| Abstract|| |
Sonoclot analysis is a point of care test to monitor the coagulation process, presenting a comprehensive evaluation of the clot formation and retraction as well as platelet function. This randomized double-blinded study was designed to investigate the utility of Sonoclot analysis in monitoring the coagulation profile as also the antifibrinolytic effects of tranexamic acid administered in patients with tetralogy of Fallot undergoing intracardiac repair. Eighty of a total 94 patients were randomly divided into two groups of 40 each. In the study group, TA was administered thrice at a dosage of 10 mg/kg, i.e. before CPB, on CPB and after CPB, whereas in the control group, placebo was administered at the same time intervals. Sonoclot analysis and D-dimer measurement were performed at baseline and following heparin neutralisation. An additional variable, DR 15 (diminishing rate of clot strength at 15 min postmaximal clot strength), was calculated from the Sonoclot graph and was compared with d-dimer levels as a measure of fibrinolysis. The three Sonoclot variables, i.e. activated clotting time, clot rate and platelet function, were deranged at baseline in all the patients. Post-CPB, the change in these variables was not significant. ACT, clot rate and platelet function showed no significant (P > 0.05) difference in both the groups at both the time intervals. DR 15 and d-dimer values were comparable at baseline in both the groups. However, a significant (P < 0.05) difference was seen in these variables in the control group as compared with the TA group following heparin neutralisation. To conclude, Sonoclot analysis is a useful, point of care method for the monitoring of coagulation and fibrinolysis in patients with tetralogy of Fallot undergoing intracardiac repair.
Keywords: Sonoclot analysis, tranexamic acid, tetralogy of Fallot, fibrinolysis
|How to cite this article:|
Aggarwal V, Kapoor PM, Choudhury M, Kiran U, Chowdhury U. Utility of Sonoclot analysis and tranexamic acid in tetralogy of Fallot patients undergoing intracardiac repair. Ann Card Anaesth 2012;15:26-31
|How to cite this URL:|
Aggarwal V, Kapoor PM, Choudhury M, Kiran U, Chowdhury U. Utility of Sonoclot analysis and tranexamic acid in tetralogy of Fallot patients undergoing intracardiac repair. Ann Card Anaesth [serial online] 2012 [cited 2013 May 24];15:26-31. Available from: http://www.annals.in/text.asp?2012/15/1/26/91477
| Introduction|| |
Children having cyanotic congenital heart disease (CCHD) are prone to excessive surgical bleeding in the early postoperative period, probably due to inherent hematological abnormalities like polycythemia, thrombocytopenia, thrombocytopathy, coagulation factor deficiencies, excessive fibrinolysis and disseminated intravascular coagulation.  Apart from these coagulation defects, a combination of surgical trauma, blood and blood product transfusion, heparin therapy and exposure to cardiopulmonary bypass (CPB) exaggerate this bleeding.  Blood and blood products may be empirically administered to these children with a hope to correct the hematological indices. This increases the cost of the surgery, leads to injudicious usage of human blood and exposes these patients to various immunological reactions and blood-borne diseases. 
Thus, the conservation of blood requires a dedicated effort by the perioperative physician. Antifibrinolytic agents have been administered perioperatively to reduce this bleeding. However, after the publication of the Blood Conservation using Antifibrinolytics in a Randomised Trial (BART)  and subsequent disfavor of aprotinin, we have a limited choice of hemostatic agents in the form of epsilon aminocaproic acid (EACA) and tranexamic acid (TA). TA is 10-times more potent than EACA, and has shown promising results in controlling perioperative bleeding in cyanotic children undergoing cardiac surgery on CPB. 
Traditionally, in cardiac surgery, the activated clotting time (ACT) is the most commonly used method to measure the effects of heparin therapy. Other coagulation tests like prothrombin time (PT), activated partial thromboplastin time (ApTT), platelet count, platelet function tests, plasma fibrinogen concentration, d-dimer and fibrin degradation products (FDPs) are laborious, time consuming, require laboratory services and measure different aspects of the clotting process without presenting an entire picture of the coagulation system. Sonoclot analysis (Sienco Inc., Arvada, Colo) utilizes the viscoelastic properties of the whole blood and provides a comprehensive evaluation of the entire coagulation process.  Although the data for Sonoclot analysis with TA administration is available in adult patients undergoing cardiac surgery on CPB,  its benefit in the perioperative care of children with CCHD is yet to be explored.
