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.

Plasmapheresis in the Treatment of Refractory Myoclonic Status. A Case Report.

A case of myoclonic status treated with plasmapheresis in a patient of 63 years of age who was admitted to a Spanish intensive care unit is reported. The patient showed clinical and radiological evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; molecular tests did not verify this.

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.

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.

Aplicación de la nueva definición Sepsis-3 en una cohorte de pacientes con sepsis grave y shock séptico ingresados en unidad de cuidados intensivos desde el Servicio de Urgencias / Application of the new Sepsis-3 definition in a cohort of patients with severe sepsis and septic shock admitted to Intensive Care Unit from the Emergency Department

Antecedentes y objetivo: Tras la publicación de la nueva definición de sepsis y shock séptico, nuestro objetivo es analizar la evolución de los pacientes que ingresan en UCI por enfermedad infecciosa utilizando la definición clásica y los nuevos criterios. Material y métodos: Subanálisis de un estudio observacional y prospectivo. Incluye a 98 pacientes ingresados en UCI por enfermedad infecciosa desde Urgencias durante 18 meses. Se estudió la evolución clínica en UCI y la mortalidad hospitalaria. Resultados: El 78% de los pacientes tuvieron shock séptico con la definición Sepsis-2 y el 52% con los criterios Sepsis-3. La mortalidad hospitalaria fue del 29 y del 41%, respectivamente. El RR de mortalidad hospitalaria de los pacientes con shock séptico fue 10,3 (IC 95%: 2,8-37,5) respecto a los pacientes sin shock. La probabilidad de supervivencia a los 30 días de los pacientes con sepsis y shock séptico fue del 78 y 68%, respectivamente (long Rank < 0,001). Conclusiones: En nuestra experiencia, la incorporación de la puntuación SOFA y el lactato a la nueva definición puede mejorar la valoración del riesgo de muerte hospitalaria

Background and objectives: After the publication of the new definition for sepsis and septic shock, our objective is to analyse the evolution of patients admitted to ICU with an infection process using the previous and new recommendations. Materials and methods: This is a sub-analysis of a previous observational prospective study. We included 98 patients admitted to ICU from the emergency department due to infection during an 18-month period. We studied the clinical evolution during ICU admission and hospital mortality. Results: According to Sepsis-2 definition, 78% percent had septic shock and using Sepsis-3 criteria, 52%; hospital mortality was 29 and 41%, respectively. The RR of hospital mortality of septic shock was 10.3 (95% CI: 2.8-37.5) compared to patients without shock. The 30-day probability survival of patients with sepsis and septic shock were 78% and 68%, respectively (long rank < 0.001). Conclusions: In our experience, the incorporation of the SOFA score and lactate levels to the new definition could help improve the evaluation of risk of hospital death

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.

Application of the new Sepsis-3 definition in a cohort of patients with severe sepsis and septic shock admitted to Intensive Care Unit from the Emergency Department. / Aplicación de la nueva definición Sepsis-3 en una cohorte de pacientes con sepsis grave y shock séptico ingresados en unidad de cuidados intensivos desde el Servicio de Urgencias.

BACKGROUND AND OBJECTIVES: After the publication of the new definition for sepsis and septic shock, our objective is to analyse the evolution of patients admitted to ICU with an infection process using the previous and new recommendations. MATERIALS AND METHODS: This is a sub-analysis of a previous observational prospective study. We included 98 patients admitted to ICU from the emergency department due to infection during an 18-month period. We studied the clinical evolution during ICU admission and hospital mortality. RESULTS: According to Sepsis-2 definition, 78% percent had septic shock and using Sepsis-3 criteria, 52%; hospital mortality was 29 and 41%, respectively. The RR of hospital mortality of septic shock was 10.3 (95% CI: 2.8-37.5) compared to patients without shock. The 30-day probability survival of patients with sepsis and septic shock were 78% and 68%, respectively (long rank < 0.001). CONCLUSIONS: In our experience, the incorporation of the SOFA score and lactate levels to the new definition could help improve the evaluation of risk of hospital death.

