Efficacy and safety of intravenous tranexamic acid in microscopic modified radical mastoidectomy: a study protocol for a prospective, randomised, double-blind controlled trial


  • This will be the first RCT to evaluate the safety and efficacy of intravenous tranexamic acid (TXA) on the improvement of the clarity of the surgical field of microscopic modified radical mastoidectomy.

  • The Modena Bleeding Score used in our study has been demonstrated to be an effective method to rate the surgical field during endoscopic ear surgery, with good-to-excellent performances.

  • The 90-day follow-up time may be sufficient in fully assessing the risk of adverse events for TXA in our trial.

  • Controlled intraoperative hypotension will be used in all patients in our study, which may have underestimated the effectiveness of TXA.


Modified radical mastoidectomy is the primary treatment method for suppurative otitis media.1 2 The main objective is to remove the lesion, achieve a dry ear and preserve or reconstruct hearing.3 This surgical procedure involves limited operating space and numerous important anatomical structures,4 which is typically conducted under a microscope, maintaining a clear surgical field of view is crucial, as a blurred field may lead to several issues, including difficulty in identifying anatomical landmarks, longer operative time and increased risk of surgical complications.5 Surgeons and anaesthesiologists are committed to exploring methods that can effectively reduce surgical bleeding and improve the clarity of the surgical field.6 The most commonly used techniques are the local administration of topical vasoconstrictors,7 controlled hypotension8 and using a head-up position.9 Combined, these factors threaten haemodynamic stability and may result in severe consequences for elderly patients with cardiovascular and cerebrovascular disease.10

Tranexamic acid (TXA), also known as trans-4-aminomethyl-cyclohexanecarboxylic acid, is a synthetic compound derived from lysine.11 In recent years, scholars have conducted numerous studies on the haemostatic effects of TXA in various surgeries with high bleeding, such as cardiac surgery, major orthopaedic surgery and traumatic bleeding.12–14 These studies have confirmed the feasibility and tolerability of using TXA.15 Furthermore, TXA has been found to possess anti-inflammatory properties.16 However, there is a lack of studies investigating the additional hemostatic effects of TXA in procedures with lower levels of bleeding. We hypothesise that intravenous administration of TXA during microscopic modified radical mastoidectomy may reduce bleeding and improve the clarity of the surgical field without increasing the incidence of adverse events. To verify our hypothesis, we designed the following randomised controlled trial.

Methods and analysis

Our protocol followed the principles of Standard Protocol Items: Recommendations for Interventional Trials17 and has been approved by the Ethics Committee of Peking University People’s Hospital (2021PHB173-001). The planned start and end dates for the study are December 2021 and December 2024, respectively. All trial procedures are summarised in table 1.

Table 1

The schedule of trial enrolment, allocation and assessments

Study design

This is a randomised, double-blind, controlled trial to investigate whether TXA can safely improve surgical vision in microscopic modified radical mastectomy. Subjects who will undergo modified radical mastectomy for otitis media will be recruited from Peking University People’s Hospital from 2021 to 2023. This study was approved by the Ethics Committee of Peking University People’s Hospital (2021PHB173-001) and has been registered in the research register (ChiCTR2100049183). Preoperative interviews were conducted by specially trained anaesthesiologists designed to inform patients about the purpose of the study and the possible risks and benefits. Participants or their legal representatives make a written consent statement. The flow chart of the study is shown in figure 1.

Figure 1
Figure 1

The flow chart of the study. TXA, tranexamic acid.


Inclusion criteria

  1. Aged 18–65 years, male or female.

  2. Patients suffering from chronic otitis media, for whom conservative drug treatment has proven ineffective will undergo microscopic modified radical mastoidectomy.

  3. Patients with American Society of Anaesthesiologists physical status I–II.

Exclusion criteria

  1. Allergic to TXA or local anaesthetics.

  2. Lack of patient consent.

  3. Coagulation dysfunction (coagulation parameters such as activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, D-dimer are out of the normal range).

  4. Systematic thromboembolisms (deep vein thrombosis, pulmonary embolism, myocardial infarction, etc).

  5. Taking anticoagulant or antiplatelet drugs (aspirin, clopidogrel, warfarin, etc) within 2 weeks before surgery.

  6. Hypertension (systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure≥90 mm Hg).

  7. Severe liver and kidney disease (the liver and kidney function were decompensated).

  8. History of epilepsy (including epilepsy caused by various causes).

  9. Any additional surgical procedures to be undergone concurrently.

Elimination criteria

After the patient was enrolled, participants may not be fit or able to continue to complete the trial for some reason, if any of the following elimination criteria were met during the study period, further intervention will be discontinued and the patient will be excluded from the study. In clinical practice, it is possible to temporarily change surgeons for reasons unrelated to medical difficulty. Additionally, variations in a patient’s response to anaesthesia drugs during surgery can cause significant fluctuations in blood pressure, potentially leading to increased bleeding in the surgical area and affecting the observation results. Therefore, these elimination criteria are postrandomisation exclusions and will not bias the effect size calculation and outcomes.

