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Neutrophil extracellular traps (NETs) have recently emerged as a potential link between inflammation, immunity, and thrombosis, as well as other coagulation disorders which present a major challenge in the context of extracorporeal membrane oxygenation (ECMO). By examining blood from ECMO patients for NETs and their precursors and correlating them with clinical and laboratory biomarkers of coagulation and inflammation, this study aims to evaluate the association between the presence of NETs in the bloodstream of ECMO patients and the development of potentially severe coagulation disorders during ECMO therapy. Therefore, blood samples were collected from healthy volunteers (n=13) and patients receiving veno-venous (VV) ECMO therapy (n=10). To identify NETs and their precursors, DNA and myeloperoxidase as well as granulocyte marker CD66b were visualized simultaneously by immunofluorescence staining in serial blood smears. Differentiation of DNA-containing objects and identification of NETs and their precursors was performed semiautomatically by a specific algorithm using the shape and size of DNA staining and the intensity of MPO and CD66b signal. Neutrophil extracellular traps and their precursors could be detected in blood smears from patients requiring VV ECMO. Compared to volunteers, ECMO patients presented significantly higher rates of NETs and NET precursors as well as an increased proportion of neutrophil granulocytes in all detected nucleated cells. A high NET rate prior to the initiation of ECMO therapy was associated with both increased IL-6 and TNF-α levels as an expression of a high cytokine burden. These patients with increased NET release also presented an earlier and significantly more pronounced decrease in platelet counts and ATIII activity following initiation of therapy compared with patients with less elevated NETs. These findings provide further indications for the development of immune-mediated acquired thrombocytopenia in ECMO patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Haus, Foltan, Philipp, Mueller, Gruber, Lingel, Krenkel and Lehle.)

Background: Thrombosis remains a critical complication during venovenous extracorporeal membrane oxygenation (VV ECMO). The involvement of neutrophil extracellular traps (NETs) in thrombogenesis has to be discussed. The aim was to verify NETs in the form of cell-free DNA (cfDNA) in the plasma of patients during ECMO., Methods: A fluorescent DNA-binding dye (QuantifFluor®, Promega) was used to detect cell-free DNA in plasma samples. cfDNA concentrations from volunteers (n = 21) and patients (n = 9) were compared and correlated with clinical/technical data before/during support, ECMO end and time of a system exchange., Results: Before ECMO, patients with a median (IQR) age of 59 (51/63) years, SOFA score of 11 (10/15), and ECMO run time of 9.0 (7.0/19.5) days presented significantly higher levels of cfDNA compared to volunteers (6.4 (5.8/7.9) ng/μL vs. 5.9 (5.4/6.3) ng/μL; p = 0.044). Within 2 days after ECMO start, cfDNA, inflammatory, and hemolysis parameters remained unchanged, while platelets decreased (p = 0.005). After ECMO removal at the end of therapy, cfDNA, inflammation, and coagulation data (except antithrombin III) remained unchanged. The renewal of a system resulted in known alterations in fibrinogen, d-dimers, and platelets, while cfDNA remained unchanged., Conclusion: Detection of cfDNA in plasma of ECMO patients was not an indicator of acute and circuit-induced thrombogenesis., (© 2023 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Antithrombogenic coatings of artificial surfaces within extracorporeal membrane oxygenation (ECMO) circuits improved its bio- and hemocompatibility. However, there is still a risk of thrombus formation in particular within the membrane oxygenator (MO). Since inflammatory cells are essential components within clots, the aim was to identify the extent of cellular accumulations on gas exchange capillaries from different ECMO systems. Thirty-four MOs (PLS, n = 27, Getinge; Hilite 7000 LT, n = 7, Fresenius Medical Care, Germany) were collected from adult patients. The extent of cellular deposits on gas exchange capillaries was classified using nuclear 4',6-diamidino-2-phenylindole staining and fluorescence microscopy. All Hilite oxygenators exhibited small cellular deposits. In contrast, the cellular distribution was heterogeneous on capillaries from PLS oxygenators: small deposits (34%), clusters (44%) and membrane-spanning cell structures (pseudomembranes) (22%). Overall, the median fluorescence intensity was significantly higher in the PLS group. Nevertheless, within 3 days before MO removal, there was no alteration in critical parameters ( d -dimer and fibrinogen levels, platelet counts, and pressure drop across the MO). In conclusion, despite the histological differences on the gas capillaries from different types of oxygenators, there was no further evidence of increased inflammation and coagulation parameters that indicate clot formation within oxygenators., Competing Interests: Disclosure: M.L. received lecture honoraries from Fresenius Medical Care. The remaining authors have no conflicts of interest to report. This was an inhouse funding., (Copyright © ASAIO 2023.)