Pronóstico a corto y largo plazo de los pacientes críticos ingresados en la Unidad de Cuidados Intensivos desde el Servicio de Urgencias de un hospital terciario / Short- and long-term prognosis of critically-ill patients referred to the ICU from the Emergency Department of a tertiary hospital

Antecedentes y objetivo. Un origen frecuente de los pacientes que ingresan en la UCI es el Servicio de Urgencias. Es necesario analizar el pronóstico a corto plazo de estos pacientes, pero también su evolución tras el alta hospitalaria, puesto que es una preocupación importante de los enfermos. Nuestro objetivo es describir las características epidemiológicas de los pacientes que ingresan en la UCI desde Urgencias y analizar su evolución. Pacientes y método. Estudio de cohortes observacional y prospectivo. Incluye 269 pacientes ingresados consecutivamente en la UCI desde Urgencias durante 18 meses. Los factores asociados a la mortalidad hospitalaria se presentan en odds ratio (OR) y a la mortalidad a largo plazo como hazard ratio (HR). El nivel de significación aceptado fue del 5%. La supervivencia global se analizó mediante curvas de Kaplan-Meier. Resultados. La mortalidad hospitalaria fue del 15%, las complicaciones desarrolladas en la UCI fueron las variables con mayor impacto en la misma: insuficiencia renal aguda (OR 22,7) y distrés respiratorio (OR 51,2). Tras el alta hospitalaria, la mortalidad acumulada a los 12, 24 y 36 meses fue del 6, 11 y 15%, respectivamente. El grado de dependencia funcional (HR 3,7), el cáncer (HR 3,4) y las arritmias (HR 2,4) fueron los factores relacionados con la mortalidad a largo plazo. Conclusiones. El pronóstico a corto plazo de los pacientes que ingresan en la UCI se relaciona con su edad y comorbilidad, pero sobre todo con las características de la enfermedad aguda. Sin embargo, la evolución a largo plazo está más asociada a las características del paciente (AU)

Background and objective. A frequent source of critically-ill patients admitted to the ICU is the Emergency Department. It is essential to analyse the short-term prognosis of these patients, but also their evolution after their discharge from the hospital, since this is one of the major concerns of these patients. The aim of this study is to describe the epidemiological characteristics of patients admitted to the ICU from the Emergency Department and to analyse their outcome. Patients and method. This consisted of an observational prospective cohorts study which included 269 Emergency Department patients consecutively admitted to the ICU over an 18-month period. Factors associated with hospital mortality were presented as an odds ratio (OR) and factors associated with long-term mortality were presented as a hazard ratio (HR). A P-value lower than .05 was accepted as significant. The overall survival was analysed on the basis of the Kaplan-Meier curves. Results. Hospital mortality was 15%, ICU complications where the variables with the greatest impact on short-term mortality: acute renal failure (OR 22.7) and respiratory distress syndrome (OR 51.2). After hospital discharge, the cumulative mortality at 12, 24 and 36 months was 6, 11 and 15%, respectively. The degree of functional dependence (HR 3.7), cancer (HR 3.4) and arrhythmias (HR 2.4) were factors related to long-term mortality. Conclusions. The short-term outcome of ICU patients is related to age and comorbidity, but more significantly to the characteristics of the acute illness. However, the long-term outcome is more closely associated with the patients’ characteristics (AU)

Short- and long-term prognosis of critically-ill patients referred to the ICU from the Emergency Department of a tertiary hospital. / Pronóstico a corto y largo plazo de los pacientes críticos ingresados en la Unidad de Cuidados Intensivos desde el Servicio de Urgencias de un hospital terciario.

