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 Table of Contents  
RESEARCH ARTICLE
Year : 2019  |  Volume : 4  |  Issue : 1  |  Page : 17-23

Effects of intravenous tranexamic acid on bleeding during and after pelvic fracture surgery: protocol for a prospective, randomized, parallel-controlled trial


Department of Orthopedics, The General Hospital of Western Theater Command, Chengdu, Sichuan Province, China

Date of Submission13-Oct-2018
Date of Acceptance11-Nov-2018
Date of Web Publication13-Mar-2019

Correspondence Address:
Wei Zheng
Department of Orthopedics, The General Hospital of Western Theater Command, Chengdu, Sichuan Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-4157.253725

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  Abstract 

Background and objectives: Numerous studies have shown that tranexamic acid effectively reduces the amount of bleeding and drainage, and reduces the blood transfusion rate during and after various operations. The present study aims to investigate whether tranexamic acid effectively reduces the amount of bleeding during and after pelvic fracture surgery.
Subjects and methods: This prospective, single-center, randomized, parallel-controlled trial includes 70 patients with pelvic fracture who received treatment from April 2015 to January 2017 at the Department of Orthopedics, General Hospital of Western Theater Command, China. These patients were randomly divided into a tranexamic acid group and a control group. Fifteen minutes prior to the skin incision, the tranexamic acid and control groups respectively received an intravenous infusion of 100 mL normal saline alone or with 10 mg/kg tranexamic acid. Patients were followed up at postoperative 1, 3, and 5 days. This study was approved by the Ethics Committee of the General Hospital of Western Theater Command on February 16, 2015 (approval No. 2015-keyan-04). All patients provided written informed consent for study inclusion. Data collection: April 1, 2015 to January 30, 2017; study completed: March 31, 2017; study status: completed with data analysis ongoing.
Outcome measures: The primary outcome measure is intraoperative blood loss, as a measure of intraoperative hemostasis. The secondary outcome measures are intraoperative blood transfusion, drainage volume at postoperative 1, 3, and 5 days, and hemoglobin level, D-dimer level, international normalized ratio, prothrombin time, and activated partial thromboplastin time preoperatively and at postoperative 1, 3, and 5 days.
Discussion: This study will provide evidence to validate whether intravenous tranexamic acid administered 15 minutes prior to pelvic fracture surgery reduces intra- and postoperative bleeding.
Trial registration: This study protocol was registered with Chinese Clinical Trial Registry (registration number: ChiCTR-ICC-15006070) on March 13, 2015.

Keywords: tranexamic acid; pelvic fracture surgery; intravenous administration; intraoperative bleeding; postoperative drainage; D-dimer; hemoglobin; randomized controlled trial


How to cite this article:
Sheng J, Liao DF, Liu D, Chen Y, Jiang K, Zheng W. Effects of intravenous tranexamic acid on bleeding during and after pelvic fracture surgery: protocol for a prospective, randomized, parallel-controlled trial. Clin Trials Orthop Disord 2019;4:17-23

How to cite this URL:
Sheng J, Liao DF, Liu D, Chen Y, Jiang K, Zheng W. Effects of intravenous tranexamic acid on bleeding during and after pelvic fracture surgery: protocol for a prospective, randomized, parallel-controlled trial. Clin Trials Orthop Disord [serial online] 2019 [cited 2019 Mar 19];4:17-23. Available from: http://www.clinicalto.com/text.asp?2019/4/1/17/253725


  Introduction Top


Research background

There is extensive bleeding during and after pelvic trauma surgery because of the complex anatomy of the pelvis, difficulty in exposure, and rich blood supply to the pelvis.[1],[2],[3],[4],[5],[6] When the local coagulation system is activated to form a thrombus to stop bleeding, it also activates the fibrinolytic system, which dissolves the local unstable thrombus, thereby leading to continuous bleeding.[7],[8] Massive bleeding in pelvic trauma has a large negative effect on the patient's prognosis.[9],[10],[11],[12]

