The use of heparin is important, as discussed in the guidelines for using extracorporeal membrane oxygenation (ECMO), to reduce thrombotic complications and to maximize usage of the membrane oxygenator.1 However, heparin usage and the unique clinical situations of individual patients undergoing ECMO treatment may result in many challenges, such as thrombocytopenia or bleeding. An ideal anticoagulant for ECMO treatment should inhibit platelet and coagulation system activation within the great vessels, heart chambers, and extracorporeal circuit, but still allow sufficient endogenous coagulation activity to prevent bleeding in the patient. Unfractionated heparin remains the main anticoagulant used for ECMO. However, the literature contains no consensus opinion on how to decrease or stop heparin administration in the case of bleeding events or in patients at high risk of bleeding (e.g., patients who develop thrombocytopenia or those who require surgical interventions). As a result, protocols for anticoagulation vary among clinical centers.
Ninety-four adult (age ≥ 18 years) patients were treated with ECMO from January 2011 to March 2015, in Chung-Ang University Hospital, Seoul, Korea. Among these 94 patients, 55 patients underwent ECMO treatment for three or more days (median of 8.0 days). Electronic medical records and ECMO data for these 55 patients were reviewed.
Cannula size was chosen according to the individual weight of the patient, and venous or arterial cannulae were then inserted into the femoral vein or femoral artery, depending on the type of ECMO. As a result, 17–28 Fr cannulae were used as venous (draining) cannulae, and 14–22 Fr cannulae were used as perfusion cannulae. Cannulae used in this patient series were DLP or Bio-Medicus (Medtronic, MN) cannulae. In case of veno-venous (VV) ECMO, the tip of the draining catheter was placed in the inferior vena cava, and the tip of the perfusion catheter was placed in the right atrium through both femoral veins, and the positions of the cannulae were adjusted to minimize recirculation. For veno-arterial (VA) ECMO, the draining catheter was placed in the inferior vena-cava through the femoral vein, and the perfusion catheter was placed in the femoral artery. Percutaneous Seldinger method with or without Doppler guidance was our preferred method. Distal-perfusion cannula for lower leg perfusion was routinely inserted and connected to the arterial cannula when VA ECMO was planned. Poly-methyl-pentene membrane oxygenators were used (PLS Quadrox, Maquet Cardiopulmonary, Hirrlingen, Germany) in combination with a centrifugal pump (Rotaflow, Maquet Cardiopulmonary, Hirrlingen, Germany). Recombinant human albumin and heparin (Bioline, Maquet Cardiopulmonary)-coated tubes were used in all circuits. Per the anticoagulation protocol of our center, all patients received an initial bolus of heparin of 100 units/kg body weight at the time of cannulation, which was adjusted based on clinical factors. After the initial bolus, a continuous heparin infusion was started at 10 units/kg/hr, unless there was excessive bleeding. We then used the activated clotting time (ACT) parameter to control the amount of heparin infused within the target range of ACT of 170–230 seconds. Packed red blood cells or packed platelets were transfused to achieve a hemoglobin level above 8 g/dl and platelet level above 50,000 cells/mm3.
For intergroup comparisons, the distribution of continuous data was first evaluated for normality using the Shapiro–Wilk test. Normally distributed data were compared using Student’s t-test, and data are presented as the mean ± SD. Non normally distributed data were analyzed using the Mann-Whitney U test and are expressed as median (P 25–P 75).
Descriptive variables are presented as n (%) and were analyzed using a χ 2 test or Fisher’s exact test, as appropriate. A p value <0.05 was considered statistically significant. All analyses were performed using SPSS statistical software, version 18.0 (IBM Corp., Armonk, NY) for Windows.
Ethics approval for this study was obtained from the Institutional Review Board of Chung-Ang University Hospital. The institutional review board waived the requirement for informed consent because data had already been collected.
