Ceftaroline and Avibactam Removal by Continuous Renal Replacement Therapies: An in vitro Study.

INTRODUCTION: Continuous renal replacement therapies (CRRTs) are frequently used in critically ill patients; however, there are scarce in vitro and in vivo studies showing the extracorporeal elimination of ceftaroline and avibactam. The aim of this study was to assess, through an in vitro model, the extracorporeal elimination of ceftaroline and avibactam by continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodiafiltration (CVVHDF), and continuous veno-venous hemodialysis (CVVHD), using a polysulfone hemofilter. METHODS: Simulated in vitro experiments were performed using a multiFiltrate machine with a 1.4 m2 Ultraflux® AV600S polysulfone hemofilter. Isofundin® without or with bovine serum albumin was circulated as vehicle for ceftaroline or avibactam. Pre-filter, post-filter, and effluent samples were taken over a period of 60 min, and they were immediately stored at 4°C until processed in the same day. The quantification of ceftaroline and avibactam in the samples was performed by high-performance liquid chromatography with ultraviolet detection. Protein binding, extraction coefficient (EC), and extracorporeal clearance (CLCRRT) were calculated. RESULTS: The elimination of both ceftaroline and avibactam during the three extracorporeal modalities followed first-order pharmacokinetics. Regardless of the CRRT technique, EC values for both molecules were around 1, similar to the unbound fraction of avibactam (0.96) and higher than the unbound fraction of ceftaroline (0.79). CLCRRT of ceftaroline ranged from 15.63 to 17.66 mL/min when CVVH and CVVHD were used with a flow rate of 1,000 mL/h, and from 29.25 to 32.95 mL/min for the CVVHDF modality with a flow rate of 2,000 mL/h. For avibactam, CLCRRT ranged from 15.07 to 18.82 mL/min for CVVH and CVVHD, and from 33.74 to 34.13 mL/min for CVVHDF. DISCUSSION: Avibactam and ceftaroline are extensively removed through the polysulfone membrane, and a dose adjustment may be recommended for patients under CRRT to ensure pharmacodynamic target achievement.

Optimization of levetiracetam dosing regimen in critically ill patients with augmented renal clearance: a Monte Carlo simulation study.

BACKGROUND: Levetiracetam pharmacokinetics is extensively altered in critically ill patients with augmented renal clearance (ARC). Consequently, the dosage regimens commonly used in clinical practice may not be sufficient to achieve target plasma concentrations. The aim of this study is to propose alternative dosage regimens able to achieve target concentrations in this population. Furthermore, the feasibility of the proposed dosing regimens will be discussed from a clinical point of view. METHODS: Different dosage regimens for levetiracetam were evaluated in critically ill patients with ARC. Monte Carlo simulations were conducted with extended or continuous infusions and/or high drug doses using a previously developed population pharmacokinetic model. To assess the clinical feasibility of the proposed dosages, we carried out a literature search to evaluate the information on toxicity and efficacy of continuous administration or high doses, as well as the post-dilution stability of levetiracetam. RESULTS: According to the simulations, target concentrations in patients with CrCl of 160 or 200 mL/min can be achieved with the 3000 mg daily dose by prolonging the infusion time of levetiracetam. For patients with CrCl of 240 mL/min, it would be necessary to administer doses higher than the maximum recommended. Available evidence suggests that levetiracetam administration in continuous infusion or at higher doses than those approved seems to be safe. It would be desirable to re-examinate the current recommendations about drug stability and to achieve a consensus in this issue. CONCLUSIONS: Conventional dosage regimens of levetiracetam (500-1500 mg twice daily in a short infusion) do not allow obtaining drug plasma concentrations among the defined target in critically ill patients with ARC. Therefore, new dosing guidelines with specific recommendations for patients in this subpopulation are needed. This study proposes new dosages for levetiracetam, including extended (4 or 6 h) infusions, continuous infusions or the administration of doses higher than the recommended in the summary of product characteristics (> 3000 mg). These new dosage recommendations take into account biopharmaceutical and pharmacokinetic aspects and meet feasibility criteria, which allow them to be transferred to the clinical environment with safety and efficacy. Nevertheless, further clinical studies are needed to confirm these results.

Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function.

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

Quantification of Ceftaroline in Human Plasma Using High-Performance Liquid Chromatography with Ultraviolet Detection: Application to Pharmacokinetic Studies.

This study was conducted to develop a rapid, simple and reproducible method for the quantification of ceftaroline in plasma samples by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Sample processing consisted of methanol precipitation and then, after centrifugation, the supernatant was injected into the HPLC system, working in isocratic mode. Ceftaroline was detected at 238 nm at a short acquisition time (less than 5 min). The calibration curve was linear over the concentration range from 0.25 to 40 µg/mL, and the method appeared to be selective, precise and accurate. Ceftaroline in plasma samples was stable at -80 °C for at least 3 months. The method was successfully applied to characterize the pharmacokinetic profile of ceftaroline in two critically ill patients and to evaluate whether the pharmacokinetic/pharmacodynamic (PK/PD) target was reached or not with the dose regimen administered.

SARS-CoV-2 in Spanish Intensive Care Units: Early experience with 15-day survival in Vitoria.

PURPOSE: Community transmission of SARS-CoV-2 was detected in Spain in February 2020, with 216% intensive care unit (ICU) capacity expanded in Vitoria by March 18th, 2020. METHODS: We identified patients from the two public hospitals in Vitoria who were admitted to ICU with confirmed infection by SARS-CoV-2. Data reported here were available in April 6th, 2020. Mortality was assessed in those who completed 15-days of ICU stay. RESULTS: We identified 48 patients (27 males) with confirmed SARS-CoV-2. Median [interquartile range (IQR)] age of patients was 63 [51-75] years. Symptoms began a median of 7 [5-12] days before ICU admission. The most common comorbidities identified were obesity (48%), arterial hypertension (44%) and chronic lung disease (37%). All patients were admitted by hypoxemic respiratory failure and none received non-invasive mechanical ventilation. Forty-five (94%) underwent intubation, 3 (6%) high flow nasal therapy (HFNT), 1 (2%) extracorporeal membrane oxygenation (ECMO) and 22 (46%) required prone position. After 15 days, 14/45 (31%) intubated patients died (13% within one week), 10/45 (22%) were extubated, and 21/45 (47%) underwent mechanical ventilation. Six patients had documented super-infection. Procalcitonin plasma above 0.5µg/L was associated with 16% vs. 19% (p=0.78) risk of death after 7 days. CONCLUSION: This early experience with SARS-CoV-2 in Spain suggests that a strategy of right oxygenation avoiding non-invasive mechanical ventilation was life-saving. Seven-day mortality in SARS-CoV-2 requiring intubation was lower than 15%, with 80% of patients still requiring mechanical ventilation. After 15 days of ICU admission, half of patients remained intubated, whereas one third died.

Impact of augmented renal clearance on the pharmacokinetics of linezolid: Advantages of continuous infusion from a pharmacokinetic/pharmacodynamic perspective.

OBJECTIVES: The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. METHODS: Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h). RESULTS: In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations ≥2 mg/l in 70% of the ARC patients. MCS revealed that concentrations ≥2 mg/l would be reached in >90% of patients receiving 75 mg/h. CONCLUSIONS: ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations ≥2 mg/ml.

Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation.

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

ACUsmart Continuous Renal Replacement Therapy Platform: Multicenter Pilot Study for Technical and Clinical Assessment (A.M.P. Study).

