A digital tool combined with an in vitro model for improving patient's care requiring Continuous Renal Replacement Therapy (CRRT)

The French adult Intensive Care Unit (ICU) is a leader in kidney transplantation and handles a great variety of extracorporeal devices, which are used in patients presenting acute liver failure not requiring transplantation. The last 20 years have witnessed an extraordinary development of treatment methods using extracorporeal circulation devices- arterio-venous and vein-venous extracorporeal membrane oxygenation (ECMO); continuous extra-renal purification; molecular Adsorbent Recirculating System – which require long-lasting supportive treatment. These medical devices tend to be associated to the same patient. This situation can be partially justified by the fact that, in opposition to pharmaceuticals, the efficacy and safety of these devices are determined during the clinical development phase only, as no prior preclinical studies are required. To date, a limited number of adverse effects associated with extracorporeal devices have been identified: haemorrhages; thrombosis; biocompatibility and intravascular hemolysis. Most extracorporeal circulation device manufacturers focus their development strategies on these events, in order to achieve satisfactory levels of material biocompatibility, reduction of hemolysis (non-occlusive pumps) and diminution of hemorrhagic events. But a severe adverse effect related to the adsorption of drugs administered during continuous extracorporeal blood purification sessions remains poorly documented. Indeed, in routine medical care, clinicians have frequently experienced difficulties in balancing drug administration, which can decrease or even yield complete loss of efficacy resulting in death. Detection of adsorption in vivo can be challenging among patients presenting multiple organ failures, as there are no current approaches that allow for its quantification. Also, no in vitro models are able to respond to the problem of detection and quantification of adsorption in filters sessions in real life. Indeed they never compare this quantity with those carried out by conventional elimination routes (hemofiltration and hemodialysis). Hence, no in vitro model has yielded effective countermeasures for adsorption. This failure of in vitro models is regularly underlined, whereas the recommended therapeutic monitoring is unable to provide a useful response just in time. This situation applies for all drugs of interest in intensive care, including anti-infective agents, even though the effectiveness of the first dose is a decisive parameter for the vital prognosis. This French solution combines an in-vitro model and software. With a focus on continuous renal replacement therapy (CRRT), this model mimics a session in the different modes of RRT as those used in critically ill patients (dialysis, filtration, and diafiltration). Importantly, it only uses a crystalloid solution in all compartments of the model. The crystalloid solution provides a number of advantages including high standardization and reproducibility of the medium, and understanding on the disposition of the free fraction of drugs; therefore resulting in accurate measurement of the sieving coefficient in the filtration model. The software does not make any assumption about the time or concentration-dependency of the pharmacokinetics (PK) in the central compartment (CC). It was extended to the molecular adsorbent recirculating system providing support to acute liver failure and could be extended to all extracorporeal devices requiring the presence of a filter for various purposes. Commercial agreements with technical assistance are sought with manufacturers of extracorporeal devices who are willing to test the solution through the implementation of in-vitro studies, in order to assess the performance of their filters/membranes.