Search

(1) Purpose of this study: To determine whether patient weight influences the probability of target attainment (PTA) over 72 h of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, ertapenem, meropenem) antibiotics in the critical care setting. This is the first paper to address the question of whether patient size affects antibiotic PTA in the ICU. (2) Methods: We performed a post hoc analysis of Monte Carlo simulations conducted in virtual critically ill patients receiving antibiotics and continuous renal replacement therapy. The PTA was calculated for each antibiotic on the following pharmacodynamic (PD) targets: (a) were above the target organism’s minimum inhibitory concentration (≥%fT≥1×MIC), (b) were above four times the MIC (≥%fT≥4×MIC), and (c) were always above the MIC (≥100%fT≥MIC) for the first 72 h of antibiotic therapy. The PTA was analyzed in patient weight quartiles [Q1 (lightest)-Q4 (heaviest)]. Optimal doses were defined as the lowest dose achieving ≥90% PTA. (3) Results: The PTA for fT≥1×MIC led to similarly high rates regardless of weight quartiles. Yet, patient weight influenced the PTA for higher PD targets (100%fT≥MIC and fT≥4×MIC) with commonly used beta-lactams and carbapenems. Reaching the optimal PTA was more difficult with a PD target of 100%fT≥MIC compared to fT≥4×MIC. (4) Conclusions: The Monte Carlo simulations showed patients in lower weight quartiles tended to achieve higher antibiotic pharmacodynamic target attainment compared to heavier patients.

(1) Purpose of this study: determination of adsorption and transmembrane clearances (CLTM) of imipenem and relebactam in ex vivo continuous hemofiltration (CH) and continuous hemodialysis (CHD) models. These clearances were incorporated into a Monte Carlo Simulation (MCS), to develop drug dosing recommendations for critically ill patients requiring continuous renal replacement therapy (CRRT), (2) Methods: A validated ex vivo bovine blood CH and CHD model using two hemodiafilters. Imipenem/relebactam and urea CLTM at different ultrafiltrate/dialysate flow rates were evaluated in both CH and CHD. MCS was performed to determine dose recommendations for patients receiving CRRT, (3) Results: Neither imipenem nor relebactam adsorbed to the CRRT apparatus. The CLTM of imipenem, relebactam, and urea approximated the effluent rates (ultrafiltrate/dialysate flow rates). The types of hemodiafilter and effluent rates did not influence CLTM except in a dialysis flow rate of 1 L/h and 6 L/h in the CHD with relebactam (p &lt, 0.05). Imipenem and relebactam 200 mg/100 mg every 6 h were sufficient to meet the standard time above the MIC pharmacodynamic targets in the modeled CRRT regimen of 25 kg/mL/h. (4) Conclusions: Imipenem and relebactam are not removed by adsorption to the CRRT apparatus, but readily cross the hemodiafilter membrane in CH and CHD. Dosage adjustment of imipenem/relebactam is likely required for critically ill patients receiving CRRT.

Objectives To determine whether the probability of target attainment over 72 hours of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, meropenem) antibiotics were substantially influenced between intensive and less-intensive continuous renal replacement therapy groups in the Acute Renal Failure Trial Network trial and The RENAL Replacement Therapy Study trial. Design The probability of target attainment was calculated using pharmacodynamic targets of percentage of time that free serum concentrations (fT): 1) were above the target organism's minimum inhibitory concentration (≥ fT > 1 × minimum inhibitory concentration); 2) were above four times the minimum inhibitory concentration (≥ % fT > 4 × minimum inhibitory concentration); and 3) were always above the minimum inhibitory concentration (≥ 100% fT > minimum inhibitory concentration) for the first 72 hours of antibiotic therapy. Demographic data and effluent rates from the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials were used. Optimal doses were defined as the dose achieving greater than or equal to 90% probability of target attainment. Setting Monte Carlo simulations using demographic data from Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials. Patients Virtual critically ill patients requiring continuous renal replacement therapy. Interventions None. Measurements and main results The pharmacodynamic target of fT greater than 1 × minimum inhibitory concentration led to similarly high rates of predicted response with antibiotic doses often used in continuous renal replacement therapy. Achieving 100% fT greater than minimum inhibitory concentration is a more stringent benchmark compared with T greater than 4 × minimum inhibitory concentration with standard antibiotic dosing. The intensity of effluent flow rates (less intensive vs intensive) did not substantially influence the probability of target attainment of antibiotic dosing regimens regardless of pharmacodynamic target. Conclusions Antibiotic pharmacodynamic target attainment rates likely were not meaningfully different in the low- and high-intensity treatment arms of the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study Investigators trials.

Purpose: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis. Methods: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier {"type":"clinical-trial","attrs":{"text":"NCT01435174","term_id":"NCT01435174"}}NCT01435174 at Clinicaltrials.gov). Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters. Results: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%. Conclusions: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population.

Introduction: Critically ill patients with acute kidney injury often require renal replacement therapy and antibiotic therapy. Mortality rates are high in these patients, possibly due to ineffective dosing due to altered pharmacokinetic profiles and drug removal by renal replacement therapy. Areas covered: The main types of renal replacement therapies are intermittent hemodialysis, prolonged intermittent renal replacement therapy and continuous renal replacement therapy. Each of these renal replacement therapies may have drastic, yet different, effects on antibiotic serum concentration profiles. Moreover, three antibiotic administration strategies are often used: (1) standard infusion; (2) extended infusion; and (3) continuous infusion. A literature review was conducted on Medline in December 2019 to identify pertinent research. Expert opinion: Renal replacement therapies used in the treatment of acute kidney injury in critically ill patients usually complicates antibiotic use. Although antibiotic toxicity can be seen, most studies find that these patients do not receive sufficient antibiotic doses to achieve desired pharmacodynamic targets. Clinicians should dose antibiotics to match renal replacement therapy drug clearance characteristics to antibiotic pharmacodynamic profiles.

