Determination of VIT 45 (IND#63,243 - American Regent) removal by closed loop in vitro hemodialysis system.

BACKGROUND: Intravenous iron is typically administered during the hemodialysis (HD) procedure. The extent of VIT 45, a novel intravenous iron formulation, removal by high-flux (HF) or high-efficiency (HE) dialysis membranes at various ultrafiltration rates (UFR) is unknown. METHODS: An in vitro HD system was constructed to determine the dialyzability of iron from a normal saline compartment (NSC) containing 1000 mg iron of VIT 45. The in vitro system utilized a 6-L closed-loop SBS system that was subject to 4 different HD conditions conducted over 4 hours: HE membrane + 0 ml/h UFR; HE membrane + 500 ml/h UFR; HF membrane + 0 ml/h UFR; HF membrane + 500 ml/h UFR. Blood flow and dialysate flow rates were 500 ml/min and 800 ml/min, respectively. The dialysate compartment was a 6-L closed-loop system. A volumetric HD machine controlled all blood, dialysate, and ultrafiltration rates. NSC and dialysate compartment samples were taken at various time points and iron elimination rate (khd) and HD clearance (Clhd) was determined. Iron removal from the NSC > 15% was considered clinically significant. RESULTS: The percent removal of iron from the NSC was < 0.5% at all time points in the study. Dialysate recovery of iron was negligible: 1.7-5.1 mg. VIT 45 removal elimination rates from NSC were less than -0.001 h(-1) (range -0.0002 +/- 0.0001 to -0.0001 +/- 0.0002 h (-1)) for all study conditions. Dialyzer type or UFR did not effect iron removal. CONCLUSION: HF or HE dialysis membranes do not remove clinically significant amounts of VIT 45 over a 4-hour in vitro HD session. This effect remained constant even controlling for UFR up to 500 ml/hour. VIT 45 is not dialyzed by HE or HF dialysis membranes irrespective of UFR.

Pharmacokinetics of intraperitoneal cefazolin and ceftazidime coadministered to CAPD patients.

PURPOSE: Guidelines for empiric treatment of PD-related peritonitis published in 2000 recommend concurrent intraperitoneal (IP) cefazolin and ceftazidime. The pharmacokinetics (PK) of these agents combined have not been studied. This study was designed to determine the PK of combined IP cefazolin and ceftazidime in CAPD patients. DESIGN: Prospective PK study in seven non-infected CAPD patients. PROCEDURES: Patients had a peritoneal equilibration test (PET), then received one IP dose of cefazolin and ceftazidime (15 mg/kg each) co-administered over a 4-hour dwell, then performed three CAPD exchanges over the next 16 hours. Serum and dialysate samples collected over the 20-hour study period were assayed for drug concentrations by HPLC. OUTCOME MEASURES: PK parameters. STATISTICAL METHODS: Correlations were tested between PET and PK parameters using the Pearson-product correlation coefficient. MAIN FINDINGS: Serum cefazolin and ceftazidime levels exceeded the minimum inhibitory concentrations for susceptible organisms (8 mg/L) throughout the 20 hour study period. Mean cefazolin and ceftazidime PK parameters included: bioavailability, 71% and 63%; elimination rate constant, 0.031 and 0.045 h -1 ; total clearance, 5.8 and 16.0 ml/min; peritoneal clearance, 1.6 and 3.9 ml/min; renal clearance, 2.3 and 3.9 ml/min, respectively. Predictive equations suggest that 1000 mg IP of cefazolin and of ceftazidime every 24 hours would produce average steady-state trough serum cefazolin and ceftazidime concentrations of 70 +/- 52 mg/L and 17 +/- 7 mg/L, respectively. There was no correlation between PET and PK parameters. CONCLUSIONS: Co-administration did not adversely affect the PK of either agent. IP cefazolin and ceftazidime (15 mg/kg) produced adequate serum and dialysate concentrations in CAPD patients for 20 hours. PK predictions suggest that most patients would achieve adequate cefazolin and ceftazidime concentrations with 1000 mg IP once-daily. Anuric patients and those with significant residual renal function may require a more individualized approach.

Intravenous vancomycin pharmacokinetics in automated peritoneal dialysis patients.

