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Table of Contents
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 15  |  Issue : 2  |  Page : 105-110
A randomized prospective analysis of alteration of hemostatic function in patients receiving tranexamic acid and hydroxyethyl starch (130/0.4) undergoing off pump coronary artery bypass surgery


Department of Anesthesia, Critical Care & Pain Management, Fortis Hospitals, Bannerghatta Road, Bangalore, India

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Date of Web Publication16-Apr-2012
 

   Abstract 

Postoperative hemorrhagic complications is still one of the major problems in cardiac surgeries. It may be caused by surgical issues, coagulopathy caused by the side effects of the intravenous fluids administered to produce plasma volume expansion such as hydroxyl ethyl starch (HES). In order to thwart this hemorrhagic issue, few agents are available. Fibrinolytic inhibitors like tranexamic acid (TA) may be effective modes to promote blood conservation; but the possible complications of thrombosis of coronary artery graft, precludes their generous use in coronary artery bypass graft surgery. The issue is a balance between agents that promote coagulation and those which oppose it. Therefore, in this study we have assessed the effects of concomitant use of HES and TA. Thromboelastogram (TEG) was used to assess the effect of the combination of HES and TA. With ethical committee approval and patient's consent, 100 consecutive patients were recruited for the study. Surgical and anesthetic techniques were standardized. Patients fulfilling our inclusion criteria were randomly allocated into 4 groups of 25 each. The patients in group A received 20 ml/kg of HES (130/0.4), 10 mg/kg of T.A over 30 minutes followed by infusion of 1 mg/kg/hr over the next 12 hrs. The patients in group B received Ringer's lactate + TA at same dose. The patients in the Group C received 20 ml/kg of HES. Group D patients received RL. Fluid therapy was goal directed. Total blood loss was assessed. Reaction time (r), α angle, maximum amplitude (MA) values of TEG were assessed at baseline, 12, 36 hrs. The possible perioperative myocardial infraction (MI) was assessed by electrocardiogram (ECG) and troponin T values at the baseline, postoperative day 1. Duration on ventilator, length of stay (LOS) in the intensive care unit (ICU) were also assessed. The demographical profile was similar among the groups. Use of HES increased blood loss significantly (P < 0.05). Concomitant use of TA reduced blood loss when used along with HES. r value was prolonged at 12 hours in all the groups and α angle was reduced at 12 hours in all the groups, where as MA value was reduced at 12 th hour in the HES group compared to the baseline and increased in TA + HES group. These findings were statistically significant. No significant change in Troponin T values/ ECG, duration of ventilation and LOS ICU was observed. No adverse events was noticed in any of the four groups. HES (130/0.4) used at a dose of 20 ml/kg seems to produce coagulopathy causing increased blood loss perioperatively. Hemodilution produced by fluid therapy seems to produce Coagulopathy as observed by TEG parameters. Concomitant use of TA with HES appears to reverse these changes without causing any adverse effects in patients undergoing OPCAB surgery.

Keywords: Hydroxyl ethyl starch, off-pump coronary bypass, tranexamic acid, thromboelastogram

How to cite this article:
Chakravarthy M, Muniraj G, Patil S, Suryaprakash S, Mitra S, Shivalingappa B. A randomized prospective analysis of alteration of hemostatic function in patients receiving tranexamic acid and hydroxyethyl starch (130/0.4) undergoing off pump coronary artery bypass surgery. Ann Card Anaesth 2012;15:105-10

How to cite this URL:
Chakravarthy M, Muniraj G, Patil S, Suryaprakash S, Mitra S, Shivalingappa B. A randomized prospective analysis of alteration of hemostatic function in patients receiving tranexamic acid and hydroxyethyl starch (130/0.4) undergoing off pump coronary artery bypass surgery. Ann Card Anaesth [serial online] 2012 [cited 2020 Aug 3];15:105-10. Available from: http://www.annals.in/text.asp?2012/15/2/105/95072