  1. Patients who will undergo severe intraoperative haemodynamic fluctuations requiring repeated use of vasopressors.

  2. The surgeon will change during the operation.

  3. Patients who will drop out of the study.

Sample size calculation

In the preliminary pilot study, a total of 20 subjects were included, with an equal ratio of 1:1 between the TXA and control groups. All standard modified radical mastectomy were performed by the same team of surgeons and anaesthesiologists. All patients underwent total intravenous anaesthesia. The mean arterial pressure (MAP) ranged from 65 to 75 mm Hg, and the end-expiratory carbon dioxide partial pressure ranged from 35 to 40 mm Hg during the surgery. Following the procedure, a researcher, unaware of the participant allocation and the surgical anaesthesia process, evaluated the clarity of the operating field based on the Modena Bleeding Score (MBS) criteria by watching the operation video. Other details in the experiment are consistent with the study protocol. The primary outcome of the MBS (table 2) for the TXA group and control group were 2.5±0.71 and 3±0.47, respectively. To ensure 80% power at a significance level of 0.05, accounting for a potential drop-out rate of 15%, a total of 56 patients were required for the trial. Sample size calculation was performed using PASS V.11 software.

Table 2

The Modena Bleeding Score

Randomisation and blinding

In this study, a total of 56 patients will be randomly assigned to receive either TXA or normal saline (figure 1). Randomisation will be performed using a computer-generated randomisation checklist. Subsequently, an independent third person prepared an opaque, sealed envelope containing information about the participant’s group assignment. Pharmacy staff will prepare blinded medications for each subject, which are identified by a unique digital identifier, have an identical appearance and are blinded to the subject, surgeon, anaesthesiologist and data collector/analyst.


No premedication will be given. On arrival in the operating room, standard monitors including non-invasive blood pressure, ECG, pulse oxygen saturation and bispectral index (BIS) will be established and baseline will be recorded. Anaesthesia will be induced with intravenous injection of propofol 1.5–2.5 mg/kg, sufentanil 0.3–0.4 µg/kg and rocuronium 0.6 mg/kg. After tracheal intubation, anaesthesia will be maintained with propofol 4–12 mg/kg/hour, remifentanil 0.1–0.2 µg/kg/min to maintain a BIS value of 40 and 60 and the MAP 65–75 mm Hg. Controlled mechanical ventilation will be performed with an initial tidal volume of 6–8 mL/kg, respiratory rate 12–15/min to maintain an end-tidal carbon dioxide partial pressure of 35–40 mm Hg. Before induction of anaesthesia, both the TXA group and the control group will be administered 1 g of TXA diluted in 20 mL of normal saline and an equal volume of normal saline. All anaesthetics will be discontinued 10 min before the procedure ends, the neuromuscular block was reversed with neostigmine 1 mg and atropine 0.5 mg. After confirming adequate spontaneous breathing, the endotracheal tube will be extubated. Perioperative haemodynamic instability such as bradycardia (heart rate <50 beats/min) and hypotension (SBP <80 mm Hg) will be corrected with ephedrine 6 mg. In addition, tropisetron 5 mg will be given at the end of the procedure to prevent nausea and vomiting.


The patient will be positioned supine with the head tilted towards the healthy side and the head of the bed elevated by 10 degrees. Initially, 10 mL of 1% lidocaine will be combined with epinephrine to create a concentration of 1:100 000 epinephrine for local infiltration, followed by a preauricular or retroauricular incision to expose the surface of the mastoid bone. The posterior superior spine of the external auditory canal is identified and the mastoid, tympanic sinus, and tympanic chamber are opened through the mastoid pathway with microscopic assistance. Standard modified radical mastectomy will be performed by the same team of experienced surgeons.


Before induction of anaesthesia, patients in the TXA group receive 1 g of TXA diluted in 20 mL of 0.9% normal saline and patients in the control group receive 20 mL of 0.9% normal saline. The chief anaesthesiologist, blinded to the group assignment, will administer the product to be examined.

Study objectives

The objective of this study is to determine whether intravenous TXA can effectively and safely improve surgical field clarity in microscopic modified mastoid radical surgery. The primary and secondary outcomes will be assessed by proficient clinical researchers.

Outcome measures

Primary outcome measures

In this study, the surgical procedure will be performed under a microscope and the entire procedure will be videotaped. After the procedure, the video will be viewed by an independent investigator not involved in the surgical anaesthesia process and the clarity of the surgical field will be evaluated based on the MBS.18

The MBS is an effective method to estimate the quality of the surgical field in relation to bleeding during the endoscopic ear surgery. It is composed of five different levels (from ‘grade 1—no bleeding’ to ‘grade 5—bleeding that prevents every surgical procedure except those dedicated to bleeding control’) (table 2).

