Single-Dose Pharmacokinetics of Cidofovir in Continuous Venovenous Hemofiltration

Dosage recommendations for cidofovir are available for renally competent as well as impaired patients; however, there are no data for patients undergoing continuous renal replacement therapy. We determined the single-dose concentration-versus-time profile of cidofovir in a critically ill patient undergoing continuous venovenous hemofiltration (CVVH). One dose of 450 mg cidofovir (5 mg/kg) was administered intravenously due to a proven cytomegalovirus (CMV) infection and failure of first-line antiviral therapy. Additionally, 2 g of probenecid was administered orally 3 h prior to and 1 g was administered 2 h as well as 8 h after completion of the infusion. The concentrations of cidofovir in serum and ultrafiltrate were assessed by high-performance liquid chromatography. The peak serum concentration measured at 60 min postinfusion was 28.01 mg/liter at the arterial port. The trough serum level was 19.33 mg/liter at the arterial port after 24 h. The value of the area under the concentration-versus-time curve from 0 to 24 h was 543.8 mg · h/liter. The total body clearance was 2.46 ml/h/kg, and the elimination half-life time was 53.32 h. The sieving coefficient was 0.138 ± 0.022. Total removal of the drug was 30.99% after 24 h. Because of these data, which give us a rough idea of the concentration profile of cidofovir in patients undergoing CVVH, a toxic accumulation of the drug following repeated doses may be expected. Further trials have to be done to determine the right dosage of cidofovir in patients undergoing CVVH to avoid toxic accumulation of the drug.     

Clearance of ceftazidime during continuous venovenous haemofiltration in critically ill patients.

Published recommendations for the optimal dosing regimen of ceftazidime in critically ill patients with continuous venovenous haemofiltration (CVVH) differ. The aim of this prospective study was to analyse the pharmacokinetic and pharmacodynamic parameters of ceftazidime during CVVH with a high-flux polysulphone membrane, and derive a dosage recommendation. Twelve critically ill patients (five female, seven male) with acute renal failure undergoing CVVH using a 0.7 m(2) polysulphone high-flux membrane were investigated. All patients received ceftazidime 2 g i.v. q8h. Peak ceftazidime concentrations were 58.2 +/- 11.6 mg/L, with trough concentrations 14.0 +/- 3.2 mg/L at the arterial port. The elimination half-life, haemofiltration clearance, volume of distribution and total removal were 4.3 +/- 0.6 h, 32.1 +/- 7.9 mL/min, 36.4 +/- 6.4 L and 74.5 +/- 6.5%, respectively. Based on these pharmacokinetic parameters and that maximal killing is at 4 x MIC we recommend at least ceftazidime 2 g i.v. q8h.     

Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure

Meropenem elimination was studied in six patients with acute renal failure on continuous venovenous haemofiltration (CVVH) or continuous veno-venous haemodiafiltration (CVVHDF) 1 L/h and 2 L/h for 12 h. Meropenem 1 g was given iv over three dialysis periods, and plasma, ultrafiltrate/dialysate and urine concentrations of meropenem were determined. The half-life of meropenem was significantly longer (P < 0.05) during CVVH (7.5 +/- 2.0 h; mean +/- S.D.) than during CVVHDF 1 L/h (5.6 +/- 1.4 h) or 2 L/h (4.8 +/- 1.2 h). Meropenem clearance was 3.27 +/- 2.30 L/h, 4.72 +/- 2.69 L/h and 5.71 +/- 3.58 L/h in CVVH, CVVHDF 1 L/h and CVVHDF 2 L/h, respectively (P < 0.05 between CVVH and CVVHDF). Patients with renal failure on CVVHDF 1 or 2 L/h should be treated with meropenem 1 g bid; 500 mg tid may be enough for patients on CVVH.     

Elimination of the piperacillin/tazobactam combination during continuous venovenous haemofiltration and haemodiafiltration in patients with acute renal failure.

