Adsorption within continuous renal replacement therapy (CRRT) circuits may reduce exposure to echinocandins. Because micafungin is highly protein bound, the behavior of its unbound fraction during CRRT remains difficult to characterize. We assessed unbound micafungin disappearance from a central compartment and late release/desorption in a protein-free in vitro CRRT model. Micafungin stability was assessed in a 5-L bag of Hemosol™ B0 over 8 h. In the NeckEpur model, a 5-L protein-free central compartment was circulated at 200 mL/min for 6 h through either a polyacrylonitrile hemofilter (ST™150; post-dilution continuous veno-venous hemofiltration [CVVH], 2.5 L/h) or a polysulfone hemofilter (AV™1000). For AV™1000, one run used CVVH (2.5 L/h) and one used continuous veno-venous hemodiafiltration (CVVHDF; dialysis 1.5 L/h plus filtration 1.0 L/h). Initial micafungin concentrations in the central compartment were 2.18 mg/L or approximately 6.8 mg/L. Concentrations were measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS) with a lower limit of quantification (LLOQ) of 0.1 mg/L. Apparent central-compartment clearance (Cl_CC), sieving coefficient (Sc), and extraction coefficient (EC) were used to describe disappearance from the circuit, filtration, and late release. Sensitivity analyses replaced values < LLOQ by LLOQ/2 or LLOQ/√2. Segmental sampling and within-filter mass balance were used descriptively to localize loss within the extracorporeal system. Micafungin was stable in Hemosol™ B0 over 8 h (− 5.2 ± 0.5

Introduction: Amikacin is sequestered in polyacrylonitrile filters. Methods mitigating sequestration are unknown. Amikacin elimination in a polyacrylonitrile-derived filter preloaded with amikacin was studied in a preliminary study. Methods: Amikacin concentrations were determined using an immunochemical method. Prismaflex™, Baxter-Gambro, and the ST™150 filter were used. Sessions were performed in a continuous diafiltration mode. Diafiltration flow rate was set to 2500 mL/h and filtration to 500 mL/h pre- and 1000 mL/h post-dilution. Net loss was set to zero. In sessions with preload, a 150 mg dose of amikacin was injected in the first 1 L bag of physiological saline when starting the priming. NeckEpur® method was used for pharmacokinetic calculations. Results: In the central compartment (CC), the mean initial concentration in the sessions without and with preload was 81.8 ± 6.0 mg/L. There were no significant differences in the AUCcc and AUCinlet without or with preload. The preloading dose induced a significant increase in the AUCoutlet. Compared with sessions without preload, the clearance from the CC in sessions with preload decreased from 4.94 ± 0.43 to 3.75 ± 0.32 L/h, respectively. The elimination rates by diafiltration and sequestration in the sessions without and with preload were 82.3 ± 6.2/17.8 ± 6.2% and 125 ± 9.2%/0 ± 0%, respectively. The 150 mg loading dose was eliminated by diafiltration (42.5%) and by sequestration (57.5%). Conclusion: Preloading filter with amikacin modifies the disposition of amikacin by preventing further sequestration. Studies are needed to define an efficient preloading dosage regimen in actual condition of use.

Renal replacement therapy efficiently eliminates cefepime. A published in vitro study concluded to minimal adsorption of cefepime in a polysulfone derived filter. We aimed at assessing cefepime adsorption in filters used in critically ill patients. Two filters were used, ST™150 and AV™1000. Adsorption was assessed in two modes, including diafiltration and filtration set to flow rates of from 2.5 to 1 L/h, respectively. Routes of elimination were assessed using NeckEpur® method for 6-h session duration. The mean initial concentration in the 5-L central compartment (CC) in the 10 sessions was 47.7 ± 2.9 mg/L. Using the diafiltration mode, the mean adsorption rates in the ST™150 and AV™1000 were 1.3 ± 2.3% and 19.7 ± 1.2% (n = 3), respectively. Using the filtration mode at 1 L/h, the mean adsorption rates in the ST™150 and AV™1000 were 1.7% (n = 2) and 18.5% (n = 2), respectively. ST™150 filter sequestrated very limited quantities of cefepime. In the diafiltration and filtration modes, AV™1000 sequestered cefepime at about 19%. The adsorption rate seems independent of the flow rate. Further studies would be needed to assess, in particular, the clinical relevance of these results in adults as well as drug adsorption in the pediatric population.

