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Prevalence and outcome of heparin-induced thrombocytopenia diagnosed under veno-arterial extracorporeal membrane oxygenation: a retrospective nationwide study
Abstract
Purpose
Thrombocytopenia is a frequent and serious adverse event in patients treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for refractory cardiogenic shock. Similarly to postcardiac surgery patients, heparin-induced thrombocytopenia (HIT) could represent the causative underlying mechanism. However, the epidemiology as well as related mortality regarding HIT and VA-ECMO remains largely unknown. We aimed to define the prevalence and associated 90-day mortality of HIT diagnosed under VA-ECMO.
Methods
This retrospective study included patients under VA-ECMO from 20 French centers between 2012 and 2016. Selected patients were hospitalized for more than 3 days with high clinical suspicion of HIT and positive anti-PF4/heparin antibodies. Patients were classified according to results of functional tests as having either Confirmed or Excluded HIT.
Results
A total of 5797 patients under VA-ECMO were screened; 39/5797 met the inclusion criteria, with HIT confirmed in 21/5797 patients (0.36% [95% CI] [0.21–0.52]). Fourteen of 39 patients (35.9% [20.8–50.9]) with suspected HIT were ultimately excluded because of negative functional assays. Drug-induced thrombocytopenia tended to be more frequent in Excluded HIT at the time of HIT suspicion (p = 0.073). The platelet course was similar between Confirmed and Excluded HIT (p = 0.65). Mortality rate was 33.3% [13.2–53.5] in Confirmed and 50% [23.8–76.2] in Excluded HIT (p = 0.48).
Conclusions
Prevalence of HIT among patients under VA-ECMO is extremely low at 0.36% with an associated mortality rate of 33.3%, which appears to be in the same range as that observed in patients treated with VA-ECMO without HIT. In addition, HIT was ultimately ruled out in one-third of patients with clinical suspicion of HIT and positive anti-PF4/heparin antibodies.
... Also, the reliability of antibody search tests in this context remains unknown. Although previous studies have analyzed HIT in general ICU populations and in those undergoing MCS, there is limited data regarding the prevalence, diagnosis, management, and outcomes in patients with suspected and confirmed HIT suffering from CS (10)(11)(12)(13). ...
... In this retrospective dual-center analysis of ICU patients in CS, HIT was confirmed in 2.0 % of the study population, thus representing a rare complication of heparin therapy in this cohort. UFH treatment has been associated with a HIT prevalence of up to 5% in general adult populations, and 1-5% in the critically ill (10,13,(15)(16)(17)(18). HIT was diagnosed in up to 8.3% in several previous analyses including CS patients undergoing venoarterial ECMO (11,19,20). Further, the prevalence of HIT among venoarterial ECMO treated patients was 3.4% in a recently published retrospective study conducted at LMU Munich (12). ...
... In cases of clinically suspected HIT, anti-PF4/ heparin IgG antibody testing is recommended and is widely being used as part of the standard diagnostic algorithm (25). Although this strategy has yielded a high negative predictive value, the PPV in several CS (sub) population studies has ranged from 8.5% to 53%, with a value of only 35.8% in the present dataset (11,12,26,27). Additionally, adapting the initial HIT screening to specific clinical scenarios, such as CS, to increase pretest probability of antibody screening tests may help to avoid unnecessary and costly functional testing. ...
OBJECTIVES
Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT.
DESIGN
Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022.
SETTING
Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn.
PATIENTS AND INTERVENTIONS
In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated.
MEASUREMENTS AND MAIN RESULTS
In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485).
CONCLUSIONS
HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.
... 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]. ...
... 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]. According to the random-effects analysis, the pooled incidence of HIT on ECMO was 4.2% (95% CI: 2.7-5.6, ...
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.
... Previous studies showed that a platelet-reducing effect of ECMO therapy is caused by the induction of platelet aggregation on the non-endothelialised surface of the extracorporeal circuit as well as an accompanying widespread activation of the innate immune system resulting in a global generation of a proinflammatory pattern [10][11][12]. However, in addition to circuit-related thrombocytopenia, heparin-induced thrombocytopenia (HIT) is a serious differential diagnosis when platelets drop in VA-ECMO patients [13]. HIT is characterized by a decrease in platelet count of more than 50% from the highest value after the start of heparin, an onset five to ten days after the start of heparin, the presence of heparin-dependent, platelet-activating IgG antibodies, and hypercoagulability [14]. ...
... To date, HIT in VA-ECMO patients remains insufficiently understood and most studies investigating HIT occurrence are rather small studies with the inherent limitation of statistical modelling. Thus, literature findings are controversial, especially regarding the frequency and mortality of HIT in this patient cohort [13,15], but also diagnosis and clinical management of this serious, immunologically mediated adverse drug reaction to UFH [16]. Our study aims to contribute to answering these highly relevant research questions. ...
... In this comprehensive single-center analysis, HIT was confirmed in 3.5% of patients treated with VA-ECMO, which corresponds to previously reported prevalence rates ranging from 0.36% to 8.3% and the estimated overall prevalence of up to 5% in adults receiving UFH [13,15,16,[18][19][20][21][22][23][24]. A recent meta-analysis has found thrombocytopenia to occur in 23.2% of VA-ECMO-treated patients [19]. ...
Background: Heparin-induced thrombocytopenia (HIT) is a serious, immune-mediated adverse drug reaction to unfractionated heparin (UFH) affecting also patients undergoing venoarterial extracorporeal membrane oxygenation (VA-ECMO). Although the association between VA-ECMO support and the development of thrombocytopenia has long been known and discussed, HIT as one underlying cause is still insufficiently understood. Therefore, the purpose of this study was to further investigate the epidemiology, mortality, diagnosis, and clinical management of HIT occurring in VA-ECMO patients treated with UFH. Methods: We conducted a retrospective single-center study including adult patients (≥18 years) with VA-ECMO support in the cardiac intensive care unit (ICU) of the University Hospital of Munich (LMU) between January 2013 and May 2022, excluding patients with a known history of HIT upon admission. Differences in baseline characteristics and clinical outcome between excluded HIT (positive anti-platelet factor 4 (PF4)/heparin antibody test but negative functional assay) and confirmed HIT (positive anti-PF4/heparin antibody test and positive functional assay) VA-ECMO patients as well as diagnosis and clinical management of HIT were analysed. Results: Among the 373 patients included, anti-PF4/heparin antibodies were detected in 53/373 (14.2%) patients. Functional HIT testing confirmed HIT in 13 cases (3.5%) and excluded HIT in 40 cases (10.7%), corresponding to a prevalence of confirmed HIT of 13/373 (3.5%) [1.6, 5.3] and a positive predictive value (PPV) of 24.5% for the antibody screening test. The platelet course including platelet recovery following argatroban initiation was similar between all groups. One-month mortality in patients with excluded HIT was 14/40 (35%) and 3-month mortality 17/40 (43%), compared to 5/13 (38%) (p > 0.999), and 6/13 (46%) (p > 0.999) in patients with confirmed HIT. Neurological outcome in both groups measured by the cerebral performance category of survivors on hospital discharge was similar, as well as adverse events during VA-ECMO therapy. Conclusions: With a prevalence of 3.5%, HIT is a non-frequent complication in patients on VA-ECMO and was not associated with a higher mortality rate. HIT was ultimately excluded by functional essay in 75% of VA-ECMO patients with clinical suspicion of HIT and positive anti-PF4/heparin antibody test. Argatroban seems to be an appropriate and safe therapeutic option for confirmed HIT-positive patients on VA-ECMO support.
... Third, survival and neurologic outcome were similar. The prevalence of 3.2% seems to be in contrast to the largest multicenter study evaluating HIT on VA ECMO, that reported a prevalence of 0.4% [24]. However, in comparison to patients on cardiopulmonary bypass with reported rates of 1-3% [3] and 7.3% in postcardiotomy patients requiring VA ECMO [25], the current results seem to be plausible. ...
... Most of the reported data included only patients requiring VA ECMO or did not differentiate the mode of ECMO [17,18,24]. Data on HIT in VV ECMO are scarce. ...
... HIT results in several complications such as bleeding and thrombosis. Bleeding events were observed in 38% in the HIT-confirmed group (13 VV ECMO and 3 VA ECMO patients), less than in the study of Kimmoun et al. with 57% (only VA ECMO patients) [24]. Yet, the bleeding rate was higher in all, at least temporarily, argatroban treated groups compared to the ECMO-control group, which might be in part explained by the lower platelet counts in all HIT suspected groups. ...
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.
... There were 6.698 V-A ECMO patients, of whom 459 were post-cardiotomy. In 6 studies, authors did not report about the ECMO setting (post-cardiotomy, post-acute myocardial infarction, or other aetiologies) [8,16,25,26,28,39]. V-V ECMO was present in 477 patients. ...
... 12 studies). Eight trials reported about alternative therapy to heparin when HIT was suspected [8,24,26,28,29,31,36,39]. Argatroban was utilized in 6 studies, whereas bivalirudin was administered only in 2 studies [8,26,28,29,31,36,39]. ...
... Eight trials reported about alternative therapy to heparin when HIT was suspected [8,24,26,28,29,31,36,39]. Argatroban was utilized in 6 studies, whereas bivalirudin was administered only in 2 studies [8,26,28,29,31,36,39]. Fondaparinux was used in one study [24]. ...
Despite increasing improvement in extracorporeal membrane oxygenation (ECMO) technology and knowledge, thrombocytopenia and impaired platelet function are usual findings in ECMO patients and the underlying mechanisms are only partially elucidated. The purpose of this meta-analysis and systematic review was to thoroughly summarize and discuss the existing knowledge of platelet profile in adult ECMO population. All studies meeting the inclusion criteria (detailed data about platelet count and function) were selected, after screening literature from July 1975 to August 2019. Twenty-one studies from 1.742 abstracts were selected. The pooled prevalence of thrombocytopenia in ECMO patients was 21% (95% CI 12.9–29.0; 14 studies). Thrombocytopenia prevalence was 25.4% (95% CI 10.6–61.4; 4 studies) in veno-venous ECMO, whereas it was 23.2% (95% CI 11.8–34.5; 6 studies) in veno-arterial ECMO. Heparin-induced thrombocytopenia prevalence was 3.7% (95% CI 1.8–5.5; 12 studies). Meta-regression revealed no significant association between ECMO duration and thrombocytopenia. Platelet function impairment was described in 7 studies. Impaired aggregation was shown in 5 studies, whereas loss of platelet receptors was found in one trial, and platelet activation was described in 2 studies. Platelet transfusions were needed in up to 50% of the patients. Red blood cell transfusions were administered from 46 to 100% of the ECMO patients. Bleeding events varied from 16.6 to 50.7%, although the cause and type of haemorrhage was not consistently reported. Thrombocytopenia and platelet dysfunction are common in ECMO patients, regardless the type of ECMO mode. The underlying mechanisms are multifactorial, and understanding and management are still limited. Further research to design appropriate strategies and protocols for its monitoring, management, or prevention should be matter of thorough investigations.
... 11 Cardiovascular surgery and MCS implantation might result in extensive PF4 release, especially in combination with postoperative infections and sepsis. [15][16][17] In the present study, more than 80% of patients underwent cardiac surgery. 10 In combination with the standard treatment with UFH in these critically ill patients, they might be at high risk of developing HIT. ...
... 18 Slightly lower incidences of positive anti-PF4/heparin antibodies have been reported in general ICU patients 6 and MCS patients (1% to 35%). [15][16][17] Therefore, it is essential that HIT tests, especially the very sensitive but not specific immunoassays, are only performed in situations with high pre-test probability of HIT. Alternatively, the more specific SRA tests could be achieved. ...
... Establishing an HIT diagnosis is difficult in this scenario, with many false-positive results noted on PF-4 enzymelinked immunosorbent assay testing. 19,20 The strength of the heparin-PF-4 enzyme-linked immunosorbent assay test may help discern true HIT from false-positive cases. The laboratory should provide an optical density with heparin-PF4 results. ...
... The laboratory should provide an optical density with heparin-PF4 results. In a commonly used heparin antibody test systems, an optical density greater than 0.400 is a positive result, but true cases tend to have optical density greater than 1. 19 Definitive diagnosis in ECMO-treated patients should be contingent on serotonin-release assay results that, while not immediately available, can be obtained in 1 to 2 days in operational systems that have established efficient specimen delivery and result reporting. Our typical reference laboratory throughput time for serotonin release assay results is 36 to 48 h. ...
Patients with postcardiotomy cardiogenic shock refractory to conventional support can be successfully supported with extracorporeal membrane oxygenation. Management considerations are discussed to aid clinicians caring for these patients.
... A distinct disadvantage of UFH is the risk of type II heparin-induced thrombocytopenia (HIT), which has been reported in up to 4% of patients on ECMO support [9]. HIT results in high rates of thrombosis and increases mortality [10]. ...
... Interestingly, the decline in the platelet count was more pronounced in the UFH group. This often described phenomenon of decreasing platelet numbers [5,9] seems to be related to the ECMO device, possibly the pump unit, itself [29]. Whether heparin has an additional, independent effect on platelets-which may not occur with Argatroban-needs to be investigated in more detail, in particular due to the numerical inclusion imbalances between the Argatroban and the UFH group. ...