The mean age of the 55 patients in our study was 56.1 ± 16.7 years. Thirty-six (65.5%) patients underwent VA ECMO and 19 (34.5%) patients underwent VV ECMO for three or more days. The main indications for VA ECMO were cardiogenic shock and extracorporeal cardiopulmonary resuscitation (E-CPR). Indications for VV ECMO were acute respiratory distress syndrome (ARDS), and pulmonary embolism. Baseline data and patient characteristics are shown in Table 1.
Among the 55 patients included in this study, heparin was stopped for three or more days in 29 (52.7%) patients (group A) because of thrombocytopenic events (<50,000 cells/mm3), higher than target range (>230 seconds) ACT, bleeding complications, or need for other surgical procedures. In the other 24 (43.6%) patients, heparin was infused without discontinuation throughout ECMO therapy (group B). In the rest of the two patients who were not included in group A and group B, heparin was stopped and restarted within less than 3 days when the indications for heparin discontinuation resolved. Initial indications for discontinuation of heparin in group A are shown in Table 2. There was no difference in length of ECMO support between the two groups.
Before ECMO therapy, the prothrombin times were higher in group A than in group B (p = 0.038). More patients in group A were on clopidogrel before ECMO initiation than in group B (p = 0.034; Table 1).
In group A, neither intravascular thrombotic complications nor occlusion of the oxygenator due to blood clots resulting in its exchange was observed during the period of heparin discontinuation. The mean length of ECMO support after initiation of heparin discontinuation in group A was 10.2 ± 14.7 days. There were also no intracardiac, intravascular, or intracircuit thrombotic complications from heparin discontinuation during ECMO support after heparin discontinuation.
Among the 55 patients, five oxygenator exchanges were required in three patients because of decreased gas exchange capability. The mean lifespan of oxygenator of ECMO in two patients who needed oxygenator exchanges in group A was 58.3 ± 34.8 days. The longest lifespan of the oxygenator in group A was 80 days in a patient on VV ECMO in whom heparin was discontinued during the entire period of ECMO support due to chronic thrombocytopenia and bleeding. The shortest lifespan of the oxygenator was 19 days in a patient in group B.
In group A, ACT and activated partial thromboplastin time (aPTT) were significantly higher during the period of heparin infusion than the period of the heparin discontinuation [ACT: 138.0 (125.8–159.6) seconds vs. 190.3 (161.5–250.0) seconds, p < 0.001; aPTT: 94.1 ± 37.4 seconds vs. 65.5 ± 27.0 seconds, p = 0.001, respectively]. There was no difference in ACT or aPTT between groups A and B during the entire period of ECMO support [ACT: 157.0 (138.0–174.5) seconds vs. 156.0 (140.0–166.0) seconds, p = 0.71; aPTT: 74.3 ± 27.3 seconds vs. 67.0 ± 13.1 seconds, p = 0.850, respectively]. However, ACT and aPTT during heparin infusion in group A were significantly higher than in group B [ACT: 190.3 (161.5–250.0) seconds vs. 156.0 (140.0–166.0) seconds, p < 0.001; aPTT: 94.1 ± 37.4 seconds vs. 67.0 ± 13.1 seconds, p = 0.001]. Mean ECMO flow was above 3000 ml/min, and there was no significant difference in mean ECMO flow between groups A and B. In group A, mean ECMO flow was higher during heparin infusion than mean ECMO flow during heparin discontinuation (3777.0 ± 578.6 ml/min vs. 3445.8 ± 591.6 ml/min, p = 0.004), as shown in Table 3.
Twenty-six of all 55 patients (47.3%) were successfully weaned from ECMO support. Weaning success rate was 50.0% in VA ECMO (18 of 36) and 42.1% in VV ECMO (8 of 19) patients. There was no significant difference in ECMO weaning success rate between groups A and B (41.4% vs. 54.2%, p = 0.35, respectively). There was a significant difference in in-hospital mortality between groups A and B (72.4% vs. 45.8%, p = 0.049, respectively). There were 25 in-hospital mortalities in VA ECMO patients (19 in group A, five in group B, one in neither group, p = 0.001) and nine mortalities in VV ECMO patients (two in group A, six in group B, one in neither group, p = 0.067; Table 4). Causes of death were cardiogenic shock (n = 15), multiorgan failure (n = 12), sepsis (n = 6), and hypoxic brain damage (n = 1). Morbidities included renal failure requiring continuous renal replacement therapy (n = 16), pneumonia (n = 4), and hypoxic brain damage (n = 1). Mortalities or morbidities were not related to thromboembolism in either group. One patient in group A was bridged to heart transplantation, and 20 patients (36.4%) were discharged.
