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(Continued). (C) venovenous extracorporeal membrane oxygenation (VV-ECMO) (n = 28) patients. Navy blue circles indicate hemorrhagic complications, and light blue circles indicate thrombotic complications. DIC = disseminated intravascular coagulation, DVT = deep venous thromboembolism, GI = gastrointestinal, HIT = heparin-induced thrombocytopenia, ICH = intracerebral hemorrhage, PE = pulmonary embolus, SAH = subarachnoid hematoma, SDH = subdural hematoma.
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OBJECTIVES: Extracorporeal membrane oxygenation is a potentially life-saving
intervention in refractory cardiopulmonary failure, but it requires anticoagulation
to prevent circuit thromboses, which exposes the patient to hemorrhagic complications. Heparin has traditionally been the anticoagulant of choice, but the direct thrombin inhibitor bivaliru...
Similar publications
Anticoagulation is an essential component of optimal extracorporeal membrane oxygenation (ECMO) management. Unfractionated heparin is still the anticoagulant of choice in most centers due to longstanding familiarity with the agent. Disadvantages include alterations in drug responses due to its capability to bind multiple heparin-binding proteins th...
Extracorporeal membrane oxygenation (ECMO) has been established as a life-saving technique for patients with the most severe forms of respiratory or cardiac failure. It can, however, be associated with severe complications. Anticoagulation therapy is required to prevent ECMO circuit thrombosis. It is, however, associated with an increased risk of h...
Introduction:
Optimal anticoagulation therapy is essential for the prevention of thrombotic and hemorrhagic complications in pediatric patients supported with extracorporeal membrane oxygenation (ECMO). Recent data have demonstrated bivalirudin has the potential to surpass and replace heparin as the anticoagulant of choice.
Methods:
We conducted...
Bleeding and thrombosis frequently occur in pediatric patients with extracorporeal membrane oxygenation (ECMO) therapy. Until now, most patients are anticoagulated with unfractionated heparin (UFH). However, heparin has many disadvantages, such as binding to other plasma proteins and endothelial cells in addition to antithrombin, causing an unpredi...
Background: Bivalirudin is a direct thrombin inhibitor (DTI) that can be an alternative to unfractionated heparin (UFH). The efficacy and safety of bivalirudin in anticoagulation therapy in extracorporeal membrane oxygenation (ECMO) remain unknown.
Methods: This study followed the preferred reporting items for systematic reviews and meta-analyses (...
Citations
... A total of 1,625 references were screened, and 51 studies were identified as potentially relevant studies whose full texts were retrieved. After removing studies that did not meet the inclusion criteria, 19 studies [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] with 9411 patients were included in the data assessment. ...
... A total of 18 studies reported the number of patients with HIT during ECMO support [8][9][10][11][12][13][14][15][16][17][18][19][20][22][23][24][25][26]. The lowest incidence of HIT was 0.4%, while the highest was 39.3% [10,25]. ...
... Three studies used argatroban with monitoring targets of activated partial thromboplastin time (APTT) of 48-78 s [13], 50-60 s [11] and [23]60 s. In 2 studies, heparin was transferred to bivalirudin, which was monitored by APTT 50-65 s [18] and 46-65 s [21]. (Table 1) ...
Background
In recent years, extracorporeal membrane oxygenation (ECMO) has been increasingly used in critically ill patients with respiratory or cardiac failure. Heparin is usually used as anticoagulation therapy during ECMO support. However, heparin-induced thrombocytopenia (HIT) in ECMO-supported patients, which results in considerable morbidity and mortality, has not yet been well described. This meta-analysis and systematic review aimed to thoroughly report the incidence of HIT on ECMO, as well as the characteristics and outcomes of HIT patients.
Methods
We searched the PubMed, Embase, Cochrane Library, and Scopus databases for studies investigating HIT in adult patients supported by ECMO. All studies conforming to the inclusion criteria were screened from 1975 to August 2023. Nineteen studies from a total of 1,625 abstracts were selected. The primary outcomes were the incidence of HIT and suspected HIT.
