Bruce A. Mueller

Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

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 patients 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.

Impact of the Nutritional Regimen on Protein Catabolism and Nitrogen Balance in Patients With Acute Renal Failure

BACKGROUND Patients with acute renal failure are in substantial negative nitrogen balance as a result of their extremely high protein catabolic rates. We prospectively evaluated a series of patients with acute renal failure managed with continuous venovenous hemofiltration to determine which nutritional and nonnutritional variables might influence protein catabolism and nitrogen balance. METHODS Forty consecutive patients (aged 52 +/- 20 years; mean +/- SD) were monitored for 357 treatment days (average treatment duration 8.9 +/- 8.6 days). All data (including nutritional regimen, laboratory values, APACHE II score, administered blood products, hemofiltration parameters, and medications) were collected daily. RESULTS For all patients, the mean normalized protein catabolic rate was 1.4 +/- 0.5 g/kg per day. The rate did not differ between those who received nutrition support and those who did not. The net nitrogen deficit was less in those patients receiving nutrition support (-6.0 +/- 5.2 vs -14.0 +/- 5.6 g N/d; p = .02). Using regression techniques (adjusted for the within-person correlation and the previous days normalized protein catabolic rate), the level of protein and energy provision and the interaction between protein and energy provision were predictive of the normalized protein catabolic rate. Predicted values, using this equation, suggest that at low protein administration rates (< 1 g/kg per day), increasing energy provision may reduce the protein catabolism. However, at this level of protein provision, patients remain in negative nitrogen balance. At protein administration rates necessary to achieve nitrogen balance (approximately 1.5 to 1.8 g/kg per day), protein catabolism may increase. Providing relatively low levels of energy may diminish the magnitude of this increase. CONCLUSION These results suggest that the optimal nutritional regimen for patients with acute renal failure may require a high-protein (approximately 1.5 to 1.8 g/kg per day) and a relatively low-energy (approximately 25 to 35 kcal/kg per day) content.

Continuous venovenous hemofiltration: an alternative to continuous arteriovenous hemofiltration and hemodiafiltration in acute renal failure.

Continuous venovenous hemofiltration (CVVH) has been used as an alternative to continuous arteriovenous hemofiltration (CAVH) and hemodiafiltration (CAVHD) in the management of critically ill patients with acute renal failure. This report describes our experience with the first 25 patients treated with CVVH at our institution. Vascular access was obtained through a single dual-lumen venous catheter. A blood pump was used to provide ultrafiltration pressure. An ultrafiltrate pump was incorporated to ensure predictable ultrafiltrate production rates. Safety features in the extracorporeal circuit included a venous drip chamber with bubble detector and an in-line pressure monitor. CVVH was initiated by a nephrologist and dialysis nurse and was maintained by the intensive care unit (ICU) nursing staff. Fifteen females and 10 males received CVVH therapy for a total of 193.5 days (average, 7.7 +/- 10.3 days; range, 0.5 to 48 days). Four of the 25 patients (16%) survived and were discharged from the hospital. Four additional patients (16%) survived the acute phase of their illness, but died from complications of their primary disease before discharge from the hospital. The mean weight change during CVVH was -7.9 +/- 7.0 kg (range, -26.5 to +2.9 kg). Metabolic waste products and electrolytes were adequately controlled by CVVH in all but one hypercatabolic patient. The mean heparin dose required was 6.5 +/- 4.2 U/kg/h and was adjusted to prevent filter clotting rather than to achieve a predetermined activated partial thromboplastin time (PTT). The median PTT was 35.8 seconds (range, 22.0 to 100; control, 19.5 to 29.5 seconds). Four episodes of volume-responsive hypotension occurred during the 193.5 treatment days. Only one patient experienced a hemorrhagic complication during CVVH. No patient experienced a complication related to vascular access. Twelve of 111 total hemofilters were changed because of clot formation. CVVH was well tolerated by patients and managed efficiently by the ICU nursing staff.(ABSTRACT TRUNCATED AT 250 WORDS)

Noni juice (Morinda citrifolia ): Hidden potential for hyperkalemia?

We report the case of a man with chronic renal insufficiency who self-medicated with an alternative medicine product known as noni juice (Morinda citrifolia). The patient presented to the clinic with hyperkalemia despite claiming adherence to a low-potassium diet. The potassium concentration in noni juice samples was determined and found to be 56.3 mEq/L, similar to that in orange juice and tomato juice. Herbal remedies and alternative medicine products may be surreptitious sources of potassium in patients with renal disease.

Vancomycin pharmacokinetics in acute renal failure: Preservation of nonrenal clearance

The normal nonrenal clearance of vancomycin is reduced in patients with chronic renal failure (40 versus 6 ml/min). The nonrenal clearance of vancomycin in patients with acute renal failure has not been characterized extensively.

Effect of enteral feeding with ensure on oral bioavailabilities of ofloxacin and ciprofloxacin.

