Abstract
Background
Chronic rhinosinusitis, with or without nasal polyps, can have a major impact on a person's quality of life. Treatment is usually conservative and may include nasal saline, intranasal corticosteroids, antibiotics or systemic corticosteroids. If these treatments fail endoscopic sinus surgery can be considered. During surgery, visibility of the surgical field is important for the identification of important anatomic landmarks and structures that contribute to safety. Impaired visualisation can lead to complications during surgery, inability to complete the operation or a longer duration of surgery. Different methods are used to decrease intraoperative bleeding, including induced hypotension, topical or systemic vasoconstrictors or total intravenous anaesthesia. Another option is tranexamic acid, an antifibrinolytic agent, which can be administered topically or intravenously.
Objectives
To assess the effects of peri‐operative tranexamic acid versus no therapy or placebo on operative parameters in patients with chronic rhinosinusitis (with or without nasal polyps) who are undergoing functional endoscopic sinus surgery (FESS).
Search methods
The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 10 February 2022.
Selection criteria
Randomised controlled trials (RCTs) comparing intravenous, oral or topical tranexamic acid with no therapy or placebo in the treatment of patients (adults and children) with chronic rhinosinusitis, with or without nasal polyps, undergoing FESS.
Data collection and analysis
We used the standard methodological procedures expected by Cochrane. Primary outcome measures were surgical field bleeding score (e.g. Wormald or Boezaart grading system), intraoperative blood loss and significant adverse effects (seizures or thromboembolism within 12 weeks of surgery). Secondary outcomes were duration of surgery, incomplete surgery, surgical complications and postoperative bleeding (placing of packing or revision surgery) in the first two weeks after surgery. We performed subgroup analyses for methods of administration, different dosages, different forms of anaesthesia, use of thromboembolic prophylaxis and children versus adults. We evaluated each included study for risk of bias and used GRADE to assess the certainty of the evidence.
Main results
We included 14 studies in the review, with a total of 942 participants. Sample sizes in the included studies ranged from 10 to 170. All but two studies included adult patients (≥ 18 years). Two studies included children. Most studies had more male patients (range 46.6% to 80%). All studies were placebo‐controlled and four studies had three treatment arms. Three studies investigated topical tranexamic acid; the other studies reported the use of intravenous tranexamic acid.
For our primary outcome, surgical field bleeding score measured with the Boezaart or Wormald grading score, we pooled data from 13 studies. The pooled result demonstrated that tranexamic acid probably reduces the surgical field bleeding score, with a standardised mean difference (SMD) of ‐0.87 (95% confidence interval (CI) ‐1.23 to ‐0.51; 13 studies, 772 participants; moderate‐certainty evidence). A SMD below ‐0.70 represents a large effect (in either direction).
Tranexamic acid may result in a slight reduction in blood loss during surgery compared to placebo with a mean difference (MD) of ‐70.32 mL (95% CI ‐92.28 to ‐48.35 mL; 12 studies, 802 participants; low‐certainty evidence).
Tranexamic acid probably has little to no effect on the development of significant adverse events (seizures or thromboembolism) within 24 hours of surgery, with no events in either group and a risk difference (RD) of 0.00 (95% CI ‐0.02 to 0.02; 8 studies, 664 participants; moderate‐certainty evidence). However, there were no studies reporting significant adverse event data with a longer duration of follow‐up.
Tranexamic acid probably results in little difference in the duration of surgery with a MD of ‐13.04 minutes (95% CI ‐19.27 to ‐6.81; 10 studies, 666 participants; moderate‐certainty evidence). Tranexamic acid probably results in little to no difference in the incidence of incomplete surgery, with no events in either group and a RD of 0.00 (95% CI ‐0.09 to 0.09; 2 studies, 58 participants; moderate‐certainty evidence) and likely results in little to no difference in surgical complications, again with no events in either group and a RD of 0.00 (95% CI ‐0.09 to 0.09; 2 studies, 58 participants; moderate‐certainty evidence), although these numbers are too small to draw robust conclusions. Tranexamic acid may result in little to no difference in the likelihood of postoperative bleeding (placement of packing or revision surgery within three days of surgery) (RD ‐0.01, 95% CI ‐0.04 to 0.02; 6 studies, 404 participants; low‐certainty evidence). There were no studies with longer follow‐up.
Authors' conclusions
There is moderate‐certainty evidence to support the beneficial value of topical or intravenous tranexamic acid during endoscopic sinus surgery with respect to surgical field bleeding score. Low‐ to moderate‐certainty evidence suggests a slight decrease in total blood loss during surgery and duration of surgery. Whilst there is moderate‐certainty evidence that tranexamic acid does not lead to more immediate significant adverse events compared to placebo, there is no evidence regarding the risk of serious adverse events more than 24 hours after surgery. There is low‐certainty evidence that tranexamic acid may not change postoperative bleeding. There is not enough evidence available to draw robust conclusions about incomplete surgery or surgical complications.
Keywords: Adult; Child; Humans; Administration, Intranasal; Adrenal Cortex Hormones; Adrenal Cortex Hormones/therapeutic use; Hemorrhage; Nasal Polyps; Nasal Polyps/drug therapy; Tranexamic Acid; Tranexamic Acid/therapeutic use
Plain language summary
Does tranexamic acid (a medicine used to improve blood clotting) reduce bleeding during endoscopic surgery for chronic rhinosinusitis?
What is chronic rhinosinusitis?
Chronic rhinosinusitis is an inflammation of the sinuses that has lasted for at least 12 weeks. People with chronic rhinosinusitis can experience symptoms such as a blocked or runny nose, a feeling of facial pain or pressure, or a reduction or loss of the sense of smell. Some people may also have polyps in their nose, which can worsen the symptoms.
How is chronic rhinosinusitis treated?
Chronic rhinosinusitis is usually treated with medicines such as saline sprays or rinses, anti‐inflammatory sprays/drops (steroids), antibiotics or anti‐inflammatory steroid tablets. If the symptoms continue despite this treatment, surgery can be performed.
What did we want to find out?
We wanted to see if tranexamic acid, a medicine used to improve blood clotting, could be effective during endoscopic sinus surgery by reducing bleeding, which then potentially reduces the risk of complications. Less bleeding means that surgeons have a better view of the sinuses when they are operating.
What did we do?
We searched for studies that investigated tranexamic acid (either given in the vein or directly applied in the nose by sprays or drops) compared with a placebo (dummy treatment) or no tranexamic acid. We were interested in both children and adults. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 14 studies, with a total of 942 participants, which compared tranexamic acid to normal saline (placebo ‐ dummy treatment) in patients having endoscopic sinus surgery. In 10 studies the treatment was given in a vein and in three it was applied in the nose. All studies used different amounts of the drug.
We found that tranexamic acid probably greatly improves the view of the surgeon (based on 13 studies), may slightly reduce total blood loss during surgery (12 studies) and likely does not cause any serious side effects within 24 hours of surgery (i.e. blood clot formation in the brain or seizures ‐ there were no such events in either the treatment or placebo groups) (eight studies). Unfortunately, there is no evidence with respect to serious side effects at a longer duration of follow‐up.
The duration of the surgery was investigated in 10 studies. The duration of surgery is probably slightly lower with tranexamic acid.
Only two studies investigated complications related to surgery and difficulty completing the surgery as planned. In these studies no difference was seen between the tranexamic acid and placebo groups. However, because these complications are rare no conclusions can be drawn based on these studies. Nosebleeds after surgery that required intervention (placing of nasal tampons or further surgery) were investigated in six studies. Only two studies reported a patient treated with saline solution (placebo) who experienced a nosebleed after surgery. Tranexamic acid may not make a difference to the likelihood of postoperative bleeding.
Based on the evidence in the studies we cannot conclude whether tranexamic acid given either in a vein or applied in the nose is better. We also cannot conclude whether a particular dose of tranexamic acid is better.
What are the limitations of the evidence?
We are moderately confident about the evidence for the improvement of the view of the surgeon during surgery, but further research may have an impact on the estimate of the effect. We have less confidence in the evidence for lower blood loss during surgery, meaning that the true effect could be very different after more research. For the occurrence of serious side effects within 24 hours after surgery (blood clot formation in the brain or seizures) we are confident that more research would probably not change our findings.
How up‐to‐date is the evidence?
The evidence is up‐to‐date to February 2022.