Secondary outcome measures

At the end of the surgery, the surgeon will rate the satisfaction with the surgical conditions using the 0 (worst) to 10 (best) Numeric Rating Scale. In addition, time of surgery, laboratory measurements (PT, APTT, FDP, D-dimer, IL-6) at 24 hours postoperatively, general adverse events including nausea, vomiting, and dizziness, and serious adverse events such as arterial and venous thromboembolism, myocardial infarction and seizures will be recorded to assess the safety of intravenous TXA administration in this study.


To determine the risk of serious complications, such as arterial thromboembolism, pulmonary embolism, deep vein thromboembolism, myocardial infarction and seizures, an independent investigator followed the patients by telephone after 90 days. Considering that previous studies have shown a very low incidence of such complications, patients will not be routinely imaged and will be evaluated and documented only based on their self-reported relevant signs.

Reporting of adverse events

All general or serious adverse events associated with the trial will be recorded and closely monitored, and their relevance to this study will be assessed by the principal investigator and promptly addressed. In addition, all serious adverse events associated with this study will be recorded and reported to the ethics committee within 24 hours, and the principal investigator, ethics committee and all participants in the study will be unblinded.

Trial end

This trial will be completed after the final follow-up assessment data are collected for the last patient enrolled.

Data collection and statistical analysis

CRF data will be input into the computer and checked periodically by two researchers blinded to the study. After data collection, statistical analysis will be performed using SPSS V.22.0 software (IBM). Continuous variables will be expressed as mean±SD, and categorical or discrete variables as frequencies (percentages). A t-test or Mann-Whitney U test will be used for continuous variables and a χ2 test or Fisher’s exact test will be used for categorical variables. Repeated measures data will be analysed using repeated measures analysis of variance.

Ethics and dissemination

Ethical approval for this study was obtained from the Ethics Committee of the Peking University People’s Hospital (ethical approval number: 2021PHB173-001). Permission will be obtained from them for the collection and use of patient data. The results of the trial will be submitted to a peer-reviewed journal for publication.


This study presents the first randomised, double-blind, controlled trial to evaluate the effectiveness and safety of intravenous administration of TXA in improving the clarity of the surgical field during microscopic modified radical mastectomy. The measurement of blood loss during surgery is an objective quantitative assessment. However, it is important to note that rinsing fluid, for example, can interfere with the accuracy of the results.19 In addition, it is important to note that this method only provides information about the total blood loss at the end of the procedure and does not take into account any bleeding that may occur during the procedure.20 Moreover, surgeons consider surgical field quality and good visualisation to be crucial factors. In our study, we used the clarity of the operative field as the primary outcome, which was measured using a subjective scale called MBS. This scale allows for a dynamic assessment of bleeding during surgery and has been proven to be an effective method for rating the surgical field during ear surgeries. Additionally, the MBS scale is easily understandable and has demonstrated good-to-excellent reliability among both individual raters and different raters.18 So far, no clinically significant differences in MBS scores have been recognised in previous studies. In our preliminary experiment, the scores of the two groups were 2.5±0.71 and 3±0.47, respectively. Through statistical analysis of surgeons’ satisfaction with the surgical field of view and operation time, we found that the use of TXA could significantly increase surgeons’ satisfaction with the surgical field of view and significantly shorten the operation time, both of which were statistically significant. Based on these findings, we posit that a 0.5 point difference in MBS scores holds clinical significance.

The role of TXA as an antifibrinolytic agent in reducing the incidence of perioperative bleeding and transfusion in trauma, cardiac surgery, organ transplantation and neurosurgery has been well confirmed in numerous studies.21–23 The effect of perioperative blood conservation is remarkable. In recent years, many studies in otorhinolaryngology-head and neck surgery have also shown that perioperative application of TXA reduces intraoperative bleeding in nasal surgery, improves the quality of the operative field and helps to reduce postoperative oedema and petechiae in the nose.24 Considering the potential risks of risk of promoting thrombosis due to the antifibrinolytic properties of TXA,25 our study compared postoperative coagulation-related indicators between the two groups of patients and conducted a 90-day follow-up after surgery. During this period, we will carefully examine the patients’ diagnosis for any indications of the aforementioned serious adverse events such as arteriovenous thromboembolism, myocardial infarction and epilepsy. Accordingly, we suggest that our study has a certain potential to assess the safety of TXA administration.

Previous studies have shown that an intravenous administration of 1 g TXA can maintain an effective exerting antifibrinolytic effect in vivo at a blood concentration of more than 5–10 ug/mL for more than 3 hours.26 27 Considering the low intraoperative bleeding observed in our study, we chose a single intravenous administration of 1 g TXA as the dose for our study. In addition, we aimed to assess whether the use of TXA could improve surgeon satisfaction with surgical conditions and shorten the operative time. If our findings are confirmed, this study will provide a novel perspective on improving the clarity of the surgical field during microscopic modified radical mastectomy, which may have some economic benefits.

Ethics statements

Patient consent for publication

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