Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration

Objectives: To determine whether continuous venovenous hemofiltration leads to extraction of tumor necrosis factor alpha (TNFα) and cytokines from the circulation of critically ill patients with sepsis and acute renal failure and to quantitate the clearance and the removal rate of these cytokines and their effect on serum cytokine concentrations. Design: Prospective, controlled study in patients with continuous venovenous hemofiltration (24 l/24 h) using a polysulphone membrane in patients with acute renal failure. Patients: 33 ventilated patients with acute renal failure of septic (n = 18) and cardiovascular origin (n = 15) were studied. Interventions: Hemodynamic monitoring and collection of blood and ultrafiltrate samples before and during the first 72 h of continuous hemofiltration. Measurements and main results: Cardiovascular hemodynamics (Swan-Ganz catheter), Acute Physiology and Chronic Health Evaluation II score, creatinine, electrolytes, and blood urea nitrogen were recorded daily. Cytokines (TNFα, TNFα-RII, interleukin (IL) 1β , IL1RA, IL2, IL2R, IL6, IL6R, IL8, IL10) were measured in prefilter blood and in ultrafiltrate immediately preceding and 12, 24, 48, and 72 h after initiating continuous venovenous hemofiltration (CVVH). Septic patients showed elevated cardiovascular values for cardiac output (7.2 ± 2.1 l/min), cardiac index (4.2 ± 1.3 l/min per m²), and stroke volume (67 ± 23 ml) and reduced values for systemic vascular resistance (540 ± 299 dyn · s · cm^{− 5}). All hemodynamic values normalized within the first 24 h after initiating CVVH treatment. TNFα was 1833 ± 1217 pg/ml in septic patients and 42.9 ± 6.3 pg/ml in nonseptic patients (p < 0.05) prior to CVVH. TNFα was detected in ultrafiltrate but did not decrease in blood during treatment with CVVH. There was no difference in IL 1β between septic (3.8 ± 1.9 pg/ml) and nonseptic patients (1.7 ± 0.5 pg/ml). No significant elimination of cytokines was achieved in the present study by CVVH treatment. Conclusions: These findings demonstrate that CVVH can remove TNFα and special cytokines from the circulation of critically ill patients. Cardiovascular hemodynamics seemed to improve in septic patients after induction of hemofiltration treatment, although there was no evidence that extracorporeal removal of cytokines achieved a reduction in blood levels. The study indicates that low volume continuous hemofiltration with polysulphone membranes in patients with acute renal failure is not able to induce significant removal of cytokines. Received: 12 February 1996 Accepted: 27 November 1996     

Pharmacokinetics of cefpirome during continuous venovenous hemofiltration: rationale for an 8-hour dosing interval

OBJECTIVE: Cefpirome is a new semisynthetic cephalosporin, primarily eliminated by the kidneys, that requires dosage adjustment in patients with kidney failure. The optimal dosing regimen of cefpirome in patients with continuous veno-venous hemofiltration (CVVH) is unknown. METHODS: Pharmacokinetic properties of cefpirome were investigated in eight anuric patients with acute kidney failure treated by CVVH. All patients received a dosage of 2 g cefpirome every 8 hours after starting the hemofiltration with high-flux polysulfone membranes. Concentrations of cefpirome in plasma and ultrafiltrate were measured by HPLC. RESULTS: Total clearance and hemofiltration clearance of cefpirome were 589.1 +/- 164.5 mL/min and 43.3 +/- 7.8 mL/min, respectively. Serum elimination half-life was 2.36 +/- 0.59 hours. The highest plasma drug concentration was 14.8 +/- 3.2 microg/mL, and it declined to trough levels of 3.1 +/- 0.8 microg/mL at the end of the dosing interval. CONCLUSION: On the basis of previously published pharmacodynamic characteristics of cefpirome and the pharmacokinetic parameters obtained in this study, we calculated a required total daily dose of 2 g every 8 hours to achieve sufficient plasma antibiotic levels to cover the majority of target pathogens. However, this dosage may be insufficient during CVVH for intermediate resistant strains of Pseudomonas aeruginosa.     

