Benjamin Louart

Impact of 30 mg/kg amikacin and 8 mg/kg gentamicin on serum concentrations in critically ill patients with severe sepsis

OBJECTIVES Low first-dose peak serum concentrations of amikacin and gentamicin are commonly reported in ICU patients. The present study aimed to assess whether 30 mg/kg amikacin or 8 mg/kg gentamicin achieved target concentrations in ICU patients with severe sepsis. PATIENTS AND METHODS Sixty-three ICU patients (Simplified Acute Physiology Score II = 43 ± 16) with severe sepsis and an indication for intravenous amikacin (n = 47) or gentamicin (n = 16) were included. The first (30 mg/kg amikacin; 8 mg/kg gentamicin) and subsequent doses and corresponding peak concentrations (30 min after the completion of an infusion) were recorded. French guideline target concentrations were ≥60 and ≥30 mg/L for amikacin and gentamicin, respectively. A target pharmacokinetic/pharmacodynamic ratio of 10 × MIC was also measured. RESULTS Pulmonary, abdominal and urinary tract infections were diagnosed in 56 patients. Infection was confirmed in 37 patients (59%). The targeted first-dose peak concentration was achieved in 37/63 patients (59%) [amikacin 36/47 (77%) and gentamicin 1/16 (6%)], and 59/63 patients (94%) achieved the pharmacokinetic/pharmacodynamic ratio using the MIC data that were available from 21 patients. However, the second dose of aminoglycoside was withheld because of high trough concentrations in nearly half of patients who did not have renal dysfunction. CONCLUSIONS In this study, 30 mg/kg amikacin and 8 mg/kg gentamicin led to target peak serum concentrations in 59% of patients.

Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration

OBJECTIVES Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h). METHODS Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0-24 h to MIC (AUC0-24/MIC) of 80. RESULTS Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P = 0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h; volume of the central compartment, 26.5 (10.3) L; intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h; and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose. CONCLUSIONS During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.

Comparison of equal doses of continuous venovenous haemofiltration and haemodiafiltration on ciprofloxacin population pharmacokinetics in critically ill patients.

OBJECTIVES Whilst commonly performed in ICUs, renal replacement therapies (RRTs) differ in their solute clearances. There is a paucity of data on ciprofloxacin clearances in different RRT techniques. The aim of this study was to compare the population pharmacokinetics of ciprofloxacin during equal doses of continuous venovenous haemofiltration (CVVHF) and continuous venovenous haemodiafiltration (CVVHDF) in septic patients. METHODS Patients receiving 400 mg of ciprofloxacin intravenously 8 or 12 hourly and undergoing either CVVHF or CVVHDF were eligible. Up to 10 blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo simulation was undertaken using Pmetrics. RESULTS Eighteen sampling intervals were included (8 CVVHDF and 10 CVVHF) from 11 patients (6 patients having sampling during both RRT modes). A two-compartment linear model best described the data. Increasing patient weight was the only covariate associated with increasing drug clearance. The mean (SD) parameter estimates were: clearance, 10.7 (5.3) L/h; volume of distribution of the central compartment, 21.3 (11.3) L; rate constant for drug distribution from the central compartment to the peripheral compartment, 10.9 (4.3) L/h; and rate constant for drug distribution from the peripheral compartment to the central compartment, 2.3 (1.8) L/h. After accounting for patient weight, the mean ciprofloxacin clearance was not statistically different between CVVHF and CVVHDF [11.8 (9.9) and 10.3 (7.4) L/h, respectively, P = 0.43]. CONCLUSIONS The present study indicates a high pharmacokinetic variability of ciprofloxacin during CVVHF and CVVHDF with no significant differences in clearance apparent. Based on patient weight, higher ciprofloxacin dosing regimens should be used in critically ill patients when difficult-to-treat pathogens are suspected.

Indices de réponse au remplissage vasculaire lors de la prise en charge d’un choc septique : utilisation par les médecins urgentistes

INTRODUCTION Fluid therapy is one of the major elements of severe sepsis and septic shock management. A systematic initial fluid bolus is recommended before evaluation of left ventricular filling pressure by the use of indicators of fluid responsiveness, preferentially dynamic ones. A massive fluid therapy could be damaging for the patient. Dynamic indicators of fluid responsiveness are not often relevant in the emergency department. This study was aimed to evaluate the use of indicators of fluid responsiveness by emergency practitioners during septic shock management. STUDY DESIGN Cross sectional survey using anonymous self-questionnaire. METHODS We included all practitioners working in public emergency department of Languedoc-Roussillon (France). Primary-end point was the use of one indicator of fluid responsiveness at least. Uni- and multivariate analysis was conducted to find associated factors. RESULTS Of 232 practitioners included, we collected 149 questionnaires (response rate=64%). Hundred and eight practitioners (72% [64-79%]) used at least one indicator of fluid responsiveness. Fifty-six practitioners (38% [30-46%]) used echocardiography, 54 practitioners (36% [29-44%]) used blood lactate concentration, 45 practitioners (30% [23-38%]) used passive leg raising. The use of indicators of fluid responsiveness is associated with easy access to echography device (odd ratio=2.94 [1.16-7.62], P=0.03). CONCLUSION Emergency practitioners use preferentially less invasive and less time-consuming indicators of fluid responsiveness.