Abstract Background During venovenous extracorporeal membrane oxygenation (vvECMO), direct thrombin inhibitors are considered by some potentially advantageous over unfractionated heparin (UFH). We tested the hypothesis that Argatroban is non-inferior to UFH regarding thrombosis and bleeding during vvECMO. Methods We conducted a propensity-score matched observational non-inferiority study of consecutive patients without heparin-induced-thrombocytopenia (HIT) on vvECMO, treated between January 2006 and March 2019 in the medical intensive care unit at the University Hospital Regensburg. Anticoagulation was realized with UFH until August 2017 and with Argatroban from September 2017 onwards. Target activated partial thromboplastin time was 50 ± 5seconds in both groups. Primary composite endpoint was major thrombosis and/or major bleeding. Major bleeding was defined as a drop in hemoglobin of ≥ 2 g/dl/day or in transfusion of ≥ 2 packed red cells/24 h, or retroperitoneal, cerebral, or pulmonary bleeding. Major thrombosis was defined as obstruction of > 50% of the vessel lumen diameter by means of duplex sonography. We also assessed technical complications such as oxygenator defects or pump head thrombosis, the time-course of platelets, and the cost of anticoagulation (including HIT-testing). Results Out of 465 patients receiving UFH, 78 were matched to 39 patients receiving Argatroban. The primary endpoint occurred in 79% of patients in the Argatroban group and in 83% in the UFH group (non-inferiority for Argatroban, p = 0.026). The occurrence of technical complications was equally distributed (Argatroban 49% vs. UFH 42%, p = 0.511). The number of platelets was similar in both groups before ECMO therapy but lower in the UFH group after end of ECMO support (median [IQR]: 141 [104;198]/nl vs. 107 [54;171]/nl, p = 0.010). Anticoagulation costs per day of ECMO were higher in the Argatroban group (€26 [13.8;53.0] vs. €0.9 [0.5;1.5], p
... The IgGs to PF4 on platelets' surfaces activate and aggregate platelets, causing thrombosis [11]. Heparin-induced thrombocytopenia II occurs in < 5% of ECMO patients anticoagulated with UFH [12]. ...
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 that compete with antithrombin and the potential for heparin-induced thrombocytopenia. In such cases, direct thrombin inhibitors are the treatment of choice but pose difficulties in monitoring due to the limited experience and target ranges for non-aPTT-guided management (aPTT: activated partial thromboplastin time). The current trend toward low-dose anticoagulation, especially for venovenous ECMO, is supported by data associating bleeding complications with mortality but not thromboembolic events, which include circuit thrombosis. However, only prospective data will provide appropriate answers to how to individualize anticoagulation, transfusions, and bleeding management which is currently only supported by expert opinion. Empiric therapy for ECMO patients based on laboratory coagulation alone should always be critically questioned. In summary, only collaboration and future studies of coagulation management during ECMO will help us to make this life-saving therapy that has become part of daily life of the intensivist even safer and more effective. Until then, a fundamental understanding of coagulation and bleeding management, as well as pearls and pitfalls of monitoring, is essential to optimize anticoagulation during ECMO. This article is freely available.
... Moreover, the need for AT supplementation during heparin infusion is also a challenge. A national multicenter retrospective study [13] from France showed that HIT caused by using heparin as an anticoagulant under VA-ECMO therapy in adults is a rare complication with a prevalence of approximately 0.36 and an associated mortality rate 33%. Although HIT is relatively rare, it can be a lifethreatening complication. ...
Background
Extracorporeal membrane oxygenation (ECMO) is a vital technique for severe respiratory or heart failure patients. Bleeding and thrombotic events are common during ECMO and negatively impact patient outcomes. Unfractionated heparin is the primary anticoagulant, but its adverse effects limit its use, necessitating alternative anticoagulants.
Objective
Review available alternative anticoagulants for adult ECMO patients. Explore potential novel anticoagulants for future ECMO use. Aim to reduce complications (bleeding and thrombosis) and improve safety and efficacy for critically ill ECMO patients.
Methods
Comprehensive literature review of existing and emerging anticoagulants for ECMO.
Results
Identified a range of alternative anticoagulants beyond unfractionated heparin. Evaluated their potential utility in mitigating ECMO-related complications.
Conclusion
Diverse anticoagulant options are available and under investigation for ECMO. These alternatives may enhance patient safety and outcomes during ECMO support. Further research and clinical studies are warranted to determine their effectiveness and safety profiles.
... We confirm the platelet course consisting of an initial decrease, followed by a stabilization in platelet count, in case a severe thrombocytopenia was not yet present at ECMO initiation [9,18]. This initial decrease in platelet count can be multi-factorial in etiology, in which VA ECMO adds to the equation by increased platelet consumption in the device itself as well as due to increased shear stress [19][20][21]. ...
Background
Thrombocytopenia, hemorrhage and platelet transfusion are common in patients supported with venoarterial extracorporeal membrane oxygenation (VA ECMO). However, current literature is limited to small single-center experiences with high degrees of heterogeneity. Therefore, we aimed to ascertain in a multicenter study the course and occurrence rate of thrombocytopenia, and to assess the association between thrombocytopenia, hemorrhage and platelet transfusion during VA ECMO.
Methods
This was a sub-study of a multicenter ( N = 16) study on transfusion practices in patients on VA ECMO, in which a retrospective cohort (Jan-2018–Jul-2019) focusing on platelets was selected. The primary outcome was thrombocytopenia during VA ECMO, defined as mild (100–150·10 ⁹ /L), moderate (50–100·10 ⁹ /L) and severe (< 50·10 ⁹ /L). Secondary outcomes included the occurrence rate of platelet transfusion, and the association between thrombocytopenia, hemorrhage and platelet transfusion, assessed through mixed-effect models.
Results
Of the 419 patients included, median platelet count at admission was 179·10 ⁹ /L. During VA ECMO, almost all ( N = 398, 95%) patients developed a thrombocytopenia, of which a significant part severe ( N = 179, 45%). One or more platelet transfusions were administered in 226 patients (54%), whereas 207 patients (49%) suffered a hemorrhagic event during VA ECMO. In non-bleeding patients, still one in three patients received a platelet transfusion. The strongest association to receive a platelet transfusion was found in the presence of severe thrombocytopenia (adjusted OR 31.8, 95% CI 17.9–56.5). After including an interaction term of hemorrhage and thrombocytopenia, this even increased up to an OR of 110 (95% CI 34–360).
Conclusions
Thrombocytopenia has a higher occurrence than is currently recognized. Severe thrombocytopenia is strongly associated with platelet transfusion. Future studies should focus on the etiology of severe thrombocytopenia during ECMO, as well as identifying indications and platelet thresholds for transfusion in the absence of bleeding.
Trial registration : This study was registered at the Netherlands Trial Registry at February 26th, 2020 with number NL8413 and can currently be found at https://trialsearch.who.int/Trial2.aspx?TrialID=NL8413.
... One of the most significant adverse reactions resulting from UFH administration is heparin-induced thrombocytopenia (HIT) [7]. Although the number of positive HIT-ELISA tests is high [8], the number of confirmed HIT is below 5% in several reports [7,9]. Therefore, HIT does not appear to be more common among ECMO patients than among other UFH recipients. ...
Anticoagulation of patients supported by extracorporeal membrane oxygenation is challenging because of a high risk of both bleeding and thrombotic complications, and often empirical. Practice in anticoagulation management is therefore highly variable. The scope of this guidance document is to provide clinicians with practical advice on the choice of an anticoagulant agent, dosing, and the optimal anticoagulant monitoring strategy during extracorporeal membrane oxygenation support in adult patients.
... The reported incidence of HIT during ECMO in patients with COVID-19 is 10.52% (compared with 0.36%-7.8% [33][34][35][36] in the general non-COVID-19 ECMO cohorts) with 62.5% presenting with thrombosis. 1 This may be an underestimate given the difficulties of diagnosing HIT in this context, with several other plausible causes of thrombocytopenia possible. 37 A higher incidence of HIT is likely to be contributory to the increased incidence of thrombosis. ...
Extracorporeal membrane oxygenation (ECMO) is an established part of the treatment algorithm for coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). An intense inflammatory response may cause an imbalance in the coagulation cascade making both thrombosis and bleeding common and notable features of the clinical management of these patients. Large observational and retrospective studies provide a better understanding of the pathophysiology and management of bleeding and thrombosis in COVID-19 patients requiring ECMO. Clinically significant bleeding, including intracerebral hemorrhage is an independent predictor of mortality, and thrombosis (particularly pulmonary embolism) is associated with mortality, especially if occurring with right ventricular dysfunction. The incidence of heparin-induced thrombocytopenia is higher than the general patient cohort with acute respiratory distress syndrome or other indications for ECMO. The use of laboratory parameters to predict bleeding or thrombosis has a limited role. In this review, we discuss the complex pathophysiology of bleeding and thrombosis observed in patients with COVID-19 during ECMO support, and their effects on outcomes.
... Patients selection differed across cohorts, ranging from people referred to hematology services due to HIT 19,20 to people hospitalized or undergoing cardiac surgery and then developing HIT. 21,22 Funnel plots revealed potential (under)reporting bias for prevalence of CVT in the context of HIT, while no specific asymmetry in mortality among people with HIT emerged ( Figure S1 and S2). ...
Background
Cerebral venous thrombosis (CVT) has recently been reported as a common thrombotic manifestation in association with vaccine-induced thrombotic thrombocytopenia, a syndrome that mimics heparin-induced thrombocytopenia (HIT) and occurs after vaccination with adenovirus-based SARS-CoV-2 vaccines. We aimed to systematically review the incidence, clinical features, and prognosis of CVT occurring in patients with HIT.
Methods
The study protocol was registered with PROSPERO (CRD42021249652). MEDLINE, EMBASE and Cochrane CENTRAL were searched up to June 1, 2021 for HIT case series including >20 patients, or any report of HIT-related CVT. Demographic, neuroradiological, clinical, and mortality data were retrieved. Meta-analysis of proportions with random-effect modeling was used to derive rate of CVT in HIT and in-hospital mortality. Pooled estimates were compared with those for CVT without HIT and HIT without CVT, to determine differences in mortality.
Results
From 19073 results, we selected 23 case series of HIT (n=1220) and 27 cases of HIT-related CVT (n=27, 71% female). CVT developed in 1.6% of 1220 patients with HIT (95% CI,1.0%–2.5%, I ² =0%). Hemorrhagic brain lesions occurred in 81.8% of cases of HIT-related CVT and other concomitant thrombosis affecting other vascular territory was reported in 47.8% of cases. In-hospital mortality was 33.3%. HIT-related CVT carried a 29% absolute increase in mortality rate compared with historical CVT controls (33.3% versus 4.3%, P <0.001) and a 17.4% excess mortality compared with HIT without CVT (33.3% versus 15.9%, P =0.046).
Conclusions
CVT is a rare thrombotic manifestation in patients with HIT. HIT-related CVT has higher rates of intracerebral hemorrhage and a higher mortality risk, when compared with CVT in historical controls. The recently reported high frequency of CVT in patients with vaccine-induced thrombotic thrombocytopenia was not observed in HIT, suggesting that additional pathophysiological mechanisms besides anti-platelet factor-4 antibodies might be involved in vaccine-induced thrombotic thrombocytopenia-related CVT.
... Although up to 70% of patients on cardiopulmonary bypass develop anti-PF4 heparin antibodies, only 0.3-4% had proven HIT. 103 A potential solution in HIT in patients with MCSs, especially when heparin is contraindicated, is DTIs, but these molecules have renal and hepatic clearance affected by shock states and challenging monitoring. 104 Unfractionated heparin monitoring can be very challenging, and the UFH dose-response effect is unpredictable because of the indirect effect on the coagulation cascade via antithrombin (AT). ...
Cardiogenic shock (CS) is a complex multifactorial clinical syndrome, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large phenotypic variability in CS, as a result of the diverse aetiologies, pathogenetic mechanisms, haemodynamics, and stages of severity. Although early revascularization remains the most important intervention for CS in settings of acute myocardial infarction, the administration of timely and effective antithrombotic therapy is critical to improving outcomes in these patients. In addition, other clinical settings or non-acute myocardial infarction aetiologies, associated with high thrombotic risk, may require specific regimens of short-term or long-term antithrombotic therapy. In CS, altered tissue perfusion, inflammation, and multi-organ dysfunction induce unpredictable alterations to antithrombotic drugs' pharmacokinetics and pharmacodynamics. Other interventions used in the management of CS, such as mechanical circulatory support, renal replacement therapies, or targeted temperature management, influence both thrombotic and bleeding risks and may require specific antithrombotic strategies. In order to optimize safety and efficacy of these therapies in CS, antithrombotic management should be more adapted to CS clinical scenario or specific device, with individualized antithrombotic regimens in terms of type of treatment, dose, and duration. In addition, patients with CS require a close and appropriate monitoring of antithrombotic therapies to safely balance the increased risk of bleeding and thrombosis.
