Preclinical and first-in-human safety studies on a novel magnetism-based haemofiltration method.

Extracorporeal haemofiltration devices that selectively remove cytokines could represent an adjunctive treatment in inflammatory diseases. One such device is the "IL-6-Sieve", wherein magnetic Anti-IL-6 Beads are introduced into an extracorporeal circuit via a Bead Adapter and then removed along with any surface-bound interleukin (IL)-6 by a Filter deployed in a Magnet, before the blood is returned to the patient. We report here on a series of animal studies, and a first-in-human study, on the safety of the IL-6-Sieve. Evaluations focused on the: (a) safety of Filter and Magnet placed in an extracorporeal circuit in sheep; (b) safety of Anti-IL-6 Beads-directly infused intravenously as worst case scenario of misuse; or injected into an extracorporeal circuit using the Bead Adapter, Filter, and Magnet as intended-in sheep; (c) biodistribution of Anti-IL-6 Beads intravenously infused in mice; and (d) safety of Filter and Magnet placed in an extracorporeal circuit in healthy volunteers. No serious adverse events or significant changes in vital signs or routine laboratory parameters occurred in any of the animals or humans. Although safety of the IL-6-Sieve requires further study, these initial evaluations represent a promising start for the translation of this new blood purification modality into clinical use.

Survival benefit of resin cartridge extracorporeal blood purification therapy in patients with septic shock.

Background/aim: Extracorporeal blood purification (EBP) therapies have shown promise as potential rescue treatments for patients with septic shock. However, precise evidence regarding their effectiveness is lacking. This case-control study aimed to evaluate the 28-day survival benefit of a resin cartridge-based EBP therapy compared to conventional therapies in patients with septic shock. Materials and methods: The study sample was collected retrospectively from the medical records of patients admitted to the intensive care unit (ICU) between 2015 and 2020. The study included patients with septic shock aged ≥18 years who had ICU stays >96 h and excluded those lost to follow-up by 28 days or readmitted. First, 28-day survival was compared between EBP patients and 1:1 matched conventionally treated controls. Second, the EBP patients were evaluated for clinical and laboratory improvements within 72 h of EBP therapy. Results: Of 3742 patients, 391 were included in this study, of whom 129 received EBP therapy and had a 28-day survival rate of 44%, compared to 262 matched controls who received conventional therapy alone and had a survival rate of 33% (p = 0.001, log-rank = 0.05, number needed to treat = 8, and odds ratio = 1.7). After receiving EBP therapy for 72 h, improvements were observed in the Sequential Organ Failure Assessment scores (p < 0.05), shock indices (p < 0.05), partial pressure of oxygen in the arterial blood to the fraction of inspiratory oxygen concentration ratios (p < 0.001), vasopressor requirements (p < 0.001), pH (p < 0.05), lactate levels (p < 0.001), and C-reactive protein levels (p < 0.05). Conclusion: The findings suggest that administering resin cartridge-based EBP therapy to patients with septic shock may improve their survival compared to conventional therapies.

Development of a new miniaturized system for ultrafiltration.

Acute decompensated heart failure and fluid overload are the most common causes of hospitalization in heart failure patients, and often, they contribute to disease progression. Initial treatment encompasses intravenous diuretics although there might be a percentual of patients refractory to this pharmacological approach. New technologies have been developed to perform extracorporeal ultrafiltration in fluid overloaded patients. Current equipment allows to perform ultrafiltration in most hospital and acute care settings. Extracorporeal ultrafiltration is then prescribed and conducted by specialized teams, and fluid removal is planned to restore a status of hydration close to normal. Recent clinical trials and European and North American practice guidelines suggest that ultrafiltration is indicated for patients with refractory congestion not responding to medical therapy. Close interaction between nephrologists and cardiologists may be the key to a collaborative therapeutic effort in heart failure patients. Further studies are today suggesting that wearable technologies might become available soon to treat patients in ambulatory and de-hospitalized settings. These new technologies may help to cope with the increasing demand for the care of chronic heart failure patients. Herein, we provide a state-of-the-art review on extracorporeal ultrafiltration and describe the steps in the development of a new miniaturized system for ultrafiltration, called AD1 (Artificial Diuresis).