Impact of Quality Bundle Enforcement by a Critical Care Pharmacist on Patient Outcome and Costs

Objectives: Surgical and medical ICU patients are at high risk of mortality and provide a significant cost to the healthcare system. The aim of this study is to describe the effect of pharmacist-led interventions on drug therapy and clinical strategies on ICU patient outcome and hospital costs. Design: Before and after study in two French ICUs (16 and 10 beds). Patients: ICU patients. Intervention: From January 1, 2013, to June 30, 2015, a pharmacist observation period was compared with an intervention period in which a critical care pharmacist provided recommendations to clinicians regarding sedative drugs and doses, choice of mechanical ventilation mode and related settings, antimicrobial de-escalation, and central venous and urinary catheters removal. Differences in ICU and hospital length of stay, duration of mechanical ventilation, mortality rate, and hospital costs per patient were quantified between groups with patients matched for severity of illness (Simplified Acute Physiology Score II) at admission. Measurements and Main Results: From the 1,519 and 1,268 admitted patients during the observation and intervention periods, respectively, 1,164 patients were evaluable in both groups after matching for Simplified Acute Physiology Score II score. The intervention period was associated with mean (95% CI) reductions in patient hospital length of stay (3.7 d [5.2–2.3 d]; p < 0.001), ICU length of stay (1.4 d [2.3–0.5 d]; p < 0.005), duration of mechanical ventilation (1.2 d [2.1–0.3 d]; p < 0.01), and hospital costs per stay (2,560 euros [3,728–1,392 euros]; p < 0.001). The overall cost savings were 10,840 euros (10,727–10,952 euros) per month, mostly due to reduced consumption of sedatives and antimicrobials. No impact on mortality rate was identified. Conclusions: Critical care pharmacist-led interventions were associated with decreases in ICU and hospital length of stays and ICU drug costs.

Does the infusion rate of fluid affect rapidity of mean arterial pressure restoration during controlled hemorrhage

OBJECTIVE This study aimed to compare 2 fluid infusion rates of lactated Ringer (LR) and hydroxyethyl starch (HES) 130/0.4 on hemodynamic restoration at the early phase of controlled hemorrhagic shock. METHODS Fifty-six anesthetized and ventilated piglets were bled until mean arterial pressure (MAP) reached 40 mm Hg. Controlled hemorrhage was maintained for 30 minutes. After this period, 4 resuscitation groups were studied (n=14 for each group): HES infused at 1 or 4mL/kg per minute or LR1 infused at 1 or 4mL/kg per minute until baseline MAP was restored. Hemodynamic assessment using PiCCO monitoring and biological data were collected. RESULTS Time to restore baseline MAP ±10% was significantly lower in LR4 group (11±11 minutes) compared to LR1 group (41±25 minutes) (P=.0004). Time to restore baseline MAP ±10% was significantly lower in HES4 group (4±3 minutes) compared to HES1 (11±4 minutes) (P=.0003). Time to restore baseline MAP ±10% was significantly lower with HES vs LR whatever the infusion rate. No statistically significant difference was observed in cardiac output, central venous saturation, extravascular lung water, and arterial lactate between 4 and 1 mL/kg per minute groups. CONCLUSIONS In this controlled hemorrhagic shock model, a faster infusion rate (4 vs 1mL/kg per minute) significantly decreased the time for restoring baseline MAP, regardless of the type of infused fluid. The time for MAP restoration was significantly shorter for HES as compared to LR whatever the fluid infusion rate.

Lung real time three-dimensional imaging in critically ill ventilated patients: a global diagnosis concordance study

Lung ultrasound (LUS) increases clinical diagnosis performance in intensive care unit (ICU). Real-time three-dimensional (3-D) imaging was compared with two-dimensional (2-D) LUS by assessing the global diagnosis concordance. In this single center, prospective, observational, pilot study, one trained operator performed a 3-D LUS immediately after a 2-D LUS in eight areas of interest on the same areas in 16 ventilated critically ill patients. All cine loops were recorded on a computer without visible link between 2-D and 3-D exams. Two experts blindly reviewed cine loops. Four main diagnoses were proposed: normal lung, consolidation, pleural effusion and interstitial syndrome. Fleiss κ and Cohen’s κ values were calculated. In 252 LUS cine loops, the concordance between 2-D and 3-D exams was 83.3% (105/126), 77.6% (99/126) and 80.2% (101/126) for the trained operator and the experts respectively. The Cohen’s κ coefficient value was 0.69 [95% Confidence Interval (CI) 0.58–0.80] for expert 1 meaning a substantial agreement. The inter-rater reliability was very good (Fleiss’ κ value = 0.94 [95% CI 0.87–1.0]) for 3-D exams. The Cohen’s κ was excellent for pleural effusion (κ= 0.93 [95% CI 0.76–1.0]), substantial for normal lung diagnosis (κ = 0.68 [95% CI 0.51–0.86]) and interstitial syndrome (κ = 0.62 [95% CI 0.45–0.80]) and fair for consolidation diagnoses (κ = 0.47 [95% CI 0.30–0.64]). In ICU ventilated patients, there was a substantial concordance between 2-D and 3-D LUS with a good inter-rater reliability. However, the diagnosis concordance for lung consolidation is poor.