Tranexamic acid is an antifibrinolytic drug that is mainly used to stop various types of bleeding caused by acute or chronic, localized or systemic fibrinolysis.[13],[14],[15],[16],[17] Tranexamic acid strongly binds to the lysine binding site of the fibrin affinity site on plasmin and plasminogen, inhibiting the binding of plasmin and plasminogen to fibrin, and thereby strongly inhibiting fibrin breakdown caused by plasmin.[18],[19] Tranexamic acid has been widely used in perioperative hemostasis in the fields of cardiac surgery, obstetrics and gynecology, and joint surgery.[20],[21],[22] There is strong evidence that tranexamic acid effectively reduces the amount of bleeding and drainage, and lowers the blood transfusion rate during and after various operations.[23],[24]

A search of the PubMed database for articles published during 2011–2013 using the search terms “tranexamic acid AND fracture” identified three randomized controlled trials that used tranexamic acid for hemostasis in fracture surgery [Table 1].[25],[26],[27]
Table 1: Three randomized controlled trials regarding use of tranexamic acid for hemostasis in fracture surgery

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However, most of these previous studies focused on the hemostatic effects of tranexamic acid in hip replacement or hip fracture. The present study is the first to investigate the effects of intravenous tranexamic acid on hemostasis during and after pelvic fracture surgery.

Study objective

This prospective, single-center, randomized, parallel, controlled trial aims to investigate the effects of intravenous tranexamic acid administered 15 minutes before surgery on hemostasis during and after pelvic fracture surgery.


  Subjects and Methods Top


Study population

Patient recruitment was performed by advertising the study on the bulletin board of the General Hospital of Western Theater Command, China, and among patients in the wards. Patients interested in participating were asked to contact the principle investigator via telephone, and those who met the eligibility criteria were enrolled after providing written informed consent. The costs of medical treatment, examination, and surgery related to this trial were borne by the patients. The costs of the test drug (tranexamic acid) and any additional medical expenses (such as the costs associated with adverse reactions) were borne by the research funds of the General Hospital of Western Theater Command.

Eligibility criteria

Inclusion criteria agreed by experts participating in this study

- Patients who were scheduled to undergo closed surgery for traumatic pelvic fracture within 2 weeks comprising open reduction and internal fixation with a steel plate and screws

- Normal coagulation function

- No deep vein thrombosis in the lower extremities detected via vascular ultrasonography

- Age 18–70 years, of either sex

- Provision of written informed consent

Exclusion criteria agreed by experts participating in this study

- Allergy to tranexamic acid

- Hemoglobin level < 90 g/L for women, and < 100 g/L for men

- Platelet count < 150, 000 mm3

- Coagulation dysfunction before surgery

- Receiving antiplatelet or anticoagulant therapy

- History of thromboembolism

- Hypercoagulable state

- Renal insufficiency

- Hepatic insufficiency

Withdrawal criteria agreed by experts participating in this study

- Uncontrolled bleeding during surgery

- Refusal to continue treatment

- Severe adverse events

- Poor compliance

- Upon the request of the physician for safety reasons

Interventions

Drug assignment and preservation

Injectable tranexamic acid (Cyklokapron), 1000 mg/ampoule, lot number: DK405004-1, was provided by Zhejiang Jinhua Conba Bio-Pharm Co., Ltd., China. Tranexamic acid was preserved in a dry specially designated cabinet at room temperature by a person not participating in the trial. This person provided the tranexamic acid in accordance with the grouping as per the study protocol. After drug administration, the remaining drug and empty ampoules were recovered, and relevant registration was performed.

Drug administration

At 15 minutes prior to the creation of a skin incision, the control and tranexamic acid groups received an intravenous infusion of either 100 mL of normal saline alone or 100 mL of normal saline containing 10 mg/kg tranexamic acid, respectively.

