Unfractionated heparin is the most commonly prescribed anticoagulant drug during extracorporeal membrane oxygenation (ECMO),1 and its dosage is generally guided by the activated partial thromboplastin time (aPTT) or by the activated clotting time (ACT) kept within 1.5–2 patient to normal ratio and 180–210 sec, respectively.2 Thromboelastography (TEG) is a well established3 and recently revisited point of care technique that, diversely from routine coagulation tests, provides information relating to the multiple phases of hemostasis including clot formation, stabilization, and dissolution. Thromboelastography is mainly used to guide transfusion after trauma,4,5 cardiac surgery,6 and liver transplantation7 and recently to assess coagulation during sepsis.8 However, the use of TEG to monitor systemic heparinization is confined to anecdotal cases,9 and it has not been extensively validated.10 A recent survey has demonstrated that TEG is used in less than half of the centers that are part of the Extracorporeal Life Support Organization1 with no specific role in titration of anticoagulation. Reasons for limited use of TEG for this purpose probably include its oversensitivity to heparin and deficiency in coagulation factors11 as well as the lack of a reference method to monitor heparin effect (to validate TEG).
Thromboelastography is usually performed adding kaolin to whole blood to activate the intrinsic pathway of coagulation. The first component of the TEG tracing is the reaction time (R time), which represents the time to initial fibrin formation and is prolonged by heparin. One peculiarity of TEG is the possibility to perform paired tests with and without heparinase to inactivate heparin ex vivo and assess the underlying coagulation in the presence of heparin. Thromboelastography samples that display a “flat line” (no clot formation) reversible with heparinase may indicate excessive heparinization that might be associated with increased risk of bleeding in vivo.12 “Flat-line TEGs” are frequently obtained after reperfusion during liver transplantation.13
We report the results of TEG tests performed in adults treated with ECMO because of severe respiratory failure and anticoagulated with heparin (dose adjusted according to aPTT ratios). The aims of this work were to evaluate the prevalence of “flat-line TEG,” to assess the reversibility with heparinase and to study the relationship between the results of TEG tests, aPTT, ACT, and bleeding events.
Materials and Methods
Thirty-two consecutive adult patients treated with ECMO for severe respiratory failure and anticoagulated with heparin, from December 2011 to August 2013, were included in this analysis. This study was approved by our Institutional Review Board (Comitato Etico Milano Area B approval number: 185/2014) with no need for informed consent.
According to our local protocol, unfractionated heparin was administered as a bolus (50–70 IU/kg intravenously [IV]) when vascular cannulas were inserted and thereafter infused continuously (10–15 IU/kg/h) to reach an aPTT of 1.5–2.0. Antithrombin (AT) concentrate was infused as needed to maintain the plasmatic AT activity above 70%.
Activated partial thromboplastin time was measured at least three times a day by the central laboratory. Activated clotting time (Hemochron Jr. Low Range ACT) TEG (Haemoscope TEG 5000 Thromboelastograph haemostasis analyzer; Haemonetics Corporation, Skokie, IL) without and with heparinase were measured at least once a day together with aPTT. Heparin dosage was adjusted according to the aPTT, independently from the results of TEG or ACT.
Thromboelastography was performed on fresh whole blood within 4 min from collection. Kaolin was used as a activator, following manufacturer’s recommendations. On the thromboelastographic tracing, five parameters were recorded: R (time to initial fibrin formation; normal values, 4–8 min), K (time to clot formation; normal values, 0–4 min), α (alpha angle, rate of clot formation; normal values, 47–74°), maximum amplitude (MA; absolute clot strength; normal values, 54–72 mm), and LY30 (fibrinolysis at 30 min after MA; normal values 0–8%). A flat-line TEG was a TEG unable to generate an R time parameter without heparinase (no initiation of fibrin formation, i.e., of clotting) within 90 min. In this case, R was considered equal to 90 min. Three examples of TEG tracing are reported in Figure 1.
Extracorporeal membrane oxygenation was always provided as femoro-femoral venovenous bypass. Extracorporeal systems included QUADROX PLS Oxygenator plus ROTAFLOW Centrifugal Pump or HLS Set Advanced 5.0 - Cardiohelp system (MAQUET Cardiopulmonary AG, Hirrlingen, Germany), a 21–23 Fr drainage cannula (HLS cannulae; MAQUET Cardiopulmonary AG), and a 21 Fr reinfusion cannula (Bio-Medicus Femoral Venous Cannulae, Medtronic Inc., Minneapolis, MN), both inserted percutaneously. All components, including oxygenators, centrifugal pumps, and tubing sets, were BIOLINE (MAQUET, Rastatt, Germany) coated. Membrane lungs were ventilated with an oxygen–air blender and maintained at 37°C with a heat exchanger. After ECMO, removal thrombosis of the common femoral or iliac veins was searched with B-mode ultrasonography.