Cefepime, ceftazidime, and piperacillin/tazobactam are commonly used beta-lactam antibiotics in the critical care setting. For critically ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic data are available to inform clinicians on the dosing of these agents. Monte Carlo simulations (MCS) can be used to guide drug dosing when pharmacokinetic trials are not feasible. For each antibiotic, MCS using previously published pharmacokinetic data derived from critically ill patients was used to evaluate multiple dosing regimens in 4 different prolonged intermittent renal replacement therapy effluent rates and prolonged intermittent renal replacement therapy duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis and hemofiltration modes). Antibiotic regimens were also modeled depending on whether drugs were administered during or well before prolonged intermittent renal replacement therapy therapy commenced. The probability of target attainment (PTA) was calculated using each antibiotic's pharmacodynamic target during the first 48 hours of therapy. Optimal doses were defined as the smallest daily dose achieving ≥90% probability of target attainment in all prolonged intermittent renal replacement therapy effluent and duration combinations. Cefepime 1 g every 6 hours following a 2 g loading dose, ceftazidime 2 g every 12 hours, and piperacillin/tazobactam 4.5 g every 6 hours attained the desired pharmacodynamic target in ≥90% of modeled prolonged intermittent renal replacement therapy patients. Alternatively, if an every 6-hours cefepime regimen is not desired, the cefepime 2 g pre-prolonged intermittent renal replacement therapy and 3 g post-prolonged intermittent renal replacement therapy regimen also met targets. For ceftazidime, 1 g every 6 hours or 3 g continuous infusion following a 2 g loading dose also met targets. These recommended doses provide simple regimens that are likely to achieve the pharmacodynamics target while yielding the least overall drug exposure, which should result in lower toxicity rates. These findings should be validated in the clinical setting.

Background/Aims: To determine adsorption and transmembrane clearances (CLTM) of rezafungin, a novel long-acting echinocandin, in continuous venovenous hemofiltration (CVVH). Methods: A validated ex vivo bovine blood CVVH model using polysulfone and AN69 hemodiafilters was used to evaluate urea and rezafungin CLTM at 3 different ultrafiltrate flow rates. Rezafungin adsorption to the CRRT apparatus was determined for each hemodiafilter. Results: The sieving coefficient (SC) from CVVH with 3 different ultrafiltrate flow rates was 0 for both HF1400 and Multiflow-150 hemodiafilters, while urea SC was approximately 1 at all flow rates. Hemodiafilter type and ultrafiltrate flow rate did not influence CLTM. Rezafungin adsorption to the CVVH apparatus was not observed for either hemodiafilter. Conclusion: Rezafungin is not removed by CVVH by membrane adsorption or via CLTM. Ultrafiltrate flow rates and hemodiafilter types are unlikely to influence rezafungin CLTM. No dosage adjustment of rezafungin is likely required for critically ill patients receiving CVVH.

Intravenous acetaminophen is an adjuvant to opioid use in critically ill and surgical patients requiring continuous renal replacement therapy (CRRT). The objective of this study was to determine the ex vivo transmembrane clearance of intravenous acetaminophen during continuous hemofiltration and hemodialysis. Transmembrane clearance was assessed using a validated ex vivo bovine blood model for CRRT using an F8 or HF1400 hemodiafilter. Ultrafiltrate and dialysate flow rates were 1, 2, and 3 L/h. Urea and acetaminophen clearances were calculated and compared. Acetaminophen was readily cleared by continuous hemofiltration with both hemodiafilters. Acetaminophen clearance rates were 92-98% of ultrafiltrate production rates. Similarly, dialytic acetaminophen clearances approximated dialysate flow rates for both hemodiafilters. Acetaminophen is readily cleared by CRRT. Patients receiving CRRT and acetaminophen may require increased doses for adequate pain control.

Background/Aims: To determine ceftolozane/tazobactam transmembrane clearances (CLTM) in continuous hemofiltration (CHF) and continuous hemodialysis (CHD) and to determine optimal ceftolozane/tazobactam dosing regimens for patients receiving continuous renal replacement therapy (CRRT). Method: Validated, ex vivo CHF and CHD bovine blood models using polysulfone (HF1400) and AN69 (Multiflow 150-M) hemofilters were used to evaluate adsorption and CLTM at different effluent flow rates. Monte Carlo simulations (MCS) using pharmacokinetic parameters from published studies and CLTM from this study were used to generate ceftolozane/tazobactam dosing for patients receiving CRRT. Results: CHF and CHD CLTM did not differ at equivalent effluent rates. CLTM approximated effluent flow rates. No adsorption of ceftolozane/tazobactam occurred for either hemofilter. Effluent flow was the most important determinant of MCS-derived doses. Conclusion: CRRT clearances of ceftolozane/tazobactam depended on effluent flow rates but not hemofilter types. MCS-derived ceftolozane/tazobactam doses of 750 (500/250)-1,500 (1,000/500) mg every 8 h met pharmacodynamic targets for virtual patients receiving CRRT at contemporary effluent rates.

Introduction The purpose of this study was to evaluate the impact of hemodialysis on the concentrations of sodium and potassium in the blood when a 25 g dose of sodium thiosulfate injection is infused over 60 minutes in combination with hemodialysis. Methods Sodium thiosulfate (25 g) was prepared by diluting 100 mL of 250 mg/mL Sodium Thiosulfate Injection with 800 mL of 5% dextrose. This was added to the circulating blood surrogate solution at a rate of 15 mL/minute using an infusion pump of an in vitro model of dialysis machine. Serial samples were collected before the administration of the sodium thiosulfate solution, after 15 minutes, 30 minutes, and 60 minutes of infusion from pre-and post-dialyzer ports in both the dialysate circuit and the extracorporeal circuit. Findings The concentration of sodium thiosulfate in pre-dialyzer and post-dialyzer samples of the circulating blood surrogate solution peaked at 30 minutes and 15 minutes, respectively and then remained relatively unchanged during the remainder of the infusion. Mean sodium concentrations (mEq/L) in the circulating blood surrogate solution collected after exposure to a dialyzer were 103.2 ± 12.2, 114.2 ± 18.8, 117.2 ± 7.5, 93.5 ± 5.9 at 0, 15, 30, and 60 minutes, respectively (p = 0.248). Mean potassium concentrations (mEq/L) in the circulating blood surrogate solution collected after exposure to a dialyzer were 1.4 ± 0.3, 1.6 ± 0.3, 1.5 ± 0.1, 1.2 ± 0.1 at 0, 15, 30, and 60 minutes, respectively (p = 0.365). Sodium and potassium concentrations in dialysate increased marginally after exposure to the dialyzer. Discussion Our study demonstrates that neither potassium nor sodium accumulated in circulating blood surrogate solution when a dose of sodium thiosulfate was infused in conjunction with hemodialysis.