Objectives: Unfractionated heparin (UFH) is the commonly used anticoagulant to prevent clotting of the ECMO circuit and thrombosis of the cannulated vessels. A side effect of UFH is heparin-induced thrombocytopenia (HIT). Little is known about HIT during ECMO and the impact of changing anticoagulation in ECMO patients with newly diagnosed HIT. The aim of the study was to determine the prevalence, complications, impact of switching anticoagulation to argatroban and outcomes of patients developing heparin-induced thrombocytopenia (HIT) during either veno-venous (VV) or veno-arterial (VA) ECMO., Methods: Retrospective observational single centre study of prospectively collected data of consecutive patients receiving VV ECMO therapy for severe respiratory failure and VA ECMO for circulatory failure from January 2006 to December 2016 of the Medical intensive care unit (ICU) of the University Hospital of Regensburg. Treatment of HIT on ECMO was done with argatroban., Results: 507 patients requiring ECMO were included. Further HIT-diagnostic was conducted if HIT-4T-score was ≥4. The HIT-confirmed group had positive HIT-enzyme-linked-immunosorbent-assay (ELISA) and positive heparin-induced-platelet-activation (HIPA) test, the HIT-suspicion group a positive HIT-ELISA and missing HIPA but remained on alternative anticoagulation until discharge and the HIT-excluded group a negative or positive HIT-ELISA, however negative HIPA. These were compared to group ECMO-control without any HIT suspicion. The prevalence of HIT-confirmed was 3.2%, of HIT-suspicion 2.0% and HIT-excluded 10.8%. Confirmed HIT was trendwise more frequent in VV than in VA (3.9 vs. 1.7% p = 0.173). Compared to the ECMO control group, patients with confirmed HIT were longer on ECMO (median 13 vs. 8 days, p = 0.002). Different types of complications were higher in the HIT-confirmed than in the ECMO-control group, but in-hospital mortality was not different (31% vs. 41%, p = 0.804)., Conclusion: HIT is rare on ECMO, should be suspected, if platelets are decreasing, but seems not to increase mortality if treated promptly., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: ML received lecture honoraria from Fresenius Medical Care. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Patients with severe coronavirus disease-19 (COVID-19)-associated acute respiratory distress on venovenous extracorporeal lung support (V-V ECLS) showed a high incidence of vascular as well as ECLS-related thrombotic complications. The latter may influence the outcome of the patients., Methods: This is a retrospective monocentric study on prospectively collected data of technical complications including 69 adult COVID-19 patients on V-V ECLS (ECLS Registry, March 2020 until April 2021) without and with system exchanges. Alterations in ECLS-specific data, hemolysis, coagulation, and hemostasis parameters were analyzed., Results: Every second COVID-19 patient on V-V ECLS developed technical complications. Optimized ECLS management at our ECLS center reduced cases of acute clot formation (pump head thrombosis, acute oxygenator thrombosis) (17%), and allowed early identification of progressive clotting processes (worsened gas transfer, coagulation disorder) (14%, 54%) with a significant overhang of hyperfibrinolysis (37%). Although COVID-19 disease and technical complications caused the prolonged length of stay at the intensive care unit and ECLS support times, the proportion of successful weaning and survival rates were comparable with patients without system exchange., Conclusion: The survival of ECLS patients with COVID-19 was independent of the requirement for system exchange due to technical-induced coagulation disorders. Close monitoring for circuit clotting is mandatory in COVID-19 patients and is one prerequisite for successful organ support in these difficult patients., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Objective: Failure of membrane oxygenator (MO) function of venovenous extracorporeal membrane oxygenators (VV ECMO) remains problematic. The development of device-induced coagulation disorder (COD) or worsened gas transfer (WGT) necessitates a system exchange. The aim was to correlate von Willebrand factor antigen (vWF:Ag) with the predisposition to MO failure and mortality., Methods: Laboratory parameters (inflammation, coagulation) and ECMO-related data from 31 VV ECMO patients were analyzed before and after the first MO exchange. Study groups were identified according to the exchange reasons (COD, WGT) and the extent of vWF:Ag (low, ≤425%; high, >425%)., Results: vWF:Ag remained unchanged after system exchange. High vWF:Ag was associated with systemic endothelial activation of older and obese patients with elevated SOFA score, increased norepinephrine and higher requirement of continuous renal replacement therapy without an effect on MO runtime and mortality. Including the mechanism of MO failure (COD, WGT), various patient group emerged. COD/low vWF:Ag summarized younger and less critically ill patients that benefit mainly from ECMO by a significant improvement of their inflammatory and coagulation status (CRP, D-dimers, fibrinogen) and highest survival rate (91%). Instead, WGT/high vWF:Ag presented older and more obese patients with a two-digit SOFA score, highest norepinephrine, and aggravated gas transfer. They benefited temporarily from system exchange but with worst survival (33%)., Conclusions: vWF:Ag levels alone cannot predict early MO failure and outcome in VV ECMO patients. Probably, the mechanism of clotting disorder in combination with the vWF:Ag level seems to be essential for clot formation within the MO. In addition, vWF:Ag levels allows the identification different patient populations In particular, WGT/high vWF:Ag represented a critically ill population with higher ECMO-associated mortality., Competing Interests: The authors have declared that no competing interests exist.