Initial experience with CytoSorb therapy in patients receiving left ventricular assist devices.

BACKGROUND: The use of left ventricular assist devices (LVAD) in patients with advance heart failure is still associated with an important risk of immune dysregulation and infections. The aim of this study was to determine whether extracorporeal blood purification using the CytoSorb device benefits patients after LVAD implantation in terms of complications and overall survival. MATERIALS AND METHODS: Between August 2010 and January 2020, 207 consecutive patients underwent LVAD implantation, of whom 72 underwent CytoSorb therapy and 135 did not. Overall survival, major adverse events, and laboratory parameters were compared between 112 propensity score-matched patients (CytoSorb: 72 patients; non-CytoSorb: 40 patients). RESULTS: WBC (p = .033), CRP (p = .001), and IL-6 (p < .001), significantly increased with LVAD implantation, while CytoSorb did not influence this response. In-hospital mortality and overall survival during follow-up were similar with CytoSorb. However, patients treated with CytoSorb were more likely to develop respiratory failure (54.2% vs. 30.0%, p = .024), need mechanical ventilation for longer than 6 days post-implant (50.0% vs. 27.5%, p = .035), and require tracheostomy during hospitalization (31.9% vs. 12.5%, p = .040). No other significant differences were observed with regard to major adverse events during follow-up. CONCLUSIONS: Overall, our results showed that CytoSorb might not convey a significant morbidity or mortality benefit for patients undergoing LVAD implantation.

Subarachnoid Hemorrhage and Extracorporeal Blood Purification with HA-380 and High-Volume Hemofiltration: A New Therapeutic Challenge at the Neurocritical Care Unit? A Case Report.

We present the case of a patient with subarachnoid hemorrhage (SAH) secondary to a ruptured cerebral aneurysm and a refractory shock with high doses of vasopressors without a proven source of infection. This patient received therapy with high-volume hemofiltration plus adsorption, resolving the hemodynamic deterioration and with good neurological evolution. Our clinical case proposes that extracorporeal therapies may have a feasibility role in the management of complications of SAH.

Opportunities, controversies, and challenges of extracorporeal hemoadsorption with CytoSorb during ECMO.

Extracorporeal membrane oxygenation (ECMO) is frequently used in many centers around the globe for various indications. However, prognosis is often poor even with all supportive therapies, and in many cases, clinical deterioration is associated with inflammation. Hemoadsorption with CytoSorb is a novel approach to limit the inflammatory response, and the device can be safely and easily installed into ECMO circuits. CytoSorb has been used more than 130.000 times to date, but because randomized controlled trials are largely lacking, there is substantial debate on its use. Here, experts from critical care medicine, cardiology, cardiac surgery, and perfusion technology discuss the pros and cons of this novel therapy and outline the future aspects for its clinical application and research.

Reliable fluid-mechanical characterization of haemofilters: Addressing the deficiencies of current standards and practices.

Facile methods for accurate fluid-mechanical characterization of haemofilters (HF) are indispensable for haemofiltration process improvements, equipment design/optimization, and reliable module specifications. Currently employed methods, implemented through specific experimental in vitro protocols, are assessed herein in detail, considering the conditions prevailing during haemofiltration. Minimum number of key parameters required to fully describe the common countercurrent flow field, in the HF active section, include membrane permeance K and friction coefficients in lumen and shell side (ff and fs ). It is shown that the countercurrent flow mode itself is incapable of yielding these parameters, based on externally measured flow rates and pressures. Similarly, the relevant ISO protocol is deficient as it can only provide rough underpredictions of permeance K. The causes of such inherent deficiencies of current standards and practices are analyzed. In contrast, a recently developed methodology, accounting for the (heretofore ignored) pressure drop in module headers and combining a mechanistic theoretical model with experimental data from 2 special haemofilter operating modes, yields an accurate determination of the key parameters (K, ff , fs ). Additionally, it permits a full description of flow field for Newtonian liquids, for both constant and axially varying viscosity in fiber-lumen due to the transmembrane flux. Development of new reliable standards is suggested, facilitated by the insights gained in this work.

