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Background: Acute treatment of atrial fibrillation often requires concomitant intravenous (IV) continuous infusions of unfractionated heparin and diltiazem. Concomitantly infusing these medications through the same IV line minimizes multiple IV sites. Diltiazem and heparin visual compatibility have been previously investigated but with limited drug dwell times and differing drug concentrations leading to inconsistent published results. Objective: To investigate the physical compatibility of diltiazem hydrochloride at concentrations of 5 and 1 mg/mL combined with an equal volume of heparin sodium 100 units/mL. Methods: Using a 0.22-µm filter, 15 mL of heparin sodium were placed into a polyvinyl chloride infusion bag followed by 15 mL of either diltiazem hydrochloride 5 or 1 mg/mL. Admixtures were prepared in triplicate. Each admixture was investigated for visual precipitation, spectrophotometric absorbance, and pH change at baseline and 1, 5, 8, and 24 hours after mixing. Physical incompatibility was determined by visual observation, increased spectrophotometric absorbance, and demonstrative pH changes. Results: Each diltiazem 5 mg/mL admixture exhibited a slight haze and enhanced absorbance readings indicating turbidity while none revealed a demonstrative pH change. None of the diltiazem 1 mg/mL assessments revealed visual precipitation or suggested turbidity. Only one pH reading at 5 hours revealed a demonstrative change from baseline. Conclusions: Our findings indicate that infusing diltiazem hydrochloride 5 mg/mL with heparin sodium 100 units/mL in the same IV line cannot be advocated. In contrast, our findings suggest that heparin sodium 100 units/mL infused with diltiazem hydrochloride 1 mg/mL is physically compatible but chemical stability was not assessed.

Continuous i.v. milrinone infusions are used to treat patients with acute decompensated heart failure.[1][1] It is conceivable that patients receiving i.v. milrinone may also be treated for infection, making it necessary to administer milrinone and i.v. antibiotics through the same i.v. line.

Levetiracetam is an anticonvulsant for partial, myoclonic, and primary generalized tonic-clonic seizures.[1][1] Levetiracetam is often administered intravenously in the intensive care setting and may require simultaneous i.v. administration with cardiovascular agents. Evidence defining compatibility

Background: Indwelling catheters deliver lifesaving medical treatments for many chronically ill patients but are frequently a source of infection. Treatment may include an antimicrobial agent(s) and anticoagulant solution dwelling within the catheter. In vitro determinations of solution compatibility and stability are necessary prior to use in patients. Objective: The aim of this study was to determine the physical compatibility, chemical stability, and antimicrobial activity of vancomycin (5 or 10 mg/mL) with gentamicin (1 mg/mL) or 40% ethanol in 4% sodium citrate lock solution over 72 hours. Methods: All solutions were prepared per manufacturer’s instructions. Samples were studied under 4 conditions: (1) 25°C with light, (2) 25°C without light, (3) 37°C with light, and (4) 37°C without light. Physical compatibility and chemical stability were assessed at 0, 24, 48, and 72 hours. Antimicrobial susceptibility testing was conducted at 0 and 72 hours. All studies were carried out in triplicate. Results: All solution combinations under each condition remained patent from baseline to 48 hours. One solution combination of vancomycin (5 mg/mL) and ethanol (40% v/v) in 4% sodium citrate revealed a slight turbidity at 72 hours. Clarity and pH remained stable in all other solutions during the entire study period. Chemical compatibility and antibiotic activity ranged from 95% to 105% and 95% to 106% of initial baseline values, respectively, for all solutions under 4 storage conditions. Conclusions: All antibiotic-anticoagulant lock solutions were found to be physically, chemically, and microbiologically stable during the 72-hour study period except vancomycin (5 mg/mL) and ethanol (40% v/v) in 4% sodium citrate solution which showed slight turbidity at 72 hours.

Catheter-related bloodstream infections (CRBSIs) are an alarming complication associated with long-term catheter use. Approximately 80,000 CRBSIs related to central venous catheters are reported each year in the United States, with up to 28,000 attributable deaths in intensive care units.[1][1] To

Valproate sodium injection is an anticonvulsant used intravenously when oral valproic acid formulations cannot be used to treat complex partial or absence seizures.[1][1] It is very likely that valproate sodium injection will need to be infused simultaneously with other i.v. medications into the

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.