   Introduction Top


The trend of practicing off pump coronary bypass (OPCAB) surgery continues to increase day by day, to avoid cardiopulmonary bypass and its potential complications. [1] Though OPCAB surgeries are associated with fewer complications, bleeding continues to be an issue that requires to be addressed. [2],[3] Hemodynamic management during OPCAB by the administration of boluses of intravenous fluids and the properties of these fluids contributing to hemorheological stability remains unclear. [4] Though colloids such as hydroxyl ethyl starch (HES) are effectively used for intraoperative volume replacement and plasma volume expansion, they may cause coagulopathy and result in postoperative blood loss. [5],[6] The search for the newer modes to facilitate reduction in perioperative blood loss continues, the use of fibrinolytic inhibitors such as TA may be an effective method to promote blood conservation; but, the possible complications of thrombosis of coronary artery graft, precludes their regular use in coronary artery bypass graft surgeries. [1],[6],[7] In this study we assessed the hemostatic effects of concomitant use of HES and TA. Thromboelastogram (TEG) was used to assess the hemostatic effect of the combination of HES and TA.


   Materials and Methods Top


The ethical committee approval was taken. Patient's consent was taken. 100 patients undergoing elective OPCAB surgery were recruited for the study.

The inclusion criteria were:

  • Adult patients aged 30 - 75 years, consenting to participation
  • Elective OPCAB surgeries
  • Patients who has stopped antiplatelet medications prior to the surgery. (As per our protocol aspirin and clopidogrel were stopped 7 days prior to the surgery)


The exclusion Criteria were:

  • Emergency OPCAB surgery
  • Preexisting coagulation disorders, Recent thrombolysis (in less than 2 days), patients on antiplatelet medications
  • Hemodynamic instability - heart rate >130, MAP<50, CVP>15, PAWP>23
  • Patient likely to need cardiopulmonary bypass (such as patients with narrow coronary arteries likely to require endarterctomy, combined valve and coronary surgery) low ejection fraction, recent MI, requirement of intra aortic balloon pump and or mechanical ventilation in the preoperative period.
  • Preoperative anemia Hb less than 9 g/dL
  • Dysfunctions of major organ such as renal and or hepatic failure
  • Patients with history of convulsion / or receiving anticonvulsant medications


Routine baseline laboratory workup Complete blood count, prothrombin time, international normalization ratio, bleeding time, clotting time, liver function tests, renal function tests, electrocardiogram, echocardiogram and TEG were performed preoperatively. Patients fulfilling our criteria were randomly allocated into 4 groups using a computer generated random chart. Interventions in the groups A to D is shown in [Table 1].
Table 1: The interventions in the group

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Patients in group A and C received 20 ml/kg of HES right from the time of induction, once the total dose was exhausted, patient were given other fluids such as RL/NS. In all the groups rate and volume of fluid administration was guided by goal directed therapy to maintain the hemodynamics to 20% of the baseline values Anesthesia and surgical techniques were standardized. All the patients were anesthetized using sevoflurane (1MAC), rocuronium (1 mg/ kg initially followed an intravenous infusion of 0.4 mg/kg/hr) and fentanyl (5 to 10 mcg/ Kg), and they received endotracheal general anesthesia. The patients received 2 mg/kg heparin and an activated clotting time (ACT) of more than 240 seconds was considered acceptable to carry out coronary artery bypass graft surgery. At the end of surgery, the residual heparin was reversed with protamine (1:1.5) to achieve an ACT to about 130 secs. The following parameters were assessed. Intraoperative blood loss - by gravimetric method and postoperative blood loss was measured by calculating blood volume lost in the drains until the time of their removal. Haemoglobin of 9 g/dl .was considered as the transfusion trigger. The transfusion rates in all the four groups were noted. Thromboelastogram machine - ® Haemoscope, Germany was used) The paramteres derived from TEG were R - reaction time, α angle which implies the coagulation kinetics and Maximum Amplitude(MA) i.e. the clot strength. They were assessed at baseline (at the time of induction), 12 and 36 hours. The appearance and the measurements of a normal TEG is shown in [Figure 1]. The occurrence of perioperative MI was assessed by ECG recorded every morning on postoperative day 1 and 2 and troponin T values (normal lab value range - 0-0.1 ng/ml) measured at baseline and 24 hours. Duration on ventilator, length of stay (LOS) intensive care unit (ICU) stay were also assessed. Any adverse events such as seizures was noted.
Figure 1: Normal thromboelastogram R - Reaction time; K- Coagulation kinetics; á angle - acceleration kinetics of clot formation; MA - Maximum amplitude - the strengrth of clot formed