Pharmacokinetic/pharmacodynamic analyses with Monte Carlo simulations (MCSs) can be used to integrate prior information on model parameters into a new renal replacement therapy (RRT) to develop optimal drug dosing when pharmacokinetic trials are not feasible. This study used MCSs to determine initial doripenem, imipenem, meropenem, and ertapenem dosing regimens for critically ill patients receiving prolonged intermittent RRT (PIRRT). Published body weights and pharmacokinetic parameter estimates (nonrenal clearance, free fraction, volume of distribution, extraction coefficients) with variability were used to develop a pharmacokinetic model. MCS of 5000 patients evaluated multiple regimens in 4 different PIRRT effluent/duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis or hemofiltration) occurring at the beginning or 14-16 hours after drug infusion. The probability of target attainment (PTA) was calculated using ≥40% free serum concentrations above 4 times the minimum inhibitory concentration (MIC) for the first 48 hours. Optimal doses were defined as the smallest daily dose achieving ≥90% PTA in all PIRRT combinations. At the MIC of 2 mg/L for Pseudomonas aeruginosa, optimal doses were doripenem 750 mg every 8 hours, imipenem 1 g every 8 hours or 750 mg every 6 hours, and meropenem 1 g every 12 hours or 1 g pre- and post-PIRRT. Ertapenem 500 mg followed by 500 mg post-PIRRT was optimal at the MIC of 1 mg/L for Streptococcus pneumoniae. Incorporating data from critically ill patients receiving RRT into MCS resulted in markedly different carbapenem dosing regimens in PIRRT from those recommended for conventional RRTs because of the unique drug clearance characteristics of PIRRT. These results warrant clinical validation.

Purpose Results of a study to determine time and cost requirements for final preparation of continuous renal replacement therapy (CRRT) products are reported. Methods A 3-phase observational study was conducted at a tertiary care university hospital to evaluate costs associated with manual addition of phosphate and/or potassium to 3 commercial 5-L CRRT products. In the first phase of the study, pharmacy workflow processes for solution preparation were established; in the second phase, pharmacist and pharmacy technician time spent in the CRRT workflow and all materials used were observed and recorded. In the third phase, time and personnel requirements were analyzed in economic terms to estimate final preparation costs. Results Through direct observation over 35 days, the CRRT workflow was observed and work times recorded for 511 bag preparations. The main cost contributors were the base CRRT solution and electrolyte additive prices. Technician compounding time differed substantially by solution brand and the need for electrolyte addition. Pharmacist verification time did not differ meaningfully by product. Conclusion Preparation and verification of premade CRRT solutions that contained physiological electrolyte concentrations required less technician and pharmacist time than solutions that needed addition of electrolytes in the pharmacy. Personnel costs, which were a small part of the total cost of dispensed CRRT bags, were higher for technicians than pharmacists. The baseline costs of the solutions and the electrolyte additives, if needed, were the main contributors to total cost.

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.

BACKGROUND Viral bronchiolitis remains a significant cause of hospitalization as well as morbidity and mortality during the first year of life, with treatment options beyond supportive care being limited. In cases of severe illness, ribavirin may offer therapeutic benefit. OBJECTIVE We report the use of intravenous (IV) ribavirin in an infant requiring concomitant venovenous extracorporeal membrane oxygenation (VV-ECMO) and continuous venovenous hemofiltration (CVVH) for respiratory syncytial virus (RSV) and parainfluenza virus (PIV) coinfection. PATIENTS AND METHODS A 5-week-old male former 33-week preterm infant was admitted with respiratory failure and subsequently tested positive for RSV and PIV-type 1 infection. Progressive clinical deterioration subsequently required the initiation of both VV-ECMO and CVVH. Although the patient received combined VV-ECMO and CVVH, IV ribavirin was administered, and serial plasma and ultrafiltrate samples were obtained for pharmacokinetic analyses after the first dose (collection period 1) and again after an estimated 5 half-lives (collection period 2). RESULTS Pharmacokinetics for collection period 1 demonstrated a calculated Cmax of 11.99 mg/L, an AUC0–24 of 43.32 mg·hr/L, ke 0.26 hr−1, t½ 2.69 hr, Vd 10.04 L (2.92 L/kg, using patient's dosing weight 3.43 kg), CLT 43.47 mL/min, and CLCVVH 6.75 mL/min. Pharmacokinetics for collection period 2 demonstrated a calculated Cmax of 10.31 mg/L, AUC0–6 of 52.55 mg· hr/L, ke 0.06 hr−1, t½ 10.69 hr, Vd 17.5 L (5.1 L/kg), and CLT 17.44 mL/min. The sieving coefficient during collection period 1 was 1.17 (range, 1.07–1.37). The percent decline between prefilter and postfilter oxygenator was 19.1%. CONCLUSION Our patient demonstrated therapeutic concentrations of ribavirin, despite drug removal via CVVH and the ECMO oxygenator. Standard ribavirin dosing used and resultant concentrations achieved were associated with viral clearance and clinical improvement.