BACKGROUND: ACUsmart (Medica S.P.A., Italy) is a new-generation, continuous renal replacement therapy (CRRT) machine for critically ill patients with acute kidney injury. We designed a multicenter international pilot study to provide a description of outlines of the ACUsmart system, evaluation aspects of functionality, usability, and feasibility, discriminating reasons of possible treatment's withdrawals or discontinuations and highlighting strong and weak points of the machine. METHODS: Data of 23 CRRT (and 11 plasma exchange) treatments were collected from 4 intensive care units. Parameters such as treatment duration, downtime, delivered dose, and number and type of alarms were recorded. The general perception of the machine was quantified through the administration of a survey to each component of the evaluating staff. RESULTS: A total treatment time of 447 h was carried with ACUsmart. Eleven continuous veno-venous hemofiltration, 4 continuous veno-venous hemodialysis , and 8 continuous veno-venous hemodiafiltration were performed. The average percentage of net treatment duration with respect to total treatment duration was 92.37%. The mean prescribed dose and delivered dose were 26.33 and 24.10 mL/kg/h, respectively. In general, the machine was rated by users involved as practical and easy to use, although few components need to be slightly improved. CONCLUSION: ACUsmart is a new multifunctional machine that meets most of the features required in a fourth-generation CRRT equipment.

Pharmacokinetics of linezolid in critically ill patients on continuous renal replacement therapy: Influence of residual renal function on PK/PD target attainment.

PURPOSE: To assess the pharmacokinetics of linezolid in septic patients undergoing continuous renal replacement therapy (CRRT) and investigate whether residual renal function affects the probability of attaining the pharmacokinetic/pharmacodynamic (PK/PD) target. MATERIAL AND METHODS: Prospective study conducted in three Spanish hospitals. Linezolid concentrations were measured in plasma and effluent samples and pharmacokinetic parameters were calculated. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) were calculated considering AUC24/MIC>80 and %T>MIC > 85% as the PK/PD indexes related to efficacy. RESULTS: In anuric patients (CrCl<10 mL/min), the contribution of extracorporeal Cl to total Cl was higher (47% vs 16%) than in patients with residual renal function (CrCl≥10 mL/min). For an MIC of 2 mg/L, AUC24/MIC>80 was achieved in >85% of the anuric patients, but in <15% of the patients with residual renal function. CONCLUSIONS: The standard dose (600 mg q12h) ensures a moderately high probability of treatment success in anuric patients when the infection is due to microorganisms with MIC≤2 mg/L; although higher doses increase the probability of treatment success, the safety is compromised. In patients with residual renal function, the standard dose is insufficient, but 900 mg q8h provide higher probability of treatment success without compromising the safety.

Mechanical thrombectomy in patients with tumour-related ischaemic stroke.

Ischaemic stroke is a common cause of death and incapacity and is related in most cases to vascular disease. Intracranial vessel occlusion due to tumour emboli is a rare entity and adequate treatment for this condition is not defined. The use of mechanical thrombectomy devices is considered the treatment of choice for major intracranial vessel occlusion; however, no recommendation can be made in the case of tumour thrombembolia. This report describes two cases who presented with a middle cerebral artery occlusion due to tumour emboli and that were treated using the Solitaire thrombectomy device.

Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis.

OBJECTIVES: To evaluate the pharmacokinetics of piperacillin/tazobactam in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to assess the success of the therapy against susceptible bacteria. PATIENTS AND METHODS: Sixteen patients undergoing CRRT with different degrees of renal function were included in the study. Blood and ultrafiltrate samples were drawn after administration of piperacillin/tazobactam (4/0.5 g) every 4, 6 or 8 h. The data were analysed by a population approach using NONMEM 7.2. The probability of target attainment (PTA) of maintaining free piperacillin levels above the MIC during the entire dosing interval was estimated by simulation of intermittent and continuous infusions. RESULTS: The pharmacokinetics of piperacillin and tazobactam were best described by two-compartment models where the elimination of both drugs was conditioned by renal [dependent on creatinine clearance (CLCR)], non-renal and extracorporeal clearances. A 20 min infusion of piperacillin/tazobactam administered every 6 h provided high PTAs against MICs ≤ 32 mg/L in patients with severe renal failure. In patients with normal or moderate renal function PTAs ≥ 90% were only obtained up to MICs ≤ 8 mg/L with short infusions. However, simulating continuous infusion, higher probabilities of success were obtained against MICs of 32 and 16 mg/L when CLCR was 50 and 100 mL/min, respectively. CONCLUSIONS: Population pharmacokinetic models have been developed and validated for piperacillin and tazobactam. Based on the pharmacokinetic/pharmacodynamic analysis, dosing recommendations are given considering the residual renal function of the patient and the MIC for the isolated bacteria.