The elimination of the piperacillin/tazobactam combination was studied in six patients with acute renal failure undergoing either continuous venovenous haemofiltration (CVVH) or continuous venovenous haemodiafiltration (CVVHDF) at 1 L/h and 2 L/h for 12 h. Piperacillin 4 g/tazobactam 0.5 g was given iv on three successive treatment periods and their concentrations in plasma, ultrafiltrate/dialysate and urine were determined for 12 h after each dose. The elimination half-life of piperacillin during CVVH (7.7 +/- 2.3 h; mean +/- s.d.) was significantly longer than during CVVHDF 1 L/h (6.7 +/- 1.9 h) or 2 L/h (6.1 +/- 2.0 h) (P< 0.05). Corresponding values for tazobactam were 13.9 +/- 3.9, 11.6 +/- 3.3 and 9.4 +/- 2.4 h, respectively (P< 0.05). Total piperacillin clearance during CVVH (3.89 +/- 1.23 L/h) was significantly lower than during CVVHDF 1 L/h (5.06 +/- 1.68 L/h) or 2 L/h (5.48 +/- 2.11 L/h) (P< 0.05). The corresponding tazobactam clearance values were 2.42 +/- 0.75, 3.13 +/- 0.66 and 3.75 +/- 1.43 L/h, respectively. The mean 12 h elimination of piperacillin and tazobactam in ultrafiltrate/dialysate was 29% and 37% during CVVH, 42% and 57% during CVVHDF (1 L/h), and 46% and 69% during CVVHDF (2 L/h). We recommend 8 hourly dosing of patients with renal failure on CVVH or CVVHDF with dialysis flow rates of 1 or 2 L/h treated with piperacillin 4 g/tazobactam 0.5 g.     

Pharmacokinetics of voriconazole during continuous venovenous haemodiafiltration

OBJECTIVES: Voriconazole is a new triazole antifungal agent that is frequently used in intensive care patients with severe fungal infections. Continuous venovenous haemodiafiltration (CVVHDF) is an important extracorporal renal replacement therapy in critically ill patients suffering from severe infections and multiple organ failure. This study investigates the pharmacokinetics of voriconazole in anuric patients undergoing CVVHDF. PATIENTS AND METHODS: Pharmacokinetic analysis was performed in nine intensive care patients-one of them with liver cirrhosis-with suspected or proven fungal infection and acute renal failure undergoing CVVHDF who received voriconazole intravenously. The concentration of voriconazole in serum and ultradiafiltrate was determined by HPLC. RESULTS: Mean peak pre-filter voriconazole concentration in eight patients without cirrhosis was 5.9 +/- 2.9 mg/L and mean pre-filter trough level was 1.1 +/- 0.3 mg/L. Mean elimination half-life, mean volume of distribution, mean AUC(0-12) and mean sieving coefficient were 14.7 +/- 6.5 h, 228 +/- 42 L, 22.4 +/- 3.7 mg.h/L and 0.56 +/- 0.16, respectively. The total clearance was 12.9 +/- 6.7 L/h and the clearance via CVVHDF was 1.1 +/- 0.3 L/h. In the patient with liver cirrhosis, elimination half-life, volume of distribution, AUC(0-12) and sieving coefficient were 52 h, 301 L, 19.8 mg.h/L and 0.31, respectively. CONCLUSIONS: Voriconazole should be given without a dosage adaptation in critically ill patients without liver cirrhosis undergoing CVVHDF. However, according to results in one patient, reduction of the maintenance dosing regimen of voriconazole seems to be meaningful in patients with liver cirrhosis.     

Argatroban and renal replacement therapy in patients with heparin-induced thrombocytopenia

BACKGROUND: Argatroban, a direct thrombin inhibitor, is an effective anticoagulant for patients who have heparin-induced thrombocytopenia (HIT). Anticoagulation is usually required for renal replacement therapy (RRT). OBJECTIVE: To prospectively evaluate the pharmacokinetics, pharmacodynamics, and safety of argatroban during RRT in hospitalized patients with or at risk for HIT. METHODS: Five patients with known or suspected HIT underwent hemodialysis (n = 4) or continuous venovenous hemofiltration (CVVH, n = 1), while receiving a continuous infusion of argatroban 0.5-2 microg/kg/min. Activated partial thromboplastin times (aPTTs), activated clotting times (ACTs), argatroban concentrations (plasma, dialysate, CVVH effluent), and safety were assessed before, during, and after a 4-hour session of RRT. Systemic and dialytic argatroban clearances were calculated. RESULTS: Among the 4 hemodialysis patients, aPTT, ACT, and plasma argatroban concentrations remained stable during RRT, with respective mean +/- SD values of 74.3 +/- 34.2 seconds, 198 +/- 23 seconds, and 499 +/- 353 ng/mL before RRT, and 70.6 +/- 21.4 seconds, 181 +/- 12 seconds, and 453 +/- 295 ng/mL 2 hours after starting RRT (p values NS). Systemic clearance was 17.7 +/- 12.8 L/h before hemodialysis and 17.0 +/- 9.5 L/h during hemodialysis (n = 2). The dialyzer clearance (dialysate recovery method) was 1.5 +/- 0.4 L/h (n = 4). Generally similar responses occurred in the CVVH patient: systemic argatroban clearance was 4.8 L/h before CVVH and 4 L/h during CVVH. The hemofilter argatroban clearance was 0.9 L/h. No bleeding or thrombosis occurred. CONCLUSIONS: Argatroban provides effective alternative anticoagulation in patients with or at risk for HIT during RRT. Argatroban clearance by high-flux membranes during hemodialysis and CVVH is clinically insignificant, necessitating no dose adjustment.     

