Effect of Mechanical Vibration on Kinetics of Solute Adsorption.

INTRODUCTION: Hemadsorption with new sorbent cartridges is an emerging extracorporeal blood purification technique. Flow distribution inside the sorbent is one of the main issues concerning the device's performance and optimal sorbent utilization. In this experiment, we aimed to investigate the efficacy of vibration during adsorption by measuring the removal of vancomycin. METHODS: In this experimental study, 1,000 mL of saline with 10 g of vancomycin was circulated in a closed circuit (set flow of 250 mL/min) simulating a hemadsorption blood run using HA380 minimodule cartridge containing 75 g of wet resin. This vibration model was implemented with a damping head device installed in front of the adsorption cartridge during the experiment. The kinetics of the vancomycin were assessed by removal ratio over 120 min. RESULTS: We found no difference between the two models. Adsorption with and without vibration did not differ significantly for partial reduction ratios, overall amount of adsorbed molecule, or adsorption kinetics. CONCLUSION: The current design and structure of the minimodule cartridge demonstrated no difference in small-middle solute removal. Further improvement with the addition of mechanical vibration to the device was not observed.

A novel recyclable hemoperfusion adsorbent based on TiO2 nanotube arrays for the selective removal of ß2-microglobulin.

Prolonged and excessive accumulation of ß2-microglobulin (ß2m) in the blood can lead to various kidney-related and other diseases. Currently, the most effective method of removing ß2m from the blood is hemoperfusion. Although some traditional hemoperfusion adsorbents such as cellulose and polystyrene microspheres have been used for the removal of ß2m, their selectivity still needs improvement. Immunosorbents have been developed to address this issue, but high cost and limited application are concerns. TiO2 nanotube arrays (TNTAs) have shown great potential in adsorption-related biomedical applications. In this study, we designed and developed a novel TNTA-based hemoperfusion adsorbent for the removal of ß2m, which has demonstrated good biocompatibility, selectivity, and reusability. We investigated the ß2m adsorption capacities of TNTAs with different pore sizes. The results indicate that TNTAs with a pore size matching the size of ß2m exhibit higher adsorption capacity while also having lower adsorption capacity for albumin, showing the importance of pore size on the selectivity of adsorbents. Additionally, green regeneration of TNTAs is achieved via the photocatalytic activity originating from TiO2. Even after five cycles, the adsorption capacity of TNTAs remained above 70%. Our work demonstrates that inorganic materials with ordered pores are capable to be candidates for hemoperfusion, possessing advantages over traditional organic materials such as high stability, security, and low cost.

Impact of Extended Duration of Polymyxin B-Immobilized Fiber Column Direct Hemoperfusion on Hemodynamics, Vasoactive Substance Requirement, and Pulmonary Oxygenation in Patients with Sepsis: An Observational Study.

INTRODUCTION: Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) is used for patients with septic shock, and the recommended hemoperfusion period is 2 h. However, it remains unclear whether the optimal duration is 2 h or longer. The purpose of this study was to compare the effects of PMX-DHP between conventional and longer duration of PMX-DHP. METHODS: We retrospectively investigated 103 patients with sepsis who underwent PMX-DHP. The demographic data, routine biochemistry, microbiological data, and primary infection site were reviewed in the medical chart. The acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, heart rate, mean arterial pressure (MAP), vasoactive-inotropic score (VIS), and PaO2/FiO2, at baseline and day 3, were compared between the standard group (2 h of PMX-DHP) and the extended group (>2 h of PMX-DHP). RESULTS: Median MAP was significantly lower and median VIS was significantly higher in the extended group at baseline (p < 0.05, 0.01, respectively) There were no significant differences in APACHE II score, SOFA score, and PaO2/FiO2 at baseline between the 2 groups. The increase of MAP and the decrease in VIS from baseline to day 3 were significantly greater in the extended group (p < 0.01, respectively). In the extended group, increase in PaO2/FiO2 was significantly larger in the patients who underwent ≥8 h duration than that in patients who underwent <8 h duration (p < 0.01). The ventilator-free days, the incidence of continuous renal replacement therapy, and the 28-day mortality were not different between the groups. DISCUSSION/CONCLUSIONS: Longer duration of PMX-DHP was associated with the improved MAP and decreased volume of vasoactive-inotropic agents compared with the conventional duration. Eight and longer hours duration of PMX-DHP was associated with the improvement in the pulmonary oxygenation. Further studies are needed to confirm the efficacy of longer duration of PMX-DHP in patients with septic shock.