Coagulative disorders, especially clotting during extracorporeal membrane oxygenation, are frequent complications. Direct visualization and analysis of deposits in membrane oxygenators using computed tomography (CT) may provide an insight into the underlying mechanisms causing thrombotic events. However, the already established multidetector CT (MDCT) method shows major limitations. Here, we demonstrate the feasibility of applying industrial micro-CT (µCT) to circumvent these restrictions. Three clinically used membrane oxygenators were investigated applying both MDCT and µCT. The scans were analyzed in terms of clot volume and local clot distribution. As validation, the clot volume was also determined from the fluid volume, which could be filled into the respective used oxygenator compared to a new device. In addition, cross-sectional CT images were compared with crosscut oxygenators. Based on the µCT findings, a morphological measure (sphericity) for assessing clot structures in membrane oxygenators is introduced. Furthermore, by comparing MDCT and µCT results, an augmentation of the MDCT method is proposed, which allows for improved clot volume determination in a clinical setting.

Venovenous (VV) and venoarterial (VA) extracorporeal membrane oxygenation (ECMO) are effective support modalities to treat critically ill patients. ECMO-associated hemolysis remains a serious complication. The aim was to disclose similarities and differences in VA- and VV ECMO-associated hemolysis. This is a retrospective single-center analysis (January 2012 to September 2018) including 1,063 adult consecutive patients (VA, n = 606; VV, n = 457). Severe hemolysis (free plasma hemoglobin, fHb > 500 mg/l) during therapy occurred in 4% (VA) and 2% (VV) (p≤0.001). VV ECMO showed significantly more hemolysis by pump head thrombosis (PHT) compared to VA ECMO (9% vs. 2%; p≤0.001). Pretreatments (ECPR, cardiac surgery) of patients who required VA ECMO caused high fHb pre levels which aggravates the proof of ECMO-induced hemolysis (median (interquartile range), VA: fHb pre: 225.0 (89.3-458.0); VV: fHb pre: 72.0 (42.0-138.0); p≤0.001). The survival rate to discharge from hospital differed depending on ECMO type (40% (VA) vs. 63% (VV); p≤0.001). Hemolysis was dominant in VA ECMO patients, mainly caused by different indications and not by the ECMO support itself. PHT was the most severe form of ECMO-induced hemolysis that occurs in both therapies with low frequency, but more commonly in VV ECMO due to prolonged support time., Competing Interests: The authors have declared that no competing interests exist.

Clot formation within membrane oxygenators (MOs) remains a critical problem during extracorporeal membrane oxygenation (ECMO). The composition of the clots-in particular, the presence of von Willebrand factor (vWF)-may be an indicator for prevalent nonphysiological flow conditions, foreign body reactions, or coagulation abnormalities in critically ill patients. Mats of interwoven gas exchange fibers from randomly collected MOs (PLS, Maquet, Rastatt, Germany) of 21 patients were stained with antibodies (anti-vWF and anti-P-selectin) and counterstained with 4',6-diamidino-2-phenylindole. The extent of vWF-loading was correlated with patient and technical data. While 12 MOs showed low vWF-loadings, 9 MOs showed high vWF-loading with highest accumulations close to crossing points of adjacent gas fibers. The presence and the extent of vWF-fibers/"cobwebs," leukocytes, platelet-leukocyte aggregates (PLAs), and P-selectin-positive platelet aggregates were independent of the extent of vWF-loading. However, the highly loaded MOs were obtained from patients with a significantly elevated SOFA score, severe thrombocytopenia, and persistent liver dysfunction. The coagulation abnormalities of these critically ill patients may cause an accumulation of the highly thrombogenic and elongated high-molecular-weight vWF multimers in the plasma which will be trapped in the MOs during the ECMO therapy., (© 2019 The Authors. Artificial Organs published by Wiley Periodicals, Inc. on behalf of International Center for Artificial Organ and Transplantation (ICAOT).)

In cases of severe cardiopulmonary deterioration, quick establishment of venoarterial extracorporeal membrane oxygenation (ECMO) represents a support modality. After successful arterial peripheral cannulation, a certain grade of peripheral limb malperfusion is a fairly common phenomenon. Detection of peripheral malperfusion is vital, since it can result in compartment syndrome or even loss of the affected limb. To prevent or resolve emerging lower limb ischaemia, a newly designed perfusion catheter is placed into the superficial femoral artery, distal to the arterial cannula via ECMO. The aim of our study was to evaluate flow and haemodynamic characteristics of this novel distal limb perfusion cannula for ECMO therapy and present these important findings for the first time. The distal perfusion cannula blood flow increases in linear correlation with ECMO blood flow The variability of distal perfusion cannula blood flow with a 15 Fr cannula ranges between 160 ± 0.40 mL min -1 at 1.5 L min -1 ECMO flow rate and 480 ± 80 mL min -1 at 5.0 L min -1 ECMO blood flow, respectively. Comparatively, the 17-Fr-sized cannula performs on a scale of 140 ± 20 to 390 ± 60 mL distal perfusion cannula blood flow at 1.5-5.0 L min -1 ECMO blood flow, respectively. The quantitative assessment of the distal perfusion cannula blood flow has revealed that distal perfusion cannula blood flow can measure up to 10% of the ECMO blood flow. Furthermore, it has been also well demonstrated that the novel distal perfusion cannula is sufficient to compensate peripheral limb ischaemia.