... Although no recommendation exists on the use of direct thrombin inhibitor as primary anticoagulation in patients on ECMO, we preferred this strategy in this extremely critically ill population and we gathered positive experiences with direct thrombin inhibitor for patients treated with extracorporeal circuits [12][13][14]. Indeed, on one hand side direct thrombin inhibitor anticoagulant effect is more specific than heparin and can be easily monitored with aPTT, while on the on the other hand side low platelet count is frequently observed in critically ill patients [23], and the risk of heparin induced thrombocytopenia is higher in patients on extracorporeal support. ...
Objective
Despite growing expertise and wide application of venovenous extracorporeal membrane oxygenation (VV ECMO) treatment for acute respiratory distress syndrome (ARDS) of different origin and during pandemics (H1N1 Influenza A virus and SARS-CoV2), large reports are few and pertain mostly to multicentre registries, while randomized trials are difficult to perform. The aim of this study was to report outcomes, trends and innovations of VV ECMO treatment over the last eleven years.
Design, setting and participants
Observational study on 142 patients treated at the IRCCS San Raffaele Hospital in Milan from June 2009 (year of the H1N1 pandemic) to May 2020 (SARS-CoV-2 pandemic).
Interventions
None.
Measurements and main results
The main causes of ARDS were H1N1 pneumonia in 36% of patients, bacterial pneumonia in 17% and Sars-CoV-2 in 9%. Seventy-two percent of patients were centralized from remote hospitals, of which 33% had implanted VV ECMO before transport. The most common cannulation strategy was the dual lumen catheter cannulation system (55%) and anticoagulation was performed with bivalirudin in most patients (79%). Refractory hypoxia was treated with iv beta-blockers (64%), nitric oxide (20%) and pronation (8%). Almost one third of patients (32%) were extubated while on ECMO. Forty-nine percent of patients were discharged from intensive care unit and hospital discharge was 46%: survival was lower in patients requiring VV ECMO for more than 3 weeks compared to lower support duration (23% vs 56%, p=0.007). Anticoagulation with bivalirudin was associated with higher survival compared to heparin (55% vs 31%, p=0.03) and lower thrombocytopenia incidence (69% vs 35%, p=0.003).
Conclusion
VV ECMO is the pivotal rescue treatment for refractory ARDS: timely treatment and optimal care are needed to optimize therapy, since duration of support is associated with outcome. Anticoagulation with bivalirudin may improve outcome.
... 60,61 The incidence of heparin-induced thrombocytopenia is relatively low (0.36%, n = 21/5797) in VA-ECMO and does not impact survival. 62 Specific, device-related complications and their management Impella devices are associated with the highest incidence of haemolysis among pVAD (5-10% in registry data). 57,58 Accurate placement, and reduction of pump speed may decrease haemolysis and associated acute kidney injury. ...
There has been a significant increase in the use of short-term percutaneous ventricular assist devices (pVADs) as acute circulatory support in cardiogenic shock and to provide haemodynamic support during interventional procedures, including high-risk percutaneous coronary interventions. Although frequently considered together, pVADs differ in their haemodynamic effects, management, indications, insertion techniques, and monitoring requirements. This consensus document summarizes the views of an expert panel by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and the Association for Acute Cardiovascular Care (ACVC) and appraises the value of short-term pVAD. It reviews the pathophysiological context and possible indications for pVAD in different clinical settings and provides guidance regarding the management of pVAD based on existing evidence and best current practice.
... HIT during ECMO can be a significant, life-threatening complication that requires additional resource utilization and has longterm detrimental effects. A multicenter study showed that prevalence of HIT among patients under VA ECMO was extremely low at 0.36%, with an associated mortality rate of 33.3% [40]. Recently, a meta-analysis reported that of 309 patients from six retrospective studies undergoing extracorporeal life support, 83% were suspected of and 17% were confirmed to have HIT [41]. ...
Background
To compare the safety and efficacy of low-dose anticoagulation (LA) with that of standardized dose anticoagulation (SA) for patients supported with extracorporeal membrane oxygenation (ECMO).
Methods
PubMed, MEDLINE, the Cochrane Library, and Web of Science were screened for original articles. Screening was performed using predefined search terms to identify cohort studies reporting the comparison of LA with SA in patients supported with ECMO from Nov 1990 to Jun 2020. The effect size was determined by the odds ratio (OR) with the 95% confidence interval (CI).
Results
An analysis of 7 studies including a total of 553 patients was performed. LA (Low-heparin group) was administered to 255 patients, whereas the other 298 patients received SA (Full-heparin group). The incidence of gastrointestinal tract hemorrhage (OR 0.36, 95% CI 0.20–0.64) and surgical site hemorrhage (OR 0.43, 95% CI 0.20–0.94) were significantly lower in patients who underwent LA compared with that in those who underwent SA. The rates of hospital mortality (OR 0.81, 95% CI 0.42–1.56), successfully weaning off of ECMO (OR 0.80, 95% CI 0.30–2.14), pulmonary embolism (OR 0.79, 95% CI 0.24–2.65), intracardiac thrombus (OR 0.34, 95% CI 0.09–1.30), intracranial hemorrhage (OR 0.62, 95% CI 0.22–1.74), and pulmonary hemorrhage (OR 0.77, 95% CI 0.30–1.93) were similar between the two groups.
Conclusions
This meta-analysis confirms that LA is a feasible and safe anticoagulation strategy in patients supported by ECMO. Future studies should focus on the long-term benefits of LA compared with SA.
... From March 2020 to April 2020, among all COVID-19 patients with severe ARDS admitted in our ICU, which serves as an ECMO referral center for the Greater Paris, and who were implanted with VV-ECMO support, 2 out of 46 (4.3%) had HIT diagnosis confirmation, while HIT prevalence is estimated to be inferior to 0.5% in this population [14,15]. This raises the question of an association between COVID-19 and HIT. ...
Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is increasingly used in Coronavirus disease-19 (COVID-19) patients with the most severe forms of acute respiratory distress syndrome (ARDS). Its use is associated with a significant hemostatic challenge, especially in COVID- 19 patients who have been demonstrated to otherwise present a COVID-19-associated coagulopathy. The systematic use of unfractionated heparin therapy to prevent circuit thrombosis is warranted during ECMO support. The clinical presentation and management of heparin-induced thrombocytopenia, which is a rare but life-threatening complication of heparin therapy, has not been described in those patients yet. We report herein two cases of laboratory-confirmed HIT in COVID-19 patients with severe ARDS admitted to our intensive care unit for VV-ECMO support and the successful use of argatroban as an alternative therapy. We also provide a brief literature review of best evidence for managing such patients. The diagnosis and management of HIT is particularly challenging in COVID-19 patients receiving ECMO support. An increased awareness is warranted in those patients who already present a procoagulant state leading to higher rates of thrombotic events which can confuse the issues. Argatroban seems to be an appropriate and safe therapeutic option in COVID-19 patients with HIT while on VV-ECMO.
... The post-meeting survey highlighted that anticoagulant activity should be monitored using activated partial thromboplastin time (aPTT) and/or anti-Xa; the monitoring approach remains dependent on local practice. For patients with proven HIT, argatroban was the group's preferred anticoagulant [37,38]. ...
Background:
With recent advances in technology, patients with acute respiratory distress syndrome (ARDS) and severe acute exacerbations of chronic obstructive pulmonary disease (ae-COPD) could benefit from extracorporeal CO2 removal (ECCO2R). However, current evidence in these indications is limited. A European ECCO2R Expert Round Table Meeting was convened to further explore the potential for this treatment approach.
Methods:
A modified Delphi-based method was used to collate European experts' views to better understand how ECCO2R therapy is applied, identify how patients are selected and how treatment decisions are made, as well as to identify any points of consensus.
Results:
Fourteen participants were selected based on known clinical expertise in critical care and in providing respiratory support with ECCO2R or extracorporeal membrane oxygenation. ARDS was considered the primary indication for ECCO2R therapy (n = 7), while 3 participants considered ae-COPD the primary indication. The group agreed that the primary treatment goal of ECCO2R therapy in patients with ARDS was to apply ultra-protective lung ventilation via managing CO2 levels. Driving pressure (≥ 14 cmH2O) followed by plateau pressure (Pplat; ≥ 25 cmH2O) was considered the most important criteria for ECCO2R initiation. Key treatment targets for patients with ARDS undergoing ECCO2R included pH (> 7.30), respiratory rate (< 25 or < 20 breaths/min), driving pressure (< 14 cmH2O) and Pplat (< 25 cmH2O). In ae-COPD, there was consensus that, in patients at risk of non-invasive ventilation (NIV) failure, no decrease in PaCO2 and no decrease in respiratory rate were key criteria for initiating ECCO2R therapy. Key treatment targets in ae-COPD were patient comfort, pH (> 7.30-7.35), respiratory rate (< 20-25 breaths/min), decrease of PaCO2 (by 10-20%), weaning from NIV, decrease in HCO3- and maintaining haemodynamic stability. Consensus was reached on weaning protocols for both indications. Anticoagulation with intravenous unfractionated heparin was the strategy preferred by the group.
Conclusions:
Insights from this group of experienced physicians suggest that ECCO2R therapy may be an effective supportive treatment for adults with ARDS or ae-COPD. Further evidence from randomised clinical trials and/or high-quality prospective studies is needed to better guide decision making.
... AT III de ciency and the onset of HIT during treatment are serious events, which affect outcome. Although it is argued that the incidence of HIT in ECMO patients is low [31], its consequences are signi cant. Patients on V-A ECMO are more likely to experience severe thrombocytopenia and arterial thromboembolism; those on V-V ECMO are more likely to require device or circuit exchange due to oxygenator thromboembolism [32]. ...
Background: Extracorporeal Membrane Oxygenation (ECMO) is an established method of circulatory support in critically ill patients. Heparin is the widely used anti-coagulation treatment for patients on ECMO in view of its features. Nevertheless, heparin-induced thrombocytopenia (HIT) and acquired anti-thrombin III (AT-III) deficiency may lead to sub-therapeutic anticoagulation with potentially serious consequences. Direct thrombin inhibitors are being proposed as potential alternatives with argatroban and bivalirudin as main agents. We aimed to review the evidence supporting the effectiveness and safety of argatroban as a potential definitive alternative to heparin in the adult patient population undergoing ECMO support.
Methods: A web based systematic literature search was performed in Medline (PubMed) and Embase from inception until June 18th 2020.
Results: The search identified 13 publications relevant to the target (4 cohort studies and 9 case series). Case reports and case series with less than 3 cases were not included in the qualitative synthesis. The aggregate number of argatroban treated patients on Extra Corporeal Life Support (ECLS) was n = 317. In the majority of studies argatroban was used as a continuous infusion without loading dose. Starting doses on ECMO varied between 0.05 and 2 μg/kg/min and were titrated to achieve the chosen therapeutic target range. The activated partial thormboplastin time (aPTT) was the anticoagulation parameter used for monitoring purposes in most studies, whereas some utilized the activated clotting time (ACT). Optimal therapeutic targets varied between 43-70 to 60-100 seconds for aPTT and 150-210 to 180-230 seconds for ACT. Bleeding and thromboembolic complication rates were comparable to patients treated with unfractionated heparin (UFH).
Conclusions: Argatroban infusion rates and anticoagulation target ranges showed substantial variations. The rational for divergent dosing and monitoring approaches are discussed in this paper. Argatroban appears to be a safe and viable alternative to UFH in patients requiring ECLS. To establish an ideal dosing strategy, larger prospective studies on well-defined patient populations are warranted.
... Patients on extracorporeal membrane oxygenation (ECMO) require curative anticoagulant treatment with intravenous UFH and therefore have a high risk of HIT [28], although still poorly defined [29,30]. ...
... The incidence of HIT in patients treated with UFH is approximately 2.6%, although this does not reflect the incidence in ECMO patients [8] . HIT is often suspected in ECMO patients; however available data are inconsistent, suggesting that the incidence ranges from less than 0.36% to 17% [9][10][11][12] . HIT reverses the anticoagulant effect of heparin and leads to massive platelet activation and thrombosis, which can be catastrophic [13] . ...
Use of extracorporeal membrane oxygenation to support patients with critical cardiorespiratory illness is increasing. Systemic anticoagulation is an essential element in the care of extracorporeal membrane oxygenation patients. While unfractionated heparin is the most commonly used agent, unfractionated heparin is associated with several unique complications that can be catastrophic in critically ill patients, including heparin-induced thrombocytopenia and acquired antithrombin deficiency. These complications can result in thrombotic events and subtherapeutic anticoagulation. Direct thrombin inhibitors (DTIs) are emerging as alternative anticoagulants in patients supported by extracorporeal membrane oxygenation. Increasing evidence supports DTIs use as safe and effective in extracorporeal membrane oxygenation patients with and without heparin-induced thrombocytopenia. This review outlines the pharmacology, dosing strategies and available protocols, monitoring parameters, and special use considerations for all available DTIs in extracorporeal membrane oxygenation patients. The advantages and disadvantages of DTIs in extracorporeal membrane oxygenation relative to unfractionated heparin will be described.