Mass transfer, clearance and plasma concentration of procalcitonin during continuous venovenous hemofiltration in patients with septic shock and acute oliguric renal failure

Objectives

To measure the mass transfer and clearance of procalcitonin (PCT) in patients with septic shock during continuous venovenous hemofiltration (CVVH), and to assess the mechanisms of elimination of PCT.

Setting

The medical department of intensive care.

Design

A prospective, observational study.

Patients

Thirteen critically ill patients with septic shock and oliguric acute renal failure requiring continuous venovenous postdilution hemofiltration with a high-flux membrane (AN69 or polyamide) and a 'conventional' substitution volume (< 2.5 l/hour).

Measurements and main results

PCT was measured with the Lumitest PCT Brahms^® in the prefilter and postfilter plasma, in the ultrafiltrate at the beginning of CVVH (T0) and 15 min (T15'), 60 min (T60') and 6 hours (T6h) after setup of CVVH, and in the prefilter every 24 hours during 4 days. Mass transfer was determined and the clearance and the sieving coefficient were calculated according to the mass conservation principle. Plasma and ultrafiltrate clearances, respectively, at T15', T60' and T6h were 37 ± 8.6 ml/min (not significant) and 1.8 ± 1.7 ml/min (P < 0.01), 34.7 ± 4.1 ml/min (not significant) and 2.3 ± 1.8 ml/min (P < 0.01), and 31.5 ± 7 ml/min (not significant) and 5 ± 2.3 ml/min (P < 0.01). The sieving coefficient significantly increased from 0.07 at T15' to 0.19 at T6h, with no difference according to the nature of the membrane. PCT plasma levels were not significantly modified during the course of CCVH.

Conclusions

We conclude that PCT is removed from the plasma of patients with septic shock during CCVH. Most of the mass is eliminated by convective flow, but adsorption also contributes to elimination during the first hours of CVVH. The effect of PCT removal with a conventional CVVH substitution fluid rate (<2.5 l/hour) on PCT plasma concentration seems to be limited, and PCT remains a useful diagnostic marker in these septic patients. The impact of high-volume hemofiltration on the PCT clearance, the mass transfer and the plasma concentration should be evaluated in further studies.     

Myoglobin clearance and removal during continuous venovenous hemofiltration

Myoglobin has a relatively high molecular weight of 17,000 Da and is poorly cleared by dialysis (diffusion). However, elimination of myoglobin might be enhanced by an epuration modality based on convection for solute clearances. We present a single case of myoglobin-induced renal failure (peak creatine kinase level: 313,500 IU/l) treated by continuous venovenous hemofiltration (CVVH). Our purpose was to evaluate the efficiency of such a modality using an ultrafiltration rate of 2 to 3 l/h for myoglobin removal and clearance. The hemofilter was a 0.9 m² polyacrylonitrile (AN69) membrane Multiflow-100 (Hospal-Gambro, St-Leonard, Canada) and the blood flow rate was maintained at 150 ml/min by an AK-10 pump (Hospal-Gambro, St-Leonard, Canada). The ultrafiltration bag was placed 60 cm below the hemofilter and was free of pump control or suction device. Serum myoglobin concentration was 92,000 μg/l at CVVH initiation and dropped to 28,600 μg/l after 18 h of the continuous modality. The mean sieving coefficient for myoglobin was 0.6 during the first 9 h of therapy and this decreased to 0.4 during the following 7 h. Mean clearance of myoglobin was 22 ml/min, decreasing to 14 ml/min during corresponding periods, while the mean ultrafiltration rates were relatively stable at 2,153 ± 148 ml/h and 2,074 ± 85 ml/h, respectively. In contrast to myoglobin, the sieving coefficeint for urea, creatinine, and phosphorus remained stable at 1.0 during the first 16 h of CVVH. More than 700 mg of myoglobin were removed by CVVH during the entire treatment.¶In conclusion, considerable amounts of myoglobin can be removed by an extracorporeal modality allowing important convective fluxes and middle molecule clearances, such as CVVH at a rate of 2 to 3 l/h using an AN69 hemofilter. If myoglobin clearance had been maintained at 22 ml/min, 32 l of serum would have been cleared per day. However, the sieving coefficient of myoglobin decreased over time, probably as a consequence of protein coating and/or blood clotting of the hemofilter. Whereas myoglobin can be removed by CVVH, it remains unknown at this point if such a modality, applied early, can alter or shorten the course of myoglobinuric acute renal failure.     