Antibiotics Removal by Continuous Venovenous Hemofiltration with a Novel Asymmetric Triacetate Membrane Hemofilter: An in vitro Study.

INTRODUCTION: Continuous renal replacement therapies (CRRTs) are essential in the treatment of critically ill patients with acute kidney injury and are also discussed as a supporting sepsis therapy. CRRT can affect antibiotics plasma concentrations. OBJECTIVE: The effect of continuous venovenous hemofiltration (CVVH) with an asymmetric triacetate (ATA) membrane hemofilter on concentrations of antibiotics with low (meropenem), medium (vancomycin), and high (daptomycin) protein binding (PB) was investigated. METHODS: 1 L human whole blood supplemented with antibiotics was recirculated and filtrated for 6 h in vitro. Clearances and sieving coefficients (SC) were determined from antibiotics concentrations measured at filter inlet, outlet, and filtrate side. Reservoir concentration data were fitted using a first-order kinetic model. RESULTS: Meropenem and vancomycin concentrations decreased to 5-10% of the initial plasma level, while only 50% of daptomycin were removed. Clearances and SCs were (10.8 [10.8-17.4] mL/min, SC = 0.72 [0.72-1.16]) for meropenem, (13.4 [12.3-13.7] mL/min, 0.89 [0.82-0.92]) for vancomycin, and (2.1 [1.8-2.1] mL/min, 0.14 [0.12-0.14]) for daptomycin. Removal by adsorption was negligible. CONCLUSIONS: The clearances and SCs presented are comparable with findings of other authors. Meropenem and vancomycin, which exhibit low and medium PB, respectively, were strongly removed, while considerably less daptomycin was removed because of its high PB. Our results suggest that in clinical use of the tested antibiotics during CRRT with the ATA hemofilter, the same factors have to be considered for determining the dosing strategy as with filters with other commonly applied membrane materials.

Adsorption kinetics of high mobility group box 1 protein in a polyacrylonitrile hemofiltration membrane.

The high mobility group box 1 protein (HMGB1) is recognized as a prototypical endogenous danger cytokine in sepsis. We previously reported that a polyacrylonitrile (AN69ST) membrane rapidly adsorbed HMGB1. Herein, an in vitro hemofiltration system was designed to assess the HMGB1 adsorption capacity, adsorption sites, and adsorption mechanism of the AN69ST membrane. HMGB1 was repeatedly added seven times during hemofiltration. A rapid decrease in circulating HMGB1 was observed after every addition with no sign of saturation. Presence of HMGB1 on the filter membrane was observed on both membrane surfaces and within the bulk layer using a high concentration of HMGB1 by immunoelectron microscopy. We hypothesized that the addition of heparin to the membrane surface or filtration rate would contribute to the adsorption mechanism. We could not measure the influence of heparin and filtration. Although the membrane was too large to saturate under the µg/mL HMGB1 conditions, our results show that the AN69ST membrane has a robust absorption capacity that could be used to treat sepsis.

Cytokine Blood Filtration Responses in COVID-19.

The real issue with the COVID-19 pandemic is that a rapidly increasing number of patients with life-threatening complications are admitted in hospitals and are not well-administered. Although a limited number of patients use the intensive care unit (ICU), they consume medical resources, safety equipment, and enormous equipment with little possibility of rapid recovery and ICU discharge. This work reviews effective methods of using filtration devices in treatment to reduce the level of various inflammatory mediators and discharge patients from the ICU faster. Extracorporeal technologies have been reviewed as a medical approach to absorb cytokines. Although these devices do not kill or remove the virus, they are a promising solution for treating patients and their faster removal from the ICU, thus relieving the bottleneck.

The haemodynamic effects of oXiris haemofilter in septic shock patients requiring renal support: A single-centre experience.