The Efficacy of Resin Hemoperfusion Cartridge on Inflammatory Responses during Adult Cardiopulmonary Bypass.

AIM: This study aimed to evaluate the efficacy of the resin hemoperfusion device (HA380 hemoperfusion cartridge) on inflammatory responses during adult cardiopulmonary bypass (CPB). METHODS: Sixty patients undergoing surgical valve replacement were randomized into the HP group (n = 30) with an HA380 hemoperfusion cartridge in the CPB circuit or the control group (n = 30) with the conventional CPB circuit. The results of routine blood tests, blood biochemical indexes, and inflammatory factors were analyzed at V0 (pre-CPB), V1 (CPB 30 min), V2 (ICU 0 h), V3 (ICU 6 h), and V4 (ICU 24 h). RESULTS: The HP group had significantly lower levels of IL-6, IL-8, and IL-10. Significant estimation of group differences in the generalized estimating equation (GEE) models was also observed in IL-6 and IL-10. The HP group had significantly lower levels of creatinine (Cr), aminotransferase (AST), and total bilirubin (TBil) compared to the control group. The estimation of differences of Cr, AST, and TBil all reached statistical significance in GEE results. The HP group had significantly less vasopressor requirement and shorter mechanical ventilation time and ICU stay time as compared to the control group. CONCLUSION: The HA380 hemoperfusion cartridge could effectively reduce the systemic inflammatory responses and improve postoperative recovery of patients during adult CPB.

The Seraph®-100 Microbind Affinity Blood Filter Does Not Affect Vancomycin, Tacrolimus, and Mycophenolic Acid Plasma Concentrations.

Extracorporeal blood purification is considered an adjunct therapy in critically ill patients with life-threatening conditions such as sepsis and septic shock. It consists of cytokine removal, removal of endotoxins, a combination of both, or the removal of pathogens themselves. The latter technique was introduced for clinical application very recently. This case study describes a case of a 69-year-old female lung transplant recipient patient with a persistent VV-ECMO-related septic deep vein thrombosis with continuous renal replacement therapy-dependent acute kidney injury initiated on the Seraph®-100 Microbind Affinity Filter in order to control the persistent bacteraemia with coagulase-negative staphylococci. Drug plasma concentrations (vancomycin, tacrolimus, and mycophenolic acid) were measured before and after the device to calculate absorber-related drug clearance.

Hemoadsorption eliminates remdesivir from the circulation: Implications for the treatment of COVID-19.

Both antiviral treatment with remdesivir and hemoadsorption using a CytoSorb® adsorption device are applied in the treatment of severe COVID-19. The CytoSorb® adsorber consists of porous polymer beads that adsorb a broad range of molecules, including cytokines but also several therapeutic drugs. In this study, we evaluated whether remdesivir and its main active metabolite GS-441524 would be adsorbed by CytoSorb® . Serum containing remdesivir or GS-441524 was circulated in a custom-made system containing a CytoSorb® device. Concentrations of remdesivir and GS-441524 before and after the adsorber were analyzed by liquid chromatography-tandem mass spectrometry. Measurements of remdesivir in the outgoing tube after the adsorber indicated almost complete removal of remdesivir by the device. In the reservoir, concentration of remdesivir showed an exponential decay and was not longer detectable after 60 mins. GS-441524 showed a similar exponential decay but, unlike remdesivir, it reached an adsorption-desorption equilibrium at ~48 µg/L. Remdesivir and its main active metabolite GS-441524 are rapidly eliminated from the perfusate by the CytoSorb® adsorber device in vitro. This should be considered in patients for whom both therapies are indicated, and simultaneous application should be avoided. In general, plasma levels of therapeutic drugs should be closely monitored under concurrent CytoSorb® therapy.