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Statistical analysis

As per prehoc analysis, 25 patients per group were considered sufficient to detect statistical significance with a and b errors of 0.05 and 0.2, respectively. SPSS 16 software was used to analyse the data. Data presented are as mean ± standard deviation. P value of < 0.05 were considered statistically significant. ANOVA was used to assess the demographical data, blood loss. Kruskal Wallis Chi square test was used to assess the significance of blood loss. Repeated measures of ANOVA was used to analyze the TEG parameters.


   Results Top


The demographical profiles were similar among the groups [Table 2]. Two patients in group D were excluded from the study. One patient crashed during grafting and was converted to on pump CABG. Other patient was infused with HES, in order to maintain the vitals and so was excluded from the study. Blood loss in various groups is shown in the descending order in [Table 3]; group C (HES)>> Group A (HES+TA) > Group D (RL) > Group B (RL+TA)this finding was statistically significant.
Table 2: Demographic profile

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Table 3: Blood loss

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TEG parameters [Table 4],[Table 5],[Table 6] and [Table 7]

The R values in all the four groups were prolonged at 12 th hour and returned to the baseline value by 36 th hour [Figure 2]. This changes within the group was statistically significant. The R values were compared among the groups and no difference was found. Reduction in the α angle suggesting reduction of acceleration kinetics of thrombus formation in all the groups 12 th hr, and normal at other intervals was noted which was statistically significant. No changes were observed in the α angle when compared among the groups [Figure 3]. The MA in the C group was reduced at 12 th hour when compared to the baseline value, returning to normal value at 36 th hour. The MA remained normal in group B and D at all times. The MA in the group A increased at the 12 th hour, this observation was statistically significant. [Table 7] shows the transfusion rate. Group C patients had higher transfusion rates among the four groups. In order Group C (HES) >> Group A (HES +TA)≥Group D (RL) > Group B( RL +TA). No significant change in Troponin T values at the baseline and 24 hours value were normal in all the 4 groups. None of the patients in the cohort had MI as assessed by changes in the ECG and troponin T. The average duration of ventilation LOS ICU were similar in all the four groups. No adverse events were noticed in any of the four groups.
Figure 2: Changes in the r value

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Figure 3: Changes in the á angle

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Table 4: Changes in R value: (normal value: 4-8 minutes)

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Table 5: Changes in α angle: (normal value: 45-74º)


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Table 6: Changes in MA: (normal value: 54-70 mm)