Single-dose pharmacokinetics of levofloxacin during continuous veno-venous haemofiltration in critically ill patients

The present study was performed to analyse the pharmacokinetics of levofloxacin during continuous veno-venous haemofiltration (CVVH) with a high-flux polyamide membrane. Twelve patients received 500 mg levofloxacin intravenously. The mean levofloxacin concentration peak was 1.9 +/- 1.0 mg/L. The elimination half-life, haemofiltration clearance and total removal were 8.3 +/- 2.6 h, 27.6 +/- 8.4 mL/min and 56 +/- 19%, respectively. Further multiple-dose studies are required to enable dosage recommendations to be made for patients receiving renal replacement therapy with CVVH.     

Pharmacokinetics of moxifloxacin in patients undergoing continuous venovenous haemodiafiltration

OBJECTIVE: Moxifloxacin is an 8-methoxy quinolone with a broad range of activity against clinically important pathogens. Therefore it is frequently administered in severe respiratory tract infections. Continuous venovenous haemodiafiltration (CVVHDF) is an important extracorporeal renal replacement therapy for intensive care patients suffering from sepsis and multiple organ failure. The aim of this study was to investigate the pharmacokinetics of intravenous moxifloxacin in anuric critically ill patients undergoing CVVHDF. PATIENTS AND METHODS: Pharmacokinetic analysis was performed in nine intensive care patients with acute renal failure and suspected or proven infection sensitive to moxifloxacin, who received moxifloxacin 400 mg intravenously once daily. The concentration of moxifloxacin in serum and ultradiafiltrate was determined by HPLC. RESULTS: Peak and trough serum concentrations were 3.76 +/- 2.02 mg/L and 0.24 +/- 0.14 mg/L, respectively, at the arterial port after the first dose. The mean elimination half-life was 9.87 +/- 3.26 h, the volume of distribution 270 +/- 133 L and the calculated AUC0-24 18.41 +/- 8.46 mg.h/L. Total clearance was 19.09 +/- 8.22 L/h and the clearance of haemodiafiltration 1.63 +/- 0.33 L/h. CONCLUSIONS: The pharmacokinetics of moxifloxacin in critically ill patients with acute renal failure undergoing CVVHDF was comparable to healthy subjects and patients without renal impairment. We recommend 400 mg of intravenous moxifloxacin once per day in anuric patients during CVVHDF.     

Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients

The pharmacokinetics of cefepime were studied in 12 adult patients in intensive care units during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) with a Multiflow60 AN69HF 0.60-m(2) polyacrylonitrile hollow-fiber membrane (Hospal Industrie, Meyzieu, France). Patients (mean age, 52.0 +/- 13.0 years [standard deviation]; mean weight, 96.7 +/- 18.4 kg) received 1 or 2 g of cefepime every 12 or 24 h (total daily doses of 1 to 4 g/day) by intravenous infusion over 15 to 30 min. Pre- and postmembrane blood (serum) samples and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, 8, and 12 or 24 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t(1/2)) of cefepime were 35.9 +/- 6.0 ml/min and 12.9 +/- 2.6 h during CVVH versus 46.8 +/- 12.4 ml/min and 8.6 +/- 1.4 h during CVVHDF, respectively. Cefepime clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 40 and 59% of CL(S), respectively. The results of this study confirm that continuous renal replacement therapy contributes substantially to total CL(S) of cefepime and that CVVHDF appears to remove cefepime more efficiently than CVVH. Cefepime doses of 2 g/day (either 2 g once daily or 1 g twice daily) appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC 相似文献   

Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration.