There have been no randomized, controlled trial studies to suggest guidelines on how much heparin should be used in cases of ongoing bleeding or in those with a high risk of bleeding during ECMO therapy. We showed here that ECMO support can be safely performed without continuous heparin infusion for three or more days, and mid- to long-term ECMO support is possible without an increased risk of thrombotic complications or oxygenator failure even after the period of heparin discontinuation in select patients. We excluded patients who were on ECMO for less than three days, because it is very uncommon for patients on short-term ECMO support to need heparin discontinuation before weaning from ECMO. Furthermore, we believe that this is too short a period of time to evaluate undesired effects when heparin administration is discontinued.
Technical improvements in ECMO, including centrifugal pumps, oxygenators, and new generation circuits with antithrombotic surface coatings play important roles in preventing thrombotic complications during and after the discontinuation of heparin in ECMO therapy. In particular, the evidence suggests that recently developed coating materials may allow a safe reduction of systemic heparinization.2,3 Despite the introduction of these effective antithrombotic surface coatings, however, there are many other factors that can lead to the activation of the coagulation/inflammation system, which might encourage the formation of thrombi and clots within the membrane oxygenator.4 This makes the use of heparin inevitable in most patients without bleeding risk, even though anticoagulation using heparin has many limitations2 such as bleeding, activation of platelets, and heparin-induced thrombocytopenia (HIT).5,6 For this reason, many centers try to keep the anticoagulation level within the lowest therapeutic range to minimize the risk of bleeding.
The earliest and most popular measure of anticoagulation during ECMO is the ACT7 parameter, which measures the integrity of intrinsic coagulation and common pathways.8 The standard goal ACT range is from 180 to 220 seconds, but varies from center to center depending on local experience and the type of monitoring equipment being used.1,9 Furthermore, anticoagulation therapy should be adjusted based on specific patient conditions and response to anticoagulation therapy.10 Because of this, in the case of thrombocytopenia, a high ACT result, bleeding, or other surgical procedures, our center stops using heparin for a period of time until the problem is resolved.
Other than the improvements to the circuits and additional mechanical factors, we assume the flow of the ECMO is also important in preventing thrombus formation in the oxygenator.8,11,12 A well-maintained ECMO flow greater than 3.0 L/min during heparin discontinuation in patients in group A may have prevented oxygenator thrombosis. In group A, ECMO flow was lower during heparin discontinuation than during heparin infusion by about 332 ml/min, but there were no thrombotic complications during heparin discontinuation because the ECMO flow was sufficiently high. We also found that 89% of patients in group A had a low platelet count (<50,000 cells/mm3), suggesting that thrombocytopenia may have been another factor in preventing clot formation. Further study is required to evaluate the relationships between ECMO flow, platelet count, and thrombus formation during ECMO treatment.
At our institute, we try to maintain left ventricular contraction as much as possible to prevent intracardiac blood flow stagnation and thus thrombus formation, particularly in cases of severe ventricular dysfunction. When there is low pulsatility of arterial pressure and echocardiographic evidence of severe left ventricular dysfunction, increasing inotropics and lowering ECMO flow are considered for more left ventricular contraction. Left ventricular distention and pulmonary edema are indications of left side heart venting.13,14 We use atrial septostomy or direct left ventricular venting through the left ventricular apex. In our series, one patient underwent left minithoracotomy for direct left ventricular venting through the left ventricular apex.