Over the past decade, veno-venous extracorporeal membrane oxygenation (vvECMO) has been increasingly utilized in respiratory failure in patients. This study presents our institution´s experience focusing on the life span of ECMO systems reflecting the performance of a particular system. A retrospective review of our ECMO database identified 461 adult patients undergoing vvECMO (2010-2017). Patients that required more than one system and survived the first exchange >24 hours (n = 139) were included. Life span until the first exchange and exchange criteria were analyzed for all systems (PLS, Cardiohelp HLS-set, both Maquet Cardiopulmonary, Rastatt, Germany; Deltastream/Hilite7000LT, iLA-activve, Xenios/NovaLung, Heilbronn, Germany; ECC.O5, LivaNova, Mirandola, Italy). At our ECMO center, the frequency of a system exchange was 30%. The median (IQR) life span was 9 (6-12) days. There was no difference regarding the different systems (p = 0.145 and p = 0.108, respectively). However, the Deltastream systems were exchanged more frequently due to elective technical complications (e. g. worsened gas transfer, development of coagulation disorder, increased bleedings complications) compared to the other exchanged systems (p = 0.013). In summary, the used ECMO systems are safe and effective for acute respiratory failure. There is no evidence for the usage of a specific system. Only the increased predictability of an imminent exchange preferred the usage of a Deltastream system. However, the decision to use a particular system should not depend solely on the possible criteria for an exchange., Competing Interests: The authors have declared that no competing interests exist.

Thrombosis is the most common technical complication with extracorporeal membrane oxygenation (ECMO). Accumulations of leukocytes on the gas exchange membranes within a membrane oxygenator (MO) may initiate thrombosis and influence outcome. MOs (n = 41) were removed routinely from adult patients on ECMO, preserved, and analyzed for their cellular deposits using nuclear (4',6-diamidino-2-phenylindole) and cell type-specific markers (CD45; von Willebrand factor, vWF). The extent of cellular colonization was correlated with patient data. Blood contact caused adhesion of leukocytes and accumulation of vWF. Six MOs contained "pseudomembranes" (PM). MOs with PM were from younger patients (median [interquartile range {IQR}]; age, 36 [30-47] vs. 61 [51-71] years; p = 0.040) and the leukocyte count before ECMO was on average higher (21 [16-24] vs. 15 [8-18] ×10 per L; p = 0.051) compared with PM-free MOs. The development of PMs did not influence pressure drop across the MO. Data indicating coagulation disorder within the MOs (d-dimers, fibrinogen, and platelets) were not significantly different between the groups. There was only one acute MO thrombosis in a PM-free MO. The support time of the analyzed MOs with PM tended to be longer when compared with PM-free MOs (11 [6-19] vs. 8 [5-11] days). Nevertheless, all patients with MOs with PMs were successfully weaned (6/6 vs. 17/35) and discharged from hospital (6/6 vs. 17/35; p = 0.027) compared with patients with PM-free MOs. In conclusion, elderly people on ECMO showed reduced PM formation that may reduce the risk of MO thrombosis. Younger patients had no negative effect.