Direct hemoperfusion with polymyxin B-immobilized cartridge in severe sepsis due to intestinal perforation: hemodynamic findings and clinical considerations in anticoagulation therapy.

BACKGROUND: High levels of endotoxin have been reported as a risk factor for mortality in critical patients. Toraymyxin® is a column designed to remove circulating blood endotoxin by direct hemoperfusion widely used in Japan. OBJECTIVES: To evaluate the effect of direct hemoperfusion with Toraymyxin® (DHP-PMX) as an adjuvant treatment in patients with severe sepsis due to intestinal perforation in terms of hemodynamic function and coagulation abnormalities. METHODS: Prospective cohort study with a historical control group. Cohort 1: prospective cohort undergoing two sessions of DHP-PMX (n=14). Cohort 2: retrospective historical cohort (n=7). The anticoagulation regime was used according to the protocol of each centre and to the special conditions of each patient. RESULTS: Mean norepinephrine dose was significantly reduced (0.9 ± 0.5 µg/kg/min pre-first DHP-PMX vs 0.3 ± 0.4 µg/kg/min post-second DHP-PMX treatment, p<0.05). Central venous pressure (CVP) and stroke volume variation (SVV) remained without significant changes during the study, as well as cardiac index (CI) in patients with initial CI ≥ 2.5 L/min/m2. CI significantly increased in patients with initial CI<2.5 L/min/m2 (2.1 ± 0.4 pre-first DHP-PMX vs 3.4 ± 0.4 pre-second DHP-PMX session, p=0.01). Mean platelet count pre-first and post-second DHP-PMX decreased significantly (213.9 x 10(3) ± 138.5 x 10(3) platelets/mm3 vs 91.0 x 10(3) ± 53.5 x 10(3) platelets/mm3, p=0.03), without significant changes during each DHP-PMX treatment. Patients did not experience bleeding nor complications derived from DHP-PMX treatments. Survival rates at 28 and 56 days did not differ significantly between cohort 1 and 2 (21.4% vs 42.9%; 42.9% vs 57.1%; respectively). CONCLUSIONS: Performing two sessions of DHP-PMX treatment in a cohort of patients with abdominal sepsis is a feasible adjuvant therapeutic approach, safe in terms of coagulation abnormalities, can be done with different anticoagulation protocols, improves hemodynamic status and may impact on survival.

Direct hemoperfusion with polymyxin B-immobilized cartridge in severe sepsis due to intestinal perforation: hemodynamic findings and clinical considerations in anticoagulation therapy

Antecedentes. Los niveles altos de endotoxina se han identificado como un factor de riesgo para la mortalidad en pacientes críticos. Toraymyxin® es un cartucho diseñado para eliminar la endotoxina de la sangre circulante por medio de hemoperfusión directa ampliamente utilizado en Japón. Objetivos. Evaluar el efecto de la hemoperfusión directa con Toraymyxin® (HPD-PMX) como tratamiento adyuvante en pacientes con sepsis grave secundaria a perforación intestinal en términos de función hemodinámica y anormalidades de la coagulación. Métodos. Estudio de cohortes prospectivo con un grupo control histórico. Cohorte 1 (n=14): tratada de forma prospectiva con dos sesiones de DHP-PMX. Cohorte 2 (n=7): grupo histórico retrospectivo. El régimen de anticoagulación utilizado fue dejado a libertad de cada centro según práctica local y condiciones especiales de cada paciente. Resultados. La dosis media de noradrenalina se redujo significativamente (0,9 ± 0,5 μg/kg/min antes de la primera hemoperfusión con DHP-PMX vs 0,3 ± 0,4 μg/kg/min tras la segunda, p<0,05). La presión venosa central (PVC) y la variación del volumen sistólico (VVS) permanecieron sin cambios significativos durante el tratamiento, así como el índice cardiaco (IC) en los pacientes con un IC inicial ≥ 2,5 L/min/m2. El IC aumentó significativamente en los pacientes con IC inicial ≤ 2,5 L/min/ m2 (2,1 ± 0,4 antes de la primera hemoperfusión vs 3,4 ± 0,4 tras la segunda sesión, p=0,01). El recuento plaquetario medio descendió significativamente entre antes de la primera sesión y después de la segunda (213,9x103 ± 138,5x103 plaquetas/ mm3 vs 91,0x103 ± 53,5x103 plaquetas/mm3, p=0,03), sin cambios significativos durante cada tratamiento. Los pacientes no experimentaron hemorragias o complicaciones derivadas de los tratamientos con HPD-PMX. La supervivencia al día 28 y día 56 no difirió significativamente entre la cohorte 1 y 2 (21,4% vs. 42,9%; 42,9% vs. 57,1%; respectivamente)...(AU)