Demographic data and causes of respiratory failure were recorded. Coagulation parameters, ECMO parameters, transfusion of packed red blood cells, fresh frozen plasma, and platelet concentrates were registered every day. Survival at intensive care unit (ICU) discharge, bleeding, and thrombotic events were also recorded. Severity of bleeding was graded according to a modified version of the Bleeding Academic Research Consortium score14: type 0 = no bleeding; type 1 = any overt bleeding that requires reduction of heparin infusion or transfusion of packed red blood cells (provided hemoglobin drop is related to bleeding); type 2 = any overt bleeding that requires reduction of heparin infusion and transfusion of packed red blood cells (provided hemoglobin drop is related to bleeding); type 3: any life-threatening bleeding that requires transfusion of packed red blood cells and surgery or discontinuation of ECMO; and type 4 = any fatal bleeding.
Continuous variables are reported as median and 25th and 75th percentile. Categorical variables are presented as absolute and relative frequencies. Differences between groups were tested using Mann–Whitney and Fisher’s exact tests, as appropriate. Correlations between heparin dose and monitoring methods were expressed using the Spearman correlation coefficient. Because the outcomes were repeated within subjects, p values were calculated using random effects models. Cohen’s κ coefficient was used to measure agreement between aPTT, ACT, and TEG anticoagulation ranges. Stuart–Maxwell marginal homogeneity test (an extension of Mc-Nemar test for comparing variable with more than two categories) was used to assess the direction of disagreement. To calculate the association between a flat-line TEG and coagulation parameters and bleeding events, we used random effect logistic models, which take into account the fact that a patient might have had repeated bleeding events. Statistical analysis was performed using Stata 13 (StataCorp, College Station, TX).
Patients’ baseline characteristics and diagnosis are summarized in Table 1. Sixteen (50%) patients started ECMO for acute respiratory distress syndrome (ARDS), 8 (25%) as a bridge to lung transplantation, and 8 (25%) for chronic obstructive pulmonary disease (COPD) exacerbation. Intensive care unit mortality was 38% (12 patients). Extracorporeal membrane oxygenation duration was 8 (6–9) days. During ECMO, blood flow was 3.1 (2.7–3.5) L/min, gas flow was 5 (3–7) L/min, revolutions per minute (RPM) was 2,260 (2,005–2,550), artificial lung shunt was 10.6% (8.5–15.0%), and transmembrane pressure drop was 16 mm Hg (11–20 mm Hg).
Only three patients received thromboprophylaxis before ECMO; none of the patients received antiplatelet therapy. Coagulation parameters were available in 15 patients before initiation of ECMO. In these patients, prothrombin time (PT) ratio was 1.20 (1.11–1.32; reference interval, 0.88–1.12), the aPTT ratio was 0.98 (0.8–1.09; reference interval 0.86–1.20), the AT activity was 70% (57–102%; reference interval, 82–112%), the platelet count was 235 (141–293) × 103/ml (reference interval, 130–400 × 103/ml), and fibrinogen level was 546 (425–763) mg/dl (reference interval, 165–350 mg/dl).
Three hundred sixteen paired TEG samples without and with heparinase (12 [9–28] paired TEG samples per patient) were analyzed. The corresponding aPTT value was available for all samples, whereas ACT value was available only for 225 samples. During ECMO, aPTT ratio was 1.67 (1.48–1.96), ACT was 173 (161–184) sec, and R time with heparinase was 9 (7–11) min. Figure 2 represents the frequency distribution of R times without heparinase showing a flat line in 46% of the samples. Distribution of flat-line TEG samples was variable among different diagnostic categories. Fifty-five percent of flat-line TEG samples belonged to patients with ARDS, 18% to patients bridged to lung transplantation, and 27% to patients with exacerbation of COPD (p = 0.053). The average proportion of flat-line TEG samples per patient was 37.5% (10–55%), and it was not correlated with the number of observations per patient (Spearman’s rho = −0.106, p = 0.035) indicating that the distribution was homogeneous among patients.
Table 2 summarizes TEG parameters and coagulation variables during ECMO in samples with a corresponding non–flat-line (R time without heparinase, <90 min) and flat-line (R time without heparinase, >90 min) TEG. For flat-line TEG, we report only TEG parameters obtained after the addition of heparinase.
Correlations Between all Heparin Monitoring Tests
Results obtained with the three heparin monitoring tests (aPTT, ACT, and R time without heparinase) were significantly but weakly correlated (Figure 3): R time without heparinase and aPTT (A, rho = 0.36, p < 0.001), R time without heparinase and ACT (B, rho = 0.31, p = 0.005), and ACT and aPTT (C, rho = 0.30, p = 0.0001).