We undertook this study to investigate the utility of Sonoclot analysis in monitoring the coagulation profile in children with tetralogy of Fallot (TOF) undergoing intracardiac repair. Sonoclot analysis was also used to demonstrate the antifibrinolytic action of TA administered in these patients.
| Materials and Methods|| |
This randomized, double-blind, placebo-controlled study was conducted on 94 children with TOF, aged 1-12 years, undergoing intracardiac repair. The approval from the institutional ethics committee and the written informed consent from the parents was taken. No patient had renal or hepatic dysfunction or seizure disorder. Patients on any antiplatelet or anticoagulant therapy in the last 2 weeks prior to surgery were excluded. The patients who were likely to have shorter CPB times i.e. if pulmonary valvotomy and patch repair was not employed for RVOT augmentation, were also excluded from the study.
The conduct of anesthesia was similar in all the patients. Morphine (0.1 mg/kg) and atropine (0.2 mg/kg) were given intramuscularly 45 min before anesthesia induction. Ketamine (1-2 mg/kg) and fentanyl (3-5 μg/kg) were administered for the induction of anesthesia, and rocuronium (1 mg/kg) was used to facilitate endotracheal intubation. anesthesia was maintainaned of with intermittent doses of fentanyl and midazolam and muscle relaxation was supplemented with vecuronium. Heparin (400 U/kg) was administered to achieve a target ACT of more than 480 s.
The conduct of CPB was as per the institutional protocol, and was uniform in all the patients. Following aortobicaval cannulation, moderate hypothermia (up to 32°C) was achieved and cold blood cardioplegia was administered. CPB circuits were prepared in a similar fashion with no special coatings or filters. Silicon or PVC tubings, plastic venous reservoirs and Minimax (Medtronic, Minneapolis, MN, USA) or Capiox SX10R (Terumo Corporation, Tokyo, Japan) oxygenators were used as appropriate for patients' weight. During CPB, hematocrit above 25% and ACT above 480 sec were maintained. Pump flows were adjusted to maintain a mean arterial pressure of 40-60 mmHg. Conventional ultrafiltration was performed in all the cases. Residual heparin was neutralized using protamine sulfate.
The patients were randomised into two groups using the random table method. In the study group, TA, in a dosage of 10 mg/kg, was administered at three points of time, i.e. after induction of anesthesia, during CPB and along with protamine during heparin neutralization, while in the control group, normal saline was administered at the same time intervals. This intervention was performed by a research assistant using unlabelled syringes filled up to 10 ml. Five milliliters of blood sample was collected twice for the Sonoclot analysis and the d-dimer measurement from the arterial line. The first sample was withdrawn at baseline, i.e. before the administration of the first dose of TA (T 0 ), and second withdrawal was carried out following heparin neutralization, i.e. 15 min after the administration of the third dose of TA (T 1 ). Blood sampling was performed by the principal investigator following an initial withdrawal of 10 ml of blood to nullify the effect of heparin present in the monitoring line.
The Sonoclot analyzer  consists of a tubular disposable probe mounted on an ultrasonic viscosity transducer, housed in a head assembly. It immerses in a cuvette containing 0.4 ml of patient's whole blood [Figure 1]. Following the manual closure of the head assembly, the probe vibrates 1 μm vertically at a frequency of 200 Hz. The increasing viscous drag due to the formation of fibrin strands impedes its vibration and increases the intensity of the clot signal. It is detected by electronic circuits, resulting in a typical Sonoclot signature [Figure 2] depicting the following variables:
- The ACT (s) (normal - 115-195 s) is the time until thrombin generation and the beginning of fibrin formation.
- The clot rate (units/min) (normal - 11-35 units/min) is the percentage of peak amplitude per unit time depicting the rate of fibrin formation from fibrinogen.
