Effects of tranexamic acid on coagulation indexes of patients undergoing heart valve replacement surgery under cardiopulmonary bypass

Abstract

This study aims to explore the effects of tranexamic acid on the coagulation indexes of patients undergoing heart valve replacement surgery under the condition of cardiopulmonary bypass (CPB). One hundred patients who conformed to the inclusive criteria were selected and divided into a tranexamic acid group and a non-tranexamic acid group. They all underwent heart valve replacement surgery under CPB. Patients in the tranexamic acid group were intravenously injected with 1 g of tranexamic acid (100 mL) at the time point after anesthesia induction and before skin incision and at the time point after the neutralization of heparin. Patients in the non-tranexamic acid group were given 100 mL of normal saline at corresponding time points, respectively. Then the coagulation indexes of the two groups were analyzed. The activated blood clotting time (ACT) of the two groups was within normal scope before CPB, while four coagulation indexes including prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), and fibrinogen (FIB) had significant increases after surgery; the PT and INR of the tranexamic acid group had a remarkable decline after surgery. All the findings suggest that the application of tranexamic acid in heart valve replacement surgery under CPB can effectively reduce intraoperative and postoperative blood loss.

Keywords

blood loss cardiopulmonary bypass coagulation index heart valve replacement tranexamic acid

Introduction

Surgery on the heart and great vessels under cardiopulmonary bypass (CPB)¹ is a high risk. Though the safety of CPB as a non-physiological operation is in constant development and improvement, its damage to blood circulation^2,3 is inevitable. Postoperative bleeding is one of the most commonly seen severe complications in surgery. In recent years, tranexamic acid⁴ as a synthesized anti-fibrinolytic drug has been applied more frequently in CPB. Many scholars in China and abroad have made certain research achievements in this aspect.

For instance, Jacob et al.⁵ studied the application of tranexamic acid in surgery for congenital heart disease of infants under CPB and its effects on coagulation function and found that tranexamic acid could effectively lower postoperative blood loss and transfusion. In 2014, Haanschoten et al.⁶ further explored the clinical safety and effect of tranexamic acid in heart surgery through studying the effects of tranexamic acid on postoperative drainage volume, blood transfusion volume, safety, and complications in heart surgery. Aoki et al.⁷ studied the protective effect of tranexamic acid to blood in valve replacement by evaluating coagulation function with thrombelastogram and further confirmed the optimal dose of tranexamic acid under CPB. A case-control study was carried out to discuss the effects of tranexamic acid on the coagulation indexes of patients undergoing heart valve replacement under the condition of CPB.

Materials and methods

Research participants

One hundred patients who conformed to inclusive and exclusive criteria were enrolled in this study. The participants were divided into a tranexamic acid group and a non-tranexamic acid group. Patients in the tranexamic acid group were given tranexamic acid injection during surgery, while patients in the non-tranexamic acid group were not given tranexamic acid injection during surgery. All research events have been approved by the participants and verified by pathologists.

Patients aged over 18 years, had American Society of Anesthesiologists (ASA) level II or III,⁸ whose extracorporeal circulation time ranged from 60 minutes to 100 minutes, and had left ventricular ejection fraction (LEVF) no less than 40 were included. Patients who aged 18 years, had underwent heart operation, or developed disease induced severe coagulation function abnormity were excluded.

Experimental instruments and major anesthetics

Experiment instruments used included monitor, micro-injection pump, anesthesia machine, blood-gas analyzer, and multi-parameter monitor. Major anesthetics used included midazolam,⁹ fentanyl injection, tranexamic acid injection, sodium chloride injection, heparin sodium injection, dopamine hydrochloride injection, and etomidate.

Anesthetic method

Preparation before anesthesia: patients were forbidden to eat and drink for 6 h before surgery. They were then injected with 1 mg of penehyclidine 30 min before surgery. The peripheral vein was opened after admission into the operating room. Electrocardiogram (ECG), heart rate (HR), and pulse oxygen saturation (SpO₂) were monitored; patients were given oxygen supply in low flow; arterial intubation was performed to monitor invasive blood pressure (IBP) under the condition of local anesthesia.^10,11

Anesthesia induction: midazolam (0.1–0.2 mg/kg), fentanyl (8–10 μg/kg), etomidate (0.3 mg/kg), and rocuronium bromide (0.8–1.2 mg/kg) were injected intravenously. Tracheal intubation was performed 2–3 min after intravenous injection.

Maintenance of anesthesia: anesthesia was maintained by giving intravenous inhalation of composite anesthetics. To be specific, fentanyl (0.2–1 μg·kg⁻¹·min⁻¹) and propofol (4–6 mg ·kg⁻¹·min⁻¹) were constantly pumped; sevoflurane was discontinuously inhaled taking blood pressure and HR of patients in anesthetic state as references; cisatracurium besylate (0.1–0.15 mg·kg⁻¹·min⁻¹) was discontinuously injected to maintain muscle relaxation. Right internal jugular vein was punctured¹² and implanted with tube to monitor central venous pressure (CVP); also, nasopharyngeal temperature and rectal temperature were monitored.