... A recent nationwide, retrospective survey of 20 French ECMO centers included 5,997 patients on va-ECMO between 2012 and 2016. 64 The diagnosis of HIT followed a strict protocol: use of the "4T Score" as a clinical scoring system, determination of IgG-specific HIT antibodies, and a positive functional HIT platelet aggregation assay. 54,57 The prevalence of HIT was only 0.37%. ...
Bivalirudin, a direct thrombin inhibitor with a fast onset of action and short half-life, is often referred to as an alternative anticoagulant to a heparin/protamine regimen. Bivalirudin demonstrated promising results as an anticoagulant in cardiac surgery with and without cardiopulmonary bypass, postcardiotomy extracorporeal membrane oxygenation, interventional cardiology and endovascular procedures, and particularly in the treatment of patients with heparin-induced thrombocytopenia undergoing high-risk cardiac surgery. Currently, bivalirudin in cardiac surgery with cardiopulmonary bypass has a limited clinical spectrum, likely because the still obvious advantages of its competitor, heparin, outweigh it in terms of medical costs, established point-of-care monitoring systems, and availability of protamine as a reversal agent. The unique pharmacology of the drug also requires adjustment of surgical and perfusion strategy. In contrast, in off-pump coronary artery surgery, established protocols from interventional cardiology can be easily translated into the operating room. In this setting bivalirudin has the potential for a more important role in the future. Through a triple mechanism of action-inhibition of plasma thrombin, clot bound thrombin, and collagen-induced platelet activation-bivalirudin may perform better than heparin by attenuating the immediate postoperative prothrombotic state and thus positively impacting the early coronary graft patency after off-pump coronary artery bypass grafting. Further studies are necessary to better evaluate this niche field and discover further applications for this unique anticoagulant.
... It is important to clarify that not all cases were confirmed by functional assays. Kimmoun et al 62 was immediately discontinued with alternative argatroban treatment. A case-control study comparing bivalirudin and heparin treatment on ECMO patients revealed four more cases of HIT on ECMO patients. ...
Heparin‐induced thrombocytopenia (HIT) is a life‐threatening prothrombotic, immune‐mediated complication of unfractionated heparin (UFH) and low molecular weight heparin therapy. HIT is characterized by moderate thrombocytopenia 5‐10 days after initial heparin exposure, detection of platelet‐activating anti‐platelet factor 4/heparin antibodies and an increased risk of venous and arterial thrombosis. Extracorporeal membrane oxygenation (ECMO) is a form of mechanical circulatory support used in critically ill patients with respiratory or cardiac failure. Systemic anticoagulation is used to alleviate the thrombotic complications that may occur when blood is exposed to artificial surfaces within the ECMO circuit. Therefore, when HIT complicates patients on ECMO support, it is associated with a high thrombotic morbidity and mortality. The risk for HIT correlates with the accumulative dosage of heparin exposure. In ECMO patients receiving continuous infusion of heparin for circuit patency, the risk for HIT is not neglected and must be thought of in the differential diagnosis of the appropriate clinical and laboratory circumstances. The following article reviews the current knowledge in HIT complicating ECMO patients, and the alternative anticoagulation options in the presence of HIT. This article is protected by copyright. All rights reserved.
... In a recent retrospective study on VA-ECMO patients hospitalized for >3 days with high clinical suspicion of HIT and positive anti-PF4/heparin antibodies, the prevalence of HIT in patients on VA-ECMO support was estimated as 0.36%. Mortality rate was noted as 33.3%, which was not statistically different from the mortality observed in patients on VA-ECMO support without HIT [26]. HIT is a complication that appears to have a low prevalence; its effects are devastating if untreated. ...
Objective
To describe the incidence of bleeding and thrombotic complications in VA-ECMO according to anticoagulation strategy.
Design
This systematic review and meta-analysis included randomised controlled trials (RCTs) and observational studies reporting bleeding and thrombotic complications in VA-ECMO. The incidence of primary outcomes according to anticoagulation drug and monitoring test was described.
Data sources
CENTRAL, MEDLINE, Embase and CINAHL (2010–January 2024).
Review methods
Data was extracted using Covidence. A meta-analysis of proportions was performed using STATA MP v18.1 metaprop.
Results
We included 159 studies with 21,942 patients. No studies were at low risk of bias. The incidence of major bleeding or thrombotic events was similar among heparin-, bivalirudin- and anticoagulation-free cohorts. The pooled incidence of major bleeding and thrombotic complications were 40% (95%CI 36–44, I² = 97.12) and 17% (95%CI 14–19, I² = 92.60%), respectively. The most common bleeding site was thoracic. The most common ischaemic complication was limb ischaemia. The incidences of major bleeding or thrombotic events, intracranial haemorrhage and ischaemic stroke were similar among all monitoring tests. Mechanical unloading was associated with a high incidence of major bleeding events (60%, 95%CI 43–77, I² = 93.32), and ischaemic strokes (13%, 95%CI 7–19, I² = 81.80).
Conclusions
Available literature assessing the association between anticoagulation strategies in VA-ECMO, and bleeding and thrombosis is of limited quality. We identified a substantially higher incidence of major bleeding events than a previous meta-analysis. Limited numbers of patients anticoagulated with alternatives to heparin were reported. Patients with additional mechanical LV unloading represent a cohort at particular risk of bleeding and thrombotic complications.
The use of biomaterials in implanted medical devices remains hampered by platelet adhesion and blood coagulation. Thrombus formation is a prevalent cause of failure of these blood‐contacting devices. Although systemic anticoagulant can be used to support materials and devices with poor blood compatibility, its negative effects such as an increased chance of bleeding, make materials with superior hemocompatibility extremely attractive, especially for long‐term applications. This review examines blood–surface interactions, the pathogenesis of clotting on blood‐contacting medical devices, popular surface modification techniques, mechanisms of action of anticoagulant coatings, and discusses future directions in biomaterial research for preventing thrombosis. In addition, this paper comprehensively reviews several novel methods that either entirely prevent interaction between material surfaces and blood components or regulate the reaction of the coagulation cascade, thrombocytes, and leukocytes.
Background
Only some studies have directly compared and analyzed the roles of activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in coagulation monitoring during argatroban administration.
Objectives
This study aims to assess the correlation of argatroban dose with ACT and aPTT values and to identify the optimal coagulation test for argatroban dose adjustment.
Methods
We evaluated 55 patients on extracorporeal membrane oxygenation (ECMO) who received argatroban for more than 72 hours. The correlation between argatroban dose and aPTT and ACT values was evaluated. To compare argatroban dose and bleeding events according to liver dysfunction, the patients were divided into 2 groups based on alanine aminotransferase and total bilirubin.
Results
Among the 55 patients, a total of 459 doses and coagulation tests were evaluated. The aPTT and ACT values showed a weak correlation with argatroban dose, with the Pearson correlation coefficients of 0.261 ( P < 0.001) and 0.194 ( P = 0.001), respectively. The agreement between the target 150 to 180 seconds for ACT and 55 to 75 seconds for aPTT was observed in 140 patients (46.1%). Twenty-four patients (43.6%) had liver dysfunction when they started argatroban. The median argatroban dose was lower in the liver dysfunction group than in the control group (0.094 mcg/kg/min vs 0.169 mcg/kg/min, P = 0.020). Difference was not observed between the 2 groups in the amount of red blood cell (0.47 vs 0.43 pack, P = 0.909) and platelet (0.60 vs 0.08 pack, P = 0.079) transfusion per day.
Conclusion and Relevance
A weak correlation was observed between argatroban dose and the aPTT and ACT values. However, the agreement between aPTT and ACT was only 46.1% regarding the scope of target range. Further research is necessary to determine how to assess the optimal argatroban dose for patients administered argatroban while undergoing ECMO at the intensive care unit.
Extracorporeal membrane oxygenation (ECMO) is a complex therapy aimed at providing mechanical support for patients with severe, life‐threating cardiac and/or respiratory failure. Research has demonstrated variability in pharmacokinetic changes in the critically ill patient population receiving ECMO. There is a need to understand the complexity of these pharmacokinetic changes to provide optimal pharmacotherapeutic regimens thereby maximizing effectiveness and mitigating harm. However, the number of pharmacokinetic studies in patients receiving ECMO remains small, and very few prospective studies have been published addressing optimal analgesic, sedative, or antimicrobial therapy. Anticoagulation is an additional important component of ECMO therapy but the preferred agent as well as dosing and monitoring strategy are unclear. The purpose of this narrative review is to discuss analgesia and sedation, antimicrobial, and anticoagulation management strategies in adult patients receiving ECMO.
Extracorporeal membrane oxygenation (ECMO) is one of the most important supporting therapies for patients with severe cardiopulmonary failure, and the core component of ECMO is the membrane oxygenator. However, in clinical application, the membrane oxygenator faces a dilemma in balancing anticoagulation and hemorrhage risks, which restrains the service life of membrane oxygenator and affects patients’ safety seriously. In this work, we introduce poly (1-vinyl-2-pyrrolidone) (PVP) and poly (acrylic acid) (PAA) into polyethersulfone (PES) membranes simply by in-situ crosslinking polymerization and nonsolvent induced phase separation (NIPS) method. All the modified membranes exhibit favorable hemocompatibility with prolonged activated partial thromboplastin time (APTT) (>10 seconds). Besides, the introduction of PAA can improve CO2 and O2 permeabilities simultaneously (increased by 36.57% and 30.86% at maximum, respectively, compared with pristine PES membrane). Finally, an ECMO-simulated gas-liquid contactor circulation device is designed, and the modified membranes show better oxygenation performance and CO2 removal performance. The membrane modification and fabrication methods in this work are simple, low-cost, and easily industrialized. The work has practical guiding significance for the subsequent membrane research and application toward oxygenators.
Extracorporeal carbon dioxide removal (ECCO2R) is a form of extracorporeal life support (ECLS) largely aimed at removing carbon dioxide in patients with acute hypoxemic or acute hypercapnic respiratory failure, so as to minimize respiratory acidosis, allowing more lung protective ventilatory settings which should decrease ventilator-induced lung injury. ECCO2R is increasingly being used despite the lack of high-quality evidence, while complications associated with the technique remain an issue of concern. This review explains the physiological basis underlying the use of ECCO2R, reviews the evidence regarding indications and contraindications, patient management and complications, and addresses organizational and ethical considerations. The indications and the risk-to-benefit ratio of this technique should now be carefully evaluated using structured national or international registries and large randomized trials.
In the United States, ~100,000 patients are hospitalized annually for cardiogenic shock with 27-51% mortality. Similarly, ~356,000 patients develop out-of-hospital cardiac arrests (OHCA) annually with 90% mortality. In the last few decades, several acute mechanical circulatory support (AMCS) devices have been developed to provide hemodynamic support and to improve outcomes in patients with cardiogenic shock and cardiac arrest. Among all the devices, venoarterial extracorporeal membrane oxy-genation (VA-ECMO) is the only AMCS device that provides immediate and complete cardiopulmonary support. With an increase in clinical experience with VA-ECMO, use of VA-ECMO has expanded beyond post-cardiotomy cardiogenic shock. In the last two decades, there has also been a rapid growth in the observational and randomized data describing the clinical and logistical considerations with successful clinical outcomes in patients with cardiogenic shock and cardiac arrest. In this review, we discuss the fundamental concepts and hemodynamic aspects of VA-ECMO, its indications, contra-indications, and the complications that are encountered in the setting of VA-ECMO in patients with cardiac arrest and cardiogenic shock of various etiologies.
Introduction
Unfractionated heparin is the most commonly utilized anticoagulant in extracorporeal membrane oxygenation (ECMO) due to clinician familiarity, ease of reversal, and low cost compared to alternative agents. However, heparin’s anticoagulant effect can be unpredictable and its use accompanies a risk of heparin induced thrombocytopenia (HIT). Successful use of bivalirudin as an alternative to heparin in non-HIT ECMO patients has previously been described. However, there is a paucity of data regarding its utilization in patients with confirmed HIT on ECMO.
Methods
This single-center retrospective chart review at Cleveland Clinic Main Campus included 12 ECMO patients who were managed with bivalirudin for a new diagnosis of HIT. Descriptive statistical analyses were performed utilizing median with interquartile range and number with percent as appropriate.
Results
Of the 12 patients included, median ECMO duration was 328.5 (218.8–502.1) h and venoarterial ECMO was the most common configuration. No patients experienced the primary outcome of in-circuit thrombosis while on bivalirudin. One patient developed a deep vein thrombosis 22.5 h after switching from heparin to bivalirudin. Major bleeding occurred during bivalirudin therapy in 8 (66.7%) patients.
Conclusions
Overall, our study results suggest that bivalirudin is effective for the management of HIT and did not show evidence of in-circuit thrombosis. A high incidence of major bleeding was observed with bivalirudin use within this study. Clinicians should view bivalirudin as an acceptable agent for the treatment of HIT in the ECMO population, but must consider bleeding risk given the lack of effective reversal agents.
Objectives
: Despite the increasing utilization of mechanical circulatory support (MCS) devices, the 4Ts and HEP scores have not been validated in patients requiring MCS with suspected heparin-induced thrombocytopenia (HIT).