Correlations Between Heparin Dosage and Coagulation Monitoring Tests
Median heparin infusion rate was 16 (12–20) IU/kg/h. Heparin dosage was significantly but poorly correlated with R time without heparinase (Spearman’s rho = 0.22, p < 0.001) and with aPTT (Spearman’s rho = 0.165, p = 0.003) but not with the ACT (Spearman’s rho = 0.12, p = 0.09).
Correlations Between AT and Coagulation Monitoring Tests
Median AT activity was 80% (67–91%). Antithrombin activity was significantly but poorly correlated only with R time without heparinase (Spearman’s rho = 0.24, p = 0.007) and with ACT (Spearman’s rho = −0.28, p = 0.016) but not with aPTT (Spearman’s rho = −0.009, p = 0.125).
Agreement Between the Three Different Heparin Monitoring Tests
Reference ranges for heparin anticoagulation therapy were defined as 1.5–2 for the aPTT ratio, 180–210 sec for the ACT,2 16–24 min for the R time without heparinase (equivalent 2–3 times normal values; Figure 3).12,15 We accordingly defined three categories for each heparin monitoring test: “low” category for aPTT < 1.5, ACT < 180 sec, and R time without heparinase <16 min; “optimal” category for aPTT 1.5–2, ACT 180–210, and R time without heparinase 16–24 min; and “high” category for aPTT > 2, ACT > 210 sec, and R time without heparinase >24 min. There was no agreement between the three heparin monitoring tests: aPTT versus R time without heparinase categories κ = 0.10 (95% confidence interval [CI], 0.07 to 0.13), ACT versus R time without heparinase categories κ = 0.03 (95% CI, 0.02 to 0.04), and aPTT versus ACT categories κ = 0.01 (95% CI, −0.02 to 0.04). As shown in Table 3 (panels A and B), the majority of the R times without heparinase were in the high range irrespective of the aPTT and ACT (57.3 and 80.0, 85.1 and 89.1, 98.5 and 100% for low, optimal, and high ranges, respectively), indicating that TEG has a tendency to overestimate the degree of anticoagulation compared with aPTT and ACT values (p < 0.001). When the aPTT was in the optimal and high range, 22.5 and 3.6% of the ACT samples were in the corresponding ranges, respectively, indicating that although in a less extent than TEG, the aPTT also tended to overestimate the degree of anticoagulation compared with the ACT (p > 0.001; (Table 3, panel C). For aPTT ratio values 1.5–2, corresponding median R time without heparinase was 76.2 min (34.9–90 min), and for R time without heparinase values of 16–24 min, corresponding median aPTT ratio was 1.37 (1.27–1.71).
Bleeding and Thrombosis
During ECMO, one patient (3%) had fatal intracranial hemorrhage. Six patients (19%) experienced major bleeding (class 3): four hemothoraces, one retroperitoneal, and one oropharingeal bleeding. Six patients (19%) had class 2 bleeding, and other 5 patients (16%) had class 1 bleeding. An average of 0.63 (0.33–1) packed red blood cells/day of ECMO was needed, whereas supplementation of fresh frozen plasma was needed in 44% of patients (14 patients) and platelet transfusion in 34% of patients (11 patients). Only one patient experienced catheter-related thrombosis. Eight (44%) bleeding patients died before ICU discharge compared with 4 (29%) of nonbleeding patients (risk ratio, 1.56; 95% CI, 0.59–4.13).
In Table 4, we report odds ratio (OR) and 95% CI of predictors of the first episode of bleeding (higher or equal to type 1 bleeding) per patient. The value of aPTT 2 days before bleeding (for every unit of aPTT increase: OR, 2.27; 95% CI, 0.99–5.21; p = 0.05) and the heparin dosage the same day of bleeding (for every IU/kg/h increase: OR, 0.92; 95% CI, 0.84–1.01; p = 0.06) were the only parameters with a tendency to predict bleeding.
Extracorporeal membrane oxygenation can save lives, but it is commonly complicated by bleeding. Monitoring of anticoagulation during ECMO relies on assays originally developed in other settings and possibly requires further refinement. The major finding of this study was the high prevalence of flat-line TEG samples when anticoagulation was maintained in the correct aPTT range. One other study on a pediatric population treated with ECMO16 has consistently shown that more than half of the samples (52%) had an excessively long R parameter.