Background. High levels of endotoxin have been reported as a risk factor for mortality in critical patients. Toraymyxin® is a column designed to remove circulating blood endotoxin by direct hemoperfusion widely used in Japan. Objectives. To evaluate the effect of direct hemoperfusion with Toraymyxin® (DHP-PMX) as an adjuvant treatment in patients with severe sepsis due to intestinal perforation in terms of hemodynamic function and coagulation abnormalities. Methods. Prospective cohort study with a historical control group. Cohort 1: prospective cohort undergoing two sessions of DHP-PMX (n=14). Cohort 2: retrospective historical cohort (n=7). The anticoagulation regime was used according to the protocol of each centre and to the special conditions of each patient. Results. Mean norepinephrine dose was significantly reduced (0.9 ± 0.5 μg/kg/min pre-first DHP-PMX vs 0.3 ± 0.4 μg/kg/min post-second DHP-PMX treatment, p<0.05). Central venous pressure (CVP) and stroke volume variation (SVV) remained without significant changes during the study, as well as cardiac index (CI) in patients with initial CI≥2.5 L/min/m2. CI significantly increased in patients with initial CI<2.5 L/min/m2 (2.1±0.4 pre-first DHP-PMX vs 3.4 ± 0.4 pre-second DHP-PMX session, p=0.01). Mean platelet count pre-first and post-second DHP-PMX decreased significantly (213.9x103 ± 138.5x103 platelets/mm3 vs 91.0x103 ± 53.5x103 platelets/mm3, p=0.03), without significant changes during each DHP-PMX treatment. Patients did not experience bleeding nor complications derived from DHP-PMX treatments. Survival rates at 28 and 56 days did not differ significantly between cohort 1 and 2 (21.4% vs 42.9%; 42.9% vs 57.1%; respectively)...(AU)

Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy.

BACKGROUND AND OBJECTIVE: Meropenem is a carbapenem antibacterial frequently prescribed for the treatment of severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT. PATIENTS AND METHODS: A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CL(CR)), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied. RESULTS: The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CL(CR) was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CL(CR) on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 x CL(CR) for septic patients and CL = 6.63 + 0.72 x CL(CR) for polytraumatized patients). The volume of distribution of the central compartment (V(1)) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V(1) were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of > or =4 mg/L are isolated. Infections caused by pathogens with an MIC of > or =8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary. CONCLUSION: A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CL(CR) and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT.

In vitro AN69 and polysulphone membrane permeability to ceftazidime and in vivo pharmacokinetics during continuous renal replacement therapies.