Design
: Retrospective cohort study
Setting
: Tertiary university hospital
Participants
: Adults requiring any MCS with suspected HIT
Interventions
: Diagnostic investigation of HIT
Measurements and Main Results
: Of the 299 patients included, there were 374 diagnostic investigations of HIT, of which 32 (8.6%) were HIT probable (heparin PF4 immunoassay optical density (OD) ≥ 1 or positive SRA). The 4Ts score ≥ 4 demonstrated a pre-test sensitivity of 0.56 (95% CI: 0.39-0.72) and specificity of 0.8 (95% CI: 0.75-0.83). The HEP score ≥ 3 demonstrated a pre-test sensitivity of 0.31 (95% CI: 0.18-0.49) and specificity of 0.83 (95% CI: 0.79-0.87). The area under the receiver-operating characteristic curve for the 4Ts and HEP scores were 0.68 (95% CI: 0.63-0.73) and 0.63 (95% CI: 0.59-0.68), respectively, and were not statistically different (p=0.21). In patients with an intra-aortic balloon pump, neither the 4Ts nor HEP score had discriminatory ability to differentiate probable HIT. The HEP score had no discriminatory ability in patients with concomitant MCS devices.
Conclusions
: The 4Ts and HEP scores have a modest predictive performance for probable HIT in patients requiring MCS devices. A low 4Ts or HEP score does not reliably rule out HIT in patients requiring MCS, and clinical suspicion for HIT should be investigated utilizing laboratory tests in this population.
Background
Accidental hypothermia (AH) sometimes leads to coagulation disorder, especially in severe AH. We previously demonstrated that intrasplenic platelet activation caused aberrant hemostasis and thrombus formation after rewarming in a murine AH model. However, no study has focused on the appropriate management of platelets causing coagulation activation after rewarming of AH. We investigated whether or not recombinant soluble thrombomodulin (rTM) can suppress thrombosis formation after rewarming using a rat AH model.
Methods
Wistar rats were exposed to an ambient temperature of −20 °C under general anesthesia until their rectal temperature decreased to 26 °C. The Hypo group rats (n = 5) were immediately euthanized, while the Hypo/Re group (n = 5) and rTM group rats (n = 5), which were administered rTM (1 mg/kg) via the tail vein, were rewarmed until the rectal temperature returned to 34 °C and then euthanized 6 h later. Tissue and blood samples were collected from all rats for histopathological and coagulation analyses at euthanasia.
Results
There was no significant change in the D-dimer level in the Hypo group rats, while the D-dimer level was significantly elevated at 6 h after rewarming in the Hypo/Re group rats (P = 0.015), and histopathology detected both fibrin and platelets in the renal glomerulus. However, the rTM group rats did not show any elevation of the D-dimer levels at 6 h after rewarming, and no fibrin was noted on histopathology.
Conclusions
rTM may be useful as an appropriate anticoagulant in cases of aberrant hemostasis after rewarming of AH.
Objective
Timing and causes of hospital mortality in adult patients undergoing veno-arterial extracorporeal membrane oxygenation (V-A ECMO) have been poorly described. Aim of the current review was to investigate the timing and causes of death of adult patients supported with V-A ECMO, and subsequently define the “V-A ECMO gap”, which represents the patients who are successfully weaned of ECMO but eventually die during hospital stay.
Data Sources
A systematic search was performed using electronic MEDLINE and EMBASE databases through PubMed. Studies reporting on adult V-A ECMO patients from January 1993 to December 2020 were screened.
Study Selection
The studies included in this review were studies that reported more than 10 adult, human patients, and no mechanical circulatory support other than V-A ECMO.
Data Extraction
Information extracted from each study included mainly mortality and causes of death on ECMO and after weaning. Complications and discharge rates were also extracted.
Data Synthesis
Sixty studies with 9,181 patients were included for analysis in this systematic review. Overall mortality was 38.0% (95% confidence intervals (CI) 34.2-41.9%) during V-A ECMO support (reported by 60 studies) and 15.3% (95% CI 11.1-19.5%, reported by 57 studies) after weaning. Finally, 44.0% of patients (95% CI 39.8-52.2) were discharged from hospital (reported by 60 studies). Most common causes of death on ECMO were multiple organ failure, followed by cardiac failure and neurological causes.
Conclusions
More than one-third of V-A ECMO patients die during ECMO support. Additionally, many of successfully weaned patients still decease during hospital stay, defining the “V-A ECMO gap”. Underreporting and lack of uniformity in reporting of important parameters remains problematic in ECMO research. Future studies should uniformly define timing and causes of death in V-A ECMO patients to better understand the effectiveness and complications of this support.
There has been a significant increase in the use of short-term percutaneous ventricular assist devices (pVADs) as acute circulatory support in cardiogenic shock and to provide haemodynamic support during interventional procedures, including high-risk percutaneous coronary interventions. Although frequently considered together, pVADs differ in their haemodynamic effects, management, indications, insertion techniques, and monitoring requirements. This consensus document summarizes the views of an expert panel by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and the Association for Acute Cardiovascular Care (ACVC) and appraises the value of short-term pVAD. It reviews the pathophysiological context and possible indications for pVAD in different clinical settings and provides guidance regarding the management of pVAD based on existing evidence and best current practice.
Bleeding and thromboembolic events are among the most frequent complications of treatment with extracorporeal membrane oxygenation (ECMO). Causative is mainly a multifactorial unspecific activation of the coagulation system, which leads to increased consumption and to functional disorders of platelets. Additionally, anticoagulation with unfractionated heparin can trigger an immunologically mediated heparin-induced thrombocytopenia (HIT). Approximately 3.7% of patients treated by ECMO are affected by this potentially life-threatening side effect of HIT. Although HIT is primarily characterized by a sudden and significant drop in the number of platelets, patients have a high risk for thromboembolic complications (50-75%). Therefore, an immediate discontinuation of heparin administration and effective alternative anticoagulation is necessary in cases of clinically suspected HIT. A confirmation of the HIT diagnosis using specific laboratory tests should not be waited for. Although the data situation is based on experience with a very limited number of patients, there is nevertheless consensus that direct thrombin inhibitors (DTI) are safe and effective alternatives to heparin for anticoagulation during ECMO treatment. With bivalirudin and argatroban two suitable drugs with different pharmacological profiles are currently available. It is important to keep in mind that no specific antidote exists and a meticulous and sometimes substantial adaptation of the dosage in cases of impairment of renal or liver function is essential to avoid bleeding complications. The anticoagulation level can be monitored by a close control of coagulation. The administration of factor Xa inhibitors as alternative anticoagulants in ECMO treatment cannot currently be recommended.
Background:
Heparin is the widely used anti-coagulation strategy for patients on extracorporeal membrane oxygenation (ECMO). Nevertheless, heparin-induced thrombocytopenia (HIT) and acquired anti-thrombin (AT) deficiency preclude the use of heparin requiring utilization of an alternative anticoagulant agent. Direct thrombin inhibitors are being proposed as potential alternatives with argatroban as one of the main agents. We aimed to review the evidence with regard to safety and efficacy of argatroban as a potential definitive alternative to heparin in the adult patient population undergoing ECMO support.
Methods:
A web-based systematic literature search was performed in Medline (PubMed) and Embase from inception until June 18, 2020.
Results:
The search identified 13 publications relevant to the target (4 cohort studies and 9 case series). Case reports and case series with less than 3 cases were not included in the qualitative synthesis. The aggregate number of argatroban treated patients on ECMO was n = 307. In the majority of studies argatroban was used as a continuous infusion without loading dose. Starting doses on ECMO varied between 0.05 and 2 μg/kg/min and were titrated to achieve the chosen therapeutic target range. The activated partial thormboplastin time (aPTT) was the anticoagulation parameter used for monitoring purposes in most studies, whereas some utilized the activated clotting time (ACT). Optimal therapeutic targets varied between 43-70 and 60-100 seconds for aPTT and between 150-210 and 180-230 seconds for ACT. Bleeding and thromboembolic complication rates were comparable to patients treated with unfractionated heparin (UFH).
Conclusions:
Argatroban infusion rates and anticoagulation target ranges showed substantial variations. The rational for divergent dosing and monitoring approaches are discussed in this paper. Argatroban appears to be a potential alternative to UFH in patients requiring ECMO. To definitively establish its safety, efficacy and ideal dosing strategy, larger prospective studies on well-defined patient populations are warranted.
Background
Heparin induced thrombocytopenia (HIT) is reported at a variable rate in extracorporeal membrane oxygenation (ECMO) patients. A critical factor impacting platelet factor-4 (PF4)-heparin antibody formation is plasma PF4 concentration. We hypothesized that PF4 concentration would be increased during veno-arterial (VA) ECMO.
Methods
Plasma PF4 concentration was measured during the first 5 ECMO days in 20 VA ECMO patients and 10 control plasma samples. PF4-heparin ratios were estimated using an assumed heparin concentration of 0.4 IU/mL. This correlates with an activated partial thromboplastin time of 60 to 80 seconds, which is the anticoagulation target in our center.
Results
Twenty VA ECMO patients were enrolled, 10 of which had pulmonary embolism. Median PF4 concentration was 0.03 µg/mL [0.01, 0.13] in control plasma. Median PF4 concentration was 0.21 µg/mL [0.12, 0.34] on ECMO day 1 or 2, 0.16 µg/mL [0.09, 0.25] on ECMO day 3, and 0.12 µg/mL [0.09, 0.22] on ECMO day 5. Estimated median PF4-heparin ratios were 0.04, 0.03, and 0.02 respectively. Two patients (10%) developed HIT that was confirmed by serotonin release assay. PF4 concentration did not differ significantly in these patients compared to non-HIT patients (p = 0.37). No patient had an estimated PF4-heparin ratio between 0.7 and 1.4, which is the reported optimal range for PF4-heparin antibody formation.
Conclusion
Our data suggest that PF4 concentration is mildly elevated during VA ECMO compared to control plasma. Estimated PF4-heparin ratios were not optimal for HIT antibody formation. These data support epidemiologic studies where HIT incidence is low during VA ECMO.
Background
Timing and causes of hospital mortality in adult patients undergoing veno-arterial extracorporeal membrane oxygenation (V-A ECMO) have been poorly described. Aim of the current review was to investigate the timing and causes of death of adult patients treated with V-A ECMO, and subsequently define the “V-A ECMO gap”, which represents the patients who are successfully weaned of ECMO but eventually die during hospital stay.
Methods
A systematic search was performed using electronic MEDLINE and EMBASE databases through PubMed. Studies reporting on adult V-A ECMO patients from January 1993 to October 2018 were screened. Timing, rates and causes of in-hospital mortality were analyzed.
Results
Sixty studies with 9,181 patients were included in this systematic review. Overall mortality was 37.6% during V-A ECMO support (reported by 60 studies) and 28.9% (57 studies) after weaning. Finally, 32.6% were discharged from hospital (60 studies). Most common causes of death on ECMO were multiple organ failure (MOF, 49.8%), followed by cardiac failure (20.6%) and neurological causes (15.7%). Most common causes of death after weaning were MOF (55.3%), followed by neurological complications (12.6%), persistent heart failure (10.7%) and pulmonary infections (6.8%).
Conclusions
More than one-third of adult V-A ECMO patients die during ECMO therapy. Additionally, almost one half of successfully weaned patients still decease during hospital stay, defining the “V-A ECMO gap”. Underreporting and lack of uniformity in reporting of important parameters remains problematic in ECMO research. Future studies should uniformly define timing and causes of death in V-A ECMO patients to better understand the effectiveness and complications of this therapy. Systematic review registration PROSPERO 2019 number CRD42019130815
Innerhalb der letzten 50 Jahre wurden auf dem Gebiet des extrakorporalen Life Support Systems (ECLS) vor allem in Bezug auf die verwendeten Materialien und der angewandten Techniken große Fortschritte erzielt. Nichtsdestotrotz stellt das Gerinnungsmanagement unter ECLS immer noch eine besondere medizinische Herausforderung dar. Durch die ECLS-Therapie wird das normalerweise fein ausbalancierte Gerinnungssystem aufgrund der großen Exposition mit gerinnungsaktivierenden Fremdkörperoberflächen innerhalb des ECLS-Umlaufs massiv gestört.
Objectives:
To ascertain: 1) the frequency of thrombocytopenia and heparin-induced thrombocytopenia; 2) positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia; and 3) clinical outcome of heparin-induced thrombocytopenia in adult patients receiving venovenous- or venoarterial-extracorporeal membrane oxygenation, compared with cardiopulmonary bypass.
Design:
A single-center, retrospective, observational cohort study from January 2016 to April 2018.
Setting:
Tertiary referral center for cardiac and respiratory failure.
Patients:
Patients who received extracorporeal membrane oxygenation for more than 48 hours or had cardiopulmonary bypass during specified period.
Interventions:
None.