Discrepancies between observed and predicted continuous venovenous hemofiltration removal of antimicrobial agents in critically ill patients and the effects on dosing

Objective Drug dosing during continuous venovenous hemofiltration (CVVH) is based partly upon the CVVH clearance (Cl_CVVH) of the drug. Cl_CVVH is the product of the sieving coefficient (SC) and ultrafiltration rate (Q_uf). Although it has been suggested that the SC can be replaced by the fraction of a drug not bound to protein (F_up), the F_up values as reported in the literature may not reflect the protein binding in critically ill patients with renal failure. We compared the observed Cl_CVVH (SC × Q_uf) with the estimated Cl_CVVH (estimated F_UP × Q_uf) and determined the effect on the maintenance dose multiplication factor (MDMF).Design and setting Clinical study in a mixed ICU in a university hospital.Patients 45 oligoanuric patients on CVVH (2 l/h).Interventions Timed blood and ultrafiltrate samples.Measurements and results Amoxicillin, ceftazidime, ciprofloxacin, fluconazole, metronidazole, and vancomycin were easily filtered (mean SC > 0.7) but not flucloxacillin (mean SC 0.3). Predicted and observed Cl_CVVH corresponded only for fluconazole and metronidazole. The difference between observed and predicted MDMF was small for all drugs, with the exception of ceftazidime (mean 0.25, 95% CI −0.96 to 1.48) and vancomycin (0.05, −1.34 to 1.45). However, this difference was clinically relevant only for vancomycin, because of its narrow therapeutic index.Conclusions Dosing based on predicted CVVH removal provides an as reliable estimate than that based on observed CVVH removal except for those antibiotics that have both a narrow therapeutic index and a predominantly renal clearance (e.g., vancomycin).     

Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients

Objective: To study the pharmacokinetics of vancoymcin in critically ill patients with acute renal failure treated with continuous venovenous haemofiltration (CVVHF).¶Design: Open-label study.¶Setting: Hospital pharmacy centre and medical intensive care unit of the University Medical Centre Utrecht.¶Materials and methods: In a laboratory setting, the sieving coefficient (s) of vancomycin by polyacrilonitrile (PAN) haemofilters of different surface areas was studied. In one patient, the pharmacokinetics of vancomycin were studied following a single dose of vancomycin. Another patient was treated with a vancomycin dosing regimen based on data from the literature, but high trough concentrations made dose reduction necessary after 24 h of withholding therapy. After two doses of 250 mg, serum and ultrafiltrate samples were collected for pharmacokinetic evaluation.¶Intervention: CVVHF with the following operational characteristics: blood flow 200 ml/min, ultrafiltrate flow 25 ml/min, postdilution, PAN 06 hollow fibre haemofilter.¶Measurements and results: The average sieving coefficient in vitro was 0.73 ± 0.06, 0.86 ± 0.11, and 0.80 ± 0.06 for the PAN 03, 06, and 10 haemofilters, respectively. Changes in the sieving coefficient by increasing the ultrafiltration rate were not clinically significant. The first patient was given a single dose of vancomycin, 1000 mg by intravenous infusion. The following pharmacokinetic data were obtained: apparent volume of distribution (Vd) 55.8 l, terminal half-life time (t_{1/2 term}) 15.4 h, total clearance (Cl_tot) 2.5 l/h, CVVHF clearance (CL_{CVVHF, form 1}) 1.4 l/h, and body clearance (Cl_body) 1.1 l/h. The average sieving coefficient during the study period was 0.89 ± 0.03. In the second patient, the pharmacokinetics of vancomycin were studied following dose reduction: Vd 41.7 l, ¶t_{1/2 term} 20.3 h, Cl_tot 1.4 l/h, Cl_{CVVHF, form 1} 1.4 l/h, and Cl_body < 0.1 l/h. The average sieving coefficient during the study period was 0.88 ± 0.03. The cumulative amount of vancomycin removed by means of CVVHF during the 12-h study period was 245 mg in patient 1 and 228 mg in patient 2.¶Conclusion: CVVHF with a PAN 06 haemofilter effectively removed vancomycin in two critically ill patients. The amount of vancomycin removed with CVVHF was about 250 mg per 12 h. A clear difference in body clearance in the two patients was observed. Our dosage recommendation for vancomycin in critically ill patients receiving CVVHF is a loading dose of 15–20 mg/kg followed after 24 h by 250 to 500 mg twice daily with close monitoring of the serum and ultrafiltrate vancomycin concentration.     