The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-performance liquid chromatography. Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances. Total clearances of imipenem and cilastatin (mean +/- standard deviations) were 122.2 +/- 28.6 and 29.2 +/- 13.7 ml/min, respectively, with hemofiltration clearances of 22.9 +/- 2.5 and 16.1 +/- 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 +/- 26.3 and 13.2 +/- 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 +/- 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.     

万古霉素在持续性静-静脉血液滤过时的药代动力学研究

目的：研究持续性静-静脉血液滤过（CVVH）时万古霉素的药代动力学特点，指导临床合理用药。方法：应用荧光偏振免疫分析仪测定万古霉素应用不同阶段的血药浓度，计算其药代动力学参数。结果：万古霉素在该患者体内的药代动力学符合开放型二室模型。用药3d主要药代参数：峰浓度（Cmax)=22.18mg/l，谷浓度（Cmin)=5.82mg/L，半衰期（T1/2）=5.75h，总体分布容积（Vd)=21.92,L,总体清除率（CL）=3.49L/h。用药16d主要药代参数；Cmax=38.70mg/L,Cmin=16.50mg/L,T1/2=33.32h,Vd=12.92L,CL=0.38L/h。结论：CVVH可以清除万古霉素，用药时应考虑多种影响因素，并监测血药浓度以提高疗效，减少药物对肾脏的损伤。     

Metabolic effects of continuous veno-venous haemofiltration in critically ill patients.

OBJECTIVE: To evaluate the short-term metabolic and haemodynamic effects of continuous veno-venous haemofiltration (CVVH) in critically ill patients with acute renal failure (ARF). DESIGN: Prospective study of nine consecutive critically ill patients with established acute oliguric renal failure. SETTING: A general ICU in an 800-bed university hospital. PATIENTS: Critically ill patients, mean age 56 +/- 6 years. Four had multi-organ failure, one had acute haemolytic uraemic syndrome, one had idiopathic lactic acidosis, two had haemorrhagic pancreatitis and one had urinary sepsis. INTERVENTIONS: All patients were mechanically ventilated with arterial and pulmonary artery catheters in situ. MEASUREMENTS AND MAIN RESULTS: Oxygen consumption (VO2), CO2 production (VCO2) resting energy expenditure (REE), continuous blood pressure, heart rate, central venous pressure (CVP), pulmonary artery pressure (PAP), and cardiac output (CO), as well as tidal and minute volumes, end-tidal CO2 and arterial blood gases, were continuously measured for one hour prior to and one hour following the institution of CVVH. Body temperature, arterial blood pressure, heart rate, CVP and pulmonary artery catheter data remained stable throughout the study period. Prior to CVVH, VO2 was 326 +/- 33 ml/min, VCO2 was 245 +/- 27 ml/min and REE was 2241 +/- 231 kcal/24 hours. Following institution of CVVH, VO2 was 324 +/- 33 ml/min, VCO2 was 244 +/- 27 ml/min and REE was 2227 +/- 230 kcal/24 hours. CONCLUSIONS: CVVH does not affect metabolic rate and haemodynamic stability in critically ill patients. The lack of any effect on the metabolic rate and haemodynamic parameters in such patients may have significant clinical importance and it further attests to the suitability of CVVH for the treatment of critically ill patients.     

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration

OBJECTIVE: To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF). DESIGN: Prospective, open-labeled study. SETTING: Medical intensive care unit of the University Medical Center Utrecht. PATIENTS: Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. INTERVENTION: All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. MEASUREMENTS AND RESULTS: Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg. CONCLUSION: In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.     

Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis

HYPOTHESIS: Amino acid (AA) loss is not equivalent on continuous venovenous hemofiltration (CVVH) compared with continuous venovenous hemodiafiltration (CVVHD). Amino acid supplementation may be necessary to adjust for a greater clearance on CVVH to maintain nitrogen balance similar to that of CVVHD. OBJECTIVE: To compare AA losses and nitrogen balance between CVVH and CVVHD in children with acute renal failure. SETTING: Pediatric patients in the pediatric intensive care unit of a tertiary referral center. DESIGN: Prospective randomized crossover study in consecutive children who required hemofiltration. PATIENTS: A total of 12 plasma clearance studies for AA and urea, consisting of 24-hr collections of ultrafiltrate and urine for nitrogen balance, was performed on six patients during CVVH and CVVHD. Patients received total parenteral nutrition (TPN) with caloric intake 20% to 30% above their resting energy expenditure measured by indirect calorimetry and 1.5 g/kg/day protein of TPN. Study conditions were comprised of 2 L/hr/1.73 m2 of dialysate or prefiltered replacement fluid and hemofilter flow rates of 4 mL/kg/min were maintained for all patients. METHODS AND MAIN RESULTS: Amino acid clearances were greater on CVVH than CWHD, except for glutamic acid, where clearance was 6.73+/-2.31 (SEM) mL/min/1.73 m2 on CVVH and 7.59+/-2.79 mL/min/1.73 m2 for CVVHD (NS). The clearance difference between the two modalities was 30%. Urea clearance was equivalent (30.1+/-1.74 mL/min/1.73 m2 and 29.0+/-.97 mL/min/1.73 m2) for CVVH and CVVHD, respectively. Amino acid loss on CVVH and CVVHD was similar (12.50+/-1.29 g/day/1.73 m2 vs. 11.61+/-1.86 g/day/1.73 m2, respectively), representing 12% and 11%, respectively, of the daily protein intake. The catabolic state, as measured by urea nitrogen appearance, was high for all patients during the 48-hr study period with a mean of 291 mg/kg/day during CVVH, and 245 mg/kg/day for CVVHD. Nitrogen balance varied from a negative 12.95 g/day/1.73 m2 to a positive 4.93 g/day/1.73 m2 on CVVH and a negative 7.69 g/day/1.73 m2 to a positive 5.50 g/day/1.73 m2 on CVVHD. CONCLUSIONS: Clearance of AA is greater on CVVH than on CVVHD, but no significant difference in AA loss was present between the two therapies. Nitrogen balance often is not met on either therapy when a standard 1.5 g/kg/day protein and a resting energy expenditure of 120% to 130% of calories is delivered by TPN.     

Pharmacokinetics of amikacin during continuous veno-venous hemofiltration

We studied the pharmacokinetics of amikacin in a patient with acute oliguric renal failure during continuous veno-venous hemofiltration (CVVH). The volume of distribution, terminal disposition rate constant and elimination half-life for amikacin were 27.9 L, 0.023.h-1 and 29.7 h, respectively. Total body clearance for amikacin was 10.54 ml/min and CVVH clearance was 10.11 ml/min. Sieving coefficient for amikacin was 0.93 +/- 0.16. Our data show that during CVVH at a filtration rate of 10 ml/min, the clearance of amikacin is similar to that reported in patients with renal failure who are not being treated with CVVH.     

Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis

OBJECTIVE: The present study was performed to test the ability of fosfomycin to penetrate into the CSF of neurointensive care patients with ventriculostomy-associated ventriculitis. PATIENTS AND METHODS: Six patients requiring neurointensive care monitoring, including extraventricular drainage due to secondary obstructive hydrocephalus, were enrolled into the study. All patients received 8 g of fosfomycin intravenously three times a day over a period of at least 5 days. Concentrations of fosfomycin in the CSF and plasma were measured after single-dose administration and at steady state. RESULTS: Mean values of the fosfomycin area under the time-concentration curves for the dosing interval of 8 h (AUC(8)) were 929 +/- 280 and 225 +/- 131 mg.h/L for plasma and CSF after single-dose administration, respectively (P < 0.03). The ratios of the AUC(8) for CSF to the AUC(8) for plasma were 0.23 +/- 0.07 after a single dose and 0.27 +/- 0.08 following multiple doses (P > 0.05, not significant). Additional in vitro experiments have shown that fosfomycin exerts non-concentration-dependent microbial growth inhibition. At steady state, the time above MIC (t > MIC) values were 98%, 92% and 61% for pathogens with MIC values of 8, 16 and 32 mg/L, respectively. CONCLUSION: The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. Thus, the co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible pathogens.     

Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients

The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n=6 patients) or hemodiafiltration (CVVHDF; n=6 patients). Patients (mean+/-standard deviation age, 50.9+/-15.9 years; weight, 98.5+/-15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t1/2) of imipenem were 145+/-18 ml/min and 2.7+/-1.3 h during CVVH versus 178+/-18 ml/min and 2.6+/-1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL(S), respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 microg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC=4 to 8 microg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.     

Detection of citrate overdose in critically ill patients on citrate-anticoagulated venovenous haemofiltration: use of ionised and total/ionised calcium.

