Heparin Reversal After Cardiopulmonary Bypass: Are Point-of-Care Coagulation Tests Interchangeable?

OBJECTIVE: Protamine is used to neutralize heparin after patient separation from cardiopulmonary bypass (CPB). Different bedside tests are used to monitor the adequacy of heparin neutralization. For this study, the interchangeability of the activated coagulation time (ACT) and thromboelastometry (ROTEM; Tem Innovations GmbH, Basel, Switzerland) clotting time (CT) ratios in children undergoing cardiac surgery was assessed. DESIGN: Single-center, retrospective, cohort study between September 2010 and January 2012. SETTING: University children's hospital. PARTICIPANTS: The study comprised children 0 to 16 years old undergoing elective cardiac surgery with CPB. Exclusion criteria were preoperative coagulopathy, Jehovah's witnesses, and children in a moribund condition (American Society of Anesthesiologists score 5). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After heparin neutralization with protamine, the ratio between ACT, with and without heparinase, and the CT measured with INTEM/HEPTEM (intrinsic test activated with ellagic acid was performed without heparinase [INTEM] and with heparinase [HEPTEM]) using tests of ROTEM were calculated. Agreement was evaluated using Cohen's kappa statistics, Passing-Bablok regression, and Bland-Altman analysis. Among the 173 patients included for analysis, agreement between both tests showed a Cohen's kappa statistic of 0.06 (95% CI: -0.02 to 0.14; p = 0.22). Bland-Altman analysis showed a bias of 0.01, with a standard deviation of 0.13, and limits of agreement between -0.24 and 0.26. Passing-Bablok regression showed a systematic difference of 0.40 (95% CI: 0.16-0.59) and a proportional difference of 0.61 (95% CI: 0.42-0.86). The residual standard deviation was 0.11 (95% CI: -0.22 to 0.22), and the test for linearity showed p = 0.10. CONCLUSION: ACT, with or without heparinase, and the INTEM/HEPTEM CT ratios are not interchangeable to evaluate heparin reversal after pediatric patient separation from CPB. Therefore, the results of these tests should be corroborated with the absence/presence of bleeding and integrated into center-specific treatment algorithms.

Efficacy and safety of heparinase I versus protamine in patients undergoing coronary artery bypass grafting with and without cardiopulmonary bypass.

BACKGROUND: Hemodynamic protamine reactions with heparin reversal during cardiac surgery are common and associated with adverse outcomes. As an alternative to protamine, the authors examined heparinase I reversal of heparin after aortocoronary bypass graft surgery. METHODS: In a randomized, double-blind, double-dummy trial, 167 on- and off-pump aortocoronary bypass graft surgery patients received either heparinase I (maximum 35 microg/kg) or protamine (maximum 650 mg) for heparin reversal, monitored by activated clotting time values and clinical assessment. Hemodynamic parameters were recorded electronically; safety evaluation was to 30 days postoperatively. Noninferiority was predefined as 400 ml or less median 12-h chest tube drainage from intensive care unit arrival for heparinase I patients, after risk adjustment. Hemodynamic instability was defined as systemic hypotension (> or = 30 mmHg decrease) and/or pulmonary hypertension (> or = 40 mmHg with an increase > or = 10 mmHg) within 30 min of heparin reversal initiation. RESULTS: Patient enrollment was terminated on advisement of the Data Safety Monitoring Board. Although heparinase I was noninferior for 12-h chest tube drainage, protamine had a superior safety profile. Overall, heparinase I subjects had longer hospital stays (P = 0.04), were more likely to experience a serious adverse event (P = 0.01), and were less likely to avoid transfusion (P = 0.006). A composite morbidity score was not different (P = 0.24), and similar rates of hemodynamic instability were observed between groups. Findings were consistent in analyses stratified by on- and off-pump surgery. CONCLUSIONS: Heparinase I reverses heparin anticoagulation after aortocoronary bypass graft surgery but is not equivalent to protamine because of its inferior safety profile.

Prediction of excessive bleeding after coronary artery bypass graft surgery: the influence of timing and heparinase on thromboelastography.

OBJECTIVE: To compare the ability of thromboelastography, when done at either 10 or 60 minutes after protamine reversal of heparin, to predict excessive bleeding after coronary artery bypass graft (CABG) surgery and to investigate, with the use of heparinase, whether heparin contamination was responsible for the difference, if any. DESIGN: Prospective study. SETTING: University hospital, single institution. PARTICIPANTS: Patients undergoing elective CABG surgery (n = 40). INTERVENTIONS: Blood samples for thromboelastography and routine coagulation tests were collected before induction of anesthesia and at 10 and 60 minutes after protamine reversal of heparin. Blood loss and blood product use were recorded postoperatively. MEASUREMENTS AND MAIN RESULTS: Of 40 patients undergoing elective CABG surgery, 10 fulfilled the criteria for excessive postoperative bleeding. The sensitivity of thromboelastography to identify patients who bled was better at 60 minutes than at 10 minutes after protamine reversal of heparin (100% v 70%). There was greater specificity (83% v 40% at 10 minutes; 73% v 20% at 60 minutes) and positive predictive value (58% v 28% at 10 minutes; 55% v 29% at 60 minutes) when heparinase was added. At both times, thromboelastography showed only moderate correlation with total blood loss and the use of fresh frozen plasma or platelets or both. Conventional coagulation tests did not predict excessive postoperative bleeding. CONCLUSION: This study suggests that timing and the use of heparinase influence the predictive ability of thromboelastography, but its usefulness as a sole predictor of post-CABG surgery bleeding is limited.