Heparin infusion is usually guided by aPTT although aPTT was originally conceived to be applied in a different setting of patients,17 and advised aPTT range (1.5–2.0) is supported by weak evidence.18 Even so, aPTT has higher sensitivity than other tests at low heparin plasmatic levels (0.1–1 UI/ml) such as those used in ECMO.12 Activated partial thromboplastin time has been recently proposed as a better heparin management tool than ACT in pediatric ECMO, reducing potentially fatal bleeding complications.19
The R time parameter of TEG represents the time to initial fibrin formation, and its prolongation may reflect heparin activity. When used to monitor low-molecular-weight heparin effect,20 a good correlation with antifactor Xa activity has been demonstrated. When used to monitor anticoagulant therapy with unfractionated heparin in patients with deep vein thrombosis, it was more sensitive than aPTT in detecting the response to heparin.9 Even so, there is no evidence that R time is superior to aPTT for monitoring anticoagulation with heparin.
Monitoring heparin therapy in patients treated with ECMO can be challenging because of concomitant diseases (such as systemic inflammatory disease and sepsis) and because ECMO per se21 variably activates coagulation. Moreover, individual response to heparin can be hardly predicted because of nonspecific binding to acute-phase reactant proteins, platelets, and activated endothelial cells.22,23 Previous studies have demonstrated that the correlation between heparin dose and aPTT during ECMO is poorer in patients with respiratory failure (venovenous ECMO) compared with those with cardiac insufficiency (venoarterial ECMO) and in those treated with hemofiltration.19,24
One possible solution to this problem may be to use a multifactorial approach, which incorporates diverse assays such as aPTT, ACT, antifactor Xa, or any other relevant laboratory coagulation parameter.12,25 One other solution is to rely on a global coagulation assay (such as TEG) to evaluate, with just one test, all the different phases of hemostasis.26 Thromboelastography can also be performed using heparinase to reverse the effect of heparin.27
When we compared non–flat line to flat-line TEG paired samples, we observed the following: (1) that TEG parameters after the addition of heparinase were impaired in the flat-line group suggesting a lower tendency to form a clot even after reversal of heparinization; (2) that PT was increased in both groups especially in the non–flat-line group; however, we were unable to distinguish whether this was because of a consumption of coagulation factors by ECMO, as previously reported,28 or to the peculiar individual abnormalities (critically ill patients)29; (3) that higher amounts of heparin and AT were given to patients with a flat-line TEG, IV. That hemostatic parameters such as platelets and fibrinogen and ECMO settings such as pump RPM/ECMO blood flow that could relate with shear stress forces and development of an acquired von Willebrand disease30,31 did not predict flat-line TEG.
In our study, the correlation between the three heparin monitoring methods (aPTT, ACT, and TEG) was equally poor/moderate, similar to what already described.16,32,33 However, R time without heparinase was the only parameter that was (weakly) positively correlated with both heparin dose and AT activity. Given the high prevalence of flat-line TEG samples, less heparin would have been used if anticoagulation had been guided by R time without heparinase with a target below 90 min. Shinoda et al.34 suggested that, in patients treated with dialysis, anticoagulation guided by TEG (to keep R time without heparinase above 20 min) is associated with minimal dialyzer clotting despite smaller infusion of heparin compared with anticoagulation guided by aPTT.
We cannot draw any definite conclusion about predictors of bleeding during ECMO. Logistic regression analysis of variables recorded up to 2 days before the bleeding episode did not produce any strongly significant result. Even so, aPTT and heparin dosage showed a positive trend, as if high level of anticoagulation have had a role in the pathogenesis of bleeding during ECMO. The higher the aPTT ratio 2 days before (a result that became significant after adjusting for duration of ECMO, p = 0.03 OR, 2.63; 95% CI, 1.10–6.30) and the higher the heparin dosage on that exact day (p = 0.06), the higher the risk for bleeding.
Our study has some limitations; first, the limited sample size. Second, heparin dosage was not standardized but left to the discretion of the treating physician. Third, we did not measure antifactor Xa activity that may be used to guide heparin use35 as it apparently correlates with heparin dose better than ACT or aPTT at least in pediatric patients33 and is associated with less thrombotic circuit/oxygenator complications during ECMO.36 However, in a pilot study, recently published by our group aimed to assess hemostatic changes during ECMO, global coagulation tests were not correlated with antifactor Xa activity.37
Based on the results of this study, a prospective randomized trial evaluating safety and feasibility of anticoagulation monitoring with R time without heparinase compared with aPTT (ClinicalTrials.gov Identifier: NCT02271126) is currently ongoing.
Targeting the aPTT 1.5–2 times, the control value for heparin titration during ECMO resulted in an elevated number of flat-line TEG (no generation of a fibrin clot within 90 min, ex vivo). Although we did not find a clear association between heparin dosage and hemorrhage, a high level of anticoagulation remains a reasonable risk factor for bleeding during ECMO. Thromboelastography may represent a valid alternative for adjusting heparin infusion; however, more evidence is required to evaluate whether this corresponds to a safer anticoagulation strategy during ECMO.
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