Summary of findings
Summary of findings 1. Tranexamic acid versus placebo (saline solution or sterile water) for the reduction of bleeding during functional endoscopic sinus surgery.
| Tranexamic acid versus placebo (saline solution or sterile water) for the reduction of bleeding during functional endoscopic sinus surgery | ||||||
| Patient population: adults and children with chronic rhinosinusitis with or without nasal polyps Setting: secondary or tertiary care hospitals (non‐European and non‐USA hospitals) Intervention: tranexamic acid Comparison: placebo (saline solution or sterile water) | ||||||
| Outcomes | Absolute effects* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo (saline solution or sterile water) | Risk with tranexamic acid | |||||
| Surgical field bleeding score (during surgery or < 30 minutes after surgery) Assessed with: Boezaart bleeding score (range 0 to 5) or Wormald grading scale (range 0 to 10) |
— | The standardised mean difference was 0.87 points lower in the intervention group (1.23 lower to 0.51 lower) | — | 772 (13 RCTs) | ⊕⊕⊕⊝ moderate1,2 | Tranexamic acid probably results in a large reduction in the surgical field bleeding score. |
| Intraoperative blood loss Assessed as: total amount of blood loss during surgery in mL |
Mean blood loss ranged from 68 mL to 439 mL in the control group | Mean blood loss ranged from 36 mL to 405 mL Mean blood loss was 70.32 mL lower in the intervention group (92.28 lower to 48.35 lower) |
— | 802 (12 RCTs) | ⊕⊕⊝⊝ low3,4 | Tranexamic acid may result in a slight reduction in intraoperative blood loss. |
| Significant adverse events (seizures, thromboembolism) within 24 hours of surgery) | Study population | RD 0.00 (‐0.02 to 0.02) | 664 (8 RCTs) | ⊕⊕⊕⊝ moderate5 | Tranexamic acid probably has little to no effect on the development of significant adverse events within 24 hours of surgery. (No studies reported up to 12 weeks). | |
| 0 per 1000 | 0 per 1000 | |||||
| Duration of surgery (minutes) Assessed as: total surgical time |
Mean duration of surgery ranged from 66 to 158 minutes in the control group | Mean duration of surgery ranged from 45 to 126 minutes. Mean duration was 13.04 minutes lower in the intervention group (19.27 lower to 6.81 lower) | — | 666 (10 RCTs) | ⊕⊕⊕⊝ moderate6 | Tranexamic acid probably results in little difference in the duration of surgery (minutes). |
| Incomplete surgery | Study population | RD 0.0 (‐0.09 to 0.09) | 58 (2 RCTs) | ⊕⊕⊕⊝ moderate7 | Tranexamic acid probably results in little to no difference in the incidence of incomplete surgery. | |
| 0 per 1000 | 0 per 1000 | |||||
| Surgical complications | Study population | RD 0.0 (‐0.09 to 0.09) | 58 (2 RCTs) | ⊕⊕⊕⊝ moderate7 | Tranexamic acid likely results in little to no difference in surgical complications. | |
| 0 per 1000 | 0 per 1000 | |||||
| Postoperative bleeding (place of packing or revision surgery within 14 days of surgery) | Study population | RD ‐0.01 (‐0.04 to 0.02) | 404 (6 RCTs) | ⊕⊕⊝⊝ low8,9 | Tranexamic acid may result in little to no difference in the likelihood of postoperative bleeding (follow‐up 1 to 3 days after surgery). | |
| 10 per 1000 | 3 per 1000 | |||||
| CI: confidence interval; RCT: randomised controlled trial; RD: risk difference; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect | ||||||
1Considerable heterogeneity (I2 = 80%). We downgraded by one level due to inconsistency.
2Decision based on confidence interval: upper limit excludes threshold of ‐0.2 (SMD).
3Probably does not cross the meaningful clinical threshold (the authors feel that > 100 mL would be relevant). Large confidence interval. We downgraded one level due to imprecision.
4Considerable heterogeneity (I2 = 95%). We downgraded by one level due to inconsistency.
5Results available for 24 hours after surgery, not 12 weeks follow‐up. Downgraded by one level for indirectness related to the measurement of the outcome.
6Considerable heterogeneity (I2 = 81%). We downgraded by one level due to inconsistency.
7Only two studies with a very limited number of participants. Downgraded by one level due to imprecision.
8The CI for the RR did not exclude no effect (1.0). We downgraded by one level.
9Does not answer the review question properly (only one to three days of follow‐up instead of two weeks). We feel that this is a too short a follow‐up for this outcome. We downgraded by one level.
Background
Description of the condition
Chronic rhinosinusitis is a disease characterised by symptomatic inflammation of the mucosa of the nose and paranasal sinuses, which lasts longer than 12 weeks. It is a common condition and can have a major impact on patients' quality of life (Slovick 2016).
In adults chronic rhinosinusitis is defined as an inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip) and/or facial pain/pressure and/or reduction or loss of smell and either endoscopic signs of nasal polyps and/or mucopurulent discharge primarily from the middle meatus and/or relevant computerised tomography (CT) changes (Fokkens 2012; Fokkens 2020). Chronic rhinosinusitis with nasal polyps (CRSwNP) is defined by bilateral polyps in the middle meatus, which can be visualised endoscopically. In chronic rhinosinusitis without nasal polyps (CRSsNP) there are no visible polyps in the middle meatus. These definitions accept that there is a spectrum of disease that includes polypoid change in the sinuses and/or middle meatus but excludes patients with polypoid disease presenting in the nasal cavity in order to avoid overlap (Fokkens 2012; Fokkens 2020).
Chronic rhinosinusitis is commonly managed with either topical or systemic medications, which include steroids, antibiotics and saline. If these conservative measures fail functional endoscopic sinus surgery (FESS) can be considered. Among patients with chronic rhinosinusitis with nasal polyps, 57% will undergo sinus surgery and 20% of these will undergo multiple procedures (Rudmik 2015). In Canada, 10,000 to 15,000 FESS procedures are undertaken per year (Rudmik 2015). The goal of FESS is to re‐establish normal ventilation and mucus drainage from the sinuses, to resect irreversibly changed mucosa and to allow direct access for topical medications (Cornet 2012).
Visibility of the surgical field is key to the safety of the FESS procedure, which can be compromised by bleeding. Bleeding can lead to difficulty in recognising important anatomic landmarks and structures. It can increase the risk of intraoperative complications, prolong the operating time and result in incomplete surgery (Timperley 2010). The degree of surgical bleeding during FESS can be measured with Boezaart's scale and/or the Wormald scale (Athanasiadis 2008; Boezaart 1995).
Multiple methods exist to improve surgical field visibility, including induced hypotension, use of various anaesthetic and vasoconstrictive agents, and the administration of total intravenous anaesthesia (TIVA) (Hathorn 2013; Ko 2008; Wormald 2005). As the presence of polyps, active infection and fungal rhinosinusitis are known to lead to significantly higher blood loss during FESS (Ko 2008; Wormald 2005), preoperative steroids have been used to reduce the degree of bleeding (Sieskiewicz 2006). Use of a microdebrider in comparison to traditional instruments for endoscopic sinus surgery has also been studied, however despite a shorter operating time no difference in blood loss has been shown (Cornet 2012; Ko 2008).
The antifibrinolytic agent tranexamic acid is a last, often overlooked, intervention used to reduce intraoperative bleeding during FESS.
Description of the intervention
There is strong evidence that tranexamic acid reduces blood loss in surgery (Ker 2012). It can be applied both locally and intravenously and it has been used in patients with hereditary bleeding disorders and haemorrhage, to increase survival in patients with acute traumatic injury (Roberts 2013b) and to lessen menorrhagia (Naoulou 2012). In surgery, tranexamic acid is widely used systemically in cardiothoracic (Hasegawa 2014; Taghaddomi 2009), orthopaedic (Huang 2014; Wang 2015), gynaecological (Wang 2015a; Wang 2017) and urological procedures (Rannikko 2004) to reduce perioperative blood loss. Topical administration is used in orthopaedic surgery (e.g. total knee replacement) (Alshryda 2014) and spinal surgery (Panteli 2013). Tranexamic acid can also be used topically as a mouth wash following dental or oral surgery (Robb 2014).
In otorhinolaryngological practice, tranexamic acid is widely used in the treatment of epistaxis (Kamhieh 2016; Mehta 2019) and in head and neck surgery (Das 2015), including parotid surgery and tonsillectomy (Robb 2014). Published literature supports the use of tranexamic acid as a means of reducing intraoperative blood loss during tonsillectomy, however it has not been shown to reduce postoperative haemorrhage (Chan 2013).
When given intravenously tranexamic acid is used at a dosage of 10 mg/kg (Novikova 2015). Slow administration is advised (1 mL/min) over the required time to avoid significant hypotension. Given orally, the recommended standard dose is 15 to 25 mg/kg two to three times daily. Tablets are produced at 500 mg strength and tranexamic acid solution at 100 mg/mL. There are no clear recommendations concerning the dosage or method of topical application.