Background/Aims: To study transmembrane clearance (CLTM) and adsorption of tedizolid, a novel oxazolidinone antibiotic, in continuous hemofiltration (CVVH) and continuous hemodialysis (CVVHD). Methods: In vitro CVVH/CVVHD models with polysulfone and AN69 hemodiafilters were used. Tedizolid CLTM during CVVH/CVVHD was assessed at various ultrafiltrate (Quf) and dialysate rates (Qd). Tedizolid adsorption was tested in a recirculating CVVH model over 4 h. Results: In CVVH, CLTM did not differ between filter types. In CVVHD, tedizolid CLTM was significantly higher with the polysulfone hemodiafilter at Qd 6 l/h (p < 0.02). Tedizolid exhibited irreversible adsorption to the CRRT apparatus and bound significantly higher to the polysulfone hemodiafilter. Conclusion: Tedizolid's CLTM is dependent on Qd, Quf, and hemodiafilter type. At conventional CRRT rates, tedizolid CLTM appears modest relative to total body clearance and is unlikely to require dose adjustments. CRRT adsorption in the clinical setting is likely less than what we observed in this in vitro, continuously recirculating blood model.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

We recently published a report of pharmacy costs associated with customizing and compounding continuous renal replacement therapy (CRRT) solutions.[1][1] The major contributor to the time required to compound the phosphate-containing solution (Phoxillum, Baxter Healthcare) compared with solutions

This proof of concept pilot study was performed to determine whether vibration can increase solute clearance when applied to an in vitro dialysis model. Urea, creatinine, gentamicin, and vancomycin transmembrane clearances were calculated at a blood flow rate of 200 ml/min, dialysate flow rates of 2 and 8 L/hr, and no concurrent ultrafiltration at various vibration intensities. Dialyzer integrity was determined by measuring transmembrane pressure, filter drop pressure, and albumin clearance, and by visually inspecting the dialysate. Comparing the highest vibration modality with no vibration, the median percentage increase in urea, creatinine, gentamicin, and vancomycin clearance was 18% (all p < 0.005). The transmembrane clearance of albumin was negligible for all experiments. When measuring transmembrane pressure and filter drop pressure, no significant differences were found between nonvibration and vibration dialysis. The addition of vibration during dialysis increased transmembrane clearance for solutes with molecular weights of 60-1450 Daltons.

Critically ill patients with acute kidney injury may be treated with a variety of renal replacement therapies (RRTs). Each of these RRTs has profound yet differing effects on drug dosing. Although the doses of some drugs can be titrated to an immediately observable pharmacodynamic effect, the effects of many drugs, such as antibiotics for example, are not immediately apparent. Attainment of desired pharmacodynamic response is a complex interplay between patient, RRT, and pharmacokinetic factors. In the case of antibiotics, microorganism-specific factors also must be considered. Rational and effective drug dosing in this clinical setting cannot occur until all these issues are addressed by the clinician. Failure to account for the pharmacokinetic influences of critical illness, kidney disease, and choice of intermittent hemodialysis or prolonged intermittent or continuous RRT can contribute to the high mortality rates seen in these patients. Pharmacotherapy considerations for each of these therapies are addressed in this article by applying them to a patient case.

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC 48–72 ) that were 48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC 48–72 values, while maintaining acceptable trough concentration ( C min ) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C min reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of C min being ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.

Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

Regadenoson is a novel pharmacological stress agent whose disposition during hemodialysis is not known. The purpose of this study was to determine the clearance of regadenoson under varying dialytic conditions using an in vitro hemodialysis model. Whole human blood was used to analyze the effect of hemodialysis on the clearance of regadenoson. Regadenoson transmembrane clearance (CLD) was assessed for both a standard permeability and a high permeability polysulfone hemodialyzer with blood/dialysate flow rates of 300/600 and 400/800 mL/min. A two-tailed, paired Student’s t test was used to compare regadenoson CLD between hemodialyzer types and flow rates. The mean ± SD regadenoson CLD values ranged between 62.5 ± 11.8 and 89.1 ± 24.0 mL/min for all dialytic conditions. There was no significant difference in regadenoson CLD between hemodialyzer types and flow rates (p > .05). Hemodialysis enhances the clearance of regadenoson independent of hemodialyzer permeability and blood/dialysate flow rate. This clearance is modest relative to total body clearance and is unlikely to produce a clinically significant outcome.

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.

Aminoglycosides for patients undergoing intermittent hemodialysis (IHD) have traditionally been dosed at half the normal dose administered at the end of a hemodialysis session. Several investigations have suggested that administering higher doses preceding or with the initiation of dialysis would more readily optimize pharmacodynamic parameters. However, the selection of an optimal aminoglycoside dosing strategy in patients receiving IHD is complex and requires consideration of numerous factors, precluding a singular approach. By reviewing aminoglycoside pharmacokinetics, pharmacodynamics, risks for toxicity and resistance development, and practical considerations, we derive indication- and setting- specific recommendations. We identify some areas (definitive therapy of gram-negative infections in patients receiving predictable hemodialysis sessions, for example) where dosing preceding or with the initiation of dialysis is optimal and feasible, and others (gram-positive synergy, unstable patients with poor/unpredictable vascular access) where postdialysis dosing remains preferred. Finally, given the dearth of data exploring the pharmacodynamics and clinical outcomes of IHD patients receiving aminoglycoside therapy, we identify several key questions in need of investigation.

This report details the pharmacokinetics of oseltamivir and oseltamivir carboxylate following administration of high-dose oseltamivir in a critically ill child receiving extracorporeal membrane oxygenation (ECMO) and continuous venovenous hemodialysis (CVVHD). A 6-year-old critically ill male patient suffering from a presumed viral illness was transferred to our institution's pediatric intensive care unit from an outside hospital after developing respiratory failure and cardiomegaly. ECMO and oseltamivir therapy were initiated upon admission, and CVVHD was started on hospital day 3. Pharmacokinetic sampling occurred at an oseltamivir dose of approximately 4 mg/kg on hospital day 6. The patient's oseltamivir and oseltamivir carboxylate area under the plasma concentration time curves for the 12-hour dosing interval (AUC0–12) were 30.5 and 905 ng/mLhr, respectively. Drug clearance by CVVHD was 31.6 mL/min for oseltamivir and 26.9 mL/min for oseltamivir carboxylate. Pre- and postoxygenator oseltamivir and oseltamivir carboxylate plasma concentrations did not differ substantially. The patient's oseltamivir carboxylate plasma concentrations remained well above the reported mean 50% inhibitory concentration for 2009 pandemic H1N1 virus. However, despite receiving twice the standard dose of oseltamivir, the oseltamivir carboxylate AUC0–12 in our patient was less than that reported in noncritically ill pediatric subjects. The reduced oseltamivir carboxylate AUC0–12 found in our patient was most likely due to decreased drug absorption.