Pharmacotherapy plays an important role in the care of a chronic kidney disease (CKD) patient but delivering this therapy can be challenging. Besides alterations in the pharmacokinetic parameters of absorption, distribution, metabolism and elimination, the average CKD patient must take multiple medications each day. The likelihood of an adverse drug reaction increases with each medication added to these patients’ daily regimen. In this article we discuss selected pharmacokinetic issues unique to CKD patients.

The use of in vitro modeling to predict in vivo drug and solute clearance during renal replacement therapy has evolved to reflect the different dialytic therapies available in clinical practice. This area of renal replacement therapy research is representative of translational research that demonstrates a correlation from bench to bedside where results generated in the laboratory can assist with clinical decisions in the absence of in vivo studies. This review describes in vitro renal replacement therapy models and compares the findings of several in vitro and in vivo studies.

Argatroban is a direct thrombin inhibitor administered as a continuous i.v. infusion to treat and prevent thrombosis in patients with heparin-induced thrombocytopenia (HIT).[1][1] For this reason, argatroban may be used in patients who develop acute atrial fibrillation and have a history of HIT.

Intravenous conivaptan infusions have been used in decompensated heart failure patients with severe hyponatremia.[1][1] Such patients are often receiving other i.v. medications, but compatibility data are limited.[2][2],[3][3] This investigation studied the compatibility of conivaptan with four

Background/Aims Telavancin is a lipoglycopeptide antimicrobial agent which has been approved in Europe and has been recently FDA approved in the United States. Telavancin's parenteral solution contains hydroxy propyl-β-cyclodextrin (HP-β-CD) to enhance its solubility. The disposition of telavancin and HP-β-CD during continuous renal replacement therapies (CRRT) has not been previously reported. Methods The transmembrane clearances (CLtm) of telavancin and HP-β-CD during continuous hemofiltration and hemodialysis were assessed using an in vitro bovine blood model with AN69 and polysulfone hemodiafilters at varying ultrafiltrate and dialysate flow rates (1, 2, 3, & 6 l/hr). Results The mean telavancin sieving coefficient ranged from 0.25 to 0.31 during continuous hemofiltration. At all ultrafiltration rates, no differences were observed in telavancin CLtm between the two hemodiafilter types. For continuous hemodialysis, mean telavancin saturation coefficients ranged from 0.10 to 0.43 and CLtm tended to be higher for the polysulfone hemodiafilter than the AN69 hemodiafilter, especially at higher flow rates. Mean HP-β-CD sieving coefficients ranged from 0.63 to 1.03 and saturation coefficients from 0.63 to 1.38, resulting in a CLtm that was similar to ultrafiltrate and dialysate flow rates. Conclusion Telavancin CLtm is dependent on hemodiafilter type, dialysate and ultrafiltration rates. CRRT with high ultrafiltrate or dialysate rates may result in sufficient telavancin clearance to alter telavancin dosing. HP-β-CD clearance by continuous hemodialysis or continuous hemofiltration is substantial and may be sufficient to prevent HP-β-CD accumulation in subjects receiving CRRT. Pharmacokinetic studies conducted in patients receiving CRRT and telavancin are needed to confirm these in vitro findings.

In 2006, there were 16 796 toxic exposures attributed to valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) reported to the US Toxic Exposure Surveillance System. Of these, 30% (5046) were treated in a health care facility with 12 cases resulting in death. These drugs are highly protein bound and poorly dialyzable; however, it has been suggested that albumin-supplemented dialysate may enhance dialytic clearance. We investigated whether the addition of albumin to dialysate affects dialytic clearance of VPA, CBZ and PHT.VPA, CBZ and PHT were added to a bovine blood-based in vitro continuous hemodialysis circuit, which included a polysulfone or an AN69 hemodialyzer. VPA, CBZ and PHT clearances were calculated from spent dialysate and pre-dialyzer plasma concentrations. VPA, CBZ and PHT clearances with control (albumin-free) dialysate were compared to clearances achieved with 2.5% or 5% human albumin-containing dialysate. The influences of blood flow (180 and 270 mL/min) and dialysate flow (1, 2 and 4 L/h) on dialysis clearance were also assessed.The addition of 2.5% albumin to dialysate significantly enhanced dialytic clearance of VPA and CBZ, but not PHT. Use of 5% albumin dialysate further increased VPA and CBZ clearance. Overall, drug clearance was related directly to dialysate flow but independent of blood flow.Continuous hemodialysis with albumin-supplemented dialysate significantly enhanced VPA and CBZ, but not PHT, clearance compared to control dialysate. Continuous hemodialysis with albumin-supplemented dialysate may be a promising therapy to enhance dialytic clearance of selected highly protein-bound drugs.