Single-dose pharmacokinetics of cefpirome in patients with renal impairment.

The pharmacokinetic parameters of cefpirome (HR 810) were examined in 22 patients with different degrees of renal impairment. HPLC was used to analyze samples of blood and urine for cefpirome; and enzymatic assay of creatinine in serum and urine was used to assess kidney function. Creatinine clearance correlated linearly with both total and renal clearance of cefpirome. The loss of kidney function resulted in a decreased renal clearance, whereas the volume of distribution remained the same. This result led to an increase in the terminal half-life of the drug, from 2 hours in healthy subjects to 14 1/2 hours in patients with uremia. This increase also resulted in a prolonged high serum concentration well above the minimum inhibitory concentration. The following dosages are thus recommended: (1) creatinine clearance greater than 50 ml/min: normal daily dose, (2) creatinine clearance from 20 to 50 ml/min: 50% of normal daily dose, and (3) creatinine clearance less than 20 ml/min: 25% of normal daily dose. An initial loading dose of 1 gm, independent of renal function, is advised. Cefpirome was safe and well tolerated.     

Influence of continuous venovenous hemofiltration and continuous venovenous hemodiafiltration on the disposition of doripenem

The pharmacokinetics, safety, and tolerability of a single 1-hour, 500-mg intravenous infusion of doripenem were assessed in dialysis-dependent subjects with stage 5 chronic kidney disease undergoing continuous renal replacement therapy (CRRT) via 12-hour continuous venovenous hemofiltration (CVVH) (n = 6) or continuous venovenous hemodiafiltration (CVVHDF) (n = 5). Healthy volunteers were also assessed (n = 12). Concentrations of doripenem and the primary metabolite doripenem-M-1 were measured in plasma and ultrafiltrate or ultrafiltrate/dialysate by a validated liquid chromatography-tandem mass spectrometry method. In dialysis-dependent subjects, levels of systemic exposure to doripenem and doripenem-M-1 were approximately 3- and 5-fold greater, respectively, than those in healthy subjects: for doripenem, 98 μg·h/ml for CVVH and 77 μg·h/ml for CVVHDF versus 32 μg·h/ml for healthy subjects, and for doripenem-M-1, 24 μg·h/ml for CVVH and 22 μg·h/ml for CVVHDF versus 4.7 μg·h/ml for healthy subjects. The mean sieving coefficients and saturation coefficients were >0.67 for both doripenem and doripenem-M-1. During CVVH and CVVHDF, respectively, the percentages of administered doripenem dose removed were 38% and 29%, and clearances of doripenem were 22 and 25 ml/min. Both CVVH and CVVHDF efficiently removed doripenem and doripenem-M-1. Despite significant removal of drug by CVVH and CVVHDF, a single 1-hour, 500-mg doripenem infusion produced significantly higher plasma concentrations of doripenem, higher systemic exposure (area under the plasma concentration-time curve from time zero to 12 h after the start of infusion [AUC(0-12)]), and longer half-life (t(1/2)) in subjects receiving CVVH or CVVHDF than in healthy volunteers. The recovery of drug in ultrafiltrate and ultrafiltrate/dialysate and the enhanced rate of reduction of plasma concentrations indicate that CVVH and CVVHDF significantly augmented residual total body clearance of doripenem in subjects receiving CRRT. Doripenem dosage regimens for patients receiving CRRT thus need to be adjusted.     

Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH)

Objective: Kinetics of piperacillin (pip), in combination with the beta-lactamase inhibitor tazobactam (taz) have been studied in volunteers and patients in relatively stable conditions. The fixed drug preparation appeared to have ideal pharmacokinetic properties if renal function was normal or slightly impaired, but no data are available for critically ill patients in anuric renal failure. This study should provide such data. Patients, design: We studied the pharmacokinetics in nine patients with multiple organ failure, including anuric renal failure, treated with continuous veno-venous hemofiltration (CVVH). Patients received a standard schedule of 4 g pip and 0.5 g taz administered over 0.5 h intravenously, 8 hourly. During 2 consecutive days, the serum levels of both compounds were determined, and total clearance (CI_T) was calculated from serum concentrations. Results: All nine patients completed day 1, and 8 completed day 2 of the protocol. On day 1, single-dose kinetics showed considerable spread, but pip/taz serum levels followed the pattern as expected, with a pip / taz concentration ratio of 20 : 1. On day 2, however, taz serum concentrations showed a relative increase as compared to pip, resulting in a change in the serum pip/taz concentration ratio to 10 : 1 on day 2. The CI_T of pip was 2.52 ± 1.38 l/h (t ¹/₂ : 5.9 ± 2.9 h), and CI_T of taz 4.44 ± 2.28 l/h (t ¹/₂ : 8.1 ± 3.7 h). The CI_T and t ¹/₂ of pip and taz correlated highly significantly with clearance by CVVH. Despite a higher CI_T, taz has a longer half-life, because of a higher volume of distribution. Conclusion: In CVVH dependent patients, pip/taz fixed drug preparations can be used initially, but the pip dosage should be increased relative to that of taz (or interval-adjusted) to prevent cumulation of taz, as compared to the active antimicrobial agent pip. Received: 19 February 1997 Accepted: 20 May 1997     

Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia

Introduction

In seriously infected patients with acute renal failure and who require continuous renal replacement therapy, data on continuous infusion of ceftazidime are lacking. Here we analyzed the pharmacokinetics of ceftazidime administered by continuous infusion in critically ill patients during continuous venovenous haemodiafiltration (CVVHDF) in order to identify the optimal dosage in this setting.

Method

Seven critically ill patients were prospectively enrolled in the study. CVVHDF was performed using a 0.6 m² AN69 high-flux membrane and with blood, dialysate and ultrafiltration flow rates of 150 ml/min, 1 l/hour and 1.5 l/hour, respectively. Based on a predicted haemodiafiltration clearance of 32.5 ml/min, all patients received a 2 g loading dose of ceftazidime, followed by a 3 g/day continuous infusion for 72 hours. Serum samples were collected at 0, 3, 15 and 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours; dialysate/ultrafiltrate samples were taken at 2, 8, 12, 24, 36 and 48 hours. Ceftazidime concentrations in serum and dialysate/ultrafiltrate were measured using high-performance liquid chromatography.

Results

The mean (± standard deviation) elimination half-life, volume of distribution, area under the concentration-time curve from time 0 to 72 hours, and total clearance of ceftazidime were 4 ± 1 hours, 19 ± 6 l, 2514 ± 212 mg/h per l, and 62 ± 5 ml/min, respectively. The mean serum ceftazidime steady-state concentration was 33.5 mg/l (range 28.8–36.3 mg/l). CVVHDF effectively removed continuously infused ceftazidime, with a sieving coefficient and haemodiafiltration clearance of 0.81 ± 0.11 and 33.6 ± 4 mg/l, respectively.

Conclusion

We conclude that a dosing regimen of 3 g/day ceftazidime, by continuous infusion, following a 2 g loading dose, results in serum concentrations more than four times the minimum inhibitory concentration for all susceptible pathogens, and we recommend this regimen in critically ill patients undergoing CVVHDF.     

Pharmacokinetics of milrinone in patients with congestive heart failure during continuous venovenous hemofiltration