The relative oral bioavailabilities of ciprofloxacin and ofloxacin when they were coadministered with water or an enteral feeding product (Ensure) were assessed in 13 healthy volunteers. The area under the concentration time curve from time zero to infinity and the maximum concentration of drug in serum for both drugs were reduced by Ensure in comparison with those by water (P < 0.01). However, Ensure reduced the percent relative bioavailability of ciprofloxacin (72% +/- 14%; range, 52 to 96%) significantly more than ofloxacin (90% +/- 8.3%; range, 74 to 105%) (P < 0.005). Coadministration of Ensure significantly diminished ciprofloxacin and ofloxacin absorption, but ciprofloxacin absorption was reduced significantly more than ofloxacin absorption.

Daptomycin clearance during modeled continuous renal replacement therapy

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.

Comparison of Imipenem Pharmacokinetics in Patients With Acute or Chronic Renal Failure Treated With Continuous Hemofiltration

The total clearance of imipenem, a carbapenem antibiotic, is reduced from approximately 230 mL/min in patients with normal renal function to approximately 50 mL/min in patients with chronic renal failure. This decline in clearance results not only from the loss of renal clearance, but also from a reduction in the nonrenal clearance from 130 to 50 mL/min. Current dosing recommendations for the administration of imipenem to patients with acute or chronic renal failure are based on this reduced clearance rate. We investigated the pharmacokinetics of imipenem in critically ill patients with acute or chronic renal failure to determine whether published dosing guidelines were applicable to both patient populations. Imipenem pharmacokinetic parameters were determined in 10 anuric patients with renal failure managed by continuous venovenous hemofiltration (CVVH). Seven patients had acute renal failure, while the other three had preexisting chronic renal failure. Imipenem serum concentration data were incorporated into a first-order, single-compartment pharmacokinetic model. Determinations of the area under the serum concentration-time curve were made by the trapezoidal rule. Dosing regimens were calculated from clearance data to achieve a mid-dose imipenem serum concentration of 12 mg/L. The total clearance of imipenem in patients with acute renal failure (108.3 +/- 13.8 mL/min; mean +/- SD) was significantly greater than the total clearance measured in patients with chronic renal failure (64.4 +/- 10.5 mL/min; P < 0.02). This increased clearance resulted from a greater nonrenal clearance of the drug in patients with acute renal failure (95.0 +/- 13.8 v 51.1 +/- 10.5 mL/min; P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis.

Objective:To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations. Design:Prospective, open-label pharmacokinetic study. Setting:Intensive care units located within a teaching medical center. Patients:Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin. Interventions:Daptomycin at 8 mg/kg intravenously over 30 mins. Serial blood and effluent samples were collected over the next 48 hrs. Daptomycin protein binding was determined by equilibrium dialysis. Daptomycin continuous venovenous hemodialysis transmembrane clearance was determined by dividing daptomycin effluent by serum concentrations and multiplying by mean effluent production rate for each subject. Equations describing a two-compartment, open-pharmacokinetic model were fitted to each subjects daptomycin concentration-time data and pharmacokinetic parameters were determined by standard methods. Serum concentration-time profiles were simulated for two daptomycin regimens (8 mg/kg every 48 hrs and 4 mg/kg every 24 hrs). Measurements and Main results:A total of 7.7 ± 0.6 mg/kg (mean ± sd) of daptomycin was administered, resulting in an observed peak concentration of 81.2 ± 19.0 &mgr;g/mL. Daptomycin steady-state volume of distribution (0.23 ± 0.14 L/kg) and free fraction (17.5% ± 5.0%) were increased in critically ill subjects receiving continuous venovenous hemodialysis compared with previous values reported in healthy volunteers. Daptomycin transmembrane clearance (6.3 ± 2.9 mL/min) accounted for more than half of total clearance (11.3 ± 4.7 mL/min). Simulations demonstrated 8 mg/kg daptomycin every 48 hrs would result in higher peak (88.8 ± 20.0 &mgr;g/mL vs. 53.0 ± 12.3 &mgr;g/mL) and lower trough concentrations (7.2 ± 5.2 &mgr;g/mL vs. 12.3 ± 5.1 &mgr;g/mL) than 4 mg/kg every 24 hrs. Conclusions:Daptomycin at 8 mg/kg every 48 hrs in critically ill patients receiving continuous venovenous hemodialysis resulted in good drug exposure, achieved high peak concentrations to maximize daptomycins concentration-dependent activity, and resulted in trough concentration that would minimize the risk of myopathy. ClinicalTrials.gov Identifier:NCT00663403.

Mucositis management practices for hospitalized patients: national survey results.

The optimal management strategies for cancer chemotherapy and radiotherapy-induced mucositis have not been identified. In 1989, the National Institutes of Health (NIH) published a consensus statement outlining a standardized approach for the prevention and treatment of oral complications. The purpose of this survey was to identify the national treatment practices for oral mucositis, mucocutaneous Herpes simplex virus infections, and oral candidiasis, and to compare them to the NIH guidelines. Surveys were mailed to clinical pharmacists at 200 hospitals throughout the United States. Sixty-two of the 200 questionnaires were completed and returned. Institutions used a diversity of agents, generating substantial variability in mucositis prophylaxis and treatment protocols. Many of these therapies included products or combinations of ingredients that lack proven clinical efficacy. Mucositis management strategies for hospitalized patients vary widely at US hospitals. Coordinated, controlled studies are needed to identify optimal therapies for these patients.