In mid- to long-term ECMO support patients, transfusion of blood products is frequently required, even without bleeding. Platelet adherence to the oxygenator, chronic bleeding, transfusion, and HIT5,6 can deplete coagulation factors and cause thrombocytopenia, which are associated with bleeding complications and mortality. Because of this, monitoring the platelet count is important during ECMO therapy.15,16 As we have observed bleeding at various sites, including cannulation and tracheostomy sites, in patients with a platelet count lower than 50,000 cells/mm3, platelets are transfused and heparin discontinuation is considered when platelet count is less than 50,000 cells/mm3 in our center. In general, a platelet transfusion is considered when the platelet count falls below 100,000 cells/mm3 to prevent generalized hemorrhaging,17 but we believe that a lower target (< 50,000 cells/mm3) can decrease adverse effects from platelet transfusions without increasing bleeding complication. Further study is required to determine the appropriate threshold for transfusion. Recent case reports of heparin-free VV-ECMO in patients with traumatic lung failure combined with severe traumatic brain or liver injury12,18 lend support to our contention that ECMO therapy without heparin infusion is safe in select patients with thrombocytopenia and coagulopathy.
There are only few reports of intracardiac or great vessel thrombus during ECMO therapy,19–21 but thrombus formation can cause serious complications in patients on ECMO. Simply relying on heparin infusion and monitoring ACT are not always adequate means to prevent both thrombotic and bleeding complications in patients on ECMO.9,17 In our study, among the three patients who required oxygenator exchange, the mean duration of oxygenator usage was 58.3 days in group A. This suggests that systemic anticoagulation can be tailored to the individual clinical situation of patients, such as poor left ventricular contractility, ECMO flow, heparin resistance, thrombocytopenia, ongoing bleeding, and so on.
Group A had significantly longer pre-ECMO prothrombin times and higher rates of anti-platelet medication use than group B. We do not think that patients with prolonged pre-ECMO prothrombin times or a history of anti-platelet medication should be exempted from anticoagulation therapy with heparin during ECMO. However, all possible factors related to bleeding and coagulation should be considered to make an informed decision regarding anticoagulation during ECMO. Higher ACT and aPTT values during heparin infusion in group A compared with group B in our study, despite use of the same anticoagulation protocol, suggest that patient-specific factors might contribute to bleeding tendency. And, assuming from abnormal aPTT level during heparin discontinuation in group A, there could be more comorbidities related to coagulation abnormality such as hepatic dysfunction in group A. Additional data such as fibrinolytic activity measurements(FDPs, XDPs), antithrombin III level, and fibrinogen level may also be important in evaluating coagulation status. However, these values are not routinely measured during ECMO therapy. Because of the complexity of hemostasis and heterogeneity of patients requiring ECMO, large comparative effectiveness trials are needed to provide anticoagulation therapeutic ranges based on a variety of monitoring tools.17
Although the difference between the two groups was not statistically significant, the VA ECMO weaning success rate was lower in group A than in group B, and the in-hospital mortality of VA ECMO was higher in group A than group B (p = 0.001). We did not find any evidence that these differences were because of thrombotic complications from heparin discontinuation. Rather, we attributed this to more comorbidities resulting in coagulation abnormalities in group A than in group B, which could also impact an individual patient’s ECMO weaning success and in-hospital mortality. However, we did not perform multivariate analysis to evaluate the impact of other comorbidities because of our small sample size.
This study had several limitations. First, we performed a nonrandomized, retrospective analysis of a relatively small sample at a single-center. Second, the study was not conducted using different types of membrane oxygenator, circuits, and pumps.22,23 Consequently, our results should only be extrapolated to other ECMO products from other manufacturers with caution. Third, we determined intra-oxygenator thrombus formation by gross inspection of the oxygenator from the outside and from the appearance of irrigation fluid on white gauze. There may have been micro-thrombi that did not decrease oxygenator function.24
Heparin discontinuation can be considered in select patients with thrombocytopenia, high ACT, coagulation abnormalities, and bleeding, even those patients undergoing mid- to long-term ECMO treatment, without increased risk of early oxygenator occlusion or intravascular thrombotic events. Further studies are needed to establish proper guidelines on how to manage anticoagulation in ECMO patients with high bleeding risk.
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