Efficacy and safety of liver support devices in acute and hyperacute liver failure: a systematic review and network meta-analysis.

Acute liver failure (ALF) is a potentially life-threatening condition. Liver support therapies can be applied as a bridging-to-transplantation or bridging-to-recovery; however, results of clinical trials are controversial. Our aim was to compare liver support systems in acute and hyperacute liver failure with network meta-analysis. After systematic search, randomized controlled trials (RCT) comparing liver support therapies in adults with acute or hyperacute liver failure were included. In-hospital mortality was the primary outcome, the secondary outcomes were hepatic encephalopathy and mortality-by-aetiology. A Bayesian-method was used to perform network meta-analysis and calculate surface under the cumulative ranking curve (SUCRA) values to rank interventions. Eleven RCTs were included. BioLogic-DT and molecular adsorbent recirculating system (MARS) resulted in the lowest mortality (SUCRAs: 76% and 73%, respectively). In non-paracetamol-poisoned patients, BioLogic-DT, charcoal hemoperfusion and MARS may be equally efficient regarding mortality (SUCRAs: 53%, 52% and 52%, respectively). Considering hepatic encephalopathy, extracorporeal liver assist device (ELAD) may be the most effective option (SUCRA: 78%). However, in pairwise meta-analysis, there were no statistically significant differences between the interventions in the outcomes. In conclusion, MARS therapy seems to be the best available option in reducing mortality. Further research is needed on currently available and new therapeutic modalities. (CRD42020160133).

Vancomycin Adsorption During in vitro Model of Hemoperfusion with HA380 Cartridge.

INTRODUCTION: A critical point for using blood purification during sepsis may be the potential interaction with antimicrobial therapy, the mainstay of sepsis treatment. The aim of our study was to investigate the vancomycin removal during hemoperfusion (HP) using HA380 cartridge. METHODS: This is an experimental study, in which 500 mL of solution was circulated in a closed-circuit (blood flow of 250 mL/min) simulating HP ran using HA380. Vancomycin was added to reach a through concentration or a very high concentration to evaluate the removal ratio (RR) during 120 min of HP. Comparison between blood-crystalloid solution and balanced solution was performed by using Kruskal-Wallis test. The kinetics of vancomycin removal and the adsorption isotherm were evaluated. RESULTS: We found a complete removal of vancomycin at baseline through concentration of 23.0 ± 7.4 mg/L. Using extremely high concentration (baseline 777.0 ± 62.2 mg/L), RR was 90.1 ± 0.6% at 5 min and 99.2 ± 0.6% at 120 min. No difference in terms of RR was found between blood-crystalloid mixture and balanced solution. The kinetics of the vancomycin reduction followed an exponential decay. Repeated boluses (total amount of 2,000 mg) resulted in cumulative adsorption of 1,919.4 mg with RR of 96.6 ± 1.4%, regardless of the amount injected (100 vs. 500 mg). Vancomycin adsorption onto HA380 followed the Langmuir isotherm model. CONCLUSIONS: A considerable amount of vancomycin was rapidly removed during in vitro HP with HA380. Clinical studies are needed to determine whether this may lead to underdosing. Drug therapeutic monitoring is highly recommended when using HA380 for blood purification in patients receiving vancomycin.

Pumpless Extracorporeal Hemadsorption Technique: A New Method for Early Cytokine Elimination?

In recent years, extracorporeal hemadsorption (HA) techniques capable of adsorbing pro- and anti-inflammatory cytokines are increasingly used in various clinical situations. The therapeutic benefit of cytokine elimination likely depends on timing. Although treatment seems to be most effective when started within the first 24 h, therapy is often delayed as it must be combined with another extracorporeal circuit. Thus, using a pumpless extracorporeal HA technique might be a valuable option in order to expedite the commencement of cytokine elimination in critically ill patients.

Rationale of Blood Purification in the Post-Resuscitation Syndrome following Out-of-Hospital Cardiac Arrest: A Narrative Review.