How the intervention might work
Tranexamic acid (trans‐4 amino methyl‐cyclohexane carboxylic acid) is a synthetic lysine analogue that binds to the lysine binding site of plasminogen, consequently preventing fibrinolysis by inhibiting the interaction between plasminogen and fibrin (Robb 2014). Its antifibrinolytic effect is quickly reached, acting within two to three hours after oral administration and immediately after intravenous administration (Novikova 2015). It has a short half‐life of approximately two hours. The most common adverse events are gastrointestinal side effects, including nausea, diarrhoea and abdominal cramping, which are dose‐dependent and uncommon (Robb 2014). The risk of thromboembolic events was found to be uncertain in a large meta‐analysis of 129 trials totalling 10,488 patients (myocardial infarction: risk ratio (RR) 0.68, 95% confidence interval (CI) 0.43 to 1.09, P = 0.11; stroke: RR 1.14, 95% CI 0.65 to 2.00, P = 0.65, deep vein thrombosis: RR 0.86, 95% CI 0.53 to 1.39, P = 0.54; pulmonary embolism: RR 0.61, 95% CI 0.25 to 1.47, P = 0.27) (Ker 2012). Data were sparse in another large meta‐analysis (Henry 2011), and findings from more recent meta‐analyses have not resolved this uncertainty (Abu‐Zaid 2022; Leverett 2022).
Why it is important to do this review
Among ear, nose and throat (ENT) professionals tranexamic acid is mainly known for its role in treating patients with epistaxis and those undergoing tonsillectomy (Chan 2013; Robb 2014).
Any intervention that is shown to reduce blood loss during endoscopic sinus surgery with consequent improvement of surgical field quality and safety will be of clinical benefit for adults, as well as children, and may reduce the duration of surgery. A meta‐analysis evaluating the evidence for the role of tranexamic acid in patients undergoing endoscopic sinus surgery has previously been performed (Pundir 2013). The authors concluded that intraoperative use of topical and intravenous tranexamic acid significantly reduces estimated blood loss and improves surgical field quality. However, the authors pooled the data irrespective of the method of application. Although it can be hypothesised that intravenous tranexamic acid is more effective than topical application, the latter may have the benefit of reducing bleeding from surgical wounds without inducing systemic toxicity and thromboembolism. In addition, since the publication of this meta‐analysis, various further studies have been published (Jahanshahi 2014; Nuhi 2015; Sahar 2015; Shehata 2014).
In view of this, an up‐to‐date Cochrane Review addressing the question of whether tranexamic acid reduces estimated blood loss and improves surgical field quality, with subgroup analyses to compare methods of administration, is of added value in evidence‐based rhinological practice.
Objectives
To assess the effects of peri‐operative tranexamic acid versus no therapy or placebo on operative parameters in patients with chronic rhinosinusitis (with or without nasal polyps) who are undergoing functional endoscopic sinus surgery (FESS).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs), including cluster‐randomised trials. We excluded cross‐over trials as they are not relevant for this intervention (since the main outcomes are evaluated at the time of surgery it would be incoherent to switch from placebo to active treatment or vice versa during surgery). We included studies irrespective of publication status, date of publication or language.
Types of participants
Patients (adults and children) with chronic rhinosinusitis (with or without nasal polyps) undergoing endoscopic sinus surgery.
Exclusion criteria
Wegener's disease
Sarcoidosis
Sinonasal malignancy
Bleeding disorders
Types of interventions
Tranexamic acid irrespective of the dose, duration or method of administration.
The comparison was:
topical or systemic tranexamic acid compared with placebo or no tranexamic acid.
Types of outcome measures
We analysed the following outcomes in the review, but did not use them as a basis for including or excluding studies.
Primary outcomes
Surgical field bleeding score (e.g. Wormald or Boezaart grading system for bleeding during endoscopic sinus surgery. Where both were reported we chose the Boezaart grading system).
Intraoperative blood loss measured at the end of surgery (mL).
Significant adverse effects: of relevance are seizures and thromboembolism within 12 weeks of surgery.
Secondary outcomes
Duration of surgery (minutes).
Incomplete surgery.
Surgical complications (during surgery or directly after surgery).
Postoperative bleeding (placing of packing or revision surgery) in the first two weeks after surgery.
Search methods for identification of studies
The Cochrane ENT Information Specialist conducted systematic searches for randomised controlled trials and controlled clinical trials. There were no language, publication year or publication status restrictions. The date of the search was 10 February 2022.
Electronic searches
The Information Specialist searched:
Cochrane ENT Trials Register (via Cochrane Register of Studies Web, searched 10 February 2022);
Central Register of Controlled Trials (CENTRAL via CRS Web, searched 10 February 2022);
Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to 10 February 2022);
Ovid EMBASE (1974 to 10 February 2022);
Web of Knowledge, Web of Science (1945 to 10 February 2022);
LILACS (BIREME) (searched 10 February 2022);
ClinicalTrials.gov (search via the Cochrane ENT Register and www.clinicaltrials.gov searched 10 February 2022);
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (searched 10 February 2022);
CNKI (searched via Google Scholar 10 February 2022).
The Information Specialist modelled subject strategies for databases on the search strategy designed for CENTRAL. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011). Search strategies for major databases including CENTRAL are provided in Appendix 1.
Searching other resources
We scanned the reference lists of identified publications for additional trials and contacted trial authors where necessary. In addition, the Information Specialist searched Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials. The Information Specialist also ran non‐systematic searches of Google Scholar to retrieve grey literature and other sources of potential trials.
Data collection and analysis
Selection of studies
Two authors (KA and EL, a rhinology fellow and a junior otorhinolaryngology trainee, respectively) independently examined the titles and abstracts of the studies to remove obviously irrelevant reports. We then retrieved the full texts of potentially relevant articles. The same two authors independently examined the full‐text reports for compliance with the eligibility criteria. We contacted the study authors, where appropriate, to clarify study eligibility. The two authors independently decided on study inclusion. Any difference in opinion regarding the inclusion of studies was resolved by discussion until a consensus was reached, or by referral to a third review author (VP).
We have included a graphical representation of the flow of citations reviewed in the course of this review in the review, as described in the PRISMA statement (Moher 2009).
Data extraction and management
Two authors (KA and EL) independently extracted data from the study reports using the generic Cochrane ENT data collection form (Appendix 2). If additional information was needed concerning details of the study or numerical results, we contacted the authors of the study reports and original investigators. We extracted data into Review Manager (RevMan) 5 (RevMan 2020). If multiple reports of the same study existed, each author collected data separately from each report and then collated this into a single study report. We resolved disagreements by discussion. If necessary, disagreements were resolved by arbitration by a third author (VP). We collected data from each study for analyses of dichotomous outcomes, continuous outcomes and other types of outcome data as described in chapter 7.7 'Extracting study results' in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of risk of bias in included studies
Two review authors (EL and KA) undertook assessment of the risk of bias of the included studies independently, with the following taken into consideration, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011):
sequence generation;
allocation concealment;
blinding;
incomplete outcome data;
selective outcome reporting; and
other sources of bias.
We used the Cochrane risk of bias tool in RevMan 2020, which involves describing each of these domains as reported in the study and then assigning a judgement about the adequacy of each entry: 'low', 'high' or 'unclear' risk of bias.
Lack of blinding in itself was sufficient to label a study as at high risk of bias if all outcomes were subjective, e.g. surgeon reporting of clarity of field.
Measures of treatment effect
For continuous outcomes we reported the mean difference (MD) with standard deviation (SD) or, when necessary, the standardised mean difference (SMD). We anticipated that different intraoperative bleeding scales would have been used in different studies: namely the Boezaart and Wormald scales. We used the SMD as the summary statistic to standardise the results of studies to a uniform scale. If studies reported both bleeding scales we chose to report the Boezaart scale. In case of different time point measurements for the intraoperative bleeding scales, we chose to use the time point closest to 30 minutes after the dose of tranexamic acid or the start of surgery. The inhibitory activity of tranexamic acid on fibrinolysis is maximal at this time point.
In the case of dichotomous outcomes, we calculated the risk ratio (RR) with a 95% confidence interval (CI). Where there were no events in either treatment group, we calculated a risk difference (RD) with a 95% CI.
Unit of analysis issues
We determined appropriate units of analysis from the included studies. We only considered split‐body trials when the administration route of treatment was intranasal, with two experimental units of analysis (both sides of the nose, which are correlated in chronic rhinosinusitis with or without nasal polyps). There would be a very low risk of a 'carry‐over effect', since the patient lies on their back during surgery and leakage would be implausible. However, there could be a risk of underestimation of the treatment effect, since the comparison is placebo. If the trial correctly analysed and reported the data (analysis for paired outcomes), we used the mean postoperative values as a summary measure and used a two‐group comparison in the review.
Cluster‐randomised trials
We analysed cluster‐randomised trials based on the level of allocation, i.e. clusters of participants.
Multi‐armed trials
When analysing multi‐armed trials, we combined all relevant experimental intervention groups in the study into a single group and all relevant control intervention groups into a single control group. If we considered one of the arms to be irrelevant, we excluded it from analysis.
For dichotomous outcomes, we summed both the sample sizes and the numbers of people with events across groups. For continuous outcomes, we combined means and standard deviations using the methods described in Chapter 7 (section 7.7.3.8) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
We contacted study authors via email whenever the outcome of interest was not reported if the methods of the study suggested that the outcome was measured. We did the same if not all data required for meta‐analysis were reported, unless the missing data were standard deviations. If standard deviation data were not available we approximated these using standard estimation methods: from P values, standard errors or 95% CIs if these were reported, as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). Where it was impossible to estimate these, we contacted the study authors.