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Table 7: Transfusion rates

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   Discussion Top


Perioperative blood loss is one of the major complications in cardiac surgery. It may be attributed to the use of colloids such as starch/gelatine administered to maintain the intravascular volume or antiplatelet medications which cardiac patients so often receive. Colloids such as HES are now routinely administered for effective intraoperative volume replacement and plasma volume expansion; they might cause coagulopathy and result in postoperative blood loss. One study evaluated the effects of HES on blood coagulation in 20 patients and found significant decrease in platelet aggregation, decrease in factor VIII activities and fibrinogen levels contributing to haemorrhagic problem. [10] Controversy exists regarding the use of HES in cardiac surgery and so are the pro and con argument. [12],[19] The on-going search for newer modes of blood conservation has led to the development of antifibrinolytics such as TA and epsilon aminocaproic acid (EACA), which has been now routinely used in other major surgeries to effectively reduce the blood loss. Their use in cardiac surgery has been restricted due to likely thrombotic complications, graft thrombosis, renal failure, cerebrovascular accidents and seizures. [1] A study was conducted to evaluate the hemostatic effects and safety of TA, aprotinin and placebo in OPCAB surgery. The authors concluded that both TA and aprotinin were similarly effective in the reduction of postoperative blood loss, TA seems to be cost effective and safe alternative options to aprotinin. [8] Another meta-analytic conducted from 138 trials to evaluate the safety and effectiveness of antifibrinolytics in cardiac surgery. The authors concluded that all antifibrinolytics were effective in reducing the blood loss and transfusion. There were no significant risks or benefits for mortality, stroke, MI, renal failure. [11] In this study, we observed that colloids increased the blood loss marginally. This finding correlates with another study conducted by Schramko and coworkers who compared the effects of HES, gelatin and RL in patients undergoing cardiac surgery and concluded that colloids produced defective hemostasis in a dose dependent fashion without any clinical effect on blood loss. [12],[13] The findings of the TEG in our study, the abnormalities of r, α angle could be in part due to hemodilution. Previous studies have shown that hemodilution with HES at a dilution of 33%, while crystalloid hemodilution at 50% impairs coagulation. [14],[15] Reduced thrombin generation and fibrin clot formation are the mechanism attributed to hemodilutional effects. In our study we found that the MA was reduced at 12 th hour in the colloid group, which returned to baseline by 36 th hour, whereas increase in the MA noted in the TA group .There are several mechanisms put forth to describe the impairment of blood coagulation due to colloids use. It is mainly dose dependent and the molecular weight of colloid. Larger molecules of colloids interfere greater with fibrinogen, factor VIII and platelet dysfunction leading to less stable thrombus. [16] Although, the manufacturers recommend a dose up to 50 ml/kg, [12],[19] we used reasonable dose of HES i.e. 20 ml/kg/day, which explains the findings in our study. Addition of TA to the colloid group increased the MA at 12 th hour, and its effect was noted at 36 th hour too. The overall effect of TA is by inhibiting the conversion of plasminogen to plasmin on the surface of fibrin, it also prevents plasmin degradation of platelet glycoprotein 1b receptors. TA also stabilizes ADP granules in platelets and inhibits platelet dysfunction. TA acts wells in a situation associated with primary hyperfibrinolysis states such as major surgery. TA is 10 times more potent than EACA, 100 times cheaper than aprotinin, and hence it may become the drug of choice in routine cardiac surgery. The issue of withdrawing aprotinin and its effect on surgical hemorrhage and use of blood products to counter them has been revisited recently [20] Its effectiveness in reducing the blood transfusion postoperatively when started early as been demonstrated in various studies. [6],[17] In our study we did not find any differences in troponin values, perioperative ECG changes [Table 8], which correlates with Well's study as they too concluded that TA can be used safely and effectively in patients undergoing cardiac surgery. [18] The potential drawback of our study could be that Group A and C received RL in addition to HES, and the amount of RL not quantified. Influence of other factors such as surgical stress induced coagulation changes, transfusion of blood products perioperatively, and the antiplatelets started within 6 hours of surgery as per our routine protocol can all have an effect on TEG parameters.
Table 8: Other parameters

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   Conclusion Top


HES (130/0.4) used at a dose of 20 ml/kg increases blood loss perioperatively and concomitant use of tranexamic acid blocks this without having any adverse effects in patients undergoing OPCAB surgery.

 
   References Top

1.Mehr-Aein A, Sadeghi M, Madani-civi M. Does tranexamic acid reduce blood loss in off-pump coronary artery bypass? Asian Cardiovasc Thorac Ann 2007;15:285-9  Back to cited text no. 1
    
2.Ascione R, Williams S, Lloyd CT, Sundaramoorthi T, Pitsis AA, Angelini GD. Reduced postoperative blood loss and transfusion requirement after beating-heart coronary operations: a prospective randomized study. J Thorac Cardiovasc Surg 2001;121:689-96.  Back to cited text no. 2
    
3. Jares M, Vanek T, Bednar F, Maly M, Snircova J, Straka Z. Offpump versus on pump coronary artery surgery. identification of fibrinolysis using rotation thromboelastography; A Preliminary, prospective, randomized study. Int Heart J 2007;48:57-67.  Back to cited text no. 3
    