Results
The pooled incidence of HIT in ECMO-supported patients was 4.2% (95% CI: 2.7–5.6; 18 studies). A total of 15.9% (95% CI: 9.0-22.8; 12 studies) of patients on ECMO were suspected of having HIT. Enzyme-linked immunosorbent assay (ELISA) is the most commonly used immunoassay. The median optical density (OD) of the ELISA in HIT-confirmed patients ranged from 1.08 to 2.10. In most studies, the serotonin release assay (SRA) was performed as a HIT-confirming test. According to the subgroup analysis, the pooled incidence of HIT in ECMO patients was 2.7% in studies whose diagnostic mode was functional assays, which is significantly lower than the incidence in studies in which the patients were diagnosed by immunoassay (14.5%). Argatroban was most commonly used as an alternative anticoagulation agent after the withdrawal of heparin. Among confirmed HIT patients, 45.5% (95% CI: 28.8–62.6) experienced thrombotic events, while 50.1% (95% CI: 24.9–75.4) experienced bleeding events. Overall, 46.6% (95% CI: 30.4–63.1) of patients on ECMO with HIT died.
Conclusion
According to our study, the pooled incidence of HIT in ECMO-supported patients is 4.2%, and it contributes to adverse outcomes. Inappropriate diagnostic methods can easily lead to misdiagnosis of HIT. Further research and development of diagnostic algorithms and laboratory assays are warranted.
... The bleeding included retroperitoneal, pulmonary, gastrointestinal, and central nervous system bleeding; bleeding that required surgical intervention; central cannulation site bleeding that required re-exploration; and fatal bleeding (type 3-5 according to BARC scale) (10). Overall, these studies suggest there is no significant difference between bivalirudin and heparin in the incidence of major bleeding (13, 16,17,[19][20][21][23][24][25][26]. Four studies showed a significant decrease in the frequency of major bleeding in the bivalirudin group (11,12,15,22). ...
... This latter finding is consistent with the fact that aPTT was more often at target, so use of bivalirudin required less frequent blood draws and adjustments (20). Two studies also showed that the bivalirudin group required significantly fewer RBC transfusions (15,16). Thus, overall findings suggest that the risk of bleeding is the same with bivalirudin and heparin, but the former may have some benefit in reducing the need for phlebotomy and potentially decreasing the risk of bleeding. ...
... Thrombotic complications can be a clinical marker of inadequate anticoagulation during an ECMO course, but they are challenging to assess retrospectively due to a lack of standardized reporting. The majority of studies (11/15) evaluating thrombotic complications of ECMO circuit reported no significant difference between the use of bivalirudin and heparin (11,13,14,16,(19)(20)(21)(22)(23)(24)(25). Two studies showed significantly fewer ECMO-associated thrombotic events per day and an increased time to thrombosis among those receiving bivalirudin versus heparin (12, 15). ...
For decades, unfractionated heparin (hereafter, heparin) has been the primary anticoagulant used for extracorporeal membrane oxygenation (ECMO) support. More recently, however, bivalirudin, a direct thrombin inhibitor, has emerged as an alternative. This systematic review based on PRISMA guidelines, aims to summarize 16 comparative studies and 8 meta-analysis and review articles published from January, 2011 till May, 2023 which directly compares ECMO courses using heparin versus bivalirudin as the anticoagulant. While this comparison is complicated by the lack of a standardized definition of major bleeding or thrombosis, our overall findings suggest there is no statistical difference between heparin and bivalirudin in incidence of bleeding and thrombosis. That said, some studies found a statistical significance favoring bivalirudin in reducing major bleeding, thrombosis, and the need for transfusions. We also offer essential guidance for appropriately selecting an anticoagulant and monitoring its effect in ECMO settings.
... Most importantly, prospective randomized controlled trials comparing the use of UFH and novel anticoagulants, such as argatroban and bivalirudin, need to be performed to provide sufficient evidence supporting a potential change in clinical practice. Increasing evidence suggests that these novel anticoagulants could be preferable to the traditionally used UFH but, at present, such evidence is not sufficient to justify the routine use of argatroban/bivalirudin in everyday clinical ECMO practice [46,[87][88][89][90][91][92][93][94][95]. ...
Extracorporeal membrane oxygenation (ECMO) has been established as a life-saving technique for patients with the most severe forms of respiratory or cardiac failure. It can, however, be associated with severe complications. Anticoagulation therapy is required to prevent ECMO circuit thrombosis. It is, however, associated with an increased risk of hemocoagulation disorders. Thus, safe anticoagulation is a cornerstone of ECMO therapy. The most frequently used anticoagulant is unfractionated heparin, which can, however, cause significant adverse effects. Novel drugs (e.g., argatroban and bivalirudin) may be superior to heparin in the better predictability of their effects, functioning independently of antithrombin, inhibiting thrombin bound to fibrin, and eliminating heparin-induced thrombocytopenia. It is also necessary to keep in mind that hemocoagulation tests are not specific, and their results, used for setting up the dosage, can be biased by many factors. The knowledge of the advantages and disadvantages of particular drugs, limitations of particular tests, and individualization are cornerstones of prevention against critical events, such as life-threatening bleeding or acute oxygenator failure followed by life-threatening hypoxemia and hemodynamic deterioration. This paper describes the effects of anticoagulant drugs used in ECMO and their monitoring, highlighting specific conditions and factors that might influence coagulation and anticoagulation measurements.
