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

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

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

Population

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.

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.

Anaesthesia

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.

Surgery

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.

Interventions

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

Follow-up

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.