Claire Roger

Standard dosing of amikacin and gentamicin in critically ill patients results in variable and subtherapeutic concentrations

Low peak plasma concentrations (Cmax) of amikacin and gentamicin are reported in intensive care unit (ICU) patients after administration of the first dose. The present study aimed to describe the proportion of ICU patients in whom an adequate Cmax was achieved throughout the course of therapy. Septic ICU patients with an indication for intravenous amikacin or gentamicin were eligible for inclusion in this single-centre observational study. The first and subsequent doses and the corresponding Cmax values were recorded. The target Cmax was ≥60mg/L for amikacin and ≥30mg/L for gentamicin. Amikacin and gentamicin plasma concentrations were available in 66 and 24 patients, respectively (59±17 years; 79±19kg; height 169±12cm; SAPS II score 46±19). Pulmonary, abdominal and urinary tract infections were diagnosed in 64 patients. Culture-positive infection was confirmed in 65 patients (72%). A target first Cmax was achieved in 17/90 patients (19%). For amikacin, the target Cmax was achieved in 16/66 patients (24%) after the initial dose. In the 50 remaining patients, a change in dosing was performed in 14 patients, leading adequate peak plasma level in 2 patients. For gentamicin, the targeted Cmax was achieved in only 1/24 patient (4%) after the initial dose and was never achieved after the third dose. In conclusion, standard dosing of amikacin or gentamicin led to adequate Cmax in only 19% of patients. Subtherapeutic Cmax were not significantly corrected after subsequent doses.

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.

Does the type of fluid affect rapidity of shock reversal in an anaesthetized-piglet model of near-fatal controlled haemorrhage? A randomized study

BACKGROUND The optimal resuscitation fluid for the early treatment of severe bleeding patients remains highly debated. The objective of this experimental study was to compare the rapidity of shock reversal with lactated Ringer (LR) or hydroxyethyl starch (HES) 130/0.4 at the early phase of controlled haemorrhagic shock. To assess the influence of vascular permeability in this model, we measured plasma vascular endothelial growth factor (VEGF) levels during the experiment. METHODS Thirty-six anaesthetized and mechanically ventilated piglets were bled (<30 ml kg(-1)) to hold mean arterial pressure (MAP) at 40 mm Hg for more than 30 min and were resuscitated in two randomized groups: LR (n=14) or HES (n=14) at 1 ml kg(-1) min(-1) until MAP reached its baseline value of ±10%. MAP was maintained at its baseline value for 1 h. The time and fluid volume necessary to restore the baseline MAP value were measured. RESULTS The time to restore the baseline MAP value of ±10% was significantly lower in the HES group (P<0.001). During the initial resuscitation phase, the infused volume was 279 (119) ml in the HES group and 1011 (561) ml in the LR group (P<0.0001). During the stabilization phase, the infused volume was 119 (124) ml in the HES group and 541 (506) ml in the LR group. Biological data and plasma VEGF levels were similar between the groups. CONCLUSIONS Restoration of MAP was four times faster with HES than with LR in the early phase of controlled haemorrhagic shock. However, there was no evidence of increased vascular permeability.

Influence of Diaphragmatic Motion on Inferior Vena Cava Diameter Respiratory Variations in Healthy Volunteers

Background:The collapsibility index of inferior vena cava (cIVC) is widely used to decide fluid infusion in spontaneously breathing intensive care unit patients. The authors hypothesized that high inspiratory efforts may induce false-positive high cIVC values. This study aims at determining a value of diaphragmatic motion recorded by echography that could predict a high cIVC (more than or equal to 40%) in healthy volunteers. Methods:The cIVC and diaphragmatic motions were recorded for three levels of inspiratory efforts. Right and left diaphragmatic motions were defined as the maximal diaphragmatic excursions. Receiver operating characteristic curves evaluated the performance of right diaphragmatic motion to predict a cIVC more than or equal to 40% defining the best cutoff value. Results:Among 52 included volunteers, interobserver reproducibility showed a generalized concordance correlation coefficient (&rgr;c) above 0.9 for all echographic parameters. Right diaphragmatic motion correlated with cIVC (r = 0.64, P < 0.0001). Univariate analyses did not show association between cIVC and age, sex, weight, height, or body mass index. The area under the receiver operating characteristic curves for cIVC more than or equal to 40% was 0.87 (95% CI, 0.81 to 0.93). The best diaphragmatic motion cutoff was 28 mm (Youden Index, 0.65) with sensitivity of 89% and specificity of 77%. The gray zone area was 25 to 43 mm. Conclusions:Inferior vena cava collapsibility is affected by diaphragmatic motion. During low inspiratory effort, diaphragmatic motion was less than 25 mm and predicted a cIVC less than 40%. During maximal inspiratory effort, diaphragmatic motion was more than 43 mm and predicted a cIVC more than 40%. When diaphragmatic motion ranged from 25 to 43 mm, no conclusion on cIVC value could be done.