Objective: To evaluate the pharmocokinetics of intravenous milrinone in patients with severe congestive heart failure during continuous venovenous hemofiltration (CVVH). Design: Prospective study of patients with congestive heart failure admitted to the intensive care unit (ICU). Setting: ICU between September 1997 and August 1999. Patients and methods: Six patients with severe congestive heart failure during CVVH: all patients received a continuous infusion of milrinone of 0.25 μg · kg^{− 1}· min^{− 1}. The hemodynamics and plasma concentration of milrinone were measured before and after the infusion. Pharmacokinetics were analyzed with one-compartment model featuring constant rate infusion. Results: The steady-state concentration (Css) was 845 ± 135 (mean ± SD) ng/ml, and the half-life time (t_1/2) was 20.1 ± 3.3 h. Cardiac index and stroke volume index after the infusion of milrinone increased significantly compared with pre-infusion levels. Other hemodynamic parameters did not change significantly. All patients died within 1 month after the injection of milrinone because of severe forms of arrhythmia, such as ventricular tachycardia and ventricular fibrillation. Conclusions: We found that the mean Css and the mean t_1/2 of milrinone in subjects during CVVH were much higher and longer than those previously reported for subjects with normal renal function. It is therefore essential to adjust the dose or modify the dosing interval of milrinone during renal replacement therapy for patients with severe congestive heart failure. However, further studies are needed to determine the details of pharmacokinetics of milrinone and therapeutic procedures for patients with severe heart failure during CVVH. Received: 1 December 1999 Final revision received: 9 March 2000 Accepted: 11 April 2000     

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.     

Population pharmacokinetics and pharmacodynamics of cefpirome in critically ill patients against Gram-negative bacteria

Objectives To develop a population pharmacokinetics model for cefpirome in ICU patients, to assess pharmacokinetic-pharmacodynamic profiles vs. MIC distribution of likely ICU pathogens, and to assess their expected cumulative fraction of response (CFR). Design and setting Prospective observational study in a multidisciplinary ICU. Measurements and results Twelve patients received 2 g cefpirome intravenously over 12 h. Thirteen blood samples were taken on two occasions. Demographic and creatinine clearance data were collected. Based on the final covariate model obtained using NONMEM, Monte Carlo simulations were undertaken to simulate free-drug concentrations for two administration methods: intermittent bolus administration (IBA) and continuous infusion (CI) with a loading dose of 0.5 g. Concentration-time profiles were evaluated by the probability of achieving free-drug concentrations above the MIC for more than 65% of dosing interval. Using MIC distributions from the EUCAST programme the CFR for each method was evaluated. A three-compartment model with zero-order input best described the concentration-time data. The CFR for Escherichia coli and Klebsiella spp. was greater than 97% in all IBA and CI doses but for Pseudomonas aeruginosa, and Acinetobacter spp. achieved target concentrations of 56% and 46%, respectively. High-dose CI cefpirome (6 g/day) for P. aeruginosa and Acinetobacter spp. was required to achieve CFR of 89%. Conclusion Measured creatinine clearance appears to be a good marker of cefpirome clearance and potentially could be used to individualise cefpirome therapy. When given as IBA or CI for E. coli and Klebsiella spp., cefpirome should be successful. Cefpirome fails to achieve the bactericidal target even when administered at high-doses such as 6 g/day for P. aeruginosa and Acinetobacter spp. Prospective clinical studies are needed to conclusively validate these findings.     

Pharmacokinetics of cefpirome during the posttraumatic systemic inflammatory response syndrome

Objective: To determine the pharmacokinetic parameters of cefpirome, a new so-called fourth-generation cephalosporin, in previously healthy trauma patients with posttraumatic systemic inflammatory response syndrome (SIRS) and to compare them to parameters obtained in matched, healthy volunteers. Design: A prospective study. Setting: 12-bed surgical intensive care unit in a university hospital. Patients: 9 severe [Injury Severity Score, median (range) 29 (16–50)] trauma patients on mechanical ventilation with proven or suspected cefpirome-susceptible nosocomial infection, with no renal or hepatic failure, and healthy volunteers matched for age ( ± 5 years), sex, and body surface area ( ± 10 %) were enrolled. All were men. Interventions: Cefpirome (2 g twice daily) was continuously infused over a 0.5 h period alone or concomitantly with ciprofloxacin (400 mg over 1 h, twice daily). Measurements and main results: Antibiotic concentrations in plasma were measured by high-performance liquid chromatography; their pharmacokinetic parameters were evaluated at 12 time points after the first drug administration using a noncompartmental model. Cefpirome pharmacokinetic parameters for the two groups were similar despite a wider variation for trauma patients. Specifically, the median (range) time during which the cefpirome concentration in plasma remained over 4 mg/l (corresponding to the French lower cutoff determining cefpirome susceptibility) was 9.5 (7– > 12) and 9 (8–12) h for trauma patients and healthy volunteers, respectively. In the group of five patients receiving combined antibiotic therapy, the interindividual variability of pharmacokinetics was wider for ciprofloxacin than for cefpirome. Conclusion: No major pharmacokinetic modification was noted when cefpirome was given to trauma patients with posttraumatic SIRS without significant organ failure, indicating that no dosage adjustment seems required in this population. However, larger studies including determination of antibiotic levels in tissues are warranted to confirm these results. Received: 3 September 1998 Final revision received: 18 January 1999 Accepted: 25 February 1999     