Surgery and CPB

The surgery was performed by the same surgical doctors. First, a standard median sternotomy was carried out.¹³ Heparin (4 mg·kg⁻¹) was injected intravenously after thoracotomy. When activated blood clotting time (ACT) was more than 480 s, CPB was established through ascending aorta intubation and superior and inferior vena cava intubation. Heparin (1 mg·kg⁻¹) needed to be supplemented if ACT was less than 480 s.

After intra-cardiac manipulation, rewarming started, the ascending aorta was opened, and respiration recovered. Vasoactive agents and positive inotropic drugs were constantly pumped according to HR and blood pressure.

Protamine reversal of heparin (the ratio of protamine to heparin: 1.5:1) was given after CPB, followed by the measurement of ACT. After surgery, the blood left in the machine was reinfused. Patients in the tranexamic acid group were intravenously injected with 1 g (100 mL) of tranexamic acid at the time point after anesthesia induction and before skin incision and at the time point after the neutralization of heparin; patients in the non-tranexamic acid group were given 100 mL of normal saline at corresponding time points.

Postoperative monitoring

After the surgery, patients were admitted into intensive care units (ICUs). ECG, SPO₂, CVP, and IBP were monitored. Blood routine examination and arterial blood gas analysis were performed discontinuously. Sedative treatment was also given to patients. Tracheal tubes were removed after autonomous respiration recovered and hemodynamic condition became stable. Vasoactive agents were adjusted according to the circumstances.

Detection indexes

General data before surgery

General data of patients such as age, gender and weight were recorded. Also, history of diseases including hypertension, diabetes, chronic obstructive pulmonary disease, and cerebral stroke as well as cardiac function were recorded.

Detection of coagulation indexes

Hb and Hct were detected before surgery, before the end of CPB, at the end of surgery, and 12 h after surgery.

ACT, dose of heparin, and dose of protamine were detected before, during, and after CPB.

Coagulation indexes such as PT, APTT, INR, and FIB were detected before and after surgery.

Monitoring of intake and output volume during perioperative period

Total volume of drainage of pericardium and mediastinum was detected 12 h after surgery.

The quantity of allogeneic blood and blood products transfused including concentrated red blood cells, fresh frozen plasma and blood platelets, and the transfusion frequency were recorded during surgery and within 12 h after surgery. The level of hemoglobin in the condensed red blood cells transfused was lower than 80 g·L⁻¹; the fresh frozen plasma and blood platelets transfused were determined by anesthetists.

Monitoring of time indexes

Duration of CPB, aorta block, operation, and stay in ICU (time from admission into ICU to leaving ICU) were recorded.

Statistical analysis

SPSS ver. 19.0 was used for statistical analysis. Measurement data were expressed as mean ± SD. Enumeration data were expressed as percentage. Comparisons between groups and within group at different time points were performed by Kruskal–Wallis test. P < 0.05 meant difference had statistical significance and P < 0.01 meant difference had significant statistical significance.

Results

General data

Differences of gender, age, weight, duration of CPB, duration of block, and duration of operation between groups had no statistical significance (P >0.05).

Volume and rate of homologous blood transfusion

Transfusion volume of homologous blood transfusion: the average transfusion volume of the condensed red blood cells of the high dose group, medium dose group, low dose group, and control group was 328.6 ± 242.9 mL, 472.0 ± 216.0 mL, 575.0 ± 195.7 mL, and 680.0 ± 204.2 mL, respectively, and the differences were statistically significant (P <0.01); the average transfusion volume of fresh frozen plasma of the four groups was 236.7 ± 103.3 mL, 297.3 ± 114.5 mL, 343.3 ± 157.7 mL, and 370.0 ± 184.3 mL, and the differences had statistical significance (P = 0.0368); condensed blood platelet was not transfused. Details are shown in Figures 1 and 2.

Figure 1.

Transfusion volume of condensed red blood cells, fresh frozen plasma, and blood platelets in the perioperative period.

Figure 2.

Transfusion rate of condensed red blood cells and fresh frozen plasma and overall transfusion rate in the perioperative period.

Homologous blood transfusion rate: the homologous blood transfusion rate of the high dose group, medium dose group, low dose group, and control group was 45.0%, 65.0%, 80.0%, and 90.0%, respectively, and the differences had statistical significance (P = 0.012); the transfusion rate of fresh frozen plasma was 30.0%, 60.0%, 65.0%, and 75.0%, respectively, and the differences were statistically significant (P = 0.04).

Overall blood transfusion rate: the overall blood transfusion rate of the four groups was 55%, 75%, 90%, and 95%, respectively, and there were significant differences (P = 0.009).