The pharmacokinetics of intravenous (i.v.) vancomycin was studied in automated peritoneal dialysis (APD) patients who received a single i.v. dose of vancomycin (15 mg/kg total body weight). Dialysate samples were collected at the beginning, middle, and end of dwells 1-3 (on-cycler), and at the end of dwells 4 and 5 (off-cycler), for a 24-hour period. Blood samples were collected at the beginning, middle, and end of dwells 1-3 (on-cycler), and at the end of dwell 5 (off-cycler) for a 24-hr period. Pharmacokinetics parameters were calculated assuming a one-compartment model. Glomerular filtration rate (GFR) and vancomycin clearance (CI) values were normalized to 1.73 m2. Ten patients [4 males, 6 females; 47.4 +/- 9.9 years of age (mean +/- SD)] who had received PD for a median 3.5 months (range 2-66 months) were studied. Dwell times were 2.3 +/- 0.1 hours on cycler and 7.3 +/- 0.1 hours off cycler. Vancomycin half-life was significantly different on-cycler than off-cycler (11.6 +/- 5.2 hr vs 62.8 +/- 33.0 hr; p < 0.001). Vancomycin total CI (CI(T)) was 7.4 +/- 2.0 mL/min. Renal CI (CI(R)) and PD CI (CI(PD)) accounted for 23.6% and 28.0% of CI(T). respectively. CI(R) correlated with GFR (CI(R) = 0.90 GFR - 1.01; r2 = 0.79; p = 0.008). Mean vancomycin serum and dialysate end-of-dwell concentrations were above minimum inhibitory concentration of susceptible organisms (5 micro/mL) for the first cycler and the second ambulatory exchanges only. The results of this study suggest that, to provide adequate concentrations for susceptible organisms over a 24-hour period, current intermittent vancomycin dosing recommendations for PD-related peritonitis need to be changed to 35 mg/kg intraperitoneally on day 1, then 15 mg/kg i.p. thereafter (i.e., once daily) in APD patients.

Cefazolin dialytic clearance by high-efficiency and high-flux hemodialyzers.

Cefazolin dialytic clearance has not been determined in patients undergoing hemodialysis with high-efficiency or high-flux dialyzers. The objective of this study is to determine the pharmacokinetics and dialytic clearance of cefazolin and develop dosing strategies in these patients. Twenty-five uninfected subjects undergoing chronic thrice-weekly hemodialysis were administered a single dose of intravenous cefazolin (15 mg/kg) after their standard hemodialysis session. Fifteen subjects underwent hemodialysis with high-efficiency hemodialyzers, and 10 subjects underwent hemodialysis with high-flux hemodialyzers. Blood and urine samples were collected serially over the interdialytic period, during the next intradialytic period, and immediately after the next hemodialysis session. Serum and urine concentrations of cefazolin were determined by high-performance liquid chromatography. Differential equations describing a two-compartment model were fit to the cefazolin serum concentration-time data over the study period, and pharmacokinetic parameters were determined. Mean dialytic clearance values for cefazolin were significantly greater in the high-flux group compared with the high-efficiency group (30.9 +/- 6.52 versus 18.0 +/- 6.26 mL/min, respectively; P: < 0.05). Cefazolin reduction ratios were significantly greater (0.62 +/- 0.08 versus 0.50 +/- 0.07; P: < 0.005) in the high-flux group compared with the high-efficiency group and correlated well with equilibrated urea reduction. The pharmacokinetic model developed from patient data was used to simulate cefazolin serum concentration data for high-efficiency and high-flux dialyzers. Cefazolin doses of 15 or 20 mg/kg after each hemodialysis session maintained adequate serum concentrations throughout a 2- or 3-day interdialytic period regardless of hemodialyzer type.

Current role of beta-adrenergic blockers in the treatment of chronic congestive heart failure.

Recent findings on the use of beta-adrenergic blockers in patients with congestive heart failure (CHF) are reviewed. CHF is a progressive, debilitating disease that afflicts 4.6 million patients in the United States. Treatment has traditionally consisted of a diuretic, an angiotensin-converting-enzyme (ACE) inhibitor, and digoxin. Despite advances in ACE-inhibitor therapy, the five-year mortality rate remains nearly 50%. Overstimulation of the sympathetic nervous system is believed to contribute to mortality. Beta-blockers have recently been added to the standard of care for patients with New York Heart Association functional class II or III heart failure. Four randomized, double-blind, placebo-controlled clinical trials were recently completed that addressed the benefits of beta-blockers in CHF. The overall mortality rate was reduced 65% by carvedilol, 34% by metoprolol, and 33% by bisoprolol; all these reductions were significant compared with placebo, and the trials were ended early. Bucindolol, however, did not have a significant effect on mortality. These drugs are hepatically metabolized and may require dosage adjustment in hepatically impaired patients. Decompensation of heart failure is another consideration; a beta-blocker should be added only for patients with stable CHF. Dosages must be slowly adjusted to targeted levels. Adverse effects do not differ significantly among beta-blockers. In addition to their effect on mortality, beta-blockers reduce CHF-related morbidity, such as all-cause hospitalization. Carvedilol, metoprolol, and bisoprolol decrease the mortality and morbidity associated with CHF and can be used with limited adverse effects. The choice among these agents does not affect clinical outcomes; bucindolol, however, has proven ineffective.