Apart from imputations for missing standard deviations, we did not conduct any other imputations. We extracted and analysed data for all outcomes using the available case analysis method.
Assessment of heterogeneity
We assessed clinical heterogeneity (which may be present even in the absence of statistical heterogeneity) by examining the included studies for potential differences between them in the types of participants recruited (including age of participants), interventions or controls used and the outcomes measured.
We assessed statistical heterogeneity by visually inspecting the forest plots and by considering the Chi² test (with a significance level set at P < 0.10) and the I² statistic, which calculates the percentage of variability that is due to heterogeneity rather than chance, with I² values over 50% suggesting substantial heterogeneity (Handbook 2011).
Assessment of reporting biases
We created a funnel plot to detect reporting biases if at least 10 studies were included in the meta‐analysis. We assessed reporting bias as between‐study publication bias and within‐study outcome reporting bias. If we identified small studies with larger treatment effects, we planned to perform a sensitivity analysis excluding these studies.
Data synthesis
We used the Cochrane software package RevMan 5 for quantitative meta‐analysis of the extracted data (RevMan 2020). We expressed continuous data as the MD or SMD with 95% CI. We expressed dichotomous data as the RR with 95% CI. We pooled the results using a random‐effects model because we expected there to be substantial clinical heterogeneity.
Subgroup analysis and investigation of heterogeneity
Where data were available, we planned to conduct some subgroup analyses regardless of whether statistical heterogeneity was observed, as these are widely suspected to be potential effect modifiers. For this review, this included the following:
Primary subgroup:
Different methods of administration of tranexamic acid (topical versus intravenous).
Secondary subgroups:
Different dosages.
Patients with chronic rhinosinusitis with and without nasal polyps.
Patients that use local corticosteroids in the month before surgery versus no corticosteroids.
Patients that use systemic corticosteroids in the month before surgery including the day of surgery versus local corticosteroids or no corticosteroids.
Different forms of anaesthesia and other intraoperative interventions.
Patients with thromboembolic prophylaxis versus patients without thromboembolic prophylaxis.
Children (< 18) versus adults (≥ 18).
Sensitivity analysis
We intended to carry out sensitivity analyses on the basis of the methodological diversity of the included studies. We considered the following when repeating the analysis:
excluding studies with high risk of bias (defined as four out of seven domains deemed to have high risk);
excluding small studies with larger treatment effects;
excluding industry‐sponsored studies;
excluding studies with significant author financial and other conflicts of interest;
statistical model of analysis (fixed‐effect versus random‐effects model);
assumptions about missing data (considering the scenarios outlined above in Dealing with missing data).
Summary of findings and assessment of the certainty of the evidence
Two authors (KA and EL) independently applied the GRADE approach to rate the overall certainty of evidence. The certainty of evidence reflects the extent to which we are confident that an estimate of effect is correct and we applied this in the interpretation of results. There are four possible ratings: high, moderate, low and very low. A rating of high certainty of evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low certainty implies that any estimate of effect obtained is very uncertain.
The GRADE approach rates evidence from RCTs that do not have serious limitations as high certainty. However, several factors can lead to the downgrading of the evidence to moderate, low or very low. The degree of downgrading is determined by the seriousness of these factors:
study limitations (risk of bias);
inconsistency;
indirectness of evidence;
imprecision; and
publication bias.
We created a summary of findings table in GRADEpro GDT, constructed according to the recommendations described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We included the following outcomes in the summary of findings table:
surgical field bleeding score;
intraoperative blood loss (mL);
significant adverse effects: seizures, thromboembolism;
duration of surgery (minutes);
incomplete surgery;
surgical complications;
postoperative bleeding (place of packing or revision surgery within three days).
Results
Description of studies
Results of the search
The search retrieved a total of 482 records (480 studies). After removing duplicates we screened 460 titles and abstracts and subsequently removed 415 studies. We assessed 45 full texts for eligibility and excluded 13 individual studies from the review. We found an additional study in the reference list of a systematic review. Five identified studies are ongoing. Seven studies are awaiting assessment, either because no full‐text report was found or we were unable to obtain the paper. We included 14 studies in the review. A flow chart of study retrieval and selection is provided in Figure 1.
1.
Process for sifting search results and selecting studies for inclusion
Included studies
We included 14 studies (Alimian 2011; Athanasiadis 2007; Baradaranfar 2017; Dongare 2018; Eldaba 2013; El Shal 2015; El‐Ozairy 2021; Jabalameli 2006; Langille 2013; Nuhi 2015; Padhy 2019; Pannerselvam 2019; Quiroga 2018; Yang 2021). See Characteristics of included studies.
Design
All studies were randomised, controlled and blinded.
Sample size and participants
The included studies ranged from a sample size of 10 (Quiroga 2018) up to 170 (Nuhi 2015). All participants underwent endoscopic sinus surgery for chronic rhinosinusitis.
Ten studies included adult patients of at least 18 years (the age range of included patients was 18 to 80 years). One study included children between 5 and 10 years old and one study included patients between 12 and 60 years of age. More male patients were included in almost all studies (range 46.6% to 80%). Only one study included male and female patients in a 50:50 ratio (Nuhi 2015). In the studies Baradaranfar 2017, Dongare 2018 and Padhy 2019 all patients had chronic rhinosinusitis with nasal polyps. In Yang 2021, more than 70% of patients had nasal polyps. Langille 2013 included five participants with chronic rhinosinusitis without nasal polyps and 23 patients with chronic rhinosinusitis with nasal polyps. No specification of presence or absence of nasal polyps was given in the other studies.
Setting
All studies were performed in single centres in secondary or tertiary care clinics of departments of Anesthesiology or Otorhinolaryngology. The Middle East was strongly represented with four studies conducted in Iran and three studies performed in Egypt. The other studies were performed in the Philippines, India, Australia, Canada and China. There were no studies from Europe or the USA.
Interventions
All studies were placebo‐controlled, although two studies had three arms, also including epsilon‐aminocaproic acid, a synthetic inhibitor of the plasmin‐plasminogen system, in the comparison (Athanasiadis 2007; El Shal 2015). We excluded this arm from the analyses. Three studies used topical application of tranexamic acid as a spray (Athanasiadis 2007), or local irrigation (Baradaranfar 2017; Jabalameli 2006), while the other 10 studies used intravenous tranexamic acid (Alimian 2011; Dongare 2018; Eldaba 2013; El Shal 2015; Langille 2013; Nuhi 2015; Padhy 2019; Pannerselvam 2019; Quiroga 2018; Yang 2021). El‐Ozairy 2021 compared topical application, intravenous application or both with placebo. Two studies compared two different dosages of tranexamic acid: topical 100 mg versus 1000 mg (Athanasiadis 2007) and intravenous 15 mg/kg and 5 mg/kg (Pannerselvam 2019).
In the studies that applied intravenous tranexamic acid, a single bolus was given in three studies (Alimian 2011; Dongare 2018; Nuhi 2015), infusion over 30 minutes in Yang 2021, and a single bolus plus infusion (over an unclear period of time) in Langille 2013. It was unclear in the other studies whether a bolus or infusion was applied (Eldaba 2013; El Shal 2015; Padhy 2019; Pannerselvam 2019; Quiroga 2018). The details of the interventions are described in Table 2 'Summary of studies comparing topical tranexamic acid with placebo', Table 3 'Summary of studies comparing intravenous application of tranexamic acid with placebo' and Table 4 'Summary of studies comparing low‐ versus high‐dose tranexamic acid with placebo'.
1. Summary of studies comparing topical tranexamic acid with placebo.
| Study ID | Intervention | Comparison | Drug delivery | Dose |
| Athanasiadis 2007 | Tranexamic acid | Placebo | Spray | 100 mg or 1000 mg once during the conclusion of surgery in one nostril; the contralateral nostril received placebo |
| Baradaranfar 2017 | Tranexamic acid | Placebo | Rinsing | 2 g in 400 mL saline in case the field became obscured |
| El‐Ozairy 2021 | Tranexamic acid | Placebo | Rinsing | 2 g in 400 mL saline solution (study also compares intravenous application with placebo, or combined) |
| Jabalameli 2006 | Tranexamic acid | Placebo | Rinsing | 1 g in 20 mL saline once during surgery |