Anesthesia

Routine general anesthesia is performed.

Pelvic fracture surgery

All patients underwent surgical treatment under routine general anesthesia. Briefly, after open reduction, internal fixation was performed with a steel plate and screws. Postoperative routine anti-infective drug treatment was performed. All surgical operations were performed by the same team of surgeons.

Study flow chart is shown in [Figure 1].
Figure 1: Study flow chart

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Outcome measures

Primary outcome measure

The primary outcome measure will be intraoperative blood loss, as a measure of intraoperative hemostasis. This was assessed by nurses unrelated to this study. The amount of intraoperative blood loss was calculated as the amount of blood in the bandage material + the amount of blood loss in the aspirator collector – the amount of flush fluid used.

Secondary outcome measures

- Total intraoperative blood transfusion volume.

- Amount of drainage at postoperative 1, 3, and 5 days calculated as the total amount in the drainage bag after surgery and before removal of the drainage tube.

- Hemoglobin level before surgery and at postoperative 1, 3, and 5 days. The hemoglobin level was measured using an automatic blood cell analyzer (Model XE2100; Shenzhen Mindray Bio-Medical Electronics Co. Ltd., Shenzhen, China). Total hemoglobin reduction was calculated as estimated whole blood volume × (preoperative hemoglobin level – hemoglobin level at postoperative 5 days) × 10 + volume of transfused hemoglobin.

- D-dimer level before surgery and at postoperative 1, 3, and 5 days. The D-dimer level was measured using an automatic blood cell analyzer (Model CA-7000; Sysmex Co., Kobe, Japan). The D-dimer level mainly reflects fibrinolytic function. Normal D-dimer levels are < 200 μg/L.

- International normalized ratio (INR) before surgery and at postoperative 1, 3, and 5 days. Prothrombin time was measured using an automatic blood cell analyzer (Sysmex Co.). INR was calculated based on the prothrombin time and the international sensitivity index of the measured reagent. A higher INR indicates a longer prothrombin time.

- Prothrombin time before surgery and at postoperative 1, 3, and 5 days. Prothrombin time refers to the time required for prothrombin to be converted to thrombin after the addition of excess tissue factor in plasma lacking platelets, resulting in plasma coagulation. Prothrombin time is used to determine coagulopathy.

- Activated partial thromboplastin time before surgery and at postoperative 1, 3, and 5 days. Activated partial thromboplastin time is used to determine coagulopathy, and was measured using an automatic blood cell analyzer (Model CA-7000; Sysmex). The normal activated partial thromboplastin time ranges are 31.5–43.5 seconds for men and 32–43 seconds for women.

Schedule for primary and secondary outcome measures is shown in [Table 2].
Table 2: Timing for primary and secondary outcome measures

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Sample size calculation

In accordance with our clinical experience, we hypothesized that tranexamic acid reduces hemoglobin loss by over 40% (approximately 60 g of blood) in patients undergoing pelvic fracture surgery.[28],[29] Assuming a two-sided α of 0.05, and a β of 0.2, a final effective sample size of n = 35 per group was calculated using PASS 11.0 software (PASS, Kaysville, UT, USA).

Grouping

A random number table was used for patient grouping. Seventy patients were each randomly assigned a number from 1–70. The 70 numbers were inputted into a random number table. Sample numbers were then randomly selected from the random number table. According to the random number table, the 70 patients were randomly divided into a tranexamic acid group and a control group, with 35 patients per group. Allocation concealment was not used.

Blinding

Double blinding was not used in this study. However, nurses not related to the trial completed the drug assignment in ac-cordance with the grouping, while the investigators participating in this trial were blinded to the drug assignment. Furthermore, the medical personnel who tested the outcome indicators were unaware of the study protocol.