Apheresis platelets are more frequently associated with adverse reactions than pooled platelets both in recipients and in donors: a study from French hemovigilance data

Controversy exists regarding the safety of the different types of platelet (PLT) concentrates. This study was aimed at comparing the rate of adverse reactions associated with apheresis PLT concentrates (APCs) and pooled PLT concentrates (PPCs) both in donors and in recipients.

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.

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

ABSTRACT Our objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n = 6) and morbidly obese (n = 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2. A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

Does physician experience influence the interpretability of focused echocardiography images performed by a pocket device

IntroductionThe use of focused cardiac ultrasound (FoCUS) in a prehospital setting is recommended. Pocket ultrasound devices (PUDs) appear to be well suited to prehospital FoCUS. The main aim of our study was to evaluate the interpretability of echocardiography performed in a prehospital setting using a PUD based on the experience of the emergency physician (EP).MethodsThis was a monocentric prospective observational study. We defined experienced emergency physicians (EEPs) and novice emergency physicians (NEPs) as echocardiographers if they had performed 50 echocardiographies since their initial university training (theoretical training and at least 25 echocardiographies performed with a mentor). Each patient undergoing prehospital echocardiography with a PUD was included. Four diagnostic items based on FoCUS were analyzed: pericardial effusions (PE), right ventricular dilation (RVD), qualitative left ventricular function assessment (LVEF), and inferior vena cava compliance (IVCC). Two independent experts blindly evaluated the interpretability of each item by examining recorded video loops. If their opinions were divided, then a third expert concluded.ResultsFourteen EPs participated: eight (57 %) EEPs and six (43 %) NEPs. Eighty-five patients were included: 34 (40 %) had an echocardiography by an NEP and 51 (60 %) by an EEP. The mean number of interpretable items by echocardiography was three [1; 4]; one [0; 2.25] in the NEP group, four [3; 4] in EEP (p < .01). The patient position was also associated with interpretable items: supine three [2; 4], “45°” three [1; 4], sitting two [1; 4] (p = .02). In multivariate analysis, only EP experience was associated with the number of interpretable items (p = .02). Interpretability by NEPs and EEPs was: 56 % vs. 96 % for LVF, 29 % vs. 98 % for PE, 26 % vs. 92 % for RVD, and 21 % vs. 67 % for IVCC (p < .01 for all).ConclusionFoCUS with PUD in prehospital conditions was possible for EEPs, It is difficult and the diagnostic yield is poor for NEPs.

Practices of end-of-life decisions in 66 southern French ICUs 4 years after an official legal framework: A 1-day audit

OBJECTIVE Since the implementation of two French laws in 2002 and 2005 and the implementation of guidelines about End-of-Life (EoL) decisions, few studies concerning EoL practices in French intensive care units (ICUs) have been reported. This study was aimed at assessing compliance with recommendations and current legislation concerning EoL decisions. METHOD Prospective observational study based on 1-day audit conducted from January to May 2009 in 66 southern French ICUs. RESULTS Six hundred and twenty-five patients were included (median age: 63 [52-76] years, median SAPS II: 46 [34-58]). The written designation of a surrogate decision-maker was reported for 87 (15%) patients. Advance directives were completed for only 4% of patients. The EoL decision-making process consisted in a multidisciplinary approach for 99 (47%) patients and was recorded in the medical chart for 63 (64%) cases. Families were informed about medical decisions in 58% of cases. This proportion was higher (87%) if a decision to forego life-sustaining therapy was made. EoL decisions consisted of withholding treatments for 72 (94%) patients and withdrawal of treatments for 5 (6%) patients. In the multivariate stepwise logistic regression, four variables were independently associated with a decision to forego life support: preexisting dependence on others (P<0.0001), advance directives (P=0.01), age (P=0.008) and the SAPS 2 score (P=0.009). CONCLUSION The major finding of the present study is the existence of a gap between the widely approved EoL recommendations made by scientific societies and the daily practice of southern French ICUs. Even if EoL decisions are mostly shared with relatives, their written documentation in medical charts remains insufficient. Concerning EoL practices, the withdrawal of treatment remains an uncommon decision.