Excessive pro-inflammatory and anti-inflammatory cytokines are mediators for haemodynamic alterations, metabolic acidosis, and multi-organ failure in sepsis. Recently, oXiris® haemofilter (Baxter, IL, USA) has been introduced as a novel haemofilter to mitigate inflammatory response during sepsis-associated acute kidney injury requiring renal replacement therapy. In the present case series, the researchers retrospectively reviewed critically ill patients with septic shock with the use of at least one oXiris haemofilter during continuous renal replacement therapy between June 2015 and December 2017. The timing for oXiris initiation was at the nephrologists' discretion. The impact of oXiris haemofilter was evaluated on mean arterial pressure, vasopressor dosage, Sequential Organ Failure Assessment score, lactate and base excess during 72 h after treatment. Thirty-five patients were enrolled in the study. An improvement of haemodynamic status was found, shown by increased mean arterial pressure by 6.1% (p = 0.35), decreased norepinephrine dose by 45.9% (p = 0.02), inotropic score by 26.4% (p = 0.02) and vasopressor dependency index by 40.5% (p = 0.01). Cardiovascular Sequential Organ Failure Assessment scores significantly decreased over 72 h (p = 0.02). Blood lactate levels and base excess also showed statistically significant improvements. The median filter lifetime was 23 (interquartile range = 14-36) hours. The intensive care unit mortality was 82.9%. Treatment with oXiris was safe and well-tolerated with no device-related adverse events. In conclusion, continuous renal replacement therapy with oXiris haemofilter is safe and may improve haemodynamic parameters in septic patients with severe renal dysfunction. Nonetheless, these findings were drawn from a retrospective analysis without a control group, and therefore cannot be generalised. Randomised controlled trials are warranted to confirm these findings.

Involvement of ionic interactions in cytokine adsorption of polyethyleneimine-coated polyacrylonitrile and polymethyl methacrylate membranes in vitro.

Polyethyleneimine-coated polyacrylonitrile (AN69ST) and polymethyl methacrylate (PMMA) membranes are effective cytokine-adsorbing hemofilters; however, the cytokine-adsorption mechanism remains elusive. This study investigated the involvement of ionic interactions in cytokine adsorption to a negatively charged AN69ST membrane and neutral-charged PMMA membrane. Experimental hemofiltration was performed for 30 min in a closed-loop circulation system using AN69ST and PMMA hemofilters. Tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 concentrations in the test solutions were measured at baseline and at 10 min and 30 min into hemofiltration. To investigate the involvement of ionic interactions in cytokine adsorption, cytokine clearance (CL) was calculated at 10 min into hemofiltration and with three types of solutions at various pH levels (7.6, 7.2, and 6.8). During AN69ST hemofiltration, the CLs of TNF-α, IL-6, and IL-8 were 38 ± 6 mL/min, 23 ± 7 mL/min, and 78 ± 3 mL/min, respectively, demonstrating a relationship with their respective isoelectric points. During PMMA hemofiltration, the CL of IL-6 peaked at 31 ± 76 mL/min, with no relationship observed between the CL and isoelectric point. When the pH of the test solution shifted from 7.6 to 6.8, the CLs of TNF-α, IL6, and IL-8 increased in the AN69ST hemofilter; whereas, no such trend was observed in the PMMA hemofilter. These results indicated that Ionic interactions play a role in cytokine adsorption by the AN69ST membrane but not the PMMA membrane and highlight the clinical relevance of this finding, as well as the potential practical applications for further hemofilter design.

Multipoint dilution hemofiltration: A new technology for maximum convective clearance.

Convection-based renal replacement therapies (RRTs) have the potential to improve patient outcomes when compared to diffusion-based RRT such as hemodialysis (HD), but have limited clearance rates. We propose and characterize multipoint dilution hemofiltration (MPD-HF), a purely convective blood purification technology which removes the fundamental filtration limit associated with convective RRT resulting in clearance rates on par with HD. In MPD-HF, filtration of liquid and solutes occurs along the length of the hollow fibers that convey the blood, and substitution fluid is pushed into the fibers at multiple points along their length. Since multiple filtration and dilution steps are contained within one pass of the blood through the hollow fiber, the fraction of fluid that can be filtered may be increased to allow a high clearance rate that removes a wide range of toxins. In vitro tests yielded an average steady-state filtrate fraction of 68%, exceeding commercial HDF cartridge filtrate fractions by a factor of approximately 3. The molecular weights of molecules cleared spans up to the cutoff of 66 kDa for albumin.