Ethical approval

This study was approved by the Medical Ethics Committee of the General Hospital of Western Theater Command, China, before the start of the clinical trial (approval No. 2015-keyan-04) (Additional file 1[Additional file 1]). This manuscript was prepared in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (Additional file 2[Additional file 2]). This study was performed in strict accordance with the Declaration of Helsinki (2002) and applicable regulations and laws.

Informed consent

All patients volunteered to participate in this study, and provided written informed consent (Additional file 3[Additional file 3]).

The clinical trial protocol was performed based on the principle of protecting the rights, safety, and health of the subjects as much as possible. Investigators made it clear to the patients that participation in the clinical trial is voluntary, patients have the right to withdraw from the trial at any time without discrimination or retaliation, and that withdrawal from trial does not affect their medical treatment and rights. Patients were made aware that the personal data involved in participation in the trial are confidential, and the ethics committee, food and drug administration, and implementer may consult the patient's information, but they may not disclose the content. Patients were informed of the nature and purpose of the trial, and of the expected benefits and the risks and inconveniences that may occur, so that they fully understood the clinical trial and had sufficient time to consider whether they were willing to participate. During the study, clinical investigators will answer patients' questions and listen to their opinions.

Statistical analysis

Data description

All data will be statistically analyzed using SPSS 22.0 software (IBM, Armonk, NY, USA). The number of patients completing the trial, and the number of dropouts will be analyzed. Demographics and baseline data in the tranexamic acid and control groups will be analyzed to evaluate the comparability of the two groups. Measurement data will be expressed as means with standard deviation values, or as medians with minimum and maximum values, and upper and lower quartiles. Count data will be expressed as number of cases and percentages.

Statistical methods

The intraoperative blood loss, intraoperative blood transfusion volume, postoperative drainage volume, hemoglobin level, D-dimer level, INR, prothrombin time, and activated partial thromboplastin time will be compared between the tranexamic acid and control groups at each timepoint using the two-sample t-test (for normally distributed data) or the Mann-Whitney U test (for non-normally distributed data). Repeated measures analysis of variance and the least significant difference test will be used to compare the abovementioned parameters at each timepoint within the same group. Correlations between the parameters within each group will be assessed using Pearson's correlation coefficient (for normally distributed data) or Spearman's correlation coefficient (for non-normally distributed data). An inspection level of α = 0.05 (two-tailed) will be considered to indicate a significant difference.

Data sets

The included patients consists of the entire population assigned to the per-protocol set; patients that completed the treatment interview and did not have any protocol violations that obviously affected the efficacy will be included.

Adverse events and complications

Patients underwent vital sign monitoring and laboratory examination. After surgery, patients received routine electrocardio-graphic monitoring and continuous blood oxygen saturation monitoring. Blood pressure, respiration, and heart rate were regularly recorded.

Adverse events refer to any adverse reactions that occur during the trial. Any adverse events, including laboratory abnormalities, will be carefully investigated and monitored. All adverse reactions were categorized in accordance with their nature, severity, and drug relevance, and were truthfully recorded in the case report form.

Any adverse event that meets one or more of the following conditions will be considered a severe adverse event: (1) death or a life-threatening event; (2) hospitalization or prolonged hospitalization; (3) disability, comprising complete or partial loss of viability. Any severe adverse event will be reported to the implementer, principle investigator, and hospital ethics committee within 24 hours.

Possible drug-related adverse reactions include intracranial thrombosis, hemorrhage, diarrhea, nausea, and vomiting. Some central nervous system symptoms, such as blurred vision, headache, dizziness, and fatigue may occur after the injection of tranexamic acid, as this drug can enter the cerebrospinal fluid. If this occurs, the drug will be withdrawn immediately, and symptomatic treatment will be promptly performed.


  Discussion Top


Study limitations

The experimental conditions mean that it is not possible to perform double-blinded evaluation and allocation concealment, which may influence the accuracy of the results.