4.Chassot PG, van der Linden P, Zaugg M, Mueller XM, Spahn DR. Off-pump coronary artery bypass surgery: physiology and anesthetic management. Br J Anaesth 2004,92:400-13.  Back to cited text no. 4
    
5.Kim JY, Lee JW, Kweon TD, Kwak YL, Kim JH, Bang SO. The effect of 6% HES 130/0.4 on hemostasis and hemodynamic efficacy in offpump coronary artery bypass surgery: a comparison with 6% HES 200/0.5 Korean J Anesthesiol 2007;53:S14-21.  Back to cited text no. 5
    
6.Kasper SM, Meinert P, Kampe S, Görg C, Geisen C, Mehlhorn U, et al. Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses. Anesthesiology 2003;99:42-7.  Back to cited text no. 6
    
7.Casati V, Della Valle P, Benussi S, Franco A, Gerli C, Baili P, et al. Effects of tranexamic acid on postoperative bleeding and related hematochemical variables in coronary surgery: Comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 2004;128:83-91.  Back to cited text no. 7
    
8.Vanek T, Jares M, Fajt R, Straka Z, Jirasek K, Kolesar M, et al. Fibrinolytic inhibitors in off-pump coronary surgery: a prospective, randomized, double-blind TAP study (tranexamic acid, aprotinin, placebo). Eur J Cardiothorac Surg 2005;28:563-8.   Back to cited text no. 8
    
9.Thai J, Reynolds EJ, Natalia N, Cornelissen C, Lemmens HJ, Hill CC, et al. Comparison between RapidTEG® and conventional thromboelastography in cardiac surgery patients. Br J Anaesth 2011;106:605-6.  Back to cited text no. 9
    
10.Türkan H, Ural AU, Beyan C, Yalçin A. Effects of hydroxyethyl starch on blood coagulation profile. Eur J Anaesthesiol 1999;16:156-9.  Back to cited text no. 10
    
11.Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801-13.  Back to cited text no. 11
    
12.Schramko A, Suojaranta-Ylinen R, Kuitunen A, Raivio P, Kukkonen S, Niemi T. Hydroxyethylstarch and gelatin solutions impair blood coagulation after cardiac surgery: a prospective randomized trial. Br J Anaesth 2010;104:691-7.  Back to cited text no. 12
    
13. Boldt J, Haisch G, Suttner S, Kumle B, Schellhaass A. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation. Br J Anaesth 2002;89:722-8.  Back to cited text no. 13
    
14.Ekseth K, Abildgaard L, Vegfors M, Berg-Johnsen J, Engdahl O. The in vitro effects of crystalloids and colloids on coagulation. Anaesthesia 2002;57:1102-8.  Back to cited text no. 14
    
15. Engström M, Reinstrup P, Schött U. An in vitro evaluation of standard rotational thromboelastography in monitoring of effects of recombinant factor VIIa on coagulopathy induced by hydroxy ethyl starch. BMC Blood Disord 2005;5:3.   Back to cited text no. 15
    
16.Schols SE, Lancé MD, Feijge MA, Damoiseaux J, Marcus MA, Hamulyák K, et al. Impaired thrombin generation and fibrin clot formation in patients with dilutional coagulopathy during major surgery. Thromb Haemost 2010;103:318-28.  Back to cited text no. 16
    
17.Mahdy AM, Webster NR. Perioperative systemic haemostatic agents. Br J Anaesth 2004;93:842-58.  Back to cited text no. 17
    
18.Well PS. Safety and efficacy of methods for reducing perioperative allogeneic transfusion: a critical review of the literature. Am J Ther 2002;9:377-88.  Back to cited text no. 18
    
19.Kasper SM, Meinert P, Kampe S, Görg C, Geisen C, Mehlhorn U, et al. Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses. Anesthesiology 2003;99:42-7.  Back to cited text no. 19
    
20.Tempe DK, Hasija S. Are tranexamic acid and e-aminocaproic acid adequate substitutes for aprotinin? Ann Card Anaesth 2012;15:4-5.  Back to cited text no. 20
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Correspondence Address:
Murali Chakravarthy
Fortis Hospitals, Bangalore - 560 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.95072

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]

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