2. Summary of studies comparing intravenous application of tranexamic acid with placebo.
| Study ID | Intervention | Comparison | Drug delivery | Dose |
| Alimian 2011 | Tranexamic acid | Placebo | Intravenous administration | Bolus of 10 mg/kg after induction of TIVA |
| Dongare 2018 | Tranexamic acid | Placebo | Intravenous administration | Bolus of 15 mg/kg pre‐operative |
| El Shal 2015 | Tranexamic acid | Placebo | Intravenous administration | 10 mg/kg diluted in 100 mL saline solution after induction of anaesthesia |
| Eldaba 2013 | Tranexamic acid | Placebo | Intravenous administration | 25 mg/kg diluted in 10 mL saline solution after induction of anaesthesia |
| El‐Ozairy 2021 | Tranexamic acid | Placebo | Intravenous administration | 15 mg/kg diluted in 20 mL saline over 30 minutes (study also compares topical treatment with placebo, or combined) |
| Langille 2013 | Tranexamic acid | Placebo | Intravenous administration | Bolus 15 mg/kg + infusion 1 mg/kg/hour in 100 mL saline |
| Nuhi 2015 | Tranexamic acid | Placebo | Intravenous administration | 15 mg/kg once on the day of surgery |
| Padhy 2019 | Tranexamic acid | Placebo | Intravenous administration | 10 mg/kg after induction phase |
| Pannerselvam 2019 | Tranexamic acid | Placebo | Intravenous administration | 5 mg/kg or 15 mg/kg 20 minutes prior to surgery |
| Quiroga 2018 | Tranexamic acid | Placebo | Intravenous administration | 500 mg per 5 mL 1 hour prior to surgery |
| Yang 2021 | Tranexamic acid | Placebo | Intravenous administration | 15 mg/kg in 100 mL normal saline over 30 minutes |
TIVA: total intravenous anaesthesia
3. Summary of studies comparing low‐ versus high‐dose tranexamic acid with placebo.
| Study ID | Intervention | Comparison | Drug delivery | Dose |
| Athanasiadis 2007 | Tranexamic acid 100 mg | Tranexamic acid 1000 mg | Topical spray | Once during the conclusion of surgery in one nostril; the contralateral nostril received placebo |
| Pannerselvam 2019 | Tranexamic acid 5 mg/kg | Tranexamic acid 15 mg/kg | Intravenous | Once 20 minutes before surgery diluted in 100 mL of saline solution |
Most studies mentioned in their exclusion criteria that participants were not allowed to use any anticoagulant medications before inclusion in the study. Jabalameli 2006 only reported that no patients on anticoagulant medication were included. Langille 2013 and Baradaranfar 2017 did not mention any prohibited medications. Langille 2013 reported that no participants used acetylsalicylic acid preoperatively and there were no baseline differences in the use of systemic corticosteroids between the tranexamic acid and placebo group. Pannerselvam 2019 mentioned the exclusion of patients with thrombotic diathesis, however it did not specifically mention anticoagulant therapy. In this study all participants received prednisolone 1 mg/kg daily pre‐operatively for five days plus intravenous amoxycillin‐clavulanic acid 1200 mg twice daily the first 48 hours. Eldaba 2013 mentioned in addition that no non‐steroidal anti‐inflammatory drugs were allowed in the seven days before surgery.
Outcomes
Surgical field bleeding score
Studies reported a surgical field bleeding score according to Wormald (Athanasiadis 2007, Langille 2013, Pannerselvam 2019) or Boezaart (Alimian 2011; Athanasiadis 2007; Baradaranfar 2017; Dongare 2018; El Shal 2015; Eldaba 2013; El‐Ozairy 2021; Jabalameli 2006; Padhy 2019; Quiroga 2018; Yang 2021). Nuhi 2015 mentioned this outcome in their methods section, however they did not report it. Eleven studies were used in our meta‐analyses.
Some studies reported the number of participants who were assigned each score (for example 0, 1, 2, 3, 4, 5). We calculated the mean score and standard deviation for each group based on these data (Alimian 2011; Dongare 2018; El Shal 2015; Eldaba 2013; Jabalameli 2006; Padhy 2019; Quiroga 2018). Langille 2013 reported median and range, which we transformed into mean and standard deviation. The study El‐Ozairy 2021 only reported median and interquartile range, therefore we transformed the data into mean and standard deviation.
El Shal 2015 assessed Boezaart's grading scale at multiple time points. We decided to use 30 minutes after starting surgery. The other time points (60, 90, 120, 150 minutes) were not used in the meta‐analysis, because they would differ too much from the reported time points in other studies. Dongare 2018 reported Boezaart bleeding scores after 15, 30 and 45 minutes. Again we decided to use 30 minutes after starting surgery.
Athanasiadis 2007 presented mean scores for 2, 4, 6, 8 and 10 minutes after application of tranexamic acid or placebo for both low‐dose and high‐dose tranexamic acid. They reported both the Wormald and Boezaart scale. We chose to use the Boezaart scale and the 10‐minute time point after surgery. In Eldaba 2013, the field was scored 15 and 30 minutes after starting surgery. We decided to use the values for 30 minutes after starting surgery. Jabalameli 2006, Quiroga 2018, Langille 2013 and Yang 2021 all reported intraoperative bleeding at one time point (unclear at what time during surgery). Pannerselvam 2019 reported the Wormald scale for the low and higher dose of tranexamic acid.
Intraoperative blood loss (mL)
Only Athanasiadis 2007 and El‐Ozairy 2021 did not report this outcome. Twelve studies could be meta‐analysed.
Significant adverse effects: seizures, thromboembolism within 12 weeks of surgery
All but five studies (Baradaranfar 2017; Jabalameli 2006; Langille 2013; Padhy 2019; Pannerselvam 2019) reported the occurrence of any significant adverse events, however none of the studies had a long follow‐up. Therefore none of the studies could report events after a full 12‐week follow‐up period. All but one of the studies reported events only on the day of surgery, therefore our analysis is limited to 24‐hour follow‐up. Dongare 2018 mentioned follow‐up for thrombotic complications until discharge home, however it remains unclear how long patients needed to be hospitalised after surgery.
Meta‐analysis could only be performed for eight studies, because Athanasiadis 2007 used the left and right nostril from each patient as the intervention and control group. This complicates the interpretation of the relation of the effect to the type of treatment.
Duration of surgery (minutes)
All but four studies reported the duration of surgery (Athanasiadis 2007; Jabalameli 2006; Nuhi 2015; Padhy 2019). Ten studies could be meta‐analysed.
Incomplete surgery and surgical complications
Langille 2013 and Padhy 2019 mentioned surgical complications and incomplete surgery. Both studies had a small sample size (N = 28 and N = 30 respectively).
Postoperative bleeding (placing of packing or revision surgery) in the first two weeks after surgery
Six studies reported on the occurrence of epistaxis, however follow‐up was very short. All studies that reported this outcome reported epistaxis at least on the day of surgery (Alimian 2011; Athanasiadis 2007; Baradaranfar 2017; Eldaba 2013; El Shal 2015; Yang 2021). Alimian 2011 had three days follow‐up. Athanasiadis 2007 and Eldaba 2013 had unclear follow‐up. Baradaranfar 2017 had follow‐up for the length of hospitalisation, which was not reported. El Shal 2015 and Yang 2021 had follow‐up for 24 hours. Due to this variability in outcome reporting we were only able to undertake a meta‐analysis with results that are most likely limited to 24 to 72 hours of follow‐up.
Funding sources
Three studies reported information about funding. Alimian 2011 was funded by department sources only. Baradaranfar 2017 was funded by a grant from Shahid Sadoughi University of Medical Sciences in Iran. Yang 2021 was supported by Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support.
Missing data
We contacted the authors of Nuhi 2015 and El‐Ozairy 2021 with a request to provide means and standard deviations (SDs) for the intervention groups for missing clinically relevant outcomes. The authors contacted did not provide us with these data.
Excluded studies
We excluded 13 studies after reading the full text. Reasons for exclusion can be found in the Characteristics of excluded studies table.
We excluded five studies because they had the wrong study design (Athanasiadis 2009; Beule 2010; Kurozumi 1977; Shehata 2014; Yaniv 2006). Beule 2010 used a human fibroblast model to investigate wound healing. Nasal fibroblasts were used from three patients with chronic rhinosinusitis with nasal polyps and three controls and were grown in culture. Kurozumi 1977 was a non‐randomised study in patients undergoing sinectomy using the Caldwell‐Luc technique. Shehata 2014 was a non‐randomised study in patients with chronic rhinosinusitis and compared topical tranexamic acid with hot water irrigation or normal saline. Yaniv 2006 was a non‐randomised study in patients that underwent combined functional endoscopic sinus surgery with conchotomy and septoplasty with or without the use of oral tranexamic acid.
NCT00671281 was a study registration for a study that was cancelled.
IRCT2015092824241N1 used patients scheduled for elective open rhinoplasty and was therefore excluded. IRCT201203242963N7 2012 compared two different dosages of tranexamic acid without a placebo group. Chhappola 2011 was a study with patients undergoing endoscopic nasal surgery for a variety of indications, including nasal mass, sinusitis and septoplasty. Also patients were operated on under different circumstances, with about 70% of patients operated under local anaesthesia and the others with more severe disease under general anaesthesia. Due to this heterogeneity in the type of patients and surgical procedures we excluded the study from this review. Kulkarni 2018 compared tranexamic acid with ethamsylate as single bolus. Jahanshahi 2014 compared topical tranexamic acid with topical phenylephrine and was therefore excluded (as was its trial registration IRCT201212139014N15). IRCT2015062021436N2 and Abbasi 2012 (with trial registration IRCT201203242963N7) investigated two different dosages of tranexamic acid, but no comparator group was present. We therefore excluded these studies.