Prediction and prevention of contrast nephropathy.

Over the last 10 years, the main advances in RCN have come in our ability to predict outcomes for an individual patient. Treatment trials have been almost all uniformly disappointing. Recent positive trials with acetylcysteine and PGE1 will require confirmation in larger trials that are adequately powered for meaningful end points in the PCI population. In the meantime, adequate prehydration and maintenance of post-PCI urine flow rates of > 150 mL/min remain the most prudent measures. As the population ages, breakthroughs with respect to new contrast agents or effective prevention measures will be needed to offer PCI to the spectrum of patients at risk for renal injury.

Role of angiotensin-converting-enzyme inhibition in patients with renal disease.

Clinical studies evaluating the benefits of angiotensin-converting-enzyme (ACE) inhibitor therapy in patients likely to develop renal disease are reviewed. Patients with diabetes or hypertension are at increased risk for development of renal disease. In patients with diabetic nephropathy, captopril therapy was associated with a 50% reduction in the risk of death, dialysis, and transplantation and a significantly smaller increase in serum creatinine compared with placebo. Therapy with enalapril or lisinopril has been shown to limit the progression of renal disease in normoalbuminuric patients with diabetes. Long-term therapy with enalapril (up to seven years) has demonstrated the ability to preserve renal function in patients with diabetes and microalbuminuria. Over 4.5 years, patients with diabetes and at least one other cardiovascular risk factor had significant reductions in the risk of overt nephropathy with ramipril therapy compared with placebo. In addition, ramipril is associated with preservation of renal function in patients with nondiabetic nephropathy. Evidence suggesting a dissociation of the renal hemodynamic and antiproteinuric effects of ACE inhibition is presented. These positive effects of ACE inhibition cannot be explained by reductions in blood pressure alone. ACE inhibitors have renoprotective properties beyond systemic blood pressure reduction.

Intermittent intravenous piperacillin pharmacokinetics in automated peritoneal dialysis patients.

BACKGROUND: Use of intermittent antibiotic dosing is increasing in the treatment of peritoneal dialysis (PD)-related peritonitis. We studied the pharmacokinetics of intravenous (i.v.) piperacillin in automated PD patients. PATIENTS AND METHODS: Eight patients (3 males, 5 females) were recruited and received a single i.v. dose of piperacillin (35 mg/kg actual body weight). Blood and dialysate samples were collected at the beginning, middle, and end of dwells 1-3 (on cycler), and end of dwells 4-5 (off cycler) for a 24-hour period. Baseline and 24-hour urine samples (nonanuric patients, n = 7) were collected. Pharmacokinetic parameters were calculated assuming a one-compartment model. Glomerular filtration rate (GFR) and piperacillin clearance (CL) values were normalized to 1.73 m2. RESULTS: The patients were 49.5 +/- 10.1 years of age (mean +/- SD) and had been receiving PD for a median of 3 months (range 2-66 months). Dwell times were 2.25 +/- 0.06 hours on cycler and 7.26 +/- 0.14 hours off cycler. Piperacillin half-life was not statistically different on or off the cycler (on cycler 1.99 +/- 0.39 hr, off cycler 4.39 +/- 5.4 hr; p = 0.12) and remained insignificant, even accounting for an outlier (on cycler 2.01 +/- 0.41 hr, off cycler 2.54 +/- 1.48 hr; p = 0.19). Piperacillin total CL (CL(T)) was 31.29 +/- 6.02 mL/minute. Renal CL (CL(R)) and PD CL (CL(PD)) accounted for 8.8% and 16.8% of CL(T); CL(R) correlated well with GFR (CL(R) = 0.86 GFR + 0.1; p < 0.00003). Mean piperacillin serum and dialysate end-of-dwell concentrations were above minimum inhibitory concentration of susceptible organisms (8 microg/mL) for the three cycler exchanges only. Serum and dialysate concentrations predicted using a one-compartment model suggest that i.v. piperacillin 4000 mg would provide adequate concentrations for susceptible organisms over a 12-hour period. CONCLUSION: The current i.v. piperacillin dosing recommendations of 4000 mg every 12 hours for PD-related peritonitis are appropriate for patients on automated PD. Intermittent intraperitoneal piperacillin is not recommended.

Correlation of intraperitoneal antibiotic pharmacokinetics and peritoneal membrane transport characteristics.