Aims: Elevated levels of plasma free hemoglobin (fHb) indicate red blood cell (RBC) damage. The aim of this study was to analyze the prevalence of hemolysis and metabolic acidosis in patients on extracorporeal life support (ECLS) and to investigate whether it is a marker for outcome., Methods and Results: This retrospective analysis included 215 adult patients with cardiac failure treated with ECLS. The cohort was divided into three groups: ECLS (1) during ongoing cardiopulmonary resuscitation (CPR, n = 110); (2) after CPR with return of spontaneous circulation and sustained cardiogenic shock (n = 45); (3) in severe cardiogenic shock without previous CPR (n = 60). Lactate, arterial pH value and fHb were measured daily before (pre-fHb) and during ECLS. CPR caused a pronounced increase in pre-fHb (group1, 318 (138/586) mg/L; group2, 212 (107/439) mg/L; group3, 79 (53/232) mg/L; p < 0.001). Within 24 hours on ECLS, fHb declined significantly. Compared to group 3 without CPR, group1 and 2 had a lower pH value (group1, 7.10 (6.93/7.20); group2, 7.21 (7.16/7.27); group3, 7.28 (7.20/7.35); p < 0.001), and an increased lactate level (group1, 88 (55/129) mg/dL; group2, 76 (36/111) mg/dL; group3, 52 (25/83) mg/dL; p < 0.0001). Multivariante analysis showed that pre-fHb had no prognostic value for survival. Only a low pre-lactate was a surrogate marker for successful weaning (p < 0.0001) and discharge from hospital (p = 0.0028)., Conclusions: CPR was associated with a strongly increased fHb irrespective of ECLS. Implantation of ECLS did not aggravate hemolysis but instead decreased it within 24 hours. In this study low pre-fHb had no predictive value for survival., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Multipotent progenitor cells were mobilized during pediatric extracorporeal membrane oxygenation (ECMO). We hypothesize that these cells also adhered onto polymethylpentene (PMP) fibers within the membrane oxygenator (MO) during adult ECMO support. Mononuclear cells were removed from the surface of explanted PMP-MOs (n = 16). Endothelial-like outgrowth and mesenchymal-like cells were characterized by flow cytometric analysis using different surface markers. Spindle-shaped attaching cells were identified early, but without proliferative activity. After long-term cultivation palisading type or cobblestone-type outgrowth cells with high proliferative activity appeared and were characterized as (i) leukocytoid CD45+/CD31+ (CD133+/VEGFR-II+/CD90+/CD14+/CD146dim/CD105dim); (ii) endothelial-like CD45-/CD31+ (VEGF-RII+/CD146+/CD105+/CD133-/CD14-/CD90-); and (iii) mesenchymal-like cells CD45-/CD31- (CD105+/CD90+/CD133dim/VEGFR-II-/CD146-/CD14-). The distribution of the cell populations depended on the MO and cultivation time. Endothelial-like cells formed capillary-like structures and did uptake Dil-acetylated low-density lipoprotein. Endothelial- and mesenchymal-like cells adhered on the surface of PMP-MOs. Further research is needed to identify the clinical relevance of these cells., (Copyright © 2015 The Authors. Artificial Organs published by Wiley Periodicals, Inc. on behalf of International Center for Artificial Organs and Transplantation (ICAOT).)

Objective: Extracorporeal membrane oxygenation is a rescue therapy for patients with severe lung failure. Major complications caused by extracorporeal membrane oxygenation are bleeding, thrombosis, and hemolysis. The aim of this study was to compare the impact of different extracorporeal membrane oxygenation systems on blood hemostasis in adults during veno-venous extracorporeal membrane oxygenation therapy., Design: Single center prospective randomized study., Setting: University Hospital Regensburg, Germany., Patients: Adult patients with severe acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation therapy., Interventions: None., Measurements and Main Results: Three different extracorporeal membrane oxygenation systems: the Cardiohelp system (Maquet Cardiopulmonary AG), the Dideco ECC.O5 (Sorin Group), and the Deltastream system with Hilite 7000 LT + DP3 pumphead (Medos Medizintechnik AG) were compared. Therefore hemostasis, anticoagulation, hemolysis, and inflammatory parameters were monitored. Of the 54 patients included in the study, 18 patients each were randomly assigned to the three different extracorporeal membrane oxygenation systems. Exclusion criteria were acute renal failure, trauma, and surgery within 2 days. The median time on veno-venous extracorporeal membrane oxygenation support was 13.5 days (4-70 d). Median platelet count had dropped from 220.5 G/L before extracorporeal membrane oxygenation therapy to a minimum of 133 G/L by the last day of extracorporeal membrane oxygenation support. During the first 5 days of extracorporeal membrane oxygenation therapy, prothrombin fragment 1.2 (F1.2) (1.36-2.4 µM), thrombin-antithrombin complex (14.5-50 µg/L), and D-dimers (6.00-27.0 mg/L) increased, whereas fibrinogen values dropped from 5.8 to 4.1 g/L. The three different extracorporeal membrane oxygenation systems did not show any differences with regard to hemostasis, anticoagulation, hemolysis, and inflammatory parameters within the first 5 days of extracorporeal membrane oxygenation therapy., Conclusions: Over time, miniaturized veno-venous extracorporeal membrane oxygenation therapy increasingly activates coagulation. The different types of membrane oxygenators and pumps did not significantly alter hemostasis.