Measurements and main results:
Clinical and laboratory data were collected retrospectively. Pretest Probability Score and heparin-induced thrombocytopenia testing results were collected prospectively. Mean age (± SD) of the extracorporeal membrane oxygenation and cardiopulmonary bypass cohorts was 45.4 (± 15.6) and 64.9 (± 13), respectively (p < 0.00001). Median duration of cardiopulmonary bypass was 4.6 hours (2-16.5 hr) compared with 170.4 hours (70-1,008 hr) on extracorporeal membrane oxygenation. Moderate and severe thrombocytopenia were more common in extracorporeal membrane oxygenation compared with cardiopulmonary bypass throughout (p < 0.0001). Thrombocytopenia increased in cardiopulmonary bypass patients on day 2 but was normal in 83% compared with 42.3% of extracorporeal membrane oxygenation patients at day 10. Patients on extracorporeal membrane oxygenation also followed a similar pattern of platelet recovery following cessation of extracorporeal membrane oxygenation. The frequency of heparin-induced thrombocytopenia in extracorporeal membrane oxygenation and cardiopulmonary bypass were 6.4% (19/298) and 0.6% (18/2,998), respectively (p < 0.0001). There was no difference in prevalence of heparin-induced thrombocytopenia in patients on venovenous-extracorporeal membrane oxygenation (8/156, 5.1%) versus venoarterial-extracorporeal membrane oxygenation (11/142, 7.7%) (p = 0.47). The positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia in patients post cardiopulmonary bypass and on extracorporeal membrane oxygenation was 56.25% (18/32) and 25% (15/60), respectively. Mortality was not different with (6/19, 31.6%) or without (89/279, 32.2%) heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation (p = 0.79).
Conclusions:
Thrombocytopenia is already common at extracorporeal membrane oxygenation initiation. Heparin-induced thrombocytopenia is more frequent in both venovenous- and venoarterial-extracorporeal membrane oxygenation compared with cardiopulmonary bypass. Positive predictive value of Pretest Probability Score in identifying heparin-induced thrombocytopenia was lower in extracorporeal membrane oxygenation patients. Heparin-induced thrombocytopenia had no effect on mortality.
Objectives:
Heparin-induced thrombocytopenia is a recognized concern in patients on extracorporeal life support. The purpose of this study was to evaluate the applicability of an enzyme-linked immunosorbent assay optical density threshold less than 1 to rule out heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation.
Design:
Retrospective, single-center study.
Setting:
Patients were recruited from a prospectively maintained database of all patients on extracorporeal membrane oxygenation from 2012 to 2018 at a tertiary referral center.
Patients:
Forty-seven patients on extracorporeal membrane oxygenation support.
Interventions:
The primary objective was to evaluate the application of enzyme-linked immunosorbent assay optical density thresholds and the serotonin release assay in patients on extracorporeal membrane oxygenation. Patients were divided into two cohorts, serotonin release assay negative and serotonin release assay positive. In order to perform a sensitivity and specificity analysis of enzyme-linked immunosorbent assay optical density thresholds, heparin-induced thrombocytopenia negative was defined as an optical density less than 1.0 and heparin-induced thrombocytopenia positive as an optical density greater than or equal to 1.0.
Measurements and main results:
Utilizing the prespecified optical density thresholds, a specificity and negative predictive value of 89% and 95% were achieved, respectively.
Conclusions:
This assessment has helped to identify optical density thresholds for patients undergoing extracorporeal membrane oxygenation. Our data suggest that an optical density threshold of 1.0 may aid clinicians in objectively ruling out heparin-induced thrombocytopenia without sending a confirmatory serotonin release assay. Increasing the optical density threshold to 1.0 resulted in a high specificity and negative predictive value.
Purpose of review:
Temporary circulatory support (TCS) with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used as a salvage therapy for patients with refractory cardiogenic shock. This article provides an overview of VA-ECMO principles, indications, management, complications, and discusses the results of recent case series and trials.
Recent findings:
VA-ECMO is utilized as a bridge to 'decision' that includes weaning after cardiac function recovery, transplantation, long-term mechanical circulatory support, and withdrawal in case of futility. VA-ECMO is considered the first-line TCS as it allows rapid improvement in oxygenation, is less expensive, and is also suitable for patients with biventricular failure. Combining Impella (Abiomed, Danvers, MA, USA) or intra-aortic balloon pump support with VA-ECMO might decrease left ventricular pressure and improve outcomes. Massive pulmonary embolism, sepsis-associated cardiomyopathy, and refractory cardiac arrest are among emerging indications for TCS.
Summary:
TCS have become the cornerstone of the management of patients with cardiogenic shock, although the evidence supporting their efficacy is limited. VA-ECMO is considered the first-line option, with a growing number of accepted and emerging indications. Randomized clinical trials are now needed to determine the place VA-ECMO in cardiogenic shock treatment strategies.
Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.
The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.
Background
Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is an effective rescue therapy for severe cardiorespiratory failure, but morbidity and mortality are high. We hypothesised that survival decreases with longer VA ECMO treatment. We examined the Extracorporeal Life Support Organization (ELSO) registry for a relationship between VA ECMO duration and in-hospital mortality, and covariates including indication for support.
Methods
All VA runs from the ELSO database from 2002 to 2012 were extracted. Multiple runs and non-VA runs were excluded. Runs were categorized into diagnostic groups. Logistic regression for analysis of the effect of duration on outcome, and multivariate regression for diagnosis and other baseline factors were performed. Non-linear models including piecewise logistic models were fitted.
Results
There were 2699 runs analysed over 14,747 days. Logistic regression analysis of the effect of duration on outcome, and multivariate regression analysis of diagnosis and other baseline factors were performed. In-hospital survival was 41.4% (95% CI 39.6–43.3). 75% of patients were supported for less than 1 week and 96% for less than 3 weeks. Median duration (4 days IQR 2.0–6.8) was greater in survivors (4.1 (IQR 2.5–6.7) vs 3.8 (IQR 1.7–7.0) p = 0.002). The final multivariate model demonstrated increasing survival to day 4 (OR 1.53 (95% CI 1.37–1.71) p < 0.001), decreasing from day 4 to 12 (OR 0.86 (95% CI 0.81–0.91), p < 0.001) with no significant change thereafter (OR 0.98 (95% CI 0.94–1.02), p = 0.400).
Conclusions
ECMO for 4 days or less is associated with higher mortality, likely reflecting early treatment failure. Survival is highest when patients are weaned on the fourth day of ECMO but likely decreases into the second week. While this does not suggest weaning at this point will produce better outcomes, it does reflect the likely time course of ECMO as a bridge in severe shock. Patients with some underlying conditions (like myocarditis and heart transplantation) achieve better outcomes despite longer support duration. These findings merit prospective study for the development of prognostic models and weaning strategies.
Extracorporeal membrane oxygenation (ECMO) is a technology capable of providing short-term mechanical support to the heart, lungs or both. Over the last decade, the number of centres offering ECMO has grown rapidly. At the same time, the indications for its use have also been broadened. In part, this trend has been supported by advances in circuit design and in cannulation techniques. Despite the widespread adoption of extracorporeal life support techniques, the use of ECMO remains associated with significant morbidity and mortality. A complication witnessed during ECMO is the inflammatory response to extracorporeal circulation. This reaction shares similarities with the systemic inflammatory response syndrome (SIRS) and has been well-documented in relation to cardiopulmonary bypass. The exposure of a patient’s blood to the non-endothelialised surface of the ECMO circuit results in the widespread activation of the innate immune system; if unchecked this may result in inflammation and organ injury. Here, we review the pathophysiology of the inflammatory response to ECMO, highlighting the complex interactions between arms of the innate immune response, the endothelium and coagulation. An understanding of the processes involved may guide the design of therapies and strategies aimed at ameliorating inflammation during ECMO. Likewise, an appreciation of the potentially deleterious inflammatory effects of ECMO may assist those weighing the risks and benefits of therapy.
Importance
Apical ballooning is broadly recognized as the classic form of takotsubo syndrome (TTS). Atypical subtypes of TTS also exist, which constitute about 20% of all cases. To date, clinical profile and course of atypical TTS types have rarely been studied.
Objective
To characterize the clinical profile and outcomes of typical vs atypical types of TTS in a large patient cohort.
Design, Setting, and Participants
Records of 1750 patients from the International Takotsubo Registry, comprising 26 participating cardiovascular centers in 9 different countries, were reviewed and data on clinical profile and outcomes collected from January 1, 2011, to December 31, 2014.
Main Outcomes and Measures
Clinical characteristics and in-hospital as well as long-term outcomes were assessed.
Results
Of 1750 patients diagnosed with TTS between 1998 and 2014, a total of 1430 (81.7%) presented with apical TTS (defined as typical TTS) and 320 (18.3%) with midventricular, basal, or focal TTS (all defined as atypical TTS). Patients with atypical TTS were younger than those with typical TTS (mean [SD], 62.5 [13.3] vs 67.3 [12.9] years; P < .001). Brain natriuretic peptide levels on admission were lower (median factor increase of the upper limit of normal, 4.18 vs 6.59; P = .02) and left ventricular ejection fraction was higher (mean [SD], 43.4% [10.7%] vs 40.6% [12.0%]; P < .001) in patients with atypical than those with typical forms of TTS. ST-segment depression was more prevalent in patients with atypical TTS (31 of 286 [10.8%] vs 90 of 1292 [7.0%]; P = .03), while ST-segment elevation was found more frequently in patients with typical TTS (593 of 1292 [45.9%] vs 97 of 286 [33.9%]; P < .001). Patients with atypical TTS more often had neurologic disorders than those with typical TTS (81 of 274 [29.6%] vs 286 of 1251 [22.9%]; P = .02). While in-hospital mortality was comparable between patients with atypical and typical TTS (10 of 320 [3.1%] vs 62 of 1430 [4.3%]; P = .32), the atypical forms showed a favorable outcome at 1 year (P = .01). However, after adjustment for confounders, only left ventricular ejection fraction less than 45%, atrial fibrillation, and neurologic disease, but not the type of TTS, were independent predictors. After 1 year, patients with both types of TTS showed a similar prognosis at long-term follow-up.
Conclusions and Relevance
Atypical TTS has different characteristics than typical TTS, including younger age of onset, more frequent ST-segment depression, higher prevalence of neurologic diseases, less pronounced reduction in left ventricular ejection fraction, and lower brain natriuretic peptide values on admission. Outcomes are comparable between patients with both types after adjustment for confounders, suggesting that both should be equally monitored.
Aims
Takotsubo syndrome (TTS) is typically provoked by negative stressors such as grief, anger, or fear leading to the popular term ‘broken heart syndrome’. However, the role of positive emotions triggering TTS remains unclear. The aim of the present study was to analyse the prevalence and characteristics of patients with TTS following pleasant events, which are distinct from the stressful or undesirable episodes commonly triggering TTS.
Methods and results
Takotsubo syndrome patients with preceding pleasant events were compared to those with negative emotional triggers from the International Takotsubo Registry. Of 1750 TTS patients, we identified a total of 485 with a definite emotional trigger. Of these, 4.1% (n = 20) presented with pleasant preceding events and 95.9% (n = 465) with unequivocal negative emotional events associated with TTS. Interestingly, clinical presentation of patients with ‘happy heart syndrome’ was similar to those with the ‘broken heart syndrome’ including symptoms such as chest pain [89.5% (17/19) vs. 90.2% (412/457), P = 1.0]. Similarly, electrocardiographic parameters, laboratory findings, and 1-year outcome did not differ. However, in a post hoc analysis, a disproportionate higher prevalence of midventricular involvement was noted in ‘happy hearts’ compared with ‘broken hearts’ (35.0 vs. 16.3%, P = 0.030).
Conclusion
Our data illustrate that TTS can be triggered by not only negative but also positive life events. While patient characteristics were similar between groups, the midventricular TTS type was more prevalent among the ‘happy hearts’ than among the ‘broken hearts’. Presumably, despite their distinct nature, happy and sad life events may share similar final common emotional pathways, which can ultimately trigger TTS.
The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood.
The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome.
Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year.
Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).
The use of extracorporeal membrane oxygenation (ECMO) support for cardiac and respiratory failure has increased in recent years. Improvements in ECMO oxygenator and pump technologies have aided this increase in utilisation. Additionally, reports of successful outcomes in supporting patients with respiratory failure during the 2009 H1N1 pandemic, and reports of ECMO during cardiopulmonary resuscitation have led to increased uptake of ECMO. Patients requiring ECMO are a heterogenous group of critically ill patients with cardiac and respiratory failure. Bleeding and thrombotic complications remain a leading cause of morbidity and mortality in patients on ECMO. In this review we describe the mechanisms and management of haemostatic, thrombotic and haemolytic complications during ECMO support.
Aim
To evaluate the prognostic value of baseline SOFA coagulation score (SOFA‐CS) and change in platelet counts in patients with severe acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT).
Methods
We performed a secondary analysis from the Randomised Evaluation of Normal versus Augmented Level of RRT (RENAL) study. The primary endpoint was all‐cause mortality at 90 days after randomisation. The association between baseline SOFA‐CS, changes in platelet counts, process of care, and clinical outcomes were analysed using multivariate Cox model adjusted for baseline variables.