Studies awaiting classification
We were unable to retrieve the full‐text articles for Kurozumi 1976, 32971 2018, IRCT2012111411455N1 2013 CRSSTD‐7068603, IRCT2013012911822N3 2013 CRSSTD‐7068595, IRCT2014031016924N1 2016 CRSSTD‐7068683 and Moise 2010. Amal Das 2012 CRSSTD‐7068696 was most likely a thesis or book chapter, although it could not be found by the Cochrane Information Specialist using a worldwide search. Athanasiadis 2009 was a full thesis exploring the progressive understanding of the interaction between haemostasis and wound healing with possible development of a novel agent. This thesis also could not be retrieved.
Ongoing studies
We found a trial registration for a double‐blind, randomised, placebo‐controlled trial in 112 adult patients with chronic rhinosinusitis requiring sinus endoscopic surgery in which intranasal pre‐operative phenylephrine 0.05% and tranexamic acid at a dose of 15 mg/kg or placebo are compared with respect to bleeding during surgery (IRCT20180730040640N1). This study is currently recruiting.
We found another ongoing randomised controlled trial in adult patients with chronic rhinosinusitis requiring endoscopic sinus surgery (NCT03965767). In this study four treatment groups were used: an intravenous dose of 15 mg/kg of tranexamic acid with irrigation fluid 400 mL of normal saline; intravenous dose of 10 mL normal saline with irrigation fluid 400 mL of normal saline with 2 g of tranexamic acid added to it; intravenous dose of 15 mg/kg of tranexamic acid in a 10 mL with irrigation fluid 400 mL of normal saline with 2 g of tranexamic acid added to it; intravenous dose of 10 mL normal saline with irrigation fluid 400 mL of normal saline. The primary outcome is bleeding during surgery. This study should have completed recruitment.
We found another trial registration for a randomised controlled trial in 40 adults scheduled to undergo elective sinus or nasal surgery. Patients will be randomised to either intravenous tranexamic acid 1000 mg or normal saline solution. The study is recruiting (NCT04754230).
Another randomised controlled trial that is currently recruiting will investigate two different nebulised tranexamic acid dosages (500 mg or 1000 mg) compared to nebulised saline solution in 90 adults patients selected for elective functional endoscopic sinus surgery (NCT04905901).
The last ongoing randomised controlled trial is being performed in 47 adult patients who are candidates for FESS. It compares an injection of 250 mg/5 mL tranexamic acid with an injection of saline solution (TCTR20210531005).
See Characteristics of ongoing studies for a more detailed description of these studies
Risk of bias in included studies
Full details of the risk of bias in the included studies can be found in the risk of bias tables (Characteristics of included studies). A risk of bias graph shows our judgements about each risk of bias item presented as percentages across all included studies (Figure 2). Details of the risk of bias for each study can be found in Figure 3.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Sequence generation and allocation concealment
All included studies were randomised and controlled. We assessed Jabalameli 2006 and El‐Ozairy 2021 as having unclear risk of bias for sequence generation, since the method of randomisation was not precisely described. We considered all other studies at low risk of bias for sequence generation. Alimian 2011, Baradaranfar 2017 and Dongare 2018 used a table of random numbers to divide participants. El Shal 2015 performed randomisation by means of computer‐generated codes. Eldaba 2013 and Padhy 2019 performed randomisation using a computer‐based random number generator. Langille 2013 and Pannerselvam 2019 used a block randomisation scheme. Nuhi 2015 performed randomisation using sequential numbers. Quiroga 2018 used simple random sampling for randomisation. Athanasiadis 2007 used computer randomisation. Yang 2021 used a computer‐generated random number list and the allocation was sealed in an envelope.
We considered allocation concealment a low risk of bias in most studies. However, Baradaranfar 2017 used a random number table, without sealed envelopes. Quiroga 2018 used folded papers with numbers on: the odd number was assigned to the treatment group. Therefore we defined these two studies as being at high risk of bias. We classified Dongare 2018 and Jabalameli 2006 as at unclear risk for allocation concealment, since no information was presented about how and by whom the randomisation was performed, or how it remained concealed.
Blinding
Performance bias
We scored all but five studies as having a low risk of performance bias. Baradaranfar 2017 and Jabalameli 2006 did not provide information on who was blinded with respect to the study personnel or patients. Eldaba 2013, Padhy 2019 and Pannerselvam 2019 reported nothing about blinding of patients, therefore we feel that these studies have an unclear risk of bias.
Alimian 2011 mentioned that only the pharmacy involved was aware of the allocation of treatment. Athanasiadis 2007 was reported as a double‐blinded study and mentioned that the surgical team was not aware of treatment allocation. Dongare 2018 reported that a blinded observer applied the contents of the syringes to the patients. It is unclear if the syringes were identical in colour/appearance. It was not specifically reported that patients were blinded to the treatment, but this is plausible. El Shal 2015 mentioned that anaesthesiologists, surgeons and patients were blinded to study treatment. An anaesthesiologist not involved in the study prepared the syringes. El‐Ozairy 2021 was double‐blinded. A pharmacist prepared the drugs. Anaesthesiologist and surgeon were blinded to the category of study group. Langille 2013 mentioned that one investigator knew the randomisation and this person was responsible for preparing the study drugs. Other personnel and patients were blinded. In Nuhi 2015, participants and study staff were blinded to treatment allocation. Quiroga 2018 was a double‐blind study and the surgeons and anaesthesiologists were blinded to treatment allocation. Yang 2021 mentioned that one researcher knew the randomisation code and prepared the sealed envelopes, which were blinded to the surgeons, patients and anaesthesiologists.
Detection bias
Most studies had low risk of detection bias. Baradaranfar 2017 and Jabalameli 2006 did not provide information on who was blinded as outcome assessor, so this is an unclear risk of bias. Padhy 2019 mentioned that the surgical team was blinded to treatment group to ensure blinding for the surgical field outcome score, however the anaesthesiologist was not blinded to the treatment group, being responsible for the calculation of total blood loss. Therefore we rated this as a high risk of bias.
Nuhi 2015 used the attending anaesthesiologist and the surgeon as outcome assessors, however it is unclear if they were part of the blinded study site staff. In Pannerselvam 2019, study staff were reported to be adequately blinded, but who assessed the primary and secondary outcome parameters remains unclear, although we can assume this was the surgical team. We rated both studies as having unclear risk of bias.
The other studies were adequately blinded. Alimian 2011 used the surgeons as outcome assessors and they were adequately blinded. Athanasiadis 2007 reported an independent observer who was adequately blinded. Dongare 2018 reported that the surgeons were blinded to treatment and performed the measurement of the bleeding score. El Shal 2015, Eldaba 2013 and El‐Ozairy 2021 seemed to have adequate blinding of outcome assessors. Langille 2013 had two investigators blinded; only one investigator not involved in data extraction knew the allocation. In Quiroga 2018, only one surgeon performed all procedures and they were blinded to treatment allocation. Yang 2021 mentioned that the primary outcome was assessed by a surgically trained researcher who was blinded to the group allocation.
Incomplete outcome data
We assessed all studies as being at low risk of bias for incomplete outcome data. All patients randomised were reported and analysed. Since almost all outcomes were assessed during surgery or shortly afterwards this finding is not unexpected.
Selective reporting
We did not find published protocols for any of the studies except for Alimian 2011, El‐Ozairy 2021, Langille 2013 and Yang 2021. In these studies all pre‐specified outcomes were reported.
We assessed Baradaranfar 2017 as having a high risk of bias, because it is unclear how much of the total amount of irrigation fluid with tranexamic acid was used in each participant during surgery. Therefore we cannot be certain how much of the tranexamic acid was actually given to each patient. We considered Dongare 2018 to have a high risk of bias since the bleeding score was not reported at 60 minutes although measured, with no reason provided. Although we did not use this time point, we feel that it adds to a higher risk of bias in this study. We assessed Nuhi 2015 as having a high risk of bias because the surgical field bleeding score was not fully reported, which made it impossible to use for meta‐analysis.
We assessed El Shal 2015, Eldaba 2013, El‐Ozairy 2021, Jabalameli 2006, Padhy 2019, Pannerselvam 2019, Quiroga 2018 and Yang 2021 as having a low risk of bias, since all outcome parameters in the methods sections were adequately reported.
Other potential sources of bias
Baseline characteristics
All 14 included studies were randomised and controlled. Thirteen studies reported on baseline differences between intervention groups, with the exception of Padhy 2019. It is unclear whether there were baseline differences between groups and what these potentially were. We do not know how many males and females were included or what the participants' ages were. We interpreted this lack of reporting as a high risk of bias.
Other
In Dongare 2018, patients were followed up for thrombotic events until discharge. This period of time was probably variable for patients and the study does not specifically report on the duration of hospitalisation.
Effects of interventions
See: Table 1
Tranexamic acid versus no treatment or placebo
See Table 1.