Comparison of blood indexes and coagulation function between the tranexamic acid group and non-tranexamic acid group after surgery

The ACT of the tranexamic acid group and non-tranexamic acid group was both within the normal scope before CPB; the ACT of the two groups had an obvious increase during CPB compared to the ACT before CPB (P <0.05), but the difference of the ACT before and after CPB had no statistical significance (P >0.05); the difference of the ACT between groups had no statistical significance before, during, and after CPB (P >0.05) (Table 1).

Table 1.

Comparison of ACT between two groups.

Group	ACT (ms)
	Before CPB	During CPB	After CPB
Tranexamic acid group	148.22 ± 21.12	690.98 ± 126.23	150.90 ± 19.01
Non-tranexamic acid group	153.12 ± 21.98	738.12 ± 128.24	156.03 ± 22.09

Four coagulation indexes including PT, APTT, INR, and FIB had significant increase after surgery (P <0.05); PT and INR of tranexamic acid group had a significant decline after surgery (P <0.01).

Comparison of amount of thoracic cavity drainage and transfusion of blood products

It was found that the drainage volume of pericardium and mediastinum of the tranexamic acid group was obviously less than that of the non-tranexamic acid group within 12 h after surgery (P <0.05); the transfusion rate of red blood cells suspension (26.7%) and the transfusion rate of frozen plasma (45%) of the tranexamic acid group were lower than those of the non-tranexamic acid group (26.6% versus 73.3%; 45% versus 85%) (P <0.01).

Comparison of blood loss within 24 h after surgery, volume of blood transfusion during surgery and within 24 h after surgery, and incidence of reoperation induced by bleeding between two groups

The blood loss of the tranexamic acid group and non-tranexamic acid group was 522.8 ± 233.1 mL and 814.1 ± 245.1 mL, respectively, within 24 h after surgery (P <0.05); the transfusion volume of plasma of the tranexamic acid group and non-tranexamic acid group was 277.1 ± 96.8 mL and 576.5 ± 166.8 mL, respectively, during surgery and within 24 h after surgery (P <0.05); the transfusion volume of red blood cells was 4.93 ± 1.18 U and 8.52 ± 2.81 U, respectively, during surgery and within 24 h after surgery (P <0.05); the transfusion volume of blood platelets was 2.28 ± 0.82 U and 3.71 ± 1.16 U, respectively, during surgery and within 24 h after surgery (P <0.05); the incidence of reoperation induced by bleeding of the tranexamic acid group and non-tranexamic acid group was 3.25% and 6.44%, respectively (P <0.05) (Table 2).

Table 2.

Comparison of blood loss within 24 h after surgery, transfusion volume of blood during surgery and within 24 hours after surgery, and incidence of reoperation induced by bleeding between two groups.

	Tranexamic acid group	Non-tranexamic acid group	P value
Blood loss (mL)	522.8 ± 233.1	814.1 ± 245.1	0.02
Condensed red blood cells (U)	4.93 ± 1.18	8.52 ± 2.81	0.03
Plasma (mL)	277.1 ± 96.8	576.5 ± 166.8	0.02
Blood platelets (U)	2.28 ± 0.82	3.71 ± 1.16	0.04
Incidence of reoperation induced by bleeding	3.25	6.44	0.02

Discussion

For heart surgery performed under CPB, massive bleeding induced by surgical factors, such as operation wound, and non-surgical factors, such as non-physiological perfusion, is a severe problem that may threaten the lives of patients. The weakening of functions of fibrinolytic system, the decline of count of blood platelets, and the abnormity of coagulation function induced by non-physiological perfusion of CPB, operation wound, and temperature changes during CPB and after heart and lung circulation are the major causes for massive bleeding.

Tranexamic acid, one kind of synthesized anti-fibrinolytic drugs,¹⁴ has a chemical structure similar to lysine; it can restrain the combination of plasmin with fibrous protein or fibrinogen as well as the decomposition of fibrous protein and stop bleeding by protecting adenosine diphosphate (ADP) and reducing damages on blood platelet. However, tranexamic acid may induce complications such as thrombosis or bring outcomes that are similar to outcomes brought by aprotinin, as tranexamic acid as an elastase inhibitor can occupy the adhesion site of blood platelet receptor which ought to be combined with plasmase.¹⁵ Currently, the Food and Drug Administration (FDA) of the United States has not approved the application of tranexamic acid in heart surgery and, moreover, the safety of tranexamic acid has not been confirmed authoritatively. We regret not having done definite research in that respect. The application of tranexamic acid in heart surgery under CPB has been proved and recognized by some researches and clinical workers. However, the dose and usage of tranexamic acid in heart surgery under CPB is still unclear.

This work is a case-control study which analyzed the effects of tranexamic acid on clinical indexes and found that tranexamic acid was effective in stopping bleeding and protecting blood. But limited by some factors, the experimental results and analysis have deficiencies. Improvements in future experiments need to be made.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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