Purpose. Drug dose recommendations are not well defined in patients undergoing continuous renal replacement therapy (CRRT) due to limited published data. Several guidelines and pharmacokinetic equations have been proposed as tools for CRRT drug dosing. Dose recommendations derived from these methods have yet to be compared or prospectively evaluated.Methods. A literature search of PubMed, Micromedex, and Embase was conducted for 40 drugs commonly used in the ICU to gather pharmacokinetic data acquired from patients with acute and chronic kidney disease as well as healthy volunteers. These data and that obtained from drug package inserts were gathered for use in three published CRRT drug dosing equations. Doses calculated for a model patient using each method were compared to doses suggested in a commonly used dosing text.Results. Full pharmacokinetic data was available for 18, 31, and 40 agents using acute kidney injury, end stage renal disease, and normal patient data, respectively. On average, calculated doses differed by 30% or more from the doses recommended by the renal dosing text for >50% of the medications.Conclusion. Wide variability in dose recommendations for patients undergoing CRRT exists when these equations are used. Alternate, validated dosing methods need to be developed for this at-risk patient population.

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patient’s kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

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.

A common cause of acute kidney injury (AKI) is sepsis, which makes appropriate dosing of antibiotics in these patients essential. Drug dosing in critically ill patients with AKI, however, can be complicated. Critical illness and AKI can both substantially alter pharmacokinetic parameters as compared with healthy individuals or patients with end-stage renal disease. Furthermore, drug pharmacokinetic parameters are highly variable within the critically ill population. The volume of distribution of hydrophilic agents can increase as a result of fluid overload and decreased binding of the drug to serum proteins, and antibiotic loading doses must be adjusted upwards to account for these changes. Although renal elimination of drugs is decreased in patients with AKI, residual renal function in conjunction with renal replacement therapies (RRTs) result in enhanced drug clearance, and maintenance doses must reflect this situation. Antibiotic dosing decisions should be individualized to take into account patient-related, RRT-related, and drug-related factors. Efforts must also be made to optimize the attainment of antibiotic pharmacodynamic goals in this population.

Background/Aims: With advanced anticoagulation, many institutions operate continuous renal replacement therapy (CRRT) circuits longer than manufacturers’ recommendations. This extended use may change hemodiafilter performance and clearance properties. However, hemodiafilter performance over time has not been assessed. We investigated solute clearance over time in modeled CRRT. Methods: In vitro continuous hemofiltration (CH) and continuous hemodialysis (CD) were operated for 48 h using AN69 polyacrylonitrile, cellulose triacetate, F70 polysulfone, and Optiflux F160NR polysulfone hemodiafilters with citrated bovine blood. Urea, creatinine, gentamicin, vancomycin, and albumin clearances were assessed in CH (ultrafiltration rates = 1 and 3 l/h). Clearances of urea, creatinine, gentamicin, and albumin, were assessed in CD with dialysate flow rate of 2 l/h. Results: Solute CH clearances were significantly higher at 3 l/h. Only creatinine and gentamicin clearances were affected by time. Creatinine CD clearance significantly declined at 48 h for all hemodiafilters, especially polysulfone hemodiafilters. Conclusions: CRRT duration affects solute transmembrane clearance. Clinicians should consider hemodiafilter age when assessing hemodialysis dose or drug clearance.

Background/Aims: Knowledge of dalbavancin renal replacement therapy (RRT) disposition is vital to ensure appropriate dosing. In vitro models of continuous RRT and intermittent hemodialysis (IHD) were used to determine dalbavancin transmembrane clearance (CLtm). Methods: Dalbavancin saturation and sieving coefficients (SCs) were determined for hemodialysis and hemofiltration therapies, respectively, using various hemodiafilter and effluent rate combinations. Dalbavancin CLtm estimates were calculated from observed saturation and SCs. Results: Saturation and SCs for both modalities of continuous dialysis and hemofiltration and IHD with high permeability hemodiafilters were small. Nonetheless, during continuous RRT with high dialysate and ultrafiltration rates, dalbavancin CLtm (0.20–1.26 ml/min) matched and often exceeded literature-derived dalbavancin renal clearances. Dalbavancin CLtm was undetectable during IHD with low-permeability hemodialyzers, but with high-permeability hemodialyzers, substantial CLtm (1.90–2.43 ml/min) was noted. Conclusion: Dalbavancin CLtm is dependent on RRT modality, hemodiafilter, and effluent flow. Dalbavancin doses may need to be adjusted depending on RRT parameters.

Background. Daptomycin has concentration-dependent antibacterial activity against Gram-positive bacteria. Its use is increasing in haemodialysis units. The manufacturer recommends a 4–6-mg/kg dose administered every 48 hrs for patients receiving haemodialysis. However, there are no published data about daptomycin pharmacokinetics and clearance during haemodialysis. The recommended dosing regimen would conflict with asymmetric thrice-weekly haemodialysis, which yields two ~44-hr and one ~68-hr interdialytic periods. This is the first study to evaluate daptomycin pharmacokinetics in haemodialysis patients, assess the extent of daptomycin dialytic removal and model serum concentrations at 44 and 68 hrs. Methods. Six otherwise healthy subjects on chronic haemodialysis (55.3 ± 16.1 years old, three females, 66.2 ± 14.2 kg) received a single 6-mg/kg dose of daptomycin post-haemodialysis infused over 30 minutes. Serial blood samples were collected for ~44 hrs (pre-next haemodialysis) and throughout the subsequent haemodialysis session with a high permeability haemodialyser. Individual pharmacokinetic parameters determined by compartmental analysis were used to model trough serum concentrations at 44 and 68 hrs with 6-, 8- and 10-mg/kg post-haemodialysis doses. Results. The haemodialysis session in this trial yielded mean urea and daptomycin reduction ratios of 79.6 ± 5.8% and 57.6 ± 9.2%, respectively. Daptomycin half-life was 19.4 ± 6.5 and 3.8 ± 1.1 hrs ‘off’ and ‘on haemodialysis’, respectively, with minimal rebound 1 hr post-haemodialysis. All modelled trough concentrations at 44 and 68 hrs at all doses exceed typical minimum inhibitory concentration (MIC90) values for Staphylococcus aureus and Enterococcus faecalis. Conclusions. Daptomycin serum concentrations declined by ~50% after a 4-hr haemodialysis session with a high permeability haemodialyser. A 6-mg/kg i.v. post-haemodialysis thrice-weekly dose should result in sufficient pre-haemodialysis daptomycin serum concentrations even after a 68-hr interdialytic period.