Ibuprofen does not impair renal function in patients undergoing infrarenal aortic surgery with epidural anaesthesia

Objective: To investigate the effect of preoperative ibuprofen administration on renal function during and after infrarenal aortic surgery under thoracolumbar epidural anaesthesia (EPA). Design: A prospective randomised, double-blinded clinical study. Setting: Operation room and intensive care unit in a university hospital. Patients: Twenty-six consecutive patients scheduled for elective infrarenal aortic surgery. Interventions: The patients were prospectively randomised to receive 400 mg ibuprofen intravenously (i. v.) or a placebo aliquot before surgery. Measurements and results: We assessed renal function by calculating creatinine clearance, and fractional sodium excretion before surgery (baseline), 1 h after cross-clamping (intraoperative), 6 h after cross-clamping (postoperative) and 24 h after cross-clamping (on the 1 st postoperative day). At each point in time, we additionally registered haemodynamics and determined the plasma concentration of 6-keto-PGF₁α (stable metabolite of prostacyclin, PGI₂), bicyclic PGE₂ (stable metabolite of PGE₁ E₂), active renin, aldosterone and vasopressin by radioimmunoassays. Throughout the observation period the renal function parameters mostly remained within the normal range without a significant difference between ibuprofen- and placebo-treated patients (creatinine clearance: baseline 41 ± 3 vs 38 ± 6, intraoperative 57 ± 8 vs 64 ± 11, postoperative 64 ± 9 vs 56 ± 9, first postoperative day 43 ± 5 vs 47 ± 6 ml · min · m^{− 2}, means ± SEM). The plasma levels of 6-keto-PGF₁α (68 ± 8 vs 380 ± 71^* ng · l^{− 1}), bicyclic PGE₂ (57 ± 5 vs 88 ± 9^* ng · l^{− 1}) and vasopressin (14 ± 7 vs 45 ± 10^* ng · l^{− 1}, p < 0.0125), however, were significantly higher during the intraoperative period in the placebo-treated patients. Conclusion: The inhibition of endogenous prostaglandin release by ibuprofen does not substantially impair renal function during infrarenal aortic surgery under EPA. Received: 24 June 1997 Accepted: 26 January 1998     

Multiple organ failure (MOF) after severe trauma — A sheep model

Objective: To perform a reproducible long-term (10 days) large animal model of multiple systems organ failure without necessity of a continuous stimulus. Design: Adult female merino sheep submitted to a 5-day stimulation period followed by a 5-day observation period. Day 1: Hemorrhagic shock was combined with a traumatic surgical insult (reamed intramedullary femoral nailing), followed by serial administrations every 12 h for 5 days of a combination of endotoxin and zymosan activated plasma. Organ function was followed for 5 further days. Results: Cardiac index increased significantly during the study (day 1: 491 ± 8 mm Hg; day 10: 427 ± 20, p < 0.05). Liver function was impaired and bilirubin levels increased significantly (day 1: 2.9 ± 0.3 μmol/l; day 10: 7.2 ± 0.9; p < 0.05). Creatinine clearance decreased initially (day 1: 54 ± 7 ml/min), increased to a peak on day 2 (104 ± 27), and then deteriorated again (day 10: 53 ± 18). Conclusion: This new large animal model of trauma-induced MOF is reproducible and may be suitable for the study of new therapeutic approaches to therapy. Received: 15 September 1997 Accepted: 3 March 1998     