Even today, little is known about the pathophysiology of the post-resuscitation syndrome. Our narrative review is one of the first summarizing all the knowledge about this phenomenon. We have focused our review upon the potential role of blood purification in attenuating the consequences of the post-resuscitation syndrome. Blood purification can decrease the cytokine storm particularly when using a CytoSorb absorber. Acrylonitrile 69-based oXiris membranes can remove endotoxin and high-mobility group box 1 protein. Blood purification techniques can quickly induce hypothermia. Blood purification can be used with veno-arterial extracorporeal membrane oxygenation to remove excess water. Further trials are needed to provide more concrete data about the use of blood purification in the post-resuscitation syndrome.

Direct hemoperfusion using a polymyxin B-immobilized polystyrene column for COVID-19.

OBJECTIVE: To evaluate the efficacy and safety of direct hemoperfusion using a polymyxin B-immobilized polystyrene column (PMX-DHP) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive pneumonia patients. METHODS: This study was a case series conducted at a designated infectious diseases hospital. Twelve SARS-CoV-2-positive patients with partial pressure of arterial oxygen/percentage of inspired oxygen (P/F) ratio < 300 were treated with PMX-DHP on two consecutive days each during hospitalization. We defined day 1 as the first day when PMX-DHP was performed. PMX-DHP efficacy was assessed on days 7 and 14 after the first treatment based on eight categories. Subsequently, improvement in P/F ratio and urinary biomarkers on days 4 and 8, malfunctions, and ventilator and extracorporeal membrane oxygenation avoidance rates were also evaluated. RESULTS: On day 14 after the first treatment, disease severity decreased in 58.3% of the patients. P/F ratio increased while urine ß2-microglobulin decreased on days 4 and 8. Cytokine measurement pre- and post-PMX-DHP revealed decreased levels of interleukin-6 and the factors involved in vascular endothelial injury, including vascular endothelial growth factor. Twenty-two PMX-DHPs were performed, of which seven and five PMX-DHPs led to increased inlet pressure and membrane coagulation, respectively. When the membranes coagulated, the circuitry needed to be reconfigured. Circuit problems were usually observed when D-dimer and fibrin degradation product levels were high before PMX-DHP. CONCLUSIONS: Future studies are expected to determine the therapeutic effect of PMX-DHP on COVID-19. Because of the relatively high risk of circuit coagulation, coagulation capacity should be assessed beforehand.

Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and Recommendation.

Critically ill COVID-19 patients are generally admitted to the ICU for respiratory insufficiency which can evolve into a multiple-organ dysfunction syndrome requiring extracorporeal organ support. Ongoing advances in technology and science and progress in information technology support the development of integrated multi-organ support platforms for personalized treatment according to the changing needs of the patient. Based on pathophysiological derangements observed in COVID-19 patients, a rationale emerges for sequential extracorporeal therapies designed to remove inflammatory mediators and support different organ systems. In the absence of vaccines or direct therapy for COVID-19, extracorporeal therapies could represent an option to prevent organ failure and improve survival. The enormous demand in care for COVID-19 patients requires an immediate response from the scientific community. Thus, a detailed review of the available technology is provided by experts followed by a series of recommendation based on current experience and opinions, while waiting for generation of robust evidence from trials.

Cytokine Adsorption to Polymyxin B-Immobilized Fiber: An in vitro Study.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are episodes of acute respiratory worsening characterized by diffuse alveolar damage superimposed on usual interstitial pneumonia. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) is reported to have beneficial effects on the respiratory status and outcome in patients with AE-IPF although its mechanism of action is not fully elucidated. OBJECTIVE: To investigate whether and how the PMX-immobilized fiber (PMX-F) adsorbs cytokines because reduction of the serum levels of various cytokines has been noted in AE-IPF patients receiving PMX-DHP. METHODS: The propensity of recombinant cytokines for adsorption onto PMX-F was examined by incubating cytokines with heparin-coated or uncoated PMX-F for 2 h at 37°C. Cytokines were quantitated by multiplex bead array assay or ELISA. RESULTS: Interleukin (IL)-8, RANTES, platelet-derived growth factor-bb, and transforming growth factor-ß were substantially adsorbed onto PMX-F without heparin coating. The adsorbed cytokines could be eluted with PMX sulfate, indicating that the PMX moiety is involved in cytokine adsorption. Importantly, although IL-1ß, monocyte chemoattractant protein-1, fibroblast growth factor 2, and vascular endothelial growth factor-A were adsorbed onto PMX-F to lesser extents, the adsorption was enhanced by heparin coating of PMX-F. Furthermore, heparin-coated PMX-F acquired the capability to adsorb IL-6, IL-12, and tumor necrosis factor α. An affinity of heparin to PMX was determined (Kd = 0.061 ± 0.032 mg/mL), which accounts for the enhanced cytokine adsorption onto PMX-F upon heparin coating. CONCLUSIONS: Various cytokines involved in inflammation, fibrosis, and vascular permeability were shown to be adsorbed onto PMX-F. Removal of multiple cytokines may be associated with positive impacts of PMX-DHP in patients with AE-IPF.