Results
The complete SOFA‐CS data were available in 1454 out of 1508 patients from the RENAL study. Among them, 708 patients had an abnormal SOFA‐CS (defined as SOFA‐CS≥1), while 746 patients had normal SOFA‐CS at baseline (SOFA‐CS=0). An abnormal SOFA‐CS was independently associated with an increased risk of death at 90 days (HR 1.27, 95% CI 1.05–1.53, p = 0.015). An abnormal SOFA‐CS was associated with prolonged length of ICU stay and duration of mechanical ventilation as well. Furthermore, there was no significant association between changes in platelet counts in patients who survived beyond 4 days and 90‐day mortality (HR 1.26, 95%CI 0.29‐5.56, p=0.76). However, on multivariable analysis a decline of ≥ 60% (HR 1.93, 95%CI 1.23‐3.05, p=0.004) was associated with 90‐day mortality in patients who survived beyond the first 4 days.
Conclusions
In the RENAL study, thrombocytopenia is a common phenomenon in patients with severe AKI receiving CRRT. An abnormal baseline SOFA‐CS and reductions in platelet counts were associated with increased mortality at 90 days.
Takotsubo syndrome (TTS) was first described in Japan in 1990. The clinical presentation is similar to that of acute coronary syndrome (ACS). Cardiac enzymes are commonly elevated. A global initiative was launched and the InterTAK Registry was established to provide a systematic database. The major goals of the International Takotsubo Registry (InterTAK Registry) are to provide a comprehensive clinical characterization on natural history, treatment, and outcomes. We linked a biorepository to identify biomarkers for the diagnosis and prognosis and to investigate the genetic basis as well as disease-related factors. We focus on the rationale, objectives, design, and first results of the InterTAK Registry.
Purpose:
This study aimed to concisely describe the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to extracorporeal membrane oxygenation (ECMO).
Methods:
Narrative review based on a systematic analysis of the medical literature, national and international guidelines, and expert opinion.
Results:
The use of venovenous ECMO (VV-ECMO) is increasing in the most severe forms of acute lung injury. In patients with cardiogenic shock, short-term veno-arterial ECMO (VA-ECMO) provides both pulmonary and circulatory support. Technological improvements and recently published studies suggest that ECMO is able to improve patients' outcomes. There are, however, many uncertainties regarding the real benefits of this technique both in hemodynamic and respiratory failure, the territorial organization to deliver ECMO, the indications and the use of concomitant treatments.
Conclusions:
Although there have been considerable advances regarding the use of ECMO in critically ill patients, the risk/benefit ratio remains underinvestigated. ECMO indications, organization of ECMO delivery, and use of adjuvant therapeutics need also to be explored. Ongoing and future studies may be able to resolve these issues.
Zusammenfassung. Das 1990 erstmalig beschriebene Takotsubo-Syndrom (TTS) fand weltweite Aufmerksamkeit als eine reversible Kardiomyopathie, ausgelost durch ein emotionales Ereignis, die altere Frauen betrifft und aufgrund ihrer Symptomatik einem akuten Koronarsyndrom gleicht. Heute weiss man, dass das TTS weitaus heterogener ist. Es kann beide Geschlechter und alle Altersgruppen betreffen und tritt in vier verschiedenen Formen auf. In der Akutphase konnen lebensbedrohliche Komplikationen auftreten und auch die Langzeitprognose ist nicht komplett benigne. Haufig geht ihm ein emotionales, haufig jedoch auch ein physisches Ereignis oder gar beide voraus. Allerdings kann die Erkrankung auch spontan auftreten. Bei bis zu 10 % der Patienten kommt es im Verlauf zu einem erneuten TTS, das durch die Einnahme von Betablockern nicht verhindert werden kann.
Objective:
The prognostic impact of thrombocytopenia in patients supported by extracorporeal membrane oxygenation after cardiac surgery is uncertain. We investigated whether thrombocytopenia is independently predictive of poor outcome and describe the incidence and time course of thrombocytopenia in extracorporeal membrane oxygenation patients.
Design:
Retrospective analysis of prospectively collected data.
Setting:
Cardiosurgical ICU at a tertiary referral center.
Patients:
Three hundred adult patients supported with venoarterial extracorporeal membrane oxygenation for more than 24 hours because of refractory cardiogenic shock after heart surgery between January 2001 and December 2014.
Interventions:
None.
Measurements and main results:
Two-way analysis of variance was used to compare the time course of platelet count changes between survivors and nonsurvivors. Using multiple Cox regression with time-dependent covariates, we investigated the impact of platelet count on 90-day mortality. In nonsurvivors, the daily incidence of moderate (< 100 - 50 × 10/L), severe (49 - 20 × 10/L), and very severe (< 20 × 10/L) thrombocytopenia was 50%, 54%, and 7%, respectively. Platelet count had a biphasic temporal pattern with an initial decrease until day 4-5 after the initiation of extracorporeal membrane oxygenation. Although a significant recovery of the platelet count was observed in survivors, a recovery did not occur in nonsurvivors (p = 0.0001). After adjusting for suspected confounders, moderate, severe, and very severe thrombocytopenia were independently associated with 90-day mortality. The highest risk was associated with severe (hazard ratio, 5.9 [2.7-12.6]; p < 0.0001) and very severe thrombocytopenia (hazard ratio, 25.9 [10.7-62.9], p < 0.0001).
Conclusion:
Thrombocytopenia is an independent risk factor for poor outcome in extracorporeal membrane oxygenation patients after cardiac surgery, with persistent severe thrombocytopenia likely reflecting a high degree of physiologic imbalance.
Objectives:
To assess the prevalence of heparin-induced thrombocytopenia and to study platelet count trends potentially suggestive of heparin-induced thrombocytopenia in a population of extracorporeal membrane oxygenator patients.
Design:
Retrospective cohort study.
Setting:
A total of 926-bed teaching hospital.
Patients:
Extracorporeal membrane oxygenator patients who survived longer than 48 hours from extracorporeal membrane oxygenator initiation between January 1, 2009, and December 31, 2013.
Interventions:
None.
Measurements and main results:
Demographic and clinical data were collected prospectively on all extracorporeal membrane oxygenator patients. Heparin-induced thrombocytopenia testing results and platelet count variables were obtained from the electronic medical record. We used our institutional algorithm to interpret the results of heparin-induced thrombocytopenia testing. Ninety-six extracorporeal membrane oxygenator patients met the inclusion criteria. Eight patients met the algorithm criteria for heparin-induced thrombocytopenia diagnosis and seven of those had documented thromboembolic event while on extracorporeal membrane oxygenator (prevalence of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia related thrombosis, 8.3 and 7.3, respectively). Heparin-induced thrombocytopenia positive patients were younger; all underwent venoarterial extracorporeal membrane oxygenator; spent more hours on extracorporeal membrane oxygenator; had significantly higher heparin-induced thrombocytopenia enzyme-linked immunosorbent assays optical density; had a higher prevalence of thromboembolic events and reached platelet count nadir later. There was no difference in mortality between heparin-induced thrombocytopenia positive and negative patients. Comparison of platelet count trends revealed that there was no statistically significant difference between the predefined study groups.
Conclusions:
Prevalence of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia-related thrombosis among extracorporeal membrane oxygenator patients at our institution is relatively high. Using platelet count trends to guide decision to test for heparin-induced thrombocytopenia is not an optimal strategy in extracorporeal membrane oxygenator patients. Without a validated pretest probability clinical score, serosurveillance in a defined high-risk group of extracorporeal membrane oxygenator patients may be needed.
Thrombocytopenia as well as anti-platelet factor 4/heparin (PF4/H) antibodies are common in cardiac surgery (CS) patients and those treated in the intensive care unit (ICU). In contrast, heparin-induced thrombocytopenia (HIT) is uncommon in these populations (~1 % and ~0.5 %, respectively). A stepwise approach where testing for anti-PF4/H antibodies is performed only in patients with typical clinical symptoms of HIT improves diagnostic specificity of the laboratory assays without losing sensitivity, thereby helping to avoid overdiagnosis and resulting HIT overtreatment. Short-term re-exposure to heparin, especially given intraoperatively for cardiovascular surgery, is a reasonable therapeutic option in patients with a history of HIT who subsequently test negative for HIT antibodies. Organ failure(s), enhanced bleeding risks, and other characteristics require special considerations regarding non-heparin anticoagulation: Argatroban is the alternative anticoagulant with pharmacokinetics independent of renal function, but it has a prolonged half-life in case of impaired liver function. For bivalirudin, protocols during cardiopulmonary bypass surgery are established, and it is suitable for patients with liver insufficiency. A major issue of direct thrombin inhibitors are false high activated partial thromboplastin time values in patients with comorbidities affecting prothrombin, which can result in systematic underdosing of the drugs. This is not the case for danaparoid and fondaparinux, which can be monitored by anti-factor Xa assays, but have long half-lives and no suitable antidote. This review includes also information on management of on- and off-pump cardiac surgery, ventricular assist devices, percutaneous interventions, continuous renal replacement therapy, and extracorporeal membrane oxygenation in patients with HIT.
Background:
Extracorporeal membrane oxygenation (ECMO) offers therapeutic options in refractory respiratory and/or cardiac failure. Systemic anticoagulation with heparin is routinely administered. However, in patients with heparin-induced thrombocytopenia or heparin resistance, the direct thrombin inhibitor bivalirudin is a valid option and has been increasingly used for ECMO anticoagulation. We aimed at evaluating its safety and its optimal dosing for ECMO.
Methods:
Systematic web-based literature search of PubMed and EMBASE performed via National Health Service Library Evidence and manually, updated until January 30, 2016.
Results:
The search revealed 8 publications relevant to the topic (5 case reports). In total, 58 patients (24 pediatrics) were reported (18 received heparin as control groups). Bivalirudin was used with or without loading dose, followed by infusion at different ranges (lowest 0.1-0.2 mg/kg/h without loading dose; highest 0.5 mg/kg/h after loading dose). The strategies for monitoring anticoagulation and optimal targets were dissimilar (activated partial thromboplastin time 45-60 seconds to 42-88 seconds; activated clotting time 180-200 seconds to 200-220 seconds; thromboelastography in 1 study).
Conclusion:
Bivalirudin loading dose was not always used; infusion range and anticoagulation targets were different. In this systematic review, we discuss the reasons for this variability. Larger studies are needed to establish the optimal approach with the use of bivalirudin for ECMO.
Background:
Because it is difficult to distinguish between focal takotsubo cardiomyopathy and aborted myocardial infarction, there is little information about the prevalence and clinical features of focal takotsubo cardiomyopathy.Methods and Results:Our cardiac catheterization databases were queried to identify patients with focal takotsubo cardiomyopathy and other types of takotsubo cardiomyopathy. We defined focal takotsubo cardiomyopathy as hypo-, a- or dyskinesis in both anterolateral and septal segments without obstructive coronary artery disease explaining the wall motion abnormality. A total of 10 patients were diagnosed with focal takotsubo cardiomyopathy. The control group comprised patients with takotsubo cardiomyopathy with apical, mid-ventricular, or basal ballooning. Clinical features and in-hospital outcomes were compared between patients with focal takotsubo cardiomyopathy and those with other types of takotsubo cardiomyopathy. Among the 144 patients with takotsubo cardiomyopathy, the apical, mid-ventricular, basal, and focal types occurred in 85 (59.0%), 49 (34.0%), 0 (0%), and 10 patients (6.9%), respectively. The left ventricular ejection fraction was significantly higher in the focal group compared with the apical and mid-ventricular group (56±13 vs. 45±13 vs. 46±12%, P=0.03). In-hospital outcome was not significantly different among the 3 groups.
Conclusions:
Focal takotsubo cardiomyopathy is not rare. Biplane left ventriculography is useful for its diagnosis.
Background:
Takotsubo stress cardiomyopathy (TSC) is a syndrome characterized by transient myocardial dysfunction with unknown etiology. Although recent studies have suggested that the syndrome is associated with comorbidity and has a dismal prognosis, there is a lack of comprehensive data describing the epidemiology and prognosis of TSC.
Objectives:
This study compared risk markers and mortality in patients with TSC with that of individuals with or without coronary artery disease (CAD).
Methods:
Patients with TSC and control subjects were identified from the Swedish Coronary Angiography and Angioplasty Register between 2009 and 2013 and linked with the Swedish national patient registry, cause of death registry, prescription drug registry, and education and income registries.
Results:
Patients with TSC were characterized by a low cardiovascular risk factor profile but with increased chronic obstructive pulmonary disease, migraine, and affective disorders. The use of beta-blockers was less common but use of β2-adrenergic agonist agents was more common in patients with TSC compared with either of the control groups. Being a patient with TSC was associated with a hazard ratio of 2.1 for death compared with the control subjects without CAD (95% confidence interval: 1.4 to 3.2). This was similar to the excess mortality risk seen among the CAD control subjects compared with control subjects without CAD (hazard ratio: 2.5; 95% confidence interval: 1.8 to 3.3). These associations remained significant after adjusting for CAD risk factors and risk markers for TSC.
Conclusions:
The findings of increased risk associated with β2-adrenergic agonist agents together with stress related to affective disorders emphasize the pathogenic role of sympathetic stimulation. The prognosis regarding mortality is worse than in control subjects without CAD and similar to patients with CAD emphasizing the urgent need for studies on optimal treatment of TSC.