In vitro Evaluation of Linezolid and Doripenem Clearance with Different Hemofilters.

INTRODUCTION: Renal replacement therapy (RRT) is widely used in the treatment of septic acute kidney injury. However, little is known about how the adsorption properties of hemofilters used in RRT affect antibiotic concentration. Because a cytokine-adsorption membrane is frequently used in RRT, it is important to determine the antibiotic adsorption capacity of this membrane. OBJECTIVE: The present study aimed to investigate the antibiotic adsorption capacity of different hemofilter membranes by in vitro experiments using 2 antibacterial agents (linezolid and doripenem). METHODS: We performed experimental hemofiltration in vitro using polyacrylonitrile (AN69ST), polymethylmethacrylate (PMMA), and polysulfone (PS) hemofilters for 1,440 min. The test solution was a 1,000-mL substitution fluid containing 30 µg/mL linezolid and 120 µg/mL doripenem. We measured drug concentrations at the inlet, outlet, and filtrate ports of the hemofilters for 1,440 min and calculated the sieving coefficient (SC) and adsorption rate (Ra) of the drugs onto the hemofilters. RESULTS: The amount of linezolid adsorbed onto AN69ST, PMMA, and PS membranes was decreased relative to that in the control group at 15 min (p < 0.05). However, no SC for linezolid was obtained thereafter. The Ra of linezolid onto AN69ST, PMMA, and PS membranes was higher than that in the control group (p < 0.05). In contrast, no significant differences were observed in the concentrations and Ra values of doripenem adsorbed onto AN69ST, PMMA, and PS membranes compared with those in the control group. CONCLUSIONS: Doripenem was not adsorbed onto PMMA, PS, and AN69ST membranes. Linezolid was adsorbed onto PMMA, PS, and AN69ST membranes, but only temporarily, and this did not affect drug bioavailability.

Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study.

BACKGROUND AND AIMS: Innovative treatment modalities have not yet shown a clinical benefit in patients with septic shock. To reduce severe cytokinaemia, CytoSorb as an add-on to continuous renal replacement therapy (CRRT) showed promising results in case reports. However, there are no clinical trials investigating outcomes. METHODS: In this investigator-initiated retrospective study, patients with septic shock were treated with CRRT + CytoSorb (n = 67) or CRRT alone (n = 49). The primary outcome was the 28-day all-cause mortality rate. Patients were weighted by stabilized inverse probability of treatment weights (sIPTW) to overcome differences in baseline characteristics. RESULTS: At the start of therapy, CytoSorb-treated patients had higher lactate levels (p < 0.001), lower mean arterial pressure (p = 0.007) and higher levels of noradrenaline (p < 0.001) compared to the CRRT group. For CytoSorb, the mean predicted mortality rate based on a SOFA of 13.8 (n = 67) was 75% (95%CI 71-79%), while the actual 28-day mortality rate was 48% (mean difference - 27%, 95%CI - 38 to - 15%, p < 0.001). For CRRT, based on a SOFA of 12.8 (n = 49), the mean predicted versus observed mortality was 68% versus 51% (mean difference - 16.9% [95%CI - 32.6 to - 1.2%, p = 0.035]). By sIPTW analysis, patients treated with CytoSorb had a significantly lower 28-day mortality rate compared to CRRT alone (53% vs. 72%, respectively, p = 0.038). Independent predictors of 28-day mortality in the CytoSorb group were the presence of pneumosepsis (adjusted odds ratio [aOR] 5.47, p = 0.029), higher levels of lactate at the start of CytoSorb (aOR 1.15, p = 0.031) and older age (aOR per 10 years 1.67, p = 0.034). CONCLUSIONS: CytoSorb was associated with a decreased observed versus expected 28-day all-cause mortality. By IPTW analysis, intervention with CytoSorb may be associated with a decreased all-cause mortality at 28 days compared to CRRT alone.