Background and objectives: Infusion of intravenous antibiotics after hemodialysis (HD) may delay initiation of treatment for the next HD shift. Intradialytic administration of drugs such as vancomycin during the final hour of HD obviates these delays. Daptomycin has potent activity against Gram-positive bacteria, but the manufacturer recommends that the dose be infused after HD ends. This study determined the pharmacokinetics of intradialytically dosed daptomycin in patients with ESRD. Design, setting, participants, & measurements: This prospective crossover study compared single-dose daptomycin (6 mg/kg, 30-min intravenous infusion) pharmacokinetics administered after HD versus during the last part of HD with high-permeability (HP) and low-permeability (LP) dialyzers to seven patients who had ESRD and were on thrice-weekly HD. Serial blood samples were collected to determine daptomycin serum concentrations and protein binding. Statistical analysis was done using linear mixed model analysis. Results: The maximum serum concentration observed with a 6 mg/kg post-HD dose was 61.1 7.6 g/ml with a mean protein binding of 89.2%. Intradialytic daptomycin administration resulted in reduced maximum serum concentration and area under the curve values that were approximately 12 to 20% lower when administered during HD with LP dialyzers and approximately 35% lower with HP dialyzers. Conclusions: Intradialytic daptomycin administration during the last 30 min of HD is feasible, provided that larger dosages are used to compensate for intradialytic drug loss. On the basis of our findings, intradialytic doses of approximately 7 mg/kg (LP) or approximately 9 mg/kg (HP) theoretically should be bioequivalent to 6 mg/kg infused after HD. The calculated dosages are mathematically driven and must be validated in prospective clinical trials.

Continuous renal replacement therapy (CRRT) is used to treat critically ill children with acute kidney injury. The effect of CRRT on trace element clearance is poorly characterized. The purpose of this study was to quantify the transmembrane clearance of chromium, copper, manganese, selenium and zinc during continuous venovenous hemodiafiltration (CVVHDF). The transmembrane clearance of trace elements was assessed prospectively in five critically ill children receiving CVVHDF at the pediatric intensive care unit of a tertiary care university hospital. Pre-filter blood and effluent samples were measured for trace element concentrations. Transmembrane clearance of trace elements was calculated, and daily loss of each trace element was determined. Daily trace element loss via CVVHDF was compared with daily standard supplementation of trace elements in pediatric parenteral nutrition. Five patients (age range 23 months to 15 years) with a body weight range of 10.5-53 kg completed the study. The median transmembrane clearance of chromium, copper, manganese, selenium and zinc during CVVHDF was calculated as 0 ml, 0.59 ml, 2.48 ml, 1.22 ml, and 1.90 ml, respectively, per 1.73 m(2) body surface area per minute. The calculated CVVHDF losses were substantially smaller than the daily parenteral supplementation for all trace elements.

Continuous renal replacement therapy (CRRT) has given clinicians an important option in the care of critically ill patients. The slow and continuous dialysate and ultrafiltrate flow rates that are employed with CRRT can yield drug clearances similar to an analogous glomerular filtration rate of the native kidneys. Advantages such as superior volume control, excellent metabolic control, and hemodynamic tolerance by critically ill patients are well documented, but an understanding of drug dosing for CRRT is still a bit of a mystery. Although some pharmaceutical companies have dedicated postmarket research in this direction, many pharmaceutical companies have chosen not to pursue this information as it is not mandated and represents a relatively small part of their market. This lack of valuable information has created many challenges in the care of the critically ill patient as intermittent hemodialysis drug dosing recommendations cannot be extrapolated to CRRT. This drug dosing review will highlight factors that clinicians should consider when determining a pharmacotherapy regimen for a patient receiving CRRT.

Objective Our objective was to determine the effects of peridialytic oral supplements on nutritional markers and quality of life (QOL) in patients receiving maintenance hemodialysis. Design This trial was open, prospective, nonrandomized, and comparative. Setting This study was performed at an outpatient hemodialysis unit in a teaching hospital. Patients This study included 88 adults with chronic kidney disease at stage 5. Intervention This study involved directly observed nutrition therapy with ≥1 can of enteral nutrition (Nepro) with each hemodialysis session thrice weekly for 3 months, or standard care. Main Outcome Measure Changes in biochemical markers of nutritional status and QOL, as measured by the Kidney Disease Quality of Life-Short Form, were determined. Results Peridialytic oral nutrition resulted in a significant difference between the nutrition and comparison groups in serum albumin change over time ( P = .03; repeated-measures analysis of variance with covariates). Mean (±SD) serum albumin concentration did not differ between baseline and month 3 in the nutrition group (3.68 ± 0.33 g/dL vs. 3.75 ± 0.40 g/dL; P = .12), but in the comparison group, serum albumin levels declined significantly (3.93 ± 0.34 g/dL at baseline versus 3.81 ± 0.37 g/dL at month 3; P = .04). The "role-physical" domain score of the Kidney Disease Quality of Life-Short Form significantly changed over time in the nutrition group versus the comparison group ( P = .02; repeated-measures analysis of variance with covariates). Nepro was well-tolerated, and greater than 80% of the prescribed therapy was consumed. Conclusion Oral nutrition, as part of structured, directly observed peridialytic therapy in chronic hemodialysis patients, was well-accepted, and resulted in the maintenance of serum albumin levels and QOL with respect to impact of physical health on daily activities. These findings need to be confirmed in a randomized, controlled trial.