Purpose:
The association between extracorporeal membrane oxygenation (ECMO) use and the development of thrombocytopenia is widely presumed yet weakly demonstrated. We hypothesized that longer duration of ECMO support would be independently associated with worsened thrombocytopenia.
Methods:
We performed a single-center retrospective cohort study of 100 adults who received ECMO for acute respiratory failure. We used generalized estimating equations to test the association between days on ECMO and daily percentage of platelets compared to the first post-cannulation platelet count. We constructed a multivariable logistic regression model with backwards stepwise elimination to identify clinical predictors of severe thrombocytopenia (≤50,000/μL) while on ECMO.
Results:
Days on ECMO was not associated with a decrease in platelet count in the unadjusted analysis (β -0.85, 95 % CI -2.05 to 0.36), nor after considering and controlling for days hospitalized prior to ECMO, APACHE II score, platelet transfusions, and potential thrombocytopenia-inducing medications (β -0.83, 95 % CI -1.9 to 0.25). Twenty-two subjects (22 %) developed severe thrombocytopenia. The APACHE II score and platelet count at the time of cannulation predicted the development of severe thrombocytopenia. The odds of developing severe thrombocytopenia increased 35 % for every 5-point increase in APACHE II score (OR 1.35, 95 % CI 0.94-1.94) and increased 35 % for every 25,000/μL platelets below a mean at cannulation of 188,000/μL (OR 1.35, 95 % CI 1.10-1.64).
Conclusions:
Duration of ECMO is not associated with the development of thrombocytopenia. The severity of critical illness and platelet count at the time of cannulation predict the development of severe thrombocytopenia while receiving ECMO for respiratory failure. Future studies should validate these findings, especially in cohorts with more venoarterial ECMO patients, and should characterize the association between thrombocytopenia and bleeding events while on ECMO.
Aims:
Despite increasing research efforts, the prognostic consequences of takotsubo cardiomyopathy (TTC) remain largely unknown. The aim of this study was therefore to compare the long-term mortality rate of TTC patients with high-risk patients presenting with ST-segment elevation myocardial infarction (STEMI).
Methods and results:
A total of 286 patients with TTC were matched for age and gender with 286 STEMI patients. Outcome was obtained with a standardized telephone follow-up. The primary analysis determined long-term mortality. A secondary analysis was performed evaluating 28-day and 1-year mortality. Follow-up was available for 96% of patients after a mean of 3.8 ± 2.5 years. In TTC patients, long-term mortality was significantly higher compared with the matched STEMI cohort [24.7% vs. 15.1%, hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.07-2.33; P = 0.02]. There was no significant difference in the rates of 28-day (5.5% vs. 5.7%, HR 0.96, 95% CI 0.47-1.94; P = 0.91) and 1-year mortality (12.5% vs. 9%, HR 1.42, 95% CI 0.85-2.38; P = 0.18). In multivariable regression analysis, male sex, a high Killip class on admission, and diabetes mellitus were identified as independent predictors of mortality in TTC patients. A risk score consisting of these factors showed a higher mortality with an increasing number of risk factors.
Conclusion:
Mortality rates in TTC patients are higher than previously expected and long-term mortality exceeded that of patients with STEMI. A simple risk score may provide an approach to identify high-risk patients and predict clinical prognosis.
BACKGROUND:
Takotsubo (or stress induced) cardiomyopathy is characterized by transient left ventricular systolic dysfunction. Recent trends in patient volume, characteristics, and outcomes in the United States are unknown.
METHODS:
Using 2007-2012 National Inpatient Sample data, we identified 22,005 adults (≥18 years) with a primary and 31,942 adults with a secondary discharge diagnosis of takotsubo cardiomyopathy (International Classification of Diseases, Ninth Revision, code 429.83) who underwent diagnostic coronary angiography.
RESULTS:
During 2007 to 2012, the incidence of takotsubo cardiomyopathy increased over 3-fold: 52/million discharges in 2007 to 178/million in 2012 (P < .001). We found a temporal increase in the prevalence of cardiac arrest, cardiogenic shock, cardiovascular risk factors (diabetes, hypertension), and psychiatric disorders (P trend < .0001 for all). In-hospital mortality was 1.1% and remained unchanged over this period (P = .22). Compared to the primary diagnosis group, mortality in the secondary diagnosis group was higher (1.1% vs 3.2%) and was associated with higher incidence of cardiogenic shock, cardiac arrest, and respiratory failure. Men represent 8% of patients in the primary diagnosis group and 12% in the secondary group. In both groups, men had a higher incidence of shock, cardiac arrest, and respiratory failure. Although their mortality was higher than women in the primary group (3.0% vs 0.9%, adjusted odds ratio 3.85, 1.74-8.51), it was comparable in the secondary group (4.8% vs 3.0%).
CONCLUSIONS:
We found a marked increase in the hospitalization for takotsubo cardiomyopathy in the United States in recent years, suggesting higher incidence than prior reports. Although outcomes have remained favorable, there is an increasing burden of cardiovascular and psychiatric disorders in this population with growing cost of care. Risk of mortality is higher in men and in patients with underlying critical illness. The excess mortality in these groups appears to be mediated by greater severity of disease.
Background:
Takotsubo syndrome is also known as stress cardiomyopathy because of the regularity with which it has been associated with physical or emotional stress. Such stress may well be a "trigger" of the syndrome.
Aims:
This analysis was undertaken to describe our experience with this disorder and in particular to examine the effects of the underlying trigger on outcomes.
Methods:
We conducted a retrospective review of the medical records of 345 consecutive patients treated at our institution from 2006 to 2014. All presented with acute cardiac symptoms, a characteristic left ventricular contraction pattern (typical, atypical), and no major obstructive coronary artery disease. Patients were grouped based on their triggering event: (a) medical illness; (b) post-operative period; (c) emotional distress; or (d) no identified trigger. Baseline demographic characteristics, death in hospital, length of stay in hospital, and cardiac complications were abstracted from the patients' medical records.
Results:
The mean±SD age of the population was 72±12 years and 91% were women. No significant difference in baseline characteristics was noted between the groups except for a higher prevalence of African Americans in the group with a medical illness. ST elevation was noted in 13.3% of patients and the average peak troponin level was 5±12 ng/dl. An inotropic drug was required in 49 (14.2%) patients, an intra-aortic balloon pump in 37 (10.7%) patients, and mechanical ventilation in 54 (15.7%) patients; 43.5% required treatment in the intensive care unit. Overall, 12 (3.5%) patients died. In only two (16.7%) patients was a there a direct cardiac cause of death. In those patients in whom the cardiac manifestations seemed to be triggered by a medical illness, the death rate was 7.1% and this was significantly higher than in the other groups (p=0.03). Medical illness (odds ratio=6.25, p=0.02) and ST elevation (odds ratio=5.71, p=0.04) were both significantly associated with death.
Conclusions:
Our study showed that different triggers for Takotsubo syndrome confer different prognoses, with medical illness conferring the worst prognosis. Overall, the in-hospital death rate was low and mostly related to non-cardiac death secondary to the underlying medical illness. Although an unidentified trigger was prevalent in a third of this population, efforts should be made to identify the triggering event to classify the risk group of patients with Takotsubo syndrome.
Identification of patients with heparin-induced thrombocytopenia is encumbered by false positive enzyme-linked immuno assay (ELISA) antibody results, therefore a serotonin release assay (SRA) is used for confirmation. Recently, several studies have demonstrated that increasing the optical density (OD) threshold (currently at 0.4) of the antibody test enhances the positive predictive value. The purpose of this study was to determine the frequency of patients who were ELISA antibody positive but SRA negative, and the costs and bleeding events associated with alternative anticoagulant treatment. We hypothesized that treating patients with a positive ELISA antibody OD value of ELISA antibodies (OD of 0.4–1.0) and an SRA result were included. Eighty-five patients were identified with positive antibodies (average OD of 0.66), 100 % of which were found to be SRA negative. A total of 59 patients (69 %) received alternative anticoagulants. The average duration of treatment was 3.1 days, and 4 patients (4.7 %) experienced a bleeding event. The cost of testing and laboratory monitoring was 47,179. The total cost was 982. This study adds to the body of literature suggesting treatment should only be initiated if the OD is one or greater. The high false positive rate caused increased cost and some bleeding events.
Rationale:
Extracorporeal membrane oxygenation (ECMO) may provide mechanical pulmonary and circulatory support for patients with cardiogenic shock refractory to conventional medical therapy. Prediction of survival in these patients may assist in management of these patients and comparison of results from different centers.
Aims:
To identify pre-ECMO factors which predict survival from refractory cardiogenic shock requiring ECMO and create the survival after veno-arterial-ECMO (SAVE)-score.
Methods and results:
Patients with refractory cardiogenic shock treated with veno-arterial ECMO between January 2003 and December 2013 were extracted from the international Extracorporeal Life Support Organization registry. Multivariable logistic regression was performed using bootstrapping methodology with internal and external validation to identify factors independently associated with in-hospital survival. Of 3846 patients with cardiogenic shock treated with ECMO, 1601 (42%) patients were alive at hospital discharge. Chronic renal failure, longer duration of ventilation prior to ECMO initiation, pre-ECMO organ failures, pre-ECMO cardiac arrest, congenital heart disease, lower pulse pressure, and lower serum bicarbonate (HCO3) were risk factors associated with mortality. Younger age, lower weight, acute myocarditis, heart transplant, refractory ventricular tachycardia or fibrillation, higher diastolic blood pressure, and lower peak inspiratory pressure were protective. The SAVE-score (area under the receiver operating characteristics [ROC] curve [AUROC] 0.68 [95%CI 0.64-0.71]) was created. External validation of the SAVE-score in an Australian population of 161 patients showed excellent discrimination with AUROC = 0.90 (95%CI 0.85-0.95).
Conclusions:
The SAVE-score may be a tool to predict survival for patients receiving ECMO for refractory cardiogenic shock (www.save-score.com).
IntroductionHeparin-induced thrombocytopenia type II (HIT) is an immune-mediated, prothrombotic serious adverse event that can occur due to heparin administration. The platelet-activating immune response is triggered by the interaction of heparin with a specific platelet protein, platelet factor 4 (PF4) [1]. Antithrombosis prophylaxis is a cornerstone in the management of critically ill patients and HIT is, therefore, a major concern in intensive care unit (ICU) patients [1].PathophysiologyIn this syndrome, PF4/heparin complexes are formed following heparin administration, triggering the release of IgG antibodies, which bind to the PF4/heparin complexes leading to clustering of the platelet Fc receptors (FcγRIIa, FcγRIIIa), platelet activation, and platelet fragmentation into prothrombotic microparticles [2, 3]. CD4 T cells play a critical role in the production of PF4/heparin antibodies [4]. Single nucleotide polymorphisms (SNPs) at the HLA-DRA have been reported to be nominally assoc ...
The use of extracorporeal membrane oxygenation (ECMO) for both respiratory and cardiac failure in adults is evolving rapidly. Advances in technology and accumulating data are spurring greater interest and explosive growth in ECMO around the world. Expanding indications and novel strategies are being employed. Yet the use of ECMO outpaces the data. The promise of a major shift in the paradigm for the treatment of respiratory and cardiac failure is tempered by a need for evidence to support many current and potential future uses. We will review cannulation strategies, indications and evidence for ECMO in respiratory and cardiac failure in adults as well as potential applications and the impact they may have on our current treatment paradigms.
Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction and prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. After antibody binding to PF4/heparin complexes, HIT antibodies are capable of intravascular platelet activation by cross-linking Fc gamma receptor IIa (FcγRIIa) on the platelet surface leading to a platelet count decrease and/or thrombosis. In contrast to most other immune-mediated disorders, the currently available laboratory tests for anti-PF4/heparin antibodies show a high sensitivity also for clinically irrelevant antibodies. This makes the diagnosis of HIT challenging and bears the risk to substantially overdiagnose HIT. The strength of the antigen assays for HIT is in ruling out HIT when the test is negative. Functional assays have a higher specificity for clinically relevant antibodies, but they are restricted to specialized laboratories. Currently, a Bayesian approach combining the clinical likelihood estimation for HIT with laboratory tests is the most appropriate approach to diagnose HIT. In this review, we give an overview on currently available diagnostic procedures and discuss their limitations.
Takotsubo cardiomyopathy (TTC) was first described in 1990 when Japanese cardiologists from the Hiroshima Asa General Hospital published their findings in a chapter of a Japanese medical text. At that time, TTC was completely unrecognised in Europe and North America, and for years the disorder was thought to affect only Asians. Then in 2003, the first study of TTC in Caucasians indicated that this was actually a widespread affliction.1 By 2013, the number of publications related to TTC had risen to 1879, a number mirroring increased awareness and interest in this disease. But while numerous case reports of TTC exist in the literature, large systematic registries or trials are lacking.
The main characteristic of TTC is transient, reversible, systolic dysfunction of the left ventricle. Relatively little definitive information is available otherwise, and as a result many cases likely remain unreported and often misdiagnosed, frequently as acute coronary syndrome (ACS