Selective Polymyxin Hemoperfusion in Complex Therapy of Sepsis in Children after Cardiac Surgery.

BACKGROUND: To date, sepsis remains one of the main challenges of intensive care in pediatrics. Newborns with low birth weight and infants with chronic diseases and congenital disorders are particularly at risk. The incidence of infectious complications in pediatric cardiac surgery is known to be approximately 15-30%. The main etiological factor of sepsis is endotoxin. AIM: To evaluate the efficiency and safety of polymyxin (PMX) B-immobilized column-direct hemoperfusion in complex intensive therapy of sepsis in children after cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective cohort study. METHODS: This study enrolled 15 children, aged 9-96 months, with congenital heart diseases and with body weights of 6.2-22.5 kg. The criteria for admission were body weight >6 kg and clinical and laboratory signs of sepsis (microbiological analysis, procalcitonin [PCT] >2 ng/mL, and endotoxin activity assay [ЕАА] >0.6). Intensive care included inotropic and vasopressor support, mechanical ventilation, broad-spectrum antibiotic therapy, and PMX hemoperfusion procedures. Extracorporeal therapy was initiated within 24 h following the sepsis diagnosis. Every patient underwent 2 hemoperfusion sessions with the use of a PMX B-immobilized column; the session duration was 180 min. RESULTS: We noted improvements in hemodynamic parameters, oxygenation index, and laboratory signs of sepsis, with decreases in the endotoxin concentration according to the EAA, PCT, and presepsin levels. The 28-day survival of the patients in this severely affected group was 80%. Main Conclusion: The inclusion of extracorporeal methods of blood purification, aimed at the selective elimination of circulating endotoxin, in the treatment of sepsis increases the survival rates of children after open heart surgery. Second Conclusion: The obtained results of sepsis therapy with PMX hemoperfusion in children after cardiac surgery enable us to suggest the sufficient safety and efficiency of the procedures in this category of severely affected patients.

Elimination of Staphylococcus aureus from the bloodstream using a novel biomimetic sorbent haemoperfusion device.

Removal of bacteria from the blood by means of extracorporeal techniques has been attempted for decades. In late 2019, the European Union licensed the first ever haemoperfusion device for removal of bacteria from the blood. The active ingredient of Seraph 100 Microbind Affinity Blood Filter is ultrahigh molecular weight polyethylene beads with endpoint-attached heparin. Bacteria have been shown to bind to heparin as they would usually do to the heparan sulfate on the cell surface, thereby being removed from the blood stream. We describe the first case of a female chronic haemodialysis patient in which this device was clinically used for a Staphylococcus aureus infection that persisted for 4 days despite antibiotic therapy. After a single treatment, the bacterial load decreased and the blood cultures at the end of a 4 hour haemoperfusion exhibited no bacterial growth.

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1.