Background/Aims: Etanercept is a tumor necrosis factor-α antagonist used in inflammation-mediated conditions. Continuous venovenous hemofiltration (CVVH) has also been used in patients with inflammatory conditions. This study evaluated etanercept clearance using an in vitro CVVH model. Methods: Etanercept clearance was assessed in vitro in bovine blood at 1–3 mg/l final serum concentration, and urea control at 750 mg/l. CVVH was performed using polyacrylonitrile, polysulfone, and polymethylmethacrylate filters at 3 l/h ultrafiltrate and 200 ml/min blood flow rates. Transmembrane clearance was estimated using sieving coefficient calculations, and adsorptive removal rate was approximated using a mass balance calculation. Results: Urea sieving coefficient remained constant (1.04 ± 0.01). Ultrafiltrate etanercept concentrations were undetectable (sieving coefficient < 0.02) and transmembrane and adsorptive clearances were negligible. Conclusion: Etanercept is not cleared appreciably by transmembrane or adsorptive mechanisms in CVVH using polyacrylonitrile, polysulfone, or polymethylmethacrylate hemofilters.

Purpose To determine ertapenem transmembrane clearance (CLtm) during continuous renal replacement therapy (CRRT) using a validated in vitro model. Methods Ertapenem clearance during continuous hemofiltration and hemodialysis was assessed with AN69 and polysulfone hemodiafilters at 4 dialysate (Qd) and ultrafiltration rates (Quf): 1, 2, 3, and 6 l/hour. Blood and dialysate samples were collected at each flow rate and assayed for urea (control solute) and ertapenem concentrations. The experiment was repeated 5 times for each hemodiafilter type. Ertapenem and urea sieving coefficient (SC) and saturation coefficient (SA) were assessed, and CLtm calculated Results: In continuous hemofiltration mode, urea and ertapenem SC ranged from 1.00 to 1.19 at all Quf and did not differ between hemodiafilter types. Consequently, convective CLtm also did not differ between hemodiafilters. In continuous dialysis mode, urea Cltm did not differ between hemodiafilter types at any Qd. However, ertapenem SA and CLtm were significantly different between hemodiafilter types at Qd 6l/hour (pConclusion Ertapenem was cleared substantially in these in vitro CRRT models. However, our findings illustrate discordance between our observed SC and SA and the published unbound fraction of ertapenem. This finding has been reported with many other drugs, including carbapenem antibiotics. If in vivo studies corroborate our SA and SC findings, dosage adjustment for patients receiving CRRT will be required.

Acute kidney injury in critically ill patients is often a complication of an underlying condition such as organ failure, sepsis, or drug therapy. In these patients, stress-induced hypercatabolism results in loss of body cell mass. Unless nutrition support is provided, malnutrition and negative nitrogen balance may ensue. Because of metabolic, fluid, and electrolyte abnormalities, optimization of nutrition to patients with acute kidney injury presents a challenge to the clinician. In patients treated with conventional intermittent hemodialysis, achieving adequate amino acid intake can be limited by azotemia and fluid restriction. With the use of continuous renal replacement therapy (CRRT), however, better control of azotemia and liberalization of fluid intake allow amino acid intake to be maximized to support the patient's metabolic needs. High amino acid doses up to 2.5 g/kg/day in patients treated with CRRT improved nitrogen balance. However, to our knowledge, no studies have correlated increased amino acid intake with improved outcomes in critically ill patients with acute kidney injury. Data from large, prospective, randomized, controlled trials are needed to optimize the dosing of amino acids in critically ill patients with acute kidney injury who are treated with CRRT and to study the safety of high doses and their effects on patient morbidity and survival.

The provision of renal replacement therapy for patients with chronic kidney disease has been reasonably standardized for decades, with thrice-weekly hemodialysis being the standard. Short-daily and nocturnal hemodialysis are 2 new hemodialysis techniques, each are administered 6 to 7 days a week but differ primarily in the duration of the treatment and blood-flow rate. The emergence of these hemodialysis regimens has shown promise in attenuating some of the complications associated with chronic kidney disease. The benefits of these daily regimens are postulated to be a result of enhanced solute clearance and improved extracellular volume management. The improved solute clearance associated with daily hemodialysis is likely to lead to altered dialytic clearance of drugs given to patients receiving these therapies. The purpose of this paper is to review the concepts pertinent to drug removal by hemodialysis and discuss the issues related to these new dialysis techniques and how they may have a impact on drug removal and the design of dosing regimens.

Background The substantial cost of erythropoietic growth factors (EGFs), darbepoetin alfa and epoetin alfa, has led many institutions to evaluate EGF usage and costs in the hospital setting. The primary objectives of this study were to determine the clinical impact on hemoglobin (Hb) concentration, postdischarge epoetin alfa dose requirements, and the economic impact of a darbepoetin alfa for epoetin alfa therapeutic interchange program in hospitalized hemodialysis patients. Methods A retrospective review was conducted in 79 patients (43 during a control period and 36 during the interchange period). The control group consisted of chronic hemodialysis patients admitted to the hospital before the therapeutic interchange program was implemented (September 2002 through September 2003); the interchange group included patients admitted after implementation of the interchange program (October 2003 through October 2004). Clinical parameters including Hb concentration, concomitant iron therapy, packed red blood cell (PRBC) transfusions, EGF dose and cost were collected beginning 2 months prior to hospitalization, during hospitalization, through 2 months post hospital discharge. Results No differences were observed between groups in baseline demographics. There was a greater decrease in Hb concentration in the control group compared to the interchange group, but this did not achieve statistical significance (0.5 g/dL vs 0.3 g/dL, respectively; P = 0.67). EGF dose requirements did not differ between the two groups, nor did the total EGF cost per patient admission before and after hospitalization. Total cost per patient during hospitalization was $164 ± 144 in the control group and $165 ± 156 in the interchange EGF group ( P= 0.97). Conclusion: In the treatment of anemia in hospitalized chronic hemodialysis patients, there were no differences seen in Hb concentration, EGF dose requirements, or overall EGF cost per patient admission. Implementation of the interchange program allowed for market share gains to permit an overall economic benefit across all patients in the amount of $300,000 annually.