... Of these records 4.031 records were excluded for not meeting inclusion criteria for titles and abstracts, leaving 51 potentially relevant articles. Among these articles we identified 25 conference abstracts , 3 studies in which patients were switched between intervention and control group [41][42][43] and 5 studies that investigated nafamostat mesilate but not DTI versus heparin [44][45][46][47][48]. These 33 studies were excluded, leaving 18 studies for inclusion into data synthesis. ...
Background
The number of patients treated with extracorporeal membrane oxygenation (ECMO) devices is increasing. Anticoagulation therapy is crucial to prevent thrombosis during ECMO therapy. Predominantly, heparin has been used as primary anticoagulant but direct thrombin inhibitors (DTI) have been established as alternatives. The aim of this systematic review and meta-analysis was to evaluate clinical outcomes in patients treated with heparin compared to different DTI during ECMO.
Methods
A systematic search was conducted. Full scientific articles were sought for inclusion if heparin anticoagulation was compared to DTI (argatroban/bivalirudin) in ECMO patients. Risk of bias was assessed by Newcastle Ottawa scale. Primary endpoint was in-hospital mortality. Bleeding events, thrombotic events, hours of ECMO support, days of hospital stay, percentage of time within therapeutic range and time to therapeutic range were extracted from full texts as secondary endpoints. Results were presented as Forrest-plots. GRADE was used for confidence assessment in outcomes.
Results
Systematic search identified 4.385 records, thereof 18 retrospective studies for a total of 1942 patients, complied with the predefined eligibility criteria:15 studies investigated bivalirudin and 3 studies investigated argatroban versus heparin. Risk of bias was high for most studies. In-hospital mortality, major bleeding events and pump-related thrombosis were less frequent in DTI group as compared to heparin [mortality—OR 0.69, 95% CI 0.54–0.86; major bleeding—OR 0.48, 95% CI 0.29–0.81; pump thrombosis—OR 0.55, 95% CI 0.40–0.76]. Additionally, percentage of time within therapeutic range was higher for DTI [SMD 0.54, 95% CI 0.14–0.94]. GRADE approach revealed a very low level of certainty for each outcome.
Conclusion
In this meta-analysis, DTI and especially bivalirudin showed beneficial effects on clinical outcomes in ECMO patients as compared to heparin . However, due to the lack of randomized trials, certainty of evidence is low.
Trial Registration
This systematic review and meta-analysis was prospectively registered at PROSPERO data base (reference number CRD42021237252 ).
Graphical Abstract
... Whilst the authors suggest that bivalirudin may provide survival benefits and reduce thrombosis in the subgroup of adult patients supported by ECMO, we highlight that three studies have been missed and should be included in an updated analysis [3][4][5]. Our intention is not to criticize, as these events happen in systematic reviews and metaanalyses [6], but rather to enlarge the amount of data available. In Table 1, we describe characteristics of the missed studies that match the PICOS criteria adopted by Di-huan et al. [1]. ...
... We applaud the authors for their extensive work and for their balanced interpretation of the results, mainly prompted by the retrospective design of all the studies included. Even if an update with the inclusion of the three missed studies [3][4][5] is warranted, bivalirudin seems a promising alternative to conventional anticoagulation with unfractionated heparin, and a randomized controlled trial is urgently needed in patients supported with ECMO. ...
... Several previous studies compared the use of unfractionated heparin and bivalirudin for anticoagulation during the use of ECMO, but they have variable designs and numbers of included patients. [12][13][14] Seelhammer et al. [10] demonstrated a lower mortality rate in the adult group receiving bivalirudin than the use of heparin for anticoagulation in a large retrospective study including 424 patients requiring ECMO, 21% of them were pediatric. However, this difference was not reported among pediatric patients. ...
... Smaller studies failed to report similar differences in terms of bleeding or thrombotic complications. [12][13] Future research also needs to consider the concern on the reported resistance to bivalirudin in patients receiving ECMO. [14] The authors also reported double the cost of using bivalirudin in patients with COVID-19 in addition to the expected added costs of longer times on using ECMO and ICU stays than those with non-COVID-19 ARDS patients. ...