Mycotoxins, such as aflatoxin B1 (AFB1), pose a serious threat as biological weapons due to their high toxicity, environmental stability, easy accessibility and lack of effective therapeutics. This study investigated if blood purification therapy with CytoSorb (CS) porous polymer beads could improve survival after a lethal aflatoxin dose (LD90). The effective treatment window and potential therapeutic mechanisms were also investigated. Sprague Dawley rats received a lethal dose of AFB1 (0.5-1.0 mg/kg) intravenously and hemoperfusion with a CS or Control device was initiated immediately, or after 30, 90, or 240-minute delays and conducted for 4 hours. The CS device removes AFB1 from circulation and significantly improves survival when initiated within 90 minutes of toxin administration. Treated subjects exhibited improved liver morphology and health scores. Changes in the levels of cytokines, leukocytes and platelets indicate a moderately-severe inflammatory response to acute toxin exposure. Quantitative proteomic analysis showed significant changes in the level of a broad spectrum of plasma proteins including serine protease/endopeptidase inhibitors, coagulation factors, complement proteins, carbonic anhydrases, and redox enzymes that ostensibly contribute to the therapeutic effect. Together, these results suggest that hemoadsorption with CS could be a viable countermeasure against acute mycotoxin exposure.

Hemoadsorption to Reduce Plasma-Free Hemoglobin During Cardiac Surgery: Results of REFRESH I Pilot Study.

Generation of plasma-free hemoglobin (pfHb) and activated complement during complex cardiac surgery contributes to end-organ dysfunction. This prospective, multicenter REFRESH I (REduction in FREe Hemoglobin) randomized controlled trial evaluated the safety and feasibility of CytoSorb hemoadsorption therapy to reduce these factors during prolonged cardiopulmonary bypass (CPB). Eligible patients underwent elective, nonemergent complex cardiac surgery with expected CPB duration ≥3 hours. Exclusions included single procedures including primary coronary artery bypass graft, single valves, transplant, and left ventricular assist device extraction. TREATMENT used 2 parallel 300 mL CytoSorb hemoadsorption cartridges in a side circuit during CPB. CONTROL was standard of care. Of 52 enrolled patients, 46 underwent surgery (Safety group, n = 23 vs Control, n = 23), and 38 were evaluated for pfHb reduction (EFFICACY group, n = 18 vs CONTROL, n = 20). Type and number of serious adverse events (44 vs 43 CONTROL) were similar, as was 30-day mortality. Transient reduction in platelets during CPB was observed in both groups, especially TREATMENT, but returned to pretreatment levels after CPB without bleeding. Peak pfHb was positively correlated with CPB length (P = 0.01) but the high variability of pfHb, due to the broad surgical procedure mix, prevented detection of changes in pfHb in the overall EFFICACY population. However, the valve replacement surgery subgroup (8 vs 10 CONTROL) had the highest peak pfHb levels, and TREATMENT demonstrated significant pfHb reductions vs CONTROL (P ≤ 0.05) in CPB ≥3 hours. In the EFFICACY group, C3a and C5a were significantly reduced by treatment throughout surgery. Intraoperative hemoadsorption with CytoSorb was safe and feasible in this randomized, controlled pilot study during complex cardiac surgery. Treatment with CytoSorb resulted in significant reductions in pfHb during valve replacement surgery and reductions in C3a and C5a in the overall EFFICACY group. Future studies will target complex cardiac surgery patients with prolonged CPB to assess hemoadsorption effect on end-organ dysfunction and outcomes.

Mortality Effects of Prolonged Hemoperfusion Therapy Using a Polymyxin B-Immobilized Fiber Column for Patients with Septic Shock: A Sub-Analysis of the DESIRE Trial.

BACKGROUND/AIMS: The optimal duration of hemoperfusion therapy with a polymyxin B-immobilized fiber column has not yet been verified. METHODS: This analysis examined whether hemoperfusion therapy with a polymyxin B-immobilized fiber column lasting longer than 2 h (prolonged polymyxin) improved outcomes for patients with septic shock compared to 2-h polymyxin therapy (sub-analysis of data from the DESIRE trial). RESULTS: The 2-h and prolonged polymyxin groups contained 22 and 14 patients, respectively. Both groups had similar characteristics. The polymyxin duration per session in the prolonged polymyxin group was significantly longer (median, 5.5 h) than in the 2-h polymyxin group (p < 0.01). The 28-day mortality rate was significantly higher in the 2-h polymyxin group (7, 31.8%) than in the prolonged polymyxin group (0, 0%; p = 0.019). CONCLUSION: Prolonged polymyxin therapy might be associated with better clinical outcomes than 2-h polymyxin therapy in patients with septic shock. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=491744.