The aim of the study was to explore the prevalence and risk factors for technical-induced hemolysis in adults supported with veno-venous extracorporeal membrane oxygenation (vvECMO) and to analyze the effect of hemolytic episodes on outcome. This was a retrospective, single-center study that included 318 adult patients (Regensburg ECMO Registry, 2009-2014) with acute respiratory failure treated with different modern miniaturized ECMO systems. Free plasma hemoglobin (fHb) was used as indicator for hemolysis. Throughout a cumulative support duration of 4,142 days on ECMO only 1.7% of the fHb levels were above a critical value of 500 mg/l. A grave rise in fHb indicated pumphead thrombosis (n = 8), while acute oxygenator thrombosis (n = 15) did not affect fHb. Replacement of the pumphead normalized fHb within two days. Neither pump or cannula type nor duration on the first system was associated with hemolysis. Multiple trauma, need for kidney replacement therapy, increased daily red blood cell transfusion requirements, and high blood flow (3.0-4.5 L/min) through small-sized cannulas significantly resulted in augmented blood cell trauma. Survivors were characterized by lower peak levels of fHb [90 (60, 142) mg/l] in comparison to non-survivors [148 (91, 256) mg/l, p≤0.001]. In conclusion, marked hemolysis is not common in vvECMO with modern devices. Clinically obvious hemolysis often is caused by pumphead thrombosis. High flow velocity through small cannulas may also cause technical-induced hemolysis. In patients who developed lung failure due to trauma, fHb was elevated independantly of ECMO. In our cohort, the occurance of hemolysis was associated with increased mortality.

Thrombosis inside the membrane oxygenator (MO) is a critical complication during venovenous extracorporeal membrane oxygenation (ECMO). The aim of this study was to prove if thrombotic clots manifest within the MO when D-dimer levels are elevated over a long-term period. Heparin-coated polymethylpentene MOs (n = 13) were exchanged due to high plasma D-dimer levels. Clot volume was calculated using multidetector computed tomography (MDCT). Coagulation parameters and MO function were analyzed before and after MO exchange. Before MO exchange, D-dimer levels increased significantly in each patient (11.5 [6.5-15.5] mg/L to 35.0 [34-35] mg/L, P ≤ 0.001). High levels of D-dimers were tolerated for 1 to 6 days. Additionally, fibrinogen concentration (n = 8) and platelet count decreased (n = 8). Within 48 h after exchange, D-dimer levels decreased significantly (n = 11, 12 [8-16] mg/L, P = 0.004). Fibrinogen concentration and platelet counts increased. Clots were found in all MOs in the inlet part of the device. Clot volume (16-106 cm(3) ) did not correlate with MO support time but increased significantly when high D-dimer levels were accepted for >2 days. An increase or high levels of D-dimers in absence of other explaining pathology during ECMO therapy reflected coagulation activity within the MO. Evidence of clots within the MO at high D-dimer levels and decrease after exchange underline the relevance of D-dimer testing during ECMO treatment. Besides, surveillance of MOs during ongoing ECMO therapy will help to predict clot formation, and to avoid system-induced coagulation disorders as well as critical situations., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Objectives: Technical complications are a known hazard in veno-venous extracorporeal membrane oxygenation (vvECMO). Identifying these complications and predictive factors indicating a developing system-exchange was the goal of the study., Methods: Retrospective study on prospectively collected data of technical complications including 265 adult patients (Regensburg ECMO Registry, 2009-2013) with acute respiratory failure treated with vvECMO. Alterations in blood flow resistance, gas transfer capability, hemolysis, coagulation and hemostasis parameters were evaluated in conjunction with a system-exchange in all patients with at least one exchange (n = 83)., Results: Values presented as median (interquartile range). Patient age was 50(36-60) years, the SOFA score 11(8-14.3) and the Murray lung injury Score 3.33(3.3-3.7). Cumulative ECMO support time 3411 days, 9(6-15) days per patient. Mechanical failure of the blood pump (n = 5), MO (n = 2) or cannula (n = 1) accounted for 10% of the exchanges. Acute clot formation within the pump head (visible clots, increase in plasma free hemoglobin (frHb), serum lactate dehydrogenase (LDH), n = 13) and MO (increase in pressure drop across the MO, n = 16) required an urgent system-exchange, of which nearly 50% could be foreseen by measuring the parameters mentioned below. Reasons for an elective system-exchange were worsening of gas transfer capability (n = 10) and device-related coagulation disorders (n = 32), either local fibrinolysis in the MO due to clot formation (increased D-dimers [DD]), decreased platelet count; n = 24), or device-induced hyperfibrinolysis (increased DD, decreased fibrinogen [FG], decreased platelet count, diffuse bleeding tendency; n = 8), which could be reversed after system-exchange. Four MOs were exchanged due to suspicion of infection., Conclusions: The majority of ECMO system-exchanges could be predicted by regular inspection of the complete ECMO circuit, evaluation of gas exchange, pressure drop across the MO and laboratory parameters (DD, FG, platelets, LDH, frHb). These parameters should be monitored in the daily routine to reduce the risk of unexpected ECMO failure.

