminemia, and changes in renal and nonrenal clearances. The lack of CRRT standardization, nonrecognition of how CRRT variability affects antibiotic removal, fear of antibiotic toxicity, and limited drug dosing resources all contribute to suboptimal antibiotic therapy. Even when antibiotic CRRT pharmacokinetic studies are available, they are often based on old CRRT methodologies that do not exist in contemporary CRRT practice, resulting in unhelpful/inaccurate dosing recommendations. Application of these older doses in Monte Carlo simulation studies reveals that many of the recommended dosing regimens will never attain pharmacodynamic targets. In this review, using cefepime as an example, we illustrate whether clinicians are likely to achieve pharmacokinetic/pharmacodynamic targets when the recommended dosing regimens are prescribed in this patient population. We encourage clinicians to aggressively dose antibiotics with large loading dose and higher maintenance doses to reach the targets.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/122407/1/sdi12496_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/122407/2/sdi12496.pd

Prevention of hypophosphatemia during continuous renal replacement therapy—An overlooked problem

Hypophosphatemia is a common and potentially serious complication occurring during continuous renal replacement therapy (CRRT). Phosphate supplementation is required in the vast majority of patients undergoing CRRT, particularly beyond the first 48 hours. Supplementation can be provided either as a standalone oral or parenteral treatment or as an additive to CRRT solutions. Each approach has advantages and disadvantages, and clinicians must weigh the individual factors most relevant in their practice setting. Currently there are no consensus protocols for phosphate replacement in CRRT, and many centers replete phosphate in response to hypophosphatemia as opposed to pre‐emptively. Repletion protocols have also been challenged in recent years by shortages in injectable phosphate solutions. More recently a commercially available phosphate‐containing CRRT solution was approved in the United States, but there has been limited clinical experience with this product. In this review, we present recommendations for phosphate repletion in CRRT to prevent hypophosphatemia, and describe our experience using phosphate‐containing CRRT solutions.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143746/1/sdi12677_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143746/2/sdi12677.pd

Safety of Daptomycin in Patients Receiving Hemodialysis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90386/1/phco.31.7.665.pd

Carbamazepine and the active epoxide metabolite are effectively cleared by hemodialysis followed by continuous venovenous hemodialysis in an acute overdose

Hemodialysis (HD) and continuous venovenous hemodialysis (CVVHD) have an unproven role in the management of carbamazepine overdose. Albumin‐enhanced CVVHD may accelerate carbamazepine (CBZ) clearance, but no pharmacokinetic data has been reported for traditional CVVHD without albumin enhancement. In addition, it is unclear whether the active CBZ‐epoxide metabolite is removed with either mode of dialysis. We present a case of CBZ intoxication successfully managed with sequential HD and CVVHD. The CBZ half‐life during CVVHD was 14.7 hours, compared with the patient's endogenous half‐life of 30.8 hours. The CBZ‐epoxide half‐life was 3.2 hours during HD. We conclude that HD and CVVHD provide effective clearance of CBZ and the epoxide metabolite and should be considered in the management of an acute toxic ingestion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86953/1/j.1542-4758.2011.00563.x.pd

Linezolid Clearance During Continuous Venovenous Hemodiafiltration: A Case Report

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90207/1/phco.23.8.1071.32874.pd

Pre dialysis of blood prime in continuous hemodialysis normalizes pH and electrolytes

In critically ill children weighing 20 mEq/l were normalized to below 5 mEq/l within 7.5 min of dialysis in all cases. Blood bank-derived blood can be “conditioned” quickly to physiological pH and electrolyte concentrations using these simple pre-dialysis regimens. Unlike some blood preparation regimens that have been published, the technique used in this trial requires no special equipment or added medications that are not already used in CRRT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47820/1/467_2003_Article_1258.pd

Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms

Oseltamivir, an inactive antiâ influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some nonâ genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1â mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the â 816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (p = 0.039), while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (p = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, â 816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, p = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134982/1/bcpt12625.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134982/2/bcpt12625_am.pd