Background. Sequestration of vancomycin in ST® filters used in continuous renal therapy is a pending question. Direct vancomycin-ST® interaction was assessed using the in vitro NeckEpur® technology. Method. ST150® filter and Prismaflex dialyzer, Baxter-Gambro, were used. Two modes were assessed in duplicate: (i) continuous diafiltration (CDF): 4 L/h, (ii) continuous dialysis (CD): 2.5 L/h post-filtration. Results. The mean initial vancomycin concentration in the central compartment (CC) was 51.4 +/− 5.0 mg/L. The mean percentage eliminated from the CC over 6 h was 91 +/− 4%. The mean clearances from the CC by CDF and CD were 2.8 and 1.9 L/h, respectively. The mean clearances assessed using cumulative effluents were 4.4 and 2.2 L/h, respectively. The mean percentages of the initial dose eliminated in the effluents from the CC by CDF and CD were 114 and 108% with no detectable sequestration of vancomycin in both modes of elimination. Discussion. Significant sequestration adds a clearance to that provided by CDF and CD. The study provides multiple evidence from the CC, the filter, and the effluents of the lack of an increase in total clearance in comparison with the flow rates without significant sequestration in the ST® filter comparing cumulative effluents to the initial dose in the CC. Conclusions. There is no evidence ST® filters directly sequestrate vancomycin.

Objectives: Critically ill patients frequently require continuous renal replacement therapy. Echinocandins are recommended as first-line treatment of candidemia. Preliminary results suggested echinocandin sequestration in a polyacrylonitrile filter. The present study aimed to determine whether increasing the dose might balance sequestration. Methods: An STX filter (Baxter-Gambro) was used. A liquid chromatography-mass spectrometry method was used for dosage of caspofungin. In vitro drug disposition was evaluated by NeckEpur (Neckepur, Versailles, France) technology using a crystalloid medium instead of diluted/reconstituted blood, focusing on the disposition of the unbound fraction of drugs. Two concentrations were assessed. Results: At the low dose, the mean measured initial concentration in the central compartment (CC) was 5.1 +/- 0.6 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.6 +/- 2.5 L/h. The mean percentages of elimination resulting from sequestration and diafiltration were 96.0 +/- 5.0 and 4.0 +/- 5.2%, respectively. At high dose, the mean measured initial concentration in the CC was 13.1 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.5 L/h. The mean percentages of elimination resulting from sequestration and filtration were 88.5% and 11.5%, respectively. Conclusion: Increasing the dose does not mitigate caspofungin sequestration in the STX filter. The results raise caution about the simultaneous use of caspofungin and polyacrylonitrile-derived filters. Intermittent modes of renal replacement therapy might be considered. For sensitive species, fluconazole might be an alternative. (c) 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Continuous renal replacement therapy (CCRT) efficiently eliminates cefotaxime. To our knowledge, there are no previous in vitro studies dealing with the disposition of cefotaxime. We studied the elimination of cefotaxime by two filters in a model mimicking a session of CRRT using the NeckEpur® technology. The ST150®-polyacrylonitrile filter with the Prismaflex, Baxter-Gambro, and the AV1000®-polysulfone filter with the Multifiltrate Pro, Fresenius, were studied. Continuous filtration used a flowrate of 1 L/h in post-dilution only. Simulated blood flowrate was set at 200 mL/min. Routes of elimination were assessed using the NeckEpur® technology. Cefotaxime concentrations were measured using ultra high-performance liquid chromatography, and tandem mass spectrometry. Two sessions were performed using the ST® filter and three using the AV® filter. Stability of cefotaxime during 6 h was assessed in triplicate with a mean variation of concentrations of 2.4 ± 1.5% at the end of the study. The mean measured initial concentration in the central compartment (CC) for the five sessions was 52.4 mg/L. The mean amount eliminated from the CC at the end of the sessions using the ST150®-polyacrylonitrile and the AV1000®-polysulfone filters were 72% and 73%, respectively. The clearances of cefotaxime from the central compartment (CC) were 1.1 and 1.2 L/h, respectively. The mean sieving coefficient were 0.99 and 0.99, respectively. The mean percentages of the amount eliminated from the CC by filtration/adsorption were 87/13% and 92/8%, respectively. Both adsorption percentages were below 15%. We conclude neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in clinically significant adsorption of cefotaxime.