A growing body of evidence supports the use of bivalirudin as an alternative to unfractionated heparin (UFH) for the prevention of thrombotic events in patients on venovenous (VV) extracorporeal membrane oxygenation (ECMO). However, data in patients bridged to lung transplantation are limited. In this case series, we describe the outcomes of six patients who were transitioned from UFH to bivalirudin during their course of VV ECMO support as a bridge to lung transplantation. All six patients were on VV ECMO support until transplant, with a median duration of 73 days. Bivalirudin demonstrated a shorter time to first therapeutic activated thromboplastin time (aPTT) level. Additionally, time in therapeutic range was longer while patients were receiving bivalirudin compared to UFH (median 92.9% vs. 74.6%). However, major bleeding and thrombotic events occurred while patients were receiving either anticoagulant. Based on our experience, bivalirudin appears to be a viable option for anticoagulation in VV ECMO patients bridged to lung transplantation. Larger studies evaluating the optimal anticoagulation strategy in patients bridged to transplant are needed.
Objectives:
Extracorporeal membrane oxygenation (ECMO) plays an important role in providing temporary life support for patients with severe cardiac or pulmonary failure, but requires strict anticoagulation and monitoring. This network meta-analysis systematically explored the most effective anticoagulation and monitoring strategies for patients receiving ECMO.
Methods:
MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched up to January 31, 2023, for studies comparing unfractionated heparin (UFH), argatroban (Arg), bivalirudin (Biv), and/or nafamostat mesylate (NM) in patients receiving ECMO. The primary outcomes included device-related thrombosis, patient-related thrombosis, and major bleeding events. The secondary outcomes included ECMO survival, ECMO duration, and in-hospital mortality.
Results:
A total of 2522 patients from 23 trials were included in the study. Biv was associated with a decreased risk of device-related thrombosis (odd ratio (OR) 0.51, 95% confidence interval (CI): 0.33-0.84) compared with UFH, whereas NM (OR 2.2, 95% CI: 0.24-65.0) and Arg (OR 0.92, 95% CI: 0.43-2.0) did not reduce the risk of device-related thrombosis compared with UFH. Biv was superior to Arg in decreasing the risk of device-related thrombosis (OR 0.14, 95% CI: 0.03-0.51). Biv reduced the risk of patient-related thrombosis compared with UFH (OR 0.44, 95% CI: 0.18-0.85); NM (OR 0.65, 95% CI: 0.14-3.3) and Arg (OR 3.1, 95% CI: 0.94-12.0) did not decrease risk of patient-related thrombosis compared with UFH. No significant difference was observed in the risk of major bleeding between three alternatives and UFH: Biv (OR 0.54, 95% CI: 0.23-1.3), Arg (OR 1.3, 95% CI: 0.34-5.8), and NM (OR 0.60, 95% CI: 0.13-2.6). NM showed a reduced risk of in-hospital mortality compared with UFH (OR 0.27, 95% CI: 0.091-0.77), whereas Arg (OR 0.43, 95% CI: 0.15-1.2) and Biv (OR 0.75, 95% CI: 0.52-1.1) did not decrease risk of in-hospital mortality.
Conclusions:
Compared with UFH and Arg, Biv reduces the risk of thrombosis and appears to be a better choice for patients requiring ECMO. NM was associated with a reduced risk of in-hospital mortality.
Extracorporeal membrane oxygenation (ECMO) is an invasive and last-resort treatment for circulatory and respiratory failure. Prolonged ECMO support can disrupt the coagulation and anticoagulation systems in a patient, leading to adverse consequences, such as bleeding and thrombosis. To address this problem, anticoagulation coatings have been developed for use in ECMO circuits. This article reviews commonly used commercial and novel anticoagulant coatings developed in recent years and proposes a new classification of coatings based on the current state. While commercial coatings have been used clinically for decades, this review focuses on comparing the effectiveness and stability of coatings to support clinical selections. Furthermore, novel anticoagulation coatings often involve complex mechanisms and elaborate design strategies, and this review summarises representative studies on mainstream anticoagulation coatings to provide a point of reference for future studies.
Coating all portions of an extracorporeal membrane oxygenation (ECMO) circuit with materials exhibiting inherent, permanent antithrombotic properties is an essential step to prevent thrombus-induced complications. However, developing antithrombotic coatings for oxygenator fibers within membrane oxygenators of ECMO systems has proven challenging. We have used polydopamine (PDA) to coat oxygenator fibers and immobilize a Cu-based metal-organic framework (MOF) on the surface to act as a nitric oxide (NO) catalyst. Importantly, the PDA/MOF coating will produce NO indefinitely from endogenous S-nitrosothiols and it has not previously been applied to ECMO oxygenator fibers.