BACKGROUND AND OBJECTIVE: A frequent source of critically-ill patients admitted to the ICU is the Emergency Department. It is essential to analyse the short-term prognosis of these patients, but also their evolution after their discharge from the hospital, since this is one of the major concerns of these patients. The aim of this study is to describe the epidemiological characteristics of patients admitted to the ICU from the Emergency Department and to analyse their outcome. PATIENTS AND METHOD: This consisted of an observational prospective cohorts study which included 269 Emergency Department patients consecutively admitted to the ICU over an 18-month period. Factors associated with hospital mortality were presented as an odds ratio (OR) and factors associated with long-term mortality were presented as a hazard ratio (HR). A P-value lower than .05 was accepted as significant. The overall survival was analysed on the basis of the Kaplan-Meier curves. RESULTS: Hospital mortality was 15%, ICU complications where the variables with the greatest impact on short-term mortality: acute renal failure (OR 22.7) and respiratory distress syndrome (OR 51.2). After hospital discharge, the cumulative mortality at 12, 24 and 36 months was 6, 11 and 15%, respectively. The degree of functional dependence (HR 3.7), cancer (HR 3.4) and arrhythmias (HR 2.4) were factors related to long-term mortality. CONCLUSIONS: The short-term outcome of ICU patients is related to age and comorbidity, but more significantly to the characteristics of the acute illness. However, the long-term outcome is more closely associated with the patients' characteristics.

Enteral Nutrition in Patients Receiving Mechanical Ventilation in a Prone Position.

BACKGROUND: Patients treated with mechanical ventilation in the prone position (PP) could have an increased risk for feeding intolerance. However, the available evidence supporting this hypothesis is limited and contradictory. OBJECTIVE: To examine the feasibility and efficacy of enteral nutrition (EN) support and its associated complications in patients receiving mechanical ventilation in PP. METHODS: Prospective observational study including 34 mechanically ventilated intensive care patients who were turned to the prone position over a 3-year period. End points related to efficacy and safety of EN support were studied. RESULTS: In total, more than 1200 patients were admitted to the intensive care unit over a period of 3 years. Of these, 34 received mechanical ventilation in PP. The mean days under EN were 24.7 ± 12.3. Mean days under EN in the supine position were significantly higher than in PP (21.1 vs 3.6; P < .001), but there were no significant differences in gastric residual volume adjusted per day of EN (126.6 vs 189.2; P = .054) as well as diet volume ratio (94.1% vs 92.8%; P = .21). No significant differences in high gastric residual events per day of EN (0.06 vs 0.09; P = .39), vomiting per day of EN (0.016 vs 0.03; P = .53), or diet regurgitation per day of EN (0 vs 0.04; P = .051) were found. CONCLUSIONS: EN in critically ill patients with severe hypoxemia receiving mechanical ventilation in PP is feasible, safe, and not associated with an increased risk of gastrointestinal complications. Larger studies are needed to confirm these findings.

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.

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.

Influence of renal function on the pharmacokinetics of piperacillin/tazobactam in intensive care unit patients during continuous venovenous hemofiltration.

The pharmacokinetics of piperacillin/tazobactam (4 g/0.5 g every 6 or 8 hours, by 20-minute intravenous infusion) were studied in 14 patients with acute renal failure who underwent continuous venovenous hemofiltration with AN69 membranes. Patients were grouped according to severity (CL(CR) < or =10 mL/min, 10 < CL(CR) < or =50 mL/min, and CL(CR) > 50 mL/min). A noncompartmental analysis was performed. The sieving coefficient (0.78 +/- 0.28) was similar to the unbound fraction (0.65 +/- 0.24) for tazobactam, but it was significantly different (0.34 +/- 0.25) from the unbound fraction (0.78 +/- 0.14) for piperacillin. Extracorporeal clearance was 37.0% +/- 28.8%, 12.7% +/- 12.6%, and 2.8% +/- 3.2% for piperacillin in each group and 62.5% +/- 44.9%, 35.4% +/- 17.0%, and 13.1% +/- 8.0% for tazobactam. No patients presented tazobactam accumulation. In patients with CL(CR) < 50 mL/min, t(%)ss >MIC90 values were 100% for a panel of 19 pathogens, but in those with CL(CR) > 50 mL/min, t(%)ss >MIC90 indexes were 55.5% and 16.6% for pathogens with MIC90 values of 32 and 64. The extracorporeal clearance of piperacillin/tazobactam is clinically significant in patients with CL(CR) > 50 mL/min, in which the risk of underdosing and clinical failure is important and extra doses are required.