Background: Prompt and definitive diagnosis of adverse drug reactions (ADRs) is a challenge for health care providers. There is a global burden of ADRs worldwide associated with a negative impact on the patient's health, in parallel with increasing costs for the community.This study aims to determine the annual incidence of ADRs in the cohort of patients requiring immediate intervention of the French prehospital emergency medical service (PEMS). The definitive diagnosis of ADR was provided by the follow-up of the entire course of hospitalization from PEMS presentation to final discharge in each suspected case.Methods: A retrospective study examining the incidence of ADR at the Paris PEMS was performed in 2015.Results: From January the 1st to December the 31st, 2015, 485 cases of suspected ADR were selected. Twentyeight patients could not be identified at the hospital and were considered as lost to follow-up. For the 457 cases with the final diagnosis and outcome available, 359 had a definitive and new diagnosis of ADR, 9 were related to substance of abuse and alcohol, 14 were duplicates and 75 were excluded by drug causality was ruled out. Long-term follow-up was performed for 359 cases. Among them, 22 patients (6.1%) died of an ADR. Twenty-five severe ADRs were notified for children ages 2 to 16 with a cluster of 9 cases (36%) resulting from an accidental outbreak of poisonings with alimemazine in a classroom. No fatality was reported among children suffering from an ADR.Conclusion: The collaboration between PEMS and in hospital Pharmacovigilance Centre is feasible from the PEMS report to the long-term follow-up. The definition of a clinical pattern for some drugs is needed to allow the medical team to anticipate the clinical outcome of the involved patient and therefore adapting the patient's support as soon as possible. (c) 2022 Elsevier Inc. All rights reserved.

Disposition of gentamicin and amikacin during extracorporeal membrane oxygenation has not been addressed in in vitro models. The HLS Advanced 7.0® circuit with the Cardio Help® monitor, Getinge, was used. The 5-L central compartment (CC) was loaded with gentamicin and amikacin at a targeted concentration of 40 and 80 mg/L in the same bag prior connection to the circuit. Samples were collected in the CC, the inlet and outlet ports from 15 min to 6 h post-connection. Pharmacokinetic analyses were performed using the NeckEpur® method. Analysis of results of gentamicin and amikacin showed in the filter-pump block (i) the extremely low value of the extraction coefficients, (ii) similar values of the areas under the curve (AUCs) at the inlet and outlet ports, (iii) using the Wilcoxon matched pairs signed rank test no significant differences of the inlet-outlet concentrations in the filter-pump. In the whole system (i) the amounts recovered in the CC at the end of the 6-h session were not significantly different from the initial values, (ii) the extremely low values of the total clearance of gentamicin and amikacin from the CC in comparison with the measured simulated blood flowrate, (iii) the lack of significant time-concentration interactions in the CC and the inlet and outlet ports. These findings allow concluding no detectable adsorption of gentamicin and amikacin occurred in the HLS Advanced 7.0 circuit.

INTRODUCTION:Adsorption of gentamicin in a polyacrylonitrile filter was previously evidenced in a session lasting 6 h using the NeckEpur model. We extended the study over three consecutive days to mimic the 72-h life span of a filter.METHODS:Prismaflex® monitor and ST150® filter were used in the continuous diafiltration (CDF) mode at a 2.5 L/h flowrate. The daily session started with a 6-h session of CDF. Thereafter, the 5-L central compartment was changed using a bag free of gentamicin to assess gentamicin release over the following 18 h. Experiments were repeated on Day 2 and stopped at the end of the 6-h session of CDF on Day 3. The experiment was performed in duplicate.RESULTS:At a 2.5 L/h diafiltration flowrate, the mean daily clearances of gentamicin were 5.5, 4.0, and 3.3 L/h, respectively. The mean diafiltration and adsorption ratios in the daily elimination of gentamicin were 32/68%, 58/42%, and 88/12%, respectively. During days 1 and 2, the mean amount of gentamicin released from the ST150® filter were 14 and 34 mg, respectively.CONCLUSION:The pharmacokinetics of gentamicin over 3 days is strongly altered by adsorption in the same filter with a progressive decrease of elimination by adsorption, suggesting saturation of the filter. One limitation of our study results from the mode of administration using a bolus dose instead of an infusion over 30 min. Adsorption adds a clearance to those of diafiltration. The time-dependency of gentamicin clearance precludes using a constant dosage regimen over the filter's life span.