Purpose: Polymethylpentene membrane oxygenators used in venovenous extracorporeal membrane oxygenation (vvECMO) differ in their physical characteristics. The aim of the study was to analyze the gas transfer capability of different ECMO systems in clinical practice, as the choice of the appropriate system may be influenced by the needs of the patient., Methods: Retrospective study on prospectively collected data of adults with severe respiratory failure requiring vvECMO support (Regensburg ECMO Registry, 2009-2013). Oxygen (O2) transfer and carbon dioxide (CO2) elimination of four different ECMO systems (PLS system, n = 163; Cardiohelp system (CH), n = 59, Maquet Cardiopulmonary, Rastatt, Germany; Hilite 7000 LT system, n = 56, Medos Medizintechnik, Stolberg, Germany; ECC.05 system, n = 39, Sorin Group, Mirandola (MO), Italy) were analyzed., Results: Gas transfer depended on type of ECMO system, blood flow, and gas flow (p ≤ 0.05, each). CO2 removal is dependent on sweep gas flow and blood flow, with higher blood flow and/or gas flow eliminating more CO2 (p ≤ 0.001). CO2 elimination capacity was highest with the PLS system (p ≤ 0.001). O2 transfer at blood flow rates below 3 l/min depended on blood flow, at higher blood flow rates on blood flow and gas flow. The system with the smallest gas exchange surface (ECC.05 system) was least effective in O2 transfer, but in terms of the gas exchange surface was the most effective., Conclusion: Our analysis suggests that patients with severe hypoxemia and need for high flow ECMO benefit more from the PLS/CH or Hilite 7000 LT system. The ECC.05 system is advisable for patients with moderate hypoxemia and/or hypercapnia.

Oxygenator thrombosis is a serious complication in extracorporeal membrane oxygenation (ECMO) and may necessitate a system exchange. Coagulation and fibrinolysis parameters, flow dynamics, and gas transfer performance are currently used to evaluate the degree of oxygenator thrombosis, but there is no technical approach for direct visualization and quantification of thrombotic deposits within the membrane oxygenator (MO). We used multidetector computed tomography (MDCT) with three-dimensional postprocessing to assess the incidence of oxygenator thrombosis, to quantify thrombus extent, and to localize clot distribution. Twenty heparin-coated MOs after successful weaning were analyzed. Mean ECMO support time was 7 ± 4 days, mean activated partial thromboplastin time (aPTT) during ECMO was 59 ± 20 seconds. Thrombotic deposits were detected in all MOs. The mean clot volume was 51.7 ± 22.3 cm. All thrombotic deposits were located in the venous, i.e., inlet part of the device, without apparent evidence of embolization in patients. There was no correlation between clot volume and ECMO support time or aPTT. Clot formation within the MO is a common finding in ECMO despite adequate systemic anticoagulation. The clinical significance of thrombus formation and its influence on gas exchange capacity and hemostatic complications have to be addressed in further studies.

Purpose: Early markers of oxygenator dysfunction during prolonged use of extracorporeal membrane oxygenation (ECMO) are important for timely exchange to avoid sudden loss of function due to clot formation within the system. The measurement of D-dimers (DDs) in plasma might be a marker for early diagnosis of thrombus formation and dysfunction of heparin-coated membrane oxygenators (MOs)., Methods: This is a retrospective study on prospectively collected data of 24 adult acute respiratory distress syndrome patients requiring long-term veno-venous ECMO with at least 1 MO exchange. Kinetics of coagulation, inflammation, and oxygenator function were analyzed before and after MO exchange., Results: Median (interquartile range) support duration is 20 (15-29) days. Thirty-four MOs had to be replaced. Exchange occurred due to visible thrombus formation in the MO (n=16), worsening gas exchange (n=11), increased blood flow resistance (n=1), and activation of coagulation with diffuse bleeding (n=6). In 15 cases, DDs were continuously elevated and, therefore, not suitable as marker for MO exchange. In the remaining 19 cases, DDs increased significantly within 3 days before exchange from 15 (9-20) to 30 (21-35) mg/dL (P=.002) and declined significantly within 1 day thereafter to 13 (7-17) mg/dL (P=.003)., Conclusions: An increase in plasma DD concentration in absence of other explaining pathology can be helpful in predicting an MO exchange in miniaturized heparin-coated ECMO systems., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Membrane oxygenator (MO) failure is a known hazard during venovenous extracorporeal membrane oxygenation (v-v ECMO) therapy. Knowledge about technical and performance details of different ECMO systems (Maquet, Rastatt, Germany; Medos, Stolberg, Germany; Sorin, Modena, Italy) licensed for adults with acute lung failure might improve their handling. This retrospective study comprises 186 adult patients (Regensburg ECMO Registry) treated with v-v ECMO. Flow dynamic data were used to analyze the performance of different blood pumps, cannula types, and MOs to maintain an adequate blood flow (1-5 L/min). Usage of the Medos ECMO system in critically ill patients required a higher pump speed and generated a higher pressure drop across the MO (dpMO), however, without an increase in free plasma hemoglobin. The dpMO depended on the type of MO and increased with blood flow as expected. Type-specific normal values are reported. A distinct increase in dpMO above normal values within 1 day required an immediate MO exchange. This was an infrequent technical complication (3%). Finally, pressure-flow performance of single dual-lumen cannulas (27 Fr) was comparable with small single-lumen cannulas (15 Fr), without an increased risk of technical-induced hemolysis. Despite different performances, all current commercially available adult v-v ECMO systems produce adequate blood flow without an increased risk in technical-induced hemolysis. Familiarity with the specific properties of individual systems allows early detection of technical complications. Additionally, the choice of an adequate cannula requires a closer consideration of the individual patient situation., (Copyright © 2013 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Despite heparin coating and systemic anticoagulation, thrombotic clot formation is a serious complication in extracorporeal membrane oxygenation (ECMO). We describe our first results of visualization of thrombotic deposits in ECMO devices using advanced multidetector computed tomography (MDCT). A bioline-coated polymethylpentene membrane oxygenator (MO) after 8 days of ECMO treatment (device 1) and a factory-sealed MO serving as an internal quality control (device 2) were analyzed with three-dimensional (3D) visualization volume rendering technique (VRT) using a 0.6 mm3 voxel isotropic MDCT dataset. After the computed tomography (CT) scan, device 1 was anatomically dissected for direct visualization of potential deposits and further analyzed by scanning electron microscopy (SEM). The VRT 3D model based on the MDCT dataset of device 1 showed red-coded areas within the gas exchange surface of the device consistent with fibrous and cellular deposits. These deposits could be confirmed by anatomical dissection of the device and by SEM. Device 2 showed no signs of clot formation in MDCT using the same VRT settings. It was demonstrated that MDCT with VRT is able to detect thrombotic deposits in ECMO devices under ex vivo conditions. MDCT allows direct visualization of the actual thrombus load of a used ECMO device as well as the quantification of the thrombus volume and could, therefore, play a significant role in better understanding the oxygenator thrombosis in modern ECMO treatment.