Kidney Support in Children using an Ultrafiltration Device: A Multicenter, Retrospective Study.

BACKGROUND AND OBJECTIVES: Provision of kidney replacement therapy (KRT) to manage kidney injury and volume overload in critically ill neonates and small children is technically challenging. The use of machines designed for adult-sized patients, necessitates large catheters, a high extracorporeal volume relative to patient size, and need for blood priming. The Aquadex FlexFlow System (CHF Solutions Inc., Eden Prairie, MN) is an ultrafiltration device designed for fluid removal in adults with diuretic resistant heart failure. It has an extracorporeal volume of 33 ml, which can potentially mitigate some complications seen at onset of KRT in smaller infants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this multicenter, retrospective case series of children who received KRT with an ultrafiltration device (n=119 admissions, 884 circuits), we report demographics, circuit characteristics, complications, and short- and long-term outcomes. Patients were grouped according to weight (<10, 10-20, and >20 kg), and received one of three modalities: slow continuous ultrafiltration, continuous venovenous hemofiltration (CVVH), or prolonged intermittent KRT. Our primary outcome was survival to end of KRT. RESULTS: Treatment patterns and outcomes varied between the groups. In patients who weighed <10 kg, the primary indication was AKI in 40%, volume overload in 46%, and ESKD in 14%. These patients primarily received CVVH (66%, n=48) and prolonged intermittent KRT (21%, n=15). In the group weighing >20 kg, volume overload was the primary indication in 91% and slow continuous ultrafiltration was the most common modality. Patients <10 kg had lower KRT survival than those >20 kg (60% versus 97%), more volume overload at onset, and received KRT for a longer duration. Cardiovascular complications at initiation were seen in 3% of treatments and none were severe. Complications during therapy were seen in 15% treatments and most were vascular access-related. CONCLUSIONS: We report the first pediatric experience using an ultrafiltration device to provide a range of therapies, including CVVH, prolonged intermittent KRT, and slow continuous ultrafiltration. We were able to initiate KRT with minimal complications, particularly in critically ill neonates. There is an unmet need for devices specifically designed for younger patients. Having size-appropriate machines will improve the care of smaller children who require kidney support.

Fluid Dynamics Analysis by CT Imaging Technique of New Sorbent Cartridges for Extracorporeal Therapies.

BACKGROUND: Recent innovations in biomaterials technology have led to the development of innovative sorbents adopted as adsorbing devices in the field of extracorporeal blood purification therapies. As removal mechanism, adsorption allows to remove specific molecules, selectively binding them to sorbent materials. In addition to the material properties, a quintessential aspect influencing device properties is blood flow distribution within the sorbent particles. OBJECTIVES: In order to adequately characterize the potential adsorbing properties for an effective blood purification therapy, an in vitro study assessing the fluid dynamics inside 3 new cartridges, HA130, HA230 and HA330 (Jafron, Zhuhai City, -China) was conducted through CT imaging technique. -Methods: The cartridges were placed in vertical position in the CT -gantry. Dye solution was circulated through the cartridges at 250 mL/min, longitudinal sections, 0.5 cm thick, were recorded for 60 s. Furthermore, an in vitro test was conducted to build pressure drop profiles. Blood was circulated at a different flow rate, 100-400 mL/min, step 50 mL/min. Pre and post cartridges pressures were acquired and pressure drop calculated. RESULTS: Sequential images demonstrated an excellent distribution of the flow inside the cartridges. Average flow velocity was 0.37 cm/s for the 3 cartridges. HA130 had a homogeneous flow profile along the entire length of the device; HA230 and HA330 showed minimal differences between central and peripheral regions. Pressure drop profiles resulted linear, increasing proportionally with blood flow rate and packing density. CONCLUSIONS: We may conclude that the structural and functional design of the studied cartridges is adequate for haemoperfusion with no channelling phenomena. This ensures maximum and optimal utilization of the sorbent contained in the devices.