- Platelet function (normal ≥1.6) depicts appropriate function of platelets and their interaction with fibrin and plasmin.
|Figure 1: The operating principle of the Sonoclot analyser (Sienco Inc, Arvada, Colo)|
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|Figure 2: Variables of the Sonoclot signature. (a) maximal clot strength; (b) clot strength 15 mins after 'a' DR15-Diminishing rate of clot strength at 15 min postmaximal clot strength|
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The process to obtain the entire Sonoclot signature takes 45-60 min. In addition to the standard information, we also calculated the clot strength at peak and at 15 min postpeak levels to obtain an additional value, DR 15 (diminishing rate of clot strength at 15 min postmaximal clot strength). This variable has been described by Kamada et al. in the Sonoclot analyzer to measure the suppressive effect of TA on hyperfibrinolysis in cardiac surgery. DR 15 reflects clot retraction and lysis over a period of 15 min, and was calculated from [Figure 2] (a - b/a x 100%, where "a" is the maximal clot strength and "b" is the clot strength at 15 min post the "a" level).
The remaining blood was centrifuged and plasma thus obtained was stored at -20°C. It was used for d-dimer measurement adopting the enzyme-linked immunosorbent assay technique (Hyphen Biomed, Neuville - Sur-oise, France) with a reference range of <400 ng/ml. D-dimer is a specific marker for fibrinolysis  and was compared with DR 15 derived from Sonoclot analysis to evaluate the antifibrinolytic effects of TA.
The statistical analysis was done using SPSS 15.0 version (SPSS Inc., Chicago, IL, USA). Nominal variables are given as frequency and percentage, nonparametric data as median (range) and parametric data as mean and standard deviation. The chi square/Fisher exact test as appropriate was used for categoric data. Two levels in the same group were tested by paired samples t-test and intergroup analysis was performed using the independent student t-test. P-value less than 0.05 was considered significant.
| Results|| |
Eighty of 94 children (40 in each group) completed the study. Of the 14 children excluded, three were receiving aspirin in the preceding 2 weeks, one had renal dysfunction and five in each group underwent intracardiac repair without pulmonary valvotomy and patch repair. There were no differences in the demographic variables, i.e. age, sex and weight of the patients. The duration of CPB and aortic cross-clamp time were comparable in both the groups [Table 1].
[Table 2] shows the coagulation parameters as derived from the Sonoclot analyzer. All the patients had deranged variables (Sonoclot-derived) at baseline. The ACT was prolonged, the clot rate was at the lower limit of normal values and the platelet function was decreased.. There was a deterioration in the values of these variables following heparin neutralization in both the groups; however, the change was not significant (P > 0.05) in either of the groups. The decrease in platelet function was observed to be higher in the control group. There was no significant (P > 0.05) difference in ACT, clot rate and platelet function values both at baseline and following heparin neutralisation in both the groups. The DR 15 was comparable at baseline in both the groups. The increase in DR 15 was significant (P < 0.01) in the control group, following heparin neutralization, and was significantly (P = 0.01) higher than that in the TA group.
|Table 2: Coagulation parameters as derived from Sonoclot analysis at baseline (T0) and following heparin neutralisation (T1), respectively|
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The d-dimer levels were comparable at baseline in both the groups. Following heparin neutralisation, the patients in the control group attained significantly (P < 0.01) higher levels of d-dimer as compared with the TA group [Table 3]. The blood loss in the 24-hr postoperative period in the TA group (12 ± 3 ml/kg) was significantly lower (P < 0.01) than that in the control group (21 ± 4 ml/kg) [Figure 3].
|Figure 3: Blood loss (ml/kg) in the control and the tranexamic acid group in the first 24 h postoperatively|
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|Table 3: D - dimer values at baseline (T0) and following heparin neutralization (T1), respectively|
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Two patients in the TA group presented with excessive bleeding (28 ml/kg and 34 ml/kg) on the first postoperative day with high DR 15 values (64% and 68%). Five patients in the control group also had increased bleeding (>25 ml/kg) with DR 15 values more than 65%. One patient in the control group was taken up for surgical reexploration.
| Discussion|| |
In our study, we have elucidated the importance of Sonoclot analysis in demonstration of the coagulation process as well as the monitoring of the antifibrinolytic effects of TA in TOF patients undergoing intracardiac repair.
Sonoclot analysis, first described in 1975 by Von Kaulla et al., is a point of care, coagulation monitoring test. The results are displayed within 1 h, guiding the perioperative physician to take appropriate steps for the maintenance of hemostasis. Pivalizza et al. conducted a study using Sonoclot analysis and compared the data between healthy pediatric surgical patients and healthy adult patients undergoing minor surgery. All the variables in all age groups were found to be within the normal range of reference values. The authors successfully demonstrated the universal applicability of Sonoclot analysis in the pediatric population.