An increase of pyroglutamic acid, or 5-oxoproline plasmatic concentration was reported in metabolic acidosis observed after chronic intake of some drugs, as acetaminophen. We developed a simple, fast and reproducible method by capillary zone electrophoresis using a commercial Anion Analysis Kit® to quantify pyroglutamic acid, in plasma after acetonitrile precipitation, and after simple dilution in urines. Fumaric acid was used as internal standard in both. In less than 7 min, the method separates pyroglutamic acid from other organic and inorganic anions. The method is linear between 0.25 and 10 mmol/L in plasma, and 0.15 and 10 mmol/L in urines. The quantification limits are 0.25 mmol/L and 0.15 mmol/L for plasma and urines, respectively. For repeatability and intermediate precision, the variation coefficients are less than 15% and the bias values are between ± 10%. For the 2 matrices, the recoveries are between 88% and 101%. The method does not interfere with physiological organic and inorganic anions. Pyroglutamic acid concentrations measured in 9 children were between 0.45 and 3.96 mmol/L in the plasma and between 0.15 and 3.2 mmol/L in the urine. No correlation between pyroglutamic acid and acetaminophen concentrations were found, regardless of the biological media. In conclusion, our method measures pathophysiological concentrations of pyroglutamic acid and highlights the increase in other organic acids that may explain metabolic acidosis due to chronic acetaminophen intake.

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) insertion techniques vary around the world. Our ECPR team has developed a hybrid technique for non-surgeons to implement ECPR for refractory cardiac arrest. Methodology: We conducted a retrospective monocentric study to evaluate this new ECPR implementation technique. Global ECPR implementation time, mean canula insertion time, and mean connection time were evaluated as well as failure rate. Results: During the 4-year study period, 187 patients were implemented with ECPR. The mean age was 51 +/- 13 years. Fourty patients survived with good neurological outcome at the ICU discharge (22,5%). Global ECPR implementation time was 21 min +/- 9. Mean canula insertion time was 15,1 min +/- 7, and mean connection time was 6,1 min +/- 4,7. The global failure rate was 7,6 %. Conclusion Our ECPR implementation technique is efficient and safe for non-surgeons. It could contribute to increase the access to ECPR in centers without on-site cardiothoracic surgeons.

Introduction: Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur(R) model. Two filters were studied. Methods: The AV1000(R)-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150(R)-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur(R) model. Results: The mean measured initial fluconazole concentration (mean +/- SD) for the four sessions in the central compartment (CC) was 14.9 +/- 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000(R)-polysulfone and the ST150(R)-polyacrylonitrile filters were 90%-93% and 96%-94%, respectively; the clearances from the central compartment (CC) were 2.5-2.6 and 2.4-2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%-0.91% and 0.99%-0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%-95/5% and 100/0%-100/0%, respectively. Conclusion: Neither the ST150(R)-polyacrylonitrile nor the AV1000(R)-polysulfone filters result in any significant adsorption of fluconazole.

L’enseignement et la pratique de la pharmacologie et de la toxicologie clinique reposent sur 4 grandes disciplines : – la pharmaco/toxicocinétique, (PK ou TK), – la pharmaco/toxico dynamique (PD ou TD), – les corrélations pharmacocinétiques/Pharmacodynamiques (relations PK/PD ou TK/TD), – les modèles pharmacocinétique basés sur les données physiologiques (modèle PK-PD) s’intéressent à la toxicité globale d’organe. En fait l’analyse des unités utilisées pour chaque discipline fait apparaître un trou de connaissance. Les unités des études PK/TK sont des concentrations en fonction du temps : C = f(t). Celles des études PD/TD sont des intensités d’effet en fonction de la dose ou de la concentration sanguine : E = f(dose ou concentration), le temps n’apparaît pas. Les corrélations PK/PD étudient la corrélation entre un effet et une concentration, mesurés en même temps. E = f(C), le temps disparaît. Une discipline a été occultée : l’évolution de l’intensité des effets toxiques au cours du temps que nous avons désigné sous l’acronyme de « toxicodynétique » terme synthétisant l’effet (Dynamie) au cours du temps (cinétique). La toxicodynétique est une discipline qui possède une méthodologie propre et résout des questions que les autres disciplines ne peuvent pas solutionner. La toxicodynétique s’adresse aux effets majeurs des toxiques [1]. Pour une même substance il existe autant de dynétiques qu’il existe d’effets importants. Elle s’adresse à tous les paramètres mesurés de façon répétée. La dynétique ne nécessite aucun dosage au prix d’un recueil anamnestique complet. Elle peut donc être réalisée pour tout médicament et toute substance. Par exemple, l’application des principes de la toxicodynétique aux intoxications par benzodiazépines permet un classement quantitatif de la toxicité de ces psychotropes selon l’intensité de l’effet maximal observé (Emax) et l’index de toxicité (rapport de la dose médiane associée à l’Emax à la dose maximale quotidienne recommandée). La toxicodynétique redonne la primauté d’étude à la molécule par rapport à la classe pharmaco-toxicologique.