Evaluation of post-cardiopulmonary bypass coagulation disorders by differential diagnosis with a multichannel modified thromboelastogram: a pilot investigation.

We assessed a modified multichannel thromboelastogram for differentiation of the causes of coagulopathy after cardiopulmonary bypass and its suitability as a therapy guide. Thirty adult patients undergoing surgery with cardiopulmonary bypass, who revealed a coagulopathy as observed by a prolonged activated clotting time of >150 sec after the application of protamine, were enrolled. Therapy was based on the results obtained by the computerized four-channel thromboelastogram with baseline, heparinase (2 IU/mL), heparinase/abciximab (5 microg/mL), and heparinase/fresh frozen plasma (25%) channels. The mean activated clotting time before therapy was 162.2+/-7.8 sec. Based on differential diagnosis with the modified multichannel thromboelastogram, two patients received protamine (30 mg), five desmopressin (0.4 microg/kg), 19 patients three units of fresh frozen plasma, two patients platelet transfusions, and two patients both protamine (30 mg) and three units of fresh frozen plasma. After therapy, there was a significant (p < .01) decrease of the activated clotting time to a mean value of 127+/-8.3 sec. Therapy based on the synoptic modified multichannel thromboelastogram analysis provides a guide for effective therapy of coagulopathy. However, elaboration is desirable, and larger clinical trials are necessary for a final evaluation of the protocol.

Assessment of the resonance thromboelastograph CS-3 for differentiation of coagulation disorders: a pilot in vitro investigation of simulated post-cardiopulmonary bypass coagulopathies.

Resonance thromboelastography (RTG), a further development of the thromboelastogram (TEG), has been designed for improved differentiation of the effect of the plasmatic coagulation factors (increasing F-leg) and platelets (decreasing P-leg) on clot formation. It is based on the effect of clot elasticity on the resonance of a swinging wire. We assessed the RTG for its ability to differentiate coagulation disorders that frequently occur after cardiac surgery. The RTG was performed with a CS-3 Analyzer. Samples from 10 healthy volunteers were investigated after the following preparations: (1) baseline values, (2) dilution to a hematocrit of 30% and 20% with either hydroxyl ethyl starch (HES) 10% or plasma; (3) addition of 0.25, 0.5, and 1.0 IU/mL porcine heparin with and without heparinase; and (4) addition of 1.0, 3.0, 4.0, and 5.0 microg/mL of the antiplatelet agent abciximab (ReoPro). Increasing concentrations of abciximab led to a slower decrease or in the case of higher concentrations, to a persistent elevation of the platelet leg of the RTG. Dilution of the hematocrit with plasma had no effect on the fibrin and platelet leg; whereas, dilution with HES 10% led to an inhibition of the fibrin and platelet leg. Dilution of the plasmatic coagulation factors resulted in an inhibition of both the fibrin and the platelet leg. The addition of 0.25 and 0.5 IU/mL of heparin led to an increased coagulation time and inhibition of the fibrin and platelet legs. These effects were eliminated by the addition of heparinase. The RTG enables the evaluation of platelet function under the condition of a nonimpaired plasma coagulation system. Depletion of plasma coagulation factors and the administration of small amounts of heparin do not enable the distinction between residual effects of an anticoagulant, coagulation factor deficiency, or impaired platelet function. However, the heparin effects can be eliminated by the addition of heparinase. Further improvement may be achieved using a modified RTG by adding plasma coagulation factors in one channel for an improved evaluation of platelet function, even under the condition of a loss of procoagulants.

Investigation of a whole blood fluidized bed Taylor-Couette flow device for enzymatic heparin neutralization.

The use of clinical bioreactors will increase as more therapeutic proteins are being cloned, expressed, and produced at a reduced cost. The proposed use of an immobilized heparinase I reactor to make heparin anticoagulation a safer therapy is an example of how the specificity and high activity of an enzyme could be incorporated into a system to ultimately benefit a patient. However, the development of a safe and efficient bioreactor is important for the use of immobilized heparinase I and other therapeutic proteins designed for use in medical extracorporeal procedures. This study examined the possibility of using Taylor-Couette flow and "flow-induced" recirculation of the agarose beads as a way to fluidize agarose-bound heparinase in whole blood. Heparinase I was immobilized onto agarose beads via cyanogen bromide activation. A reactor based on Taylor-Couette flow was designed and modified with a tangential recirculation line. The reactor was tested for efficacy and safety in vitro in human blood. Visualization studies in water and 42% glycerol were used to determine the minimum rotation rate for efficient fluidization. The strategic placement of the recirculation line allowed recirculation of the agarose without the use of an external pump. The device removed 90% of the heparin activity within 2 min from 450 cc of human blood at a blood flow rate of 100 mL/min. Furthermore, the device maintained inlet and outlet clotting times of 269 +/- 10 and 235 +/- 6 s, respectively, demonstrating the potential for regional heparinization. Blood damage was a function of gel volume fraction and rotation rate of the inner cylinder. Hemolysis of the red cells is an important issue when Taylor vortices are combined with macroscopic solid particles such as agarose beads. A modified Taylor-Couette flow device was developed to treat whole blood and operational criteria were established to minimize hemolysis.