The cyanotic children have impaired production of coagulation factors. , The impaired liver function causing decreased production and defective absorption of vitamin K from intestines (leading on to ineffective carboxylation of the coagulation factors) has been implicated in producing this. These patients also have decompensated erythrocytosis,  resulting in an iron deficiency state. This leads to the production of nondeformable microspherocytes with a resultant hyper-viscosity. This causes sludging at the capillary level with consumptive coagulopathy, further decreasing the coagulation factors, fibrinogen and platelets.  In our study, in Sonoclot analysis, the ACT was prolonged in all subjects at baseline and the clot rate was at the lower limit of reference values, suggesting the deficiency of coagulation factors in patients with TOF.
Children with CCHD have platelet dysfunction, either due to thrombocytopenia or due to thrombocytopathy. Thrombocytopenia in them has been shown to be roughly proportional to the degree of polycythemia.  The platelets in these subjects are reported to have a shortened half-life  as well as release abnormalities.  We also observed abnormal platelet function values on Sonoclot analysis signifying platelet dysfunction. The peak obtained in the Sonoclot graphs was abnormally dull as compared with healthy individuals. The platelet function deteriorated further following CPB, with a higher decrease seen in the patients who were not administered TA.
TA is a synthetic lysine analogue that exerts its antifibrinolytic action by the reversible blockade of lysine-binding sites on plasminogen molecule.  TA has been used extensively in cardiac surgery on CPB, in various dosages, ,, showing a beneficial hemostatic effect. Chauhan et al. compared different dosages of TA in cyanotic children and found the best results when it was administered in a dosage of 10 mg/kg thrice, i.e. pre-CPB, on CPB and after CPB. The decreased fibrinolysis due to TA was suitably demonstrated in our study by Sonoclot analysis. With baseline values as reference, DR 15 values increased by only 23% in the TA group as compared with 74% in the control group [Figure 4]. These results are in accordance with the conclusions derived by Karmada et al.  The antifibrinolytic action of TA was further elucidated by an increase in d-dimer levels by 223% in the control group and 40% in the TA group [Figure 5].
|Figure 4: Percentage increase in DR15 values from baseline to postheparin neutralization in the control and the tranexamic acid groups.|
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|Figure 5: Percentage increase in the d-dimer levels from baseline to postheparin neutralisation in the control and the tranexamic acid groups|
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The patients in the TA group had decreased fibrinolysis with significantly reduced blood loss in the first 24 h postoperatively. We did not investigate the use of blood and blood products considering the different transfusion protocols as adopted by different surgeons in the postoperative management. The patients who had excessive bleeding (two in the TA group and five in the control group) due to hyperfibrinolysis (increased DR 15 ) [Figure 6] were administered platelet concentrates and fibrinogen. Packed red blood cells were administered to maintain a hematocrit above 35%. One patient in the control group persisted with bleeding even though the postoperative Sonoclot analysis was comparable to the baseline value. He was taken up for reexploration and a surgical cause of bleeding was found.
0 Our study is limited, as the implications of Sonoclot analysis, in estimating the amount of blood / blood products saved in the post operative period and whether or not it translates into any improvement in morbidity or mortality of the patients or decrease in stay in ICU / hospital resulting in economic benefits, has not been investigated. The effects of preoperative hematocrit and platelet count were not evaluated considering appropriate randomization.
| Conclusion|| |
Sonoclot analysis is an easily performed, reproducible, point of care method for coagulation monitoring which diagnoses the exact nature of coagulopathy including deficiency of coagulation factors or fibrinogen or defects in platelet - fibrin interaction or platelet function. The DR 15 values have proven to be a reliable marker of hyperfibrinolysis involving the use of TA in TOF patients undergoing intracardiac repair. However further studies are required to validate the reference values of DR 15 , to initiate action in controlling the post operative bleeding due to hyperfibrinolysis.
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Poonam Malhotra Kapoor
Department of Cardiac Anaesthesia, C.N. Centre, A.I.I.M.S., New Delhi - 110 029
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]