We analysed the prespecified primary and secondary outcomes. Fourteen studies compared tranexamic acid with placebo, with a total of 942 participants (Alimian 2011; Athanasiadis 2007; Baradaranfar 2017; Dongare 2018; Eldaba 2013; El Shal 2015; El‐Ozairy 2021; Jabalameli 2006; Langille 2013; Nuhi 2015; Padhy 2019; Pannerselvam 2019; Quiroga 2018; Yang 2021). In three studies only topical tranexamic acid was applied (see Table 2). In 10 studies intravenous tranexamic acid was used (see Table 3). In one study either topical, intravenous or a combination was applied (El‐Ozairy 2021). There was a lot of variation in the dosage of tranexamic acid used. Two studies compared two different dosages of topical tranexamic acid with placebo (see Table 4).
Subgroup analysis for chronic rhinosinusitis with or without nasal polyps, use of local or systemic corticosteroids in the month before surgery and use of thrombo‐embolic prophylaxis could not be conducted due to incomplete reporting of these parameters by most studies.
Primary outcomes
Surgical field bleeding score
Thirteen studies assessed and adequately reported this outcome and were used for meta‐analysis (n = 428 tranexamic acid and n = 344 placebo) (Alimian 2011; Athanasiadis 2007; Baradaranfar 2017; Dongare 2018; Eldaba 2013; El‐Ozairy 2021; El Shal 2015; Jabalameli 2006; Langille 2013; Padhy 2019; Pannerselvam 2019; Quiroga 2018; Yang 2021). Langille 2013 and Pannerselvam 2019 used the Wormald scale. The Boezaart scale was used by the other included studies.
When we combined the studies we found evidence that tranexamic acid likely results in a large reduction in the surgical field bleeding score compared with placebo, with a standardised mean difference (SMD) of ‐0.87 (95% confidence interval (CI) ‐1.23 to ‐0.51, random‐effects model; P < 0.0001; 13 studies, 772 participants; moderate‐certainty evidence) (Analysis 1.1). This can be interpreted as a large effect (< ‐0.70) (Cohen 1988; Handbook 2011). There was considerable heterogeneity in this analysis (Chi² = 61.11; I² = 80%).
1.1. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 1: Surgical field bleeding score (during surgery)
The funnel plot showed slight asymmetry (Figure 4). After a sensitivity analysis excluding studies with a total population of fewer than 30 participants, the asymmetry did not entirely disappear from the funnel plot and the direction of treatment effect did not change compared to the main analysis (Analysis 1.7; Figure 5). A fixed‐effect model analysis did not change the overall treatment effect (Analysis 1.8).
4.
1.7. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 7: Surgical field bleeding score (during surgery) excluding small sized studies
5.
1.8. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 8: Surgical field bleeding score (during surgery) using fixed‐effect model
Subgroup analyses
The route of administration of tranexamic acid was mainly intravenous. Only four studies applied topical tranexamic acid (Athanasiadis 2007; Baradaranfar 2017; El‐Ozairy 2021; Jabalameli 2006). In the study El‐Ozairy 2021 patients received either intravenous, topical or combined intravenous/topical tranexamic acid. One can assume that the mechanism of action by which the agent diminishes bleeding is different. We therefore performed subgroup analyses, primarily for the method of administration.
When comparing routes of administration we found evidence of subgroup differences (test for subgroup differences: Chi² = 25.41, df = 2 (P < 0.00001), I² = 92.1%; Analysis 1.3). We could not use the intravenous tranexamic subgroup from El‐Ozairy 2021 for subgroup analysis because the calculated standard deviation was 0.
1.3. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 3: Surgical field bleeding score by administration route (during surgery or within 30 minutes after surgery)
Only one study was performed solely in children (Eldaba 2013). There was no evidence of a difference between the younger and adult subgroup (test for subgroup differences: Chi² = 0.02, df = 1 (P = 0.88), I² = 0%; Analysis 1.2). We could not use Padhy 2019 in this subgroup analysis because they did not report baseline characteristics in both groups.
1.2. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 2: Surgical field bleeding score by age (during surgery or within 30 minutes after surgery)
A subgroup analysis of dosages (nine different dosages used in 13 studies) showed evidence of a subgroup difference (test for subgroup differences: Chi² = 41.92, df = 9 (P < 0.00001), I² = 78.5%; Analysis 1.4). There was evidence of a difference in favour of tranexamic acid in the subgroups intravenous 10 mg/kg, intravenous 5 mg/kg or 15 mg/kg, intravenous 15 mg/kg, intravenous 25 mg/kg, topical 1000 mg and intravenous 15 mg/kg with topical 2000 mg. However, we noted no evidence of a difference between tranexamic acid and control for the other dose subgroups (intravenous 500 mg, topical 100 mg or 1000 mg, topical 2000 mg, intravenous 15 mg/kg + infusion 1 mg/kg).
1.4. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 4: Surgical field bleeding score by dosage (during surgery or within 30 minutes after surgery)
There was no evidence of a subgroup difference between types of anaesthesia (test for subgroup differences: Chi² = 0.21, df = 2 (P = 0.90), I² = 0%; Analysis 1.5). Athanasiadis 2007 and Padhy 2019 could not be used for meta‐analysis because they did not report the type of anaesthesia used.
1.5. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 5: Surgical field bleeding score by type of anaesthesia (during surgery or within 30 minutes after surgery)
Finally there was no evidence of a subgroup difference between use of pre‐ or intraoperative vasoconstrictive agents (test for subgroup differences: Chi² = 0.03, df = 1 (P = 0.86), I² = 0%; Analysis 1.6). Three studies could not be used for subgroup analysis because they did not report the use of any vasoconstrictive agents (Athanasiadis 2007; Baradaranfar 2017; El Shal 2015).
1.6. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 6: Surgical field bleeding score and use of vasoconstrictive agents (during surgery or within 30 minutes after surgery)
Intraoperative blood loss
Twelve studies reported useful data on this outcome (n = 428 tranexamic acid and n = 374 placebo) (Alimian 2011; Baradaranfar 2017; Dongare 2018; Eldaba 2013; El Shal 2015; Jabalameli 2006; Langille 2013; Nuhi 2015; Padhy 2019; Pannerselvam 2019; Quiroga 2018; Yang 2021). Combining the results of 12 studies we found that tranexamic acid may result in a slight reduction in blood loss during surgery compared to placebo with a mean difference (MD) of ‐70.32 mL (95% CI ‐92.28 to ‐48.35 mL, P < 0.00001, random‐effects model; 12 studies, 802 participants; Chi² = 204.40; I² = 95%, low‐certainty evidence) (Analysis 1.9). We feel that the mean difference of ‐70.32 mL is not clinically relevant.
1.9. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 9: Intraoperative blood loss (mL)
The funnel plot showed slight asymmetry, probably indicating larger treatment effects for smaller studies (Figure 6). After a sensitivity analysis excluding studies with a total population of fewer than 30 participants, the asymmetry did not fully disappear and the direction of treatment effect did not change compared to the main analysis (Analysis 1.15; Figure 7). A fixed‐effect model analysis showed a smaller main treatment effect than the random‐effects model, suggesting that tranexamic acid is more effective in the smaller studies (Analysis 1.16).
6.
1.15. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 15: Intraoperative blood loss (mL) excluding small sized studies
7.
1.16. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 16: Intraoperative blood loss (mL) using fixed‐effect model
Subgroup analyses
Subgroup analyses for age (adults versus children) (P = 0.10; Analysis 1.10), route of administration (P = 0.24; Analysis 1.11), type of anaesthesia (P = 0.13; Analysis 1.13) and use of vasoconstrictive agents (P = 0.56; Analysis 1.14) showed no evidence of a difference between subgroups.
1.10. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 10: Intraoperative blood loss (mL) by age
1.11. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 11: Intraoperative blood loss by administration route
1.13. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 13: Intraoperative blood loss by type of anaesthesia
1.14. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 14: Intraoperative blood loss and use of vasoconstrictive agents
A subgroup analysis of dosages (eight different dosages used in 12 studies) showed evidence of a subgroup difference (test for subgroup differences: Chi² = 64.31, df = 7 (P < 0.00001), I² = 89.1%). We noted evidence of a difference in favour of tranexamic acid in the subgroups intravenous 5 mg/kg, intravenous 10 mg/kg, intravenous 15 mg/kg, intravenous 25 mg/kg and topical 1000 mg (Analysis 1.12).
1.12. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 12: Intraoperative blood loss by dosage
We could not use Padhy 2019 in the age subgroup meta‐analysis, because they did not report baseline characteristics in both groups. Nuhi 2015 and Padhy 2019 could not be included in Analysis 1.13, because the type of anaesthesia was not reported. El Shal 2015 and Nuhi 2015 were not included in Analysis 1.14, because the use of vasoconstrictors was not reported.
Possible reasons for heterogeneity should be viewed in the light of clinical diversity and could be the following:
Participants across studies most likely had different degrees of disease.
Some studies included participants with chronic rhinosinusitis with nasal polyps and other studies only participants with chronic rhinosinusitis without nasal polyps or mixed disease.