BACKGROUND: Ceftazidime is a third-generation cephalosporin almost entirely eliminated by glomerular filtration and dose reductions are essential in patients with renal impairment. The physicochemical and pharmacokinetic properties of ceftazidime make it susceptible to be eliminated by continuous renal replacement therapies (CRRT), but there is little clinical information to guide the correct administration in patients undergoing these techniques. METHODS: In vitro procedures were carried out in three different fluids, using AN69 or polysulphone membranes. Four patients entered the in vivo study. Two patients received 1,000 mg every 6 h and the other two 2,000 mg every 6 h. Concentrations of ceftazidime were measured by high-performance liquid chromatography. RESULTS: No differences were detected in thesieving coefficients (Sc) or saturation coefficients (Sa)between membranes during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHD). Sc-Sa values were close to 1 when Ringer's lactate was used as ceftazidime vehicle, but were lower in plasma samples (p < 0.05). In patients, the Sc-Sa was 0.93 +/- 0.06 and correlated well with the unbound fraction (0.86 +/- 0.08). The contribution of CRRT to ceftazidime clearance was higher in anuric patients than in nonanuric patients. CONCLUSIONS: No differences were shown in vitro in the Sc obtained with both membranes during CVVH or the Sa obtained during CVVHD. The contribution of clearance by CRRT to total clearance is clearly dependent on the renal function. The administration of ceftazidime every 6 h could be associated with unnecessarily high trough levels which increase the risk of drug nephrotoxicity. Nonanuric patients undergoing CRRT need higher ceftazidime doses to reach adequate plasma concentrations against pathogens isolated in the critically ill.

In vitro and in vivo evaluation of enoxaparin removal by continuous renal replacement therapies with acrylonitrile and polysulfone membranes.

BACKGROUND: Enoxaparin is a low-molecular-weight heparin for which the degree of elimination through hemofilters during continuous renal replacement therapy (CRRT) is not well established. OBJECTIVE: The elimination of enoxaparin by CRRT, using acrylonitrile (AN69) or polysulfone (PS) membranes, was studied in vitro and among critically ill patients. METHODS: In vitro procedures were carried out using Ringer's lactate, bovine albumin-containing Ringer's lactate, or fresh human plasma as enoxaparin vehicle, using AN69 or PS membranes, and following continuous veno-venous hemofiltration (CVVH) or continuous veno-venous hemodialysis (CVVHD). Prefilter and ultrafiltrate samples were collected over 60 minutes. All procedures were carried out in triplicate. Patients undergoing CRRT entered the in vivo study. Enoxaparin was administered subcutaneously once daily. The sieving coefficient (Sc) and saturation coefficient (Sa) were calculated as the relation between anti-factor Xa activity in simultaneously collected dialysate/ultrafiltrate samples and plasma samples. RESULTS: Mean Sc (for CVVH) or Sa (for CVVHD) values in the in vitro procedures ranged from 0.16 to 0.57. Sc values during CVVH were significantly higher than Sa values during CVVHD in the Ringer's lactate procedures for both membranes (AN69 membrane, P = 0.014; PS membrane, P < 0.001) and in the plasma procedures with the PS membrane (P < 0.001). Six male and 2 female patients (all white) participated in the in vivo study. Their mean body weight ranged from 55 to 80 kg, and their age ranged from 71 to 82 years. In patients, Sc or Sa achieved values between 0.26 and 0.67. No significant differences were found in vivo in the permeability of the 2 membranes to enoxaparin. CONCLUSIONS: In these studies, the Sc and Sa values suggested that enoxaparin passed through AN69 and PS membranes during CRRT. Further pharmacokinetic and clinical studies are needed to determine whether a dose adjustment for enoxaparin is needed for patients undergoing CRRT.

Meropenem and continuous renal replacement therapy: in vitro permeability of 2 continuous renal replacement therapy membranes and influence of patient renal function on the pharmacokinetics in critically ill patients.

The pharmacokinetics of meropenem were characterized in 20 patients with different degrees of renal function who underwent continuous renal replacement therapy. Previously, no differences were detected in vitro in the removal of meropenem by continuous venovenous hemofiltration or continuous venovenous hemodialysis or when AN69 or polysulfone membranes were compared. In patients, no significant differences in the sieving coefficient or the saturation coefficient with the renal function were found, and the mean sieving coefficient/saturation coefficient value (0.80 +/- 0.12) was similar to the unbound fraction (0.79 +/- 0.08). An increase in total clearance and a decrease in elimination half-life were observed to the extent that the patient's creatinine clearance was higher. Likewise, the contribution of continuous renal replacement therapy to total clearance diminished in patients with less renal impairment. The results suggest that the renal function of the patient may influence meropenem pharmacokinetics during continuous renal replacement therapy. The lower trough plasma levels observed in nonrenal patients would not lead to adequate time during which serum drug concentrations are above the minimum inhibitory concentration values in many infections.