Acute hyperkalemia is a frequent and potentially life-threatening medical problem in patients on maintenance hemodialysis therapy. beta-Adrenergic receptor (betaAR) stimulation causes potassium cellular influx and a decline in plasma potassium concentrations. Therefore, betaAR agonists are used in the treatment of patients with hyperkalemia. The goal of this study is to evaluate the utility of weight-based subcutaneous terbutaline dosing to reduce plasma potassium concentrations in a group of subjects with chronic kidney disease (CKD) requiring hemodialysis.Fourteen subjects with CKD receiving long-term hemodialysis were administered terbutaline, 7 microg/kg, subcutaneously. Heart rate measurements and blood samples for potassium concentration determinations were made serially for 420 minutes. Effects of terbutaline on heart rate and potassium responses were determined in each subject.Terbutaline significantly reduced plasma potassium concentrations and significantly increased heart rates during the time course of the study (P0.001, repeated-measures analysis of variance). Mean reduction in peak potassium concentration (-1.31 +/- 0.5 [SD] mEq/L) and increase in peak heart rate (25.8 +/- 10.5 beats/min) were significantly different from baseline (P0.001, baseline versus peak for both responses). No subject reported significant adverse effects.Administration of subcutaneous terbutaline obviates the need for intravenous access and should be considered as an alternative to nebulized or inhaled beta-agonists to treat acute hyperkalemia in patients with CKD. As with the use of any beta-adrenergic agonist, close cardiovascular monitoring is necessary to avoid or minimize toxicity during therapy.

Objective Trace element loss during continuous renal replacement therapy in patients with acute renal failure has not been quantified sufficiently. Design Trace element loss was quantified using an in vitro model of continuous venovenous hemofiltration. Bovine blood was used for the experiment, and the plasma was analyzed for its chromium, copper, selenium, manganese, and zinc content. Two different polysulfone hemodiafilters, a low-flux F8 and high-flux F70 were used, and tested at two different ultrafiltrate flow rates of 1 L/hr and 2 L/hr, respectively. Trace element concentrations in the plasma and ultrafiltrate were analyzed using inductively coupled plasma mass spectrometry. The sieving coefficient and clearance of each trace element were calculated and compared between the two hemodiafilters. Setting In vitro bovine model of continuous venovenous hemofiltration. Patients or other participants Not applicable. Results Mean sieving coefficients of both F8 and F70 hemodiafilters were similar for each trace element. Copper, chromium, manganese, selenium, and zinc all were detected in the ultrafiltrate. Estimated trace element loss using typical trace element blood concentrations and study-derived sieving coefficients suggest that daily losses of selenium are greater than what is replenished with a standard daily trace element supplement in total parenteral nutrition. Conclusion These data suggest that the degree of continuous venovenous hemofiltration clearance chromium, copper, selenium, manganese, and zinc differ between elements and that selenium and copper might need to be replaced with doses that exceed typical supplementation guidelines.

In critically ill children weighing10 kg, it is necessary to use blood as a priming solution for the extracorporeal continuous renal replacement therapy (CRRT) circuit before initiating CRRT to prevent hemodilution and maintain adequate oxygenation. However, blood bank blood usually contains supra-physiological electrolyte concentrations and a non-physiological acid-base balance that may exacerbate the patient's condition. The objective of this trial was to develop a simple protocol to pre-treat blood bank-derived blood to yield a more physiological blood priming solution. Expired human blood in a recirculating in vitro CRRT circuit was dialyzed prior to the initiation of CRRT using a physiological dialysate solution. Serial blood samples were assessed for electrolyte and pH content. Regimens using maximal blood flow rates (180-200 ml/min) and aggressive dialysate flow rates (33-42 ml/min) were able to correct severely hyperkalemic and acidemic blood within 7.5 min. Initially elevated blood potassium concentrations20 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.

Background: No published data are available describing the pharmacokinetics of intravenous levofloxacin in patients with end-stage renal disease (ESRD). Objectives of this study are to determine the pharmacokinetics and dialytic clearance of levofloxacin and develop dosing strategies in these patients. Methods: Eight noninfected subjects receiving long-term thrice-weekly hemodialysis, with no measurable residual renal function, were administered intravenous levofloxacin, 250 mg, over 1 hour after a scheduled hemodialysis session. Blood samples were collected serially during the interdialytic period, during the next intradialytic period, and immediately after the next hemodialysis session. Serum concentrations of levofloxacin were determined by high-performance liquid chromatography. Differential equations describing a 2-compartment open-infusion pharmacokinetic model were fit to each individual subject's serum concentration-time data by iterative nonlinear weighted least-squares regression analysis using Adapt II (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA). Ratios of maximum serum concentration (Cmax) to minimum inhibitory concentration (MIC) were calculated for common respiratory pathogens by using MIC for 90% of isolates (MIC90) data from published studies. Results: All subjects completed the study, and no adverse events were reported. Median systemic clearance, volume of distribution at steady state, elimination half-life, and Cmax were 37.0 mL/min (range, 12.8 to 42.7 mL/min), 103.3 L (range, 39.8 to 139.3 L), 34.4 hours (range, 28.4 to 39.3 hours), and 5.2 μg/mL (range, 4.1 to 11.3 μg/mL), respectively. Median dialytic clearance and levofloxacin reduction ratios were 84.4 mL/min (range, 61.8 to 107.6 mL/min) and 0.244 (range, 0.181 to 0.412), respectively. Median Cmax-MIC90 ratios were 10 or greater for Haemophilus influenzae, Moraxella catarrhalis, Enterobacter cloacae, and Klebsiella pneumoniae, approximately 5 for Streptococcus pneumoniae, and less than 1 for Pseudomonas aeruginosa. Conclusion: The administration of levofloxacin to patients with ESRD as 500 mg initially, followed by 250 mg every 48 hours, will provide adequate Cmax-MIC ratios after the first and subsequent doses for most patients with respiratory tract infections caused by organisms with levofloxacin MICs of 1 μg/mL or less.

The dismal survival rates for critically ill patients with AKI have not improved much over the past few decades despite many advances in renal replacement therapies (RRTs). Some of the continued poor outcomes can be attributed to the fact that the demographics of patients treated in the intensive