BACKGROUND: The objective of this study was to elucidate the most practical and effective laboratory measurement for monitoring citrate in critically ill patients undergoing citrate-anticoagulated continuous venovenous haemofiltration (CVVH). METHODS: This observational study was performed at the mixed medical and surgical intensive care unit of a regional teaching hospital. The study population comprised ten consecutive critically ill patients with acute renal failure and indication for haemofiltration with the use of regional anticoagulation with citrate. Serum samples for the measurement of citrate and total and ionised calcium were taken from the pre- and post-filter compartments and from the arterial circulation of patients during citrate-anticoagulated CVVH. RESULTS: Receiver operating characteristic (ROC) curve analysis showed that for detecting citrate overdose (defined as a citrate concentration >1.0 mmol/L) the best cut-off limits for total/ionised calcium and ionised calcium were 2.1 and 0.8 mmol/L, respectively. Sensitivity and specificity for the cut-off limit of 2.1 for total/ionised calcium were 89% and 100%, and 84% and 100%, respectively, for the cut-off limit of 0.8 mmol/L for ionised calcium. CONCLUSIONS: In patients without liver insufficiency, total/ionised calcium performed slightly better than ionised calcium in detecting elevated citrate concentrations. However, because of the simplicity of its measurement, ionised calcium is preferred. Measurement of citrate is not necessary.     

Pharmacokinetics of Catecholamines During Hemofiltration in Pediatric Patients

BACKGROUND: Continuous hemofiltration is used in pediatric patients with acute renal failure. Many of these patients are treated with catecholamines for hemodynamic instability. The authors studied the pharmacokinetics of dopamine and dobutamine on patients undergoing continuous venovenous hemofiltration. METHODS AND RESULTS: Three critically ill pediatric patients with acute renal failure and cardiovascular instability treated with hemofiltration and intravenous infusion of dopamine and/or dobutamine were entered into the study. Blood samples were drawn at steady-state levels from the arterial port (inflow) of the hemofilter, from the venous port (outflow) of the hemofilter, and from the ultrafilter. Sixteen (n = 16) pharmacokinetic measurements were made, six (n = 6) for dopamine and 10 (n = 10) for dobutamine. The clearance of dopamine by the hemofilter was 0.078 +/- 0.011 mL/kg/min, and for dobutamine it was 0.036 +/- 0.008 mL/kg/min. On the average, 0.56% of the dopamine dose and 0.13% of the dobutamine dose was removed by the hemofilter. CONCLUSIONS: The pharmacokinetics of dopamine and dobutamine at the dosage range of 5-25 μg/kg/min are not altered by continuous hemofiltration. Relative to total plasma clearance, negligible amounts of the drug were removed. The dosage of these catecholamines need not be adjusted during continuous hemofiltration.     

Derivation of meropenem dosage in patients receiving continuous veno-venous hemofiltration based on pharmacodynamic target attainment

BACKGROUND: Dosage recommendations for antibiotics in patients receiving continuous veno-venous hemofiltration (CVVH) should be based on pharmacodynamic requirements. For meropenem, this would be achieving appropriate time above the minimum inhibitory concentration (T > MIC). We employed Monte Carlo simulation to calculate the bactericidal target attainment for various dosing regimens of meropenem against Pseudomonas aeruginosa and Acinetobacter species. METHODS: Target attainment at 40% T > MIC was calculated for 5,000 simulated subjects receiving meropenem 1,000 mg every 12 and 8 h, and 500 mg every 12, 8 and 6 h. Pharmacokinetics were extrapolated from primary literature sources utilizing similar methods of CVVH. MIC data for P. aeruginosa and Acinetobacter species were derived from the US 2003 MYSTIC study. Target attainment at the breakpoint of 4 microg/ml was also calculated. RESULTS: Only regimens of 1,000 mg every 8 h and 500 mg every 6 h essentially achieve 100% target attainment at the breakpoint. However, due to higher peak concentrations, 1,000 mg every 8 h is able to attain improved target attainment against more resistant populations of P. aeruginosa and Acinetobacter species, thus providing the greatest probability of bactericidal exposure. CONCLUSION: Meropenem 1,000 mg every 8 h optimizes the pharmacodynamic profile in patients undergoing CVVH. Lower doses or increased dosing intervals should not be advocated for inpatients receiving this renal replacement technique. .