Continuous renal replacement therapy (CRRT) increasingly is being used to treat critically ill patients with renal disease. CRRT removes waste products but also nutrients. Our understanding of trace element CRRT clearance has been limited by poor assay sensitivity. The development of inductively coupled plasma mass spectrometry (ICP-MS) allows for the measurement of CRRT trace element removal.Continuous venovenous haemodialysis (CVVHD) transmembrane clearances of trace elements and urea were assessed using a bovine blood-based in vitro model using two different haemodialyser types. These findings were validated in 10 critically ill adult patients receiving continuous venovenous haemodiafiltration (CVVHDF). Calculated daily trace element loss was compared with a typical dose of daily trace element supplementation.The mean +/- SD in vitro CVVHD transmembrane clearances (ml/min) for the polysulfone haemodialyser were chromium 0.97 +/- 0.23, copper 0.47 +/- 0.18, manganese 4.6 +/- 3.6, selenium 1.2 +/- 0.63 and zinc 2.3 +/- 0.32 and for the cellulose diacetate haemodialyser chromium 1.54 +/- 0.91, copper 0.21 +/- 0.07, manganese 7.8 +/- 4.1, selenium 0.76 +/- 0.39 and zinc 2.7 +/- 0.37. The in vivo CVVHDF transmembrane clearances (ml/min) were chromium 5.4 +/- 2.4, copper 0.45 +/- 0.33, manganese 1.9 +/- 4.6, selenium 1.6 +/- 1.2, and zinc 4.0 +/- 1.3.ICP-MS assays detected the five trace elements in the effluent of CVVHDF patients. Trace element CVVHD transmembrane clearance estimates for our in vitro model were supported by the in vivo CVVHDF findings. Calculated daily trace element loss attributed to CVVHD and CVVHDF with dialysate flow rates of 33.3 ml/min is less than what is provided in a daily dose of a trace element supplementation product.

Background/Aims: Pharmacotherapy in critically ill patients receiving continuous renal replacement therapies (CRRT) is challenging due to the lack of published information to base dosing regimens. Methods: Daptomycin’s transmembrane clearance during continuous hemofiltration and hemodialysis was assessed using an in vitro model with AN69 and polysulfone hemodiafilters at varying ultrafiltrate and dialysate flow rates (1, 2, 3 and 6 l/h). Results: During continuous hemofiltration, mean daptomycin sieving coefficient ranged from 0.14 to 0.20. Transmembrane clearances were significantly different between filter types for ultrafiltration rates of 2, 3 and 6 l/h. For continuous hemodialysis, mean daptomycin saturation coefficient ranged from 0.05 to 0.15. AN69-based daptomycin clearances were significantly lower than polysulfone values at dialysate flow rates of 2, 3 and 6 l/h. Conclusion: The extent of daptomycin’s transmembrane clearance is dependent on hemodiafilter type, dialysate and ultrafiltration rates. CRRT with high ultrafiltrate or dialysate rates may result in substantial daptomycin clearances.

Decreased renal drug clearance is an obvious consequence of acute kidney injury (AKI). However, there is growing evidence to suggest that nonrenal drug clearance is also affected. Data derived from human and animal studies suggest that hepatic drug metabolism and transporter function are components of nonrenal clearance affected by AKI. Acute kidney injury may also impair the clearance of formed metabolites. The fact that AKI does not solely influence kidney function may have important implications for drug dosing, not only of renally eliminated drugs but also of those that are hepatically cleared. A review of the literature addressing the topic of drug metabolism and clearance alterations in AKI reveals that changes in nonrenal clearance are highly complicated and poorly studied, but they may be quite common. At present, our understanding of how AKI affects drug metabolism and nonrenal clearance is limited. However, based on the available evidence, clinicians should be cognizant that even hepatically eliminated drugs and formed drug metabolites may accumulate during AKI, and renal replacement therapy may affect nonrenal clearance as well as drug metabolite clearance.