Therapeutic drug monitoring of tobramycin: once-daily versus twice-daily dosage schedules

Objective: To evaluate the effect of dosage regimen (once-daily vs. twice-daily) of tobramicyn on steady-state serum concentrations and toxicity. Materials and methods: Patients undergoing treatment with iv tobramycin (4 mg/kg/day) were randomised to two groups. Group OD ( n=22) received a once-daily dose of tobramycin and group TD (n=21) received the same dose divided into two doses daily. Tobramycin serum concentrations (peak and trough) were measured by enzyme multiplied immunoassay. The renal and auditorory functions of the patients were monitored before, during and immediately after treatment. Results: The two groups were comparable with respect to sex, age, body weight and renal function. No statistically significant differences were found in mean daily dose, duration of treatment, or cumulative dose. Trough concentrations were < 2 μg/ml in the two groups (100%). Peak concentrations were > 6 μg/ml in 100% of the OD group and in 67% of the TD group ( P< 0·01). Mean peak concentrations were markedly different: 11·00±2·89 μg/ml in OD vs. 6·53±1·45 μg/ml in TD ( P< 0·01). The pharmacokinetics parameters were: K_e, (0·15±0·03/h in OD vs. 0·24±0·06/h in TD), t_1/2, (4·95±1·41 h in OD vs. 3·07±0·71 h in TD), V_d (0·35±0·11 l/kg in OD vs. 0·33±0·09 l/kg in TD), Cl (0·86±0·29 ml/min/kg in OD vs. 1·28±0·33 ml/min/kg in TD). Increased serum creatinine was observed in 73% of patients in OD versus 57% of patients in TD, without evidence of nephrotoxicity. In TD group, three patients developed decreased auditory function, of which one presented with an auditory loss of –30 dB, whereas in the OD group only one patient presented decreased auditory function. Conclusion: This small study suggests that a once-daily dosing regimen of tobramycin is at least as effective as and is no more and possibly less toxic than the twice-daily regimen. Using a single-dose therapy, peak concentration determination is not necessary, only trough samples should be monitored to ensure levels below 2 μg/ml.     

Oxygen supply dependency can characterize septic shock

Objective: To demonstrate that oxygen consumption (VO₂) can be dependent on oxygen delivery (DO₂) during hemodynamic instability and independent of DO₂ following stabilization. Design: We retrospectively reviewed hemodynamic and blood gas data collected from ten patients in whom DO₂ was acutely altered during an episode of septic shock (phase A) and after recovery from this episode (phase B). Setting: General intensive care unit of a university hospital. Patients: 10 critically ill adult patients (aged 55 ± 19 years). Interventions: DO₂ was altered by fluid challenge, administration of vasoactive agents, or application of positive end-expiratory pressure. Results: In phase A, changes in VO₂ (121 ± 32 vs 165 ± 36 ml/min · m²; p < 0.001) paralleled changes in DO₂ (415 ± 153 vs 607 ± 217 ml/min · m²; p < 0.001), but oxygen extraction (O₂ER) remained stable (31.9 ± 11.2 vs. 30.2 ± 8.9 %; NS). In phase B, changes in DO₂ (412 ± 118 vs 526 ± 152 ml/min · m²; p < 0.001) were associated with opposite changes in O₂ER (36.1 ± 4.2 vs 28.9 ± 4.9 %; p < 0.001), and VO₂ was unchanged (147 ± 35 vs 149 ± 33 ml/min · m²; NS). The mean VO₂/DO₂ slope was greater in phase A than in phase B (0.26 ± 0.09 vs. 0.08 ± 0.08; p < 0.004). Blood lactate levels were higher in phase A than in phase B (3.3 ± 1.8 vs 1.6 ± 0.6 mEq/l; p < 0.05). Conclusions: Oxygen supply independency and dependency can be found at different times in the same critically ill patient. Our findings are consistent with the concept that VO₂/DO₂ dependency is a marker of septic shock. Interventions to increase DO₂ are probably justified when this phenomenon is present. Received: 17 February 1997 Accepted: 6 November 1997     

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   

Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis

Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m(2) acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m(2) polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m(2) polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CI(diffusion)) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17%+/-7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P<0.0001) were observed between CI(diffusion) of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.