OBJECTIVE: To identify correlations between the pharmacokinetic variables that describe drug disposition in peritoneal dialysis (PD) patients and the measures used to assess dialysis adequacy. DESIGN AND METHODS: This retrospective study re-evaluated data collected during previous pharmacokinetic studies for intraperitoneally administered cefazolin, ceftazidime, and gentamicin in continuous ambulatory peritoneal dialysis (CAPD) patients, and intravenous cefazolin and tobramycin in automated PD patients. Pharmacokinetic variables were compared to creatinine clearance (CCr), Kt/V, and peritoneal equilibration test data using the Pearson product correlation coefficient (r). RESULTS: Prominent correlations were found between renal CCr and renal Kt/V, with renal clearances of CAPD cefazolin and ceftazidime, and automated PD tobramycin and cefazolin (r values ranged from 0.698 to 0.986; p < 0.05). CONCLUSION: These findings support current peritonitis treatment recommendations that patients with residual renal function may require higher doses or more frequent drug administration.

Pharmacokinetics of intermittent intraperitoneal cefazolin in continuous ambulatory peritoneal dialysis patients.

OBJECTIVE: To investigate the pharmacokinetic parameters of intermittent intraperitoneal (IP) cefazolin, and recommend a cefazolin dosing regimen in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Prospective nonrandomized open study. SETTING: CAPD outpatient clinic in Albany, New York. PATIENTS: Seven volunteer CAPD patients without peritonitis. Three of the patients were nonanuric while 4 were anuric. INTERVENTIONS: Cefazolin (15 mg/kg total body weight) was given to each patient during the first peritoneal exchange. Blood and dialysate samples were collected at times 0, 0.5, 1,2,3,6 (end of the first antibiotic-containing dwell), 24, and 48 hours after the administration of IP cefazolin. Urine samples were collected in nonanuric patients over the study period. RESULTS: The mean+/-SD amount of cefazolin dose absorbed from the dialysate after the 6-hour dwell was 69.7%+/-8.0% of the administered dose. The cefazolin absorption rate constant from dialysate to serum was 0.21+/-0.1/hr (absorption half-life 3.5+/-0.8 hr). The mean serum concentrations reached at 24 and 48 hours were 52.4+/-3.7 mg/L and 30.3+/-5.9 mg/L, respectively. The mean dialysate cefazolin concentrations reached at 24 and 48 hours were 15.1+/-3.4 mg/L and 7.9+/-1.4 mg/L, respectively. The cefazolin serum elimination rate constant was 0.02+/-0.01/hr (elimination half-life 31.5+/-8.8 hr). The total cefazolin body clearance was 3.4+/-0.6 ml/min. In the 3 nonanuric patients the mean renal clearance of cefazolin was 0.6+/-0.4 ml/min. The peritoneal clearance of cefazolin was 1.0+/-0.3 mL/min. The systemic volume of distribution of cefazolin was 0.2+/-0.05 L/kg. No statistical difference was detected in pharmacokinetic parameters between anuric and nonanuric patients, although this may be due to the small number of patients in each group. CONCLUSION: A single daily dose of cefazolin dosed at 15 mg/kg actual body weight in CAPD patients is effective in achieving serum concentration levels greater than the minimum inhibitory concentration for sensitive organisms over 48 hours, and dialysate concentration levels over 24 hours. Caution is warranted in extrapolation of dosing recommendations to patients who maintain a significant degree of residual renal function.

Bilateral renal cortical necrosis associated with cefuroxime axetil.

Cefuroxime axetil has been associated with few reported adverse effects. We report a case of bilateral renal cortical necrosis in a female after receiving 7 doses over 4 treatment days. The patient presented with worsening symptoms consisting of arthralgias, pruritus, and abdominal pain. Laboratory data obtained was indicative of worsening renal failure and thrombocytopenia. The patient required hemodialysis by the third day. Kidney biopsy revealed cortical necrosis. The possible pathogenesis of cefuroxime axetil causing cortical necrosis in this case and a review of other reported cases of chemical induced renal cortical necrosis is discussed.

Subcutaneous enoxaparin for outpatient anticoagulation therapy in a patient with an aortic valve replacement.

Low-molecular-weight heparins have been administered for a variety of clinical conditions. A patient with a mechanical aortic valve replacement patient underwent elective transurethral prostatectomy. Anticoagulation was managed with unfractionated heparin immediately preoperatively and postoperatively. Warfarin was begun on postoperative day 1. The patient had a prolonged hospitalization due to subtherapeutic international normalized ratios (INR) despite warfarin administration. Because he intended to leave the hospital against medical advice before therapeutic INR was achieved, enoxaparin 1 mg/kg subcutaneously every 12 hours was prescribed to provide anticoagulation, facilitating discharge and improving the patient's quality of life. Enoxaparin was associated with an approximate saving of $4500 over warfarin. The only adverse event reported was bruising at the injection site.