Objective to report an unusual pattern of brain petechial hemorrhages in 2 patients after veno-arterial extracorporeal membrane oxygenation support (VA-ECMO) Case 1 a 28-year-old man (Marfan disease) presented in the early post-operative period a multi-organ failure associated with a disseminated intravascular coagulation (DIC). He was placed on continuous veno-venous hemofiltration and VA-ECMO. He was weaned from ECMO 4 days later. He then developed bacterial pneumoniae leading to respiratory failure and requiring mechanical ventilation. MRI 30 days later showed widespread petechial hemorrhages in the subcortical and deep white matter (WM) (optic radiations, corpus callosum, predominantly in the splenium, internal and external capsules), caudate nuclei, basal ganglia, frontal and parietal cortex and in infratentorial structures. These hemorrhages were bilateral and almost symmetric and marked at the border zones of the carotid arteries territories. Case 2 a 60-year-old man presented an out-of-hospital refractory hypothermic cardiac arrest. At arrival, cardiopulmonary resuscitation was continued; he presented bleeding at the puncture sites related to DIC and associated with multi-organ failure. VA-ECMO was implanted. After ECMO removal (day 7) he presented a severe spatial orientation deficit. MRI showed petechial hemorrhages in both hippocampi and microbleeds at the cerebral cortex and the juxta-cortical WM. Both patients had good functional outcome. Conclusion Two unusual presentations of brain hemorrhages in patients who underwent VA-ECMO are reported. If their specific cause remains unclear, there seems to be a relationship in time between DIC and microhemorrhages in these cases, even if in case 1 brain hemorrhages seem to have a multifactorial cause.

La toxicodynétique définit l'évolution temporelle des manifestations cliniques après ingestion de médicaments (seuls ou en association). L'objectif principal de l'étude était de rapporter les paramètres toxicodynétiques des mono-intoxications à l'alprazolam et au bromazépam. Les données du centre antipoison (CAP) de Paris étaient recueillies de 1999 à 2015. Les cas de mono-intoxications à l'alprazolam et au bromazépam ont été sélectionnés en éliminant la prise d'alcool concomitante. Les paramètres toxicodynétiques évalués étaient l'Emax observé (effet clinique maximal observé pour le signe ou le symptôme d'intérêt) et l'index de toxicité (IT) (rapport entre la dose supposée ingérée et la dose quotidienne maximale recommandée). Au total, 554 et 2067 cas de mono-intoxications à l'alprazolam et au bromazépam ont été inclus, respectivement. L'Emax observé pour l'alprazolam et le bromazépam était un coma survenant dans 5 et 25 cas, respectivement. L'IT était de 6,7 et 1,25, pour respectivement le bromazépam et l'alprazolam. Parmi les patients ayant présenté un coma après ingestion d'alprazolam ou de bromazépam, aucun n'était traité par les médicaments d'intérêt. La médiane du délai d'apparition du coma était de 75 min pour le bromazépam. Elle n'était pas connue pour l'alprazolam. Cependant, le délai médian des appels au CAP après intoxication à l'alprazolam était de 30 min. Le coma paraît s'être installé dans des délais très courts, de l'ordre de la dizaine de minutes après l'ingestion. La méthode toxicodynétique permet de déterminer des paramètres cliniques d'importance majeure durant l'évolution de surdosages par l'alprazolam et le bromazépam et leurs effets maximaux. En comparant les effets neurologiques de l'alprazolam et du bromazépam au nordazépam et à l'oxazépam étudiés précédemment [1], nous pouvons conclure que tous les anxiolytiques n'entraînent pas de coma. L'oxazépam et de nordazépam n'induisent pas de coma, même pour un IT médian de l'ordre de 20 pour le nordazépam, alors que l'alprazolam et le bromazépam peuvent induire des comas. Mais dans les deux cas, il est notable que le coma n'est survenu que chez des sujets naïfs, non traités par les médicaments d'intérêt. Une surveillance rapprochée est conseillée, plus particulièrement pour les patients ayant pris de l'alprazolam, car ce dernier entraîne des comas à des doses proches des doses thérapeutiques.