Treatment promotability

This study aims to provide evidence to validate the hypothesis that the administration of intravenous tranexamic acid 15 minutes prior to pelvic fracture surgery can effectively reduce intra- and postoperative bleeding, and thus reduce intra- and postoperative problems related to blood loss.

Interpretation

There is extensive bleeding during and after pelvic trauma surgery, which negatively affects the prognosis. Cumulative evidence suggests that tranexamic acid effectively reduces the bleeding and drainage volumes during and after surgery.[30],[31],[32],[33],[34] However, no study has reported the use of tranexamic acid in a clinical trial involving patients undergoing surgery for traumatic pelvic fracture. In this prospective, randomized, parallel, controlled trial, intravenous tranexamic acid was administered 15 minutes prior to pelvic surgery to evaluate its hemostatic effects during and after surgery.

Data authenticity management

Data collection

Patients' clinical records will be collected and recorded on specially designed case report forms. All data recorded on the case report forms will be checked for accuracy, completeness, and consistency with the original records. Each case report form will be signed by the principle investigators. Any corrected mistakes or comments will be signed and dated by the principle investigators or the authorized person.

Data management

In accordance with the items in the case report form, Epi-Data 3.0 software will be used to establish the corresponding entry procedure, and the logical review qualification conditions at the time of data entry will be defined. The database will be tested to determine the final database dedicated to this trial. All data recorded on the case report form will be inputted into the database using a double-entry strategy.

Data quality control

The Independent Data Monitoring Committee is composed of experts from disciplines including medicine (with related medical experience), epidemiology, clinical imaging, clinical trial management, statistics, and ethics. Members of the Independent Data Monitoring Committee have no conflicts of interest.

Study protocol modification

During the trial, research personnel may not modify the content of the study protocol (such as the inclusion criteria, outcome indicators, and data analysis) without the permission of the investigators in charge. If the research program changes substantially, the investigators need to reacquire informed consent from each patient as to whether they are willing to continue the trial.

Monitoring

The clinical monitor must visit the trial site on a regular basis or in response to a specific situation to conduct clinical audit work. The Independent Data Monitoring Committee must report the progression of the trial to the Medical Ethics Committee every 2 months. Trial registration will be updated simultaneously.

Confidentiality

The investigators confirm and support the principle that the patients have the right to protect their privacy from infringement. At all stages of the study, patient data will be identified only by the patient identifier and initials, and patient's personal information will be strictly confidential.

Competing interest statement

There are no conflicts of interest declared.

Data sharing statement and result dissemination

After de-identification (text, tables, figures, and appendices), the individual participant data that underlie the results reported in this article are available indefinitely at www.figshare.com following publication with no end date. The results are disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.

Date of registration: March 13, 2015.

Data collection: April 1, 2015 to January 30, 2017.

Study completed: March 31, 2017.

Trial status: Data analysis is ongoing.

Additional files

Additional file 1: Hospital Ethics Approval (Chinese).

Additional file 2: SPIRIT Checklist.

Additional file 3: Informed Consent Form (Chinese).

Author contributions

Study design, protocol authorization, and manuscript writing: JS; patient recruitment: DFL; data collection; YC, KJ; data analysis: DL, WZ. All authors approved the final version of this manuscript.

Conflicts of interest

All authors declare that they have not received relevant financial support and that there are no conflicts of interest.

Financial support

None.

Institutional review board statement

The study was approved by the Medical Ethics Committee, General Hospital of Western Theater Command of China (approval No. 2015-keyan-04) on February 16, 2015.

Declaration of patient consent

The authors certify that they had obtained all appropriate patient consent forms. In the form the patients had given their consent for patients' images and other clinical information to be reported in the journal. The patients understood that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This manuscript was prepared according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of the General Hospital of Western Theater Command of China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Data will be available immediately following publication, with no end date. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

C-Editor: Zhao M; S-Editors: Wang J, Li CH; L-Editor: Song LP; T-Editor: Jia Y



 
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