Study protocol: the DOse REsponse Multicentre International collaborative initiative (DO-RE-MI).

INTRODUCTION: Current practices for renal replacement therapy in intensive care units (ICUs) remain poorly defined. The DOse REsponse Multicentre International collaborative initiative (DO-RE-MI) will address the issue of how the different modes of renal replacement therapy are currently chosen and performed. Here, we describe the study protocol, which was approved by the Scientific and Steering Committees. METHODS: DO-RE-MI is an observational, multicentre study conducted in ICUs. The primary end-point will be the delivered dose of dialysis, which will be compared with ICU mortality, 28-day mortality, hospital mortality, ICU length of stay and number of days of mechanical ventilation. The secondary end-point will be the haemodynamic response to renal replacement therapy, expressed as percentage reduction in noradrenaline (norepinephrine) requirement. Based on the the sample analysis calculation, at least 162 patients must be recruited. Anonymized patient data will be entered online in electronic case report forms and uploaded to an internet website. Each participating centre will have 2 months to become acquainted with the electronic case report forms. After this period official recruitment will begin. Patient data belong to the respective centre, which may use the database for its own needs. However, all centres have agreed to participate in a joint effort to achieve the sample size needed for statistical analysis. CONCLUSION: The study will hopefully help to collect useful information on the current practice of renal replacement therapy in ICUs. It will also provide a centre-based collection of data that will be useful for monitoring all aspects of extracorporeal support, such as incidence, frequency, and duration.

Cefepime and continuous renal replacement therapy (CRRT): in vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients.

BACKGROUND: Cefepime is a fourth-generation cephalosporin with a broad spectrum of antimicrobial activity against gram-positive and gram-negative micro-organisms. It is a useful option for treating infections in critically ill patients in intensive care due to its high degree of activity and its tolerability. OBJECTIVE: The aim of this study was to characterize in vitro the permeability to cefepime of 2 membranes frequently used in continuous renal replacement therapies (CRRTs). An in vivo study was also carried out to determine the pharmacokinetics of cefepime in critically ill patients undergoing CRRT. METHODS: In vitro procedures were conducted in 3 different fluids using polyacrylonitrile (AN69) or polysulfone (PS) membranes. Continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) were simulated. Four male patients undergoing CVVH or continuous venovenous hemodiafiltration, who received 2000 mg of cefepime intravenously every 8 hours, entered the in vivo study. Prefilter and ultrafiltrate samples were collected, and concentrations of cefepime were measured using high-performance liquid chromatography. The sieving coefficient (Sc), defined as the fraction of drug eliminated across the membrane, and the saturation coefficient (Sa), defined as the fraction of drug diffused through the membrane to the dialysate fluid, were analyzed. Pharmacokinetic parameters were determined according to a noncompartmental analysis. RESULTS: The patients ranged in age from 18 to 75 years and weighed from 65 to 80 kg. By analyzing Sc and Sa values in the in vitro procedures, no differences were detected in the permeability of AN69 or PS membranes to cefepime in CVVH or CVVHD. Sc/Sa values were between 0.93 and 1.03 in Ringer's lactate and in bovine albumin-containing Ringer's lactate samples, but Sc/Sa values were lower in plasma samples (0.82-0.95). In the in vivo portion of the study, the patients' mean (SD) Sc/Sa value was 0.76 (0.21) and correlated well with the fraction unbound to proteins (0.79 [0.09]). Clearance by CRRT (mean [SD]) was 29.0 (16.8)% of the total clearance. Serum elimination t(1/2) was 4.6 (0.9) hours, and the volume of distribution at steady state was 0.6 (0.3) L/kg (mean [SD] values). CONCLUSIONS: Cefepime was significantly removed by CRRT. No significant differences were found in the Sc or Sa of cefepime between AN69 and PS membranes used in the CVVH or CVVHD procedures. The clearance of cefepime by CRRT must be considered when dosing critically ill patients.