Extracorporeal membrane oxygenation (ECMO) is the ultimate treatment option to improve gas exchange and decrease the aggressiveness of mechanical ventilation in septic patients with uncontrolled severe lung failure. However, potential microbiological colonization of the artificial surfaces of membrane oxygenator (MO) remains a critical issue in patients with bacteremia. The current study investigates the risk of MO infection in 10 consecutive septic patients on long-term treatment with ECMO. The flushing fluids of all investigated MOs were sterile. After incubation with nutrient solution for 14 days in one MO Enterococci spp. were isolated. In the patient concerned, a diffuse, unaccountable bleeding diathesis had developed, which stopped after exchange of the MO. Analysis of clinical parameters showed that D dimers had increased and fibrinogen levels had decreased before exchange of this MO, but standard markers of infection had remained unremarkable. In conclusion, circuit infection may be a potential cause for unexplained clinical deterioration of patients on ECMO, which therefore should be considered as an indication for exchange of the device., (© 2011, Copyright the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Cardiopulmonary bypass induces hemolysis and activation of inflammatory and coagulation systems as a result of a combination of mechanical trauma and biological mechanisms. The aim of our study was to evaluate the performance of two different minimized extracorporeal circulation (ECC) systems and to compare their influence on blood components. From January 2003 to December 2008, 1,218 patients underwent coronary artery bypass grafting with minimized ECC. The PRECiSe system (41%) consists of a microporous capillary membrane oxygenator (MO) and a diagonal pump (DeltaStream DP2). The MECC system (59%) is composed of a polymethylpentene MO with a plasma-tight diffusion membrane and a centrifugal pump (RotaFlow). Serial blood samples were taken preoperatively (T0), on arrival to intensive care unit (T1), 6 hours postoperatively (T2), and at discharge (T3). Demographic data, intraoperative, and technical parameters were similar in both groups. At T1 and T2, the platelet count in the PRECiSe group was significantly lower than that in the MECC group (p < 0.01). Furthermore, at T1, levels of lactate dehydrogenase were significantly higher in the PRECiSe group (p < 0.05). In addition, postoperative blood loss was significantly higher using the PRECiSe system (p < 0.05). In conclusion, cardiac surgery with the MECC system is associated with less postoperative bleeding and improved blood cell preservation.

Bioline-coated polymethylpentene (PMP) membrane oxygenators (MO) are used for extracorporeal membrane oxygenation (ECMO) to improve gas exchange in patients with severe acute respiratory distress syndrome (ARDS). However, in some patients, long-term durability is limited due to fibrous and cellular accumulations on the gas exchange surface which can increase resistance to blood flow and diffusion path. These surface deposits of PMP MO after removal were studied with scanning electron and fluorescence microscopy techniques. Three of 31 patients supported by a PMP MO in an ECMO setting required a replacement of the oxygenator after a mean support interval of 11 +/- 7 days due to an increase in flow resistance and an impairment of the gas exchange capacity. The membrane surface of the MO was covered with a fibrous network with imbedded platelets and red blood cells. A membranous structure composed of single cells and clusters of cells covered large areas of the PMP fibers. We assume that these cellular deposits lower the efficacy of ECMO. The identification of these cells could be a key for future therapeutic interventions and improvements in the development of MO.