Different methods of calculation of total blood loss were used (e.g. weight of gauze pads or sponges, blood in suction bottles).
Different surgical instruments were used (grabbing, cutting and debrider devices).
One study used topical tranexamic acid (Jabalameli 2006); the other 11 studies used intravenous tranexamic acid. We estimated the quality of Jabalameli 2006 to be low and therefore we cannot be certain whether there is an actual difference between treatment modalities in reducing intraoperative blood loss.
Significant adverse effects (seizures, thromboembolism within 12 weeks of surgery)
There were eight studies (N = 664) that could be meta‐analysed (Alimian 2011; Dongare 2018; Eldaba 2013; El Shal 2015; El‐Ozairy 2021; Nuhi 2015; Quiroga 2018; Yang 2021). When we combined studies we found that tranexamic acid probably has little to no effect on the development of significant adverse events (seizures or thromboembolism) within 24 hours of surgery, with no events in either group (risk difference (RD) 0.00, 95% CI ‐0.02 to 0.02; 8 studies, 664 participants; moderate‐certainty evidence) (Analysis 1.17). In Athanasiadis 2007, which was not included in this meta‐analysis due to a split‐body design, no adverse effects occurred in either group.
1.17. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 17: Significant adverse events (seizures, thromboembolism within 12 weeks of surgery)
Follow‐up was not as long as 12 weeks after surgery in any of the studies that reported on adverse effects. All studies reported events on the day of surgery, except for Dongare 2018, in which thrombo‐embolic events were evaluated up until discharge (but it is unknown when patients were discharged after surgery). Therefore our results are limited.
Secondary outcomes
Duration of surgery
Ten studies were suitable for meta‐analysis, comprising participants that received intravenous tranexamic acid (Alimian 2011; Dongare 2018; Eldaba 2013; El Shal 2015; Langille 2013; Pannerselvam 2019; Quiroga 2018; Yang 2021), topical tranexamic acid (Baradaranfar 2017), or either intravenous, topical or combined tranexamic acid (El‐Ozairy 2021). We found that tranexamic acid probably results in a small difference in the duration of surgery with a mean difference (MD) of ‐13.04 minutes (95% CI ‐19.27 to ‐6.81, P < 0.00001, random‐effects model; 10 studies, 666 participants; moderate‐certainty evidence) (Analysis 1.18).
1.18. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 18: Duration of surgery (minutes)
The funnel plot showed asymmetry (Figure 8). This probably does not indicate reporting bias, but might rather be the effect of heterogeneity in study design or a larger effect from the small studies. After a sensitivity analysis excluding studies with a total population of fewer than 30 participants, the asymmetry did disappear from the funnel plot (Analysis 1.24; Figure 9). Baradaranfar 2017 and Quiroga 2018 found no differences in surgical time between the two intervention groups. Quiroga 2018 was a small study with only 10 participants. Baradaranfar 2017 did not report the actual dose given to the patient. A fixed‐effect model analysis did not change the overall treatment effect (Analysis 1.25).
8.
1.24. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 24: Duration of surgery (minutes) excluding small sized studies
9.
1.25. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 25: Duration of surgery (minutes) using fixed‐effect model
Subgroup analyses
There was substantial heterogeneity in the main analysis (Chi2 = 48.41; I2= 81%). This heterogeneity might be due to diversity in the extensiveness of surgery and the presence or absence of nasal polyps. Subgroup analysis for route of administration (P = 0.33; Analysis 1.19), type of anaesthesia (P = 0.28; Analysis 1.21), use of peri‐ or preoperative vasoconstrictors (P = 0.81; Analysis 1.22) and population age (P = 0.05; Analysis 1.23) showed no evidence of a difference between subgroups.
1.19. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 19: Duration of surgery (minutes) by route of administration
1.21. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 21: Duration of surgery by type of anaesthesia (minutes)
1.22. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 22: Duration of surgery and use of vasoconstrictive agents (minutes)
1.23. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 23: Duration of surgery by age (minutes)
El Shal 2015 could not be included in Analysis 1.22, because this information was not reported by the study. There was evidence of subgroup differences in the duration of surgery for dosage, probably due to the large heterogeneity (eight different dosages used and compared, within 10 studies (test for subgroup differences: Chi² = 91.65, df = 7 (P < 0.00001), I² = 92.4%; Analysis 1.20). We noted evidence of a difference in favour of tranexamic acid in the subgroups: intravenous 5 mg/kg, intravenous 15 mg/kg, intravenous 25 mg/kg, intravenous 15 mg/kg plus 400 mL saline solution with 2 g tranexamic acid. However, we noted no evidence of a difference between tranexamic acid and control for the other dose subgroups (intravenous 500 mg, intravenous 10 mg/kg, intravenous 15 mg/kg + 1 mg/kg/hour, topical 2000 mg).
1.20. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 20: Duration of surgery by dosage (minutes)
Incomplete surgery
The only two studies reporting this outcome were Langille 2013 and Padhy 2019.There were no incidents of incomplete surgery in either treatment group (RD 0.00, 95% CI ‐0.09 to 0.09; 2 studies, 58 participants; moderate‐certainty evidence) (Analysis 1.26). Tranexamic acid probably neither increases nor decreases the incidence of incomplete surgery.
1.26. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 26: Incomplete surgery
Surgical complications
The only two studies reporting this outcome were Langille 2013 and Padhy 2019.In the total of 58 participants no surgical complications were seen (RD 0.00, 95% CI ‐0.09 to 0.09; 2 studies, 58 participants; moderate‐certainty evidence) (Analysis 1.27). Tranexamic acid likely results in little to no difference in surgical complications.
1.27. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 27: Surgical complications
Postoperative bleeding (placement of packing or revision surgery) in the first two weeks after surgery
Six studies investigated postoperative bleeding, comprising 404 patients (Alimian 2011; Athanasiadis 2007; Baradaranfar 2017; Eldaba 2013; El Shal 2015; Yang 2021). In all studies follow‐up was limited to one to three days after surgery for this outcome. There were no postoperative bleeding events in the tranexamic acid group. Alimian 2011 reported that one participant in the placebo group experienced postoperative bleeding within three days after surgery. El Shal 2015 reported that one participant in the placebo group experienced postoperative bleeding within 24 hours of surgery. Tranexamic acid may not change the likelihood of postoperative bleeding in the first three days after surgery (placement of packing or revision surgery) (RD ‐0.01, 95% CI ‐0.03 to 0.02; 6 studies, 404 participants; low‐certainty evidence) (Analysis 1.28). A fixed‐effect analysis did not change the result (Analysis 1.29).
1.28. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 28: Postoperative bleeding (place of packing or revision surgery within 14 days of surgery)
1.29. Analysis.
Comparison 1: Tranexamic acid versus placebo (saline solution or sterile water), Outcome 29: Postoperative bleeding (place of packing or revision surgery within 14 days of surgery) using fixed‐effect model
Discussion
Summary of main results
See Table 1.
The primary outcome measures in this review were surgical field bleeding score, intraoperative blood loss and significant adverse effects (seizures and thromboembolism within 12 weeks after surgery). In total, we included 14 studies. The primary subgroup analysis of interest was the method of administration of tranexamic acid (either topical or intravenous).
In the 13 included studies that evaluated surgical field bleeding score as an outcome we found moderate‐certainty evidence that tranexamic acid likely results in a large decrease in surgical field bleeding score compared to placebo. Tranexamic acid was used in a topical fashion in four studies, topical and/or intravenous in one study, and intravenous in the other eight studies. Subgroup analyses by age, type of anaesthesia and use of pre‐ or intraoperative vasoconstrictors did not indicate subgroup differences. We noted evidence of a difference in favour of tranexamic acid with the combined administration and intravenous administration. We noted evidence of a difference in favour of tranexamic acid for a dose of intravenous 5 mg/kg, intravenous 10 mg/kg, intravenous 15 mg/kg, intravenous 25 mg/kg, topical 1000 mg and intravenous 15 mg/kg with topical 2000 mg. However, no evidence of a difference was noted between tranexamic acid and control for the other dose subgroups. These other dose subgroups were used in the smallest studies, which might be an explanation. Furthermore, in the study using topical 2000 mg in 400 mL saline whenever the field became obscured, we do not know how much tranexamic acid each patient received (Baradaranfar 2017).
We combined 12 studies, which suggested that tranexamic acid may slightly reduce blood loss during surgery (mL) compared to placebo (low‐certainty evidence). Subgroup analysis for age, administration route, method of administration, population, type of anaesthesia and use of pre‐ or intraoperative vasoconstrictors did not change the direction of the overall treatment effect. Evidence of a difference in favour of tranexamic was noted in the subgroups intravenous 5 mg/kg, intravenous 10 mg/kg, intravenous 15 mg/kg, intravenous 25 mg/kg and topical 1000 mg. However, no evidence of a difference was noted between tranexamic acid and control for the other dose subgroups. Again, these other dose subgroups were used in the smallest studies and again we do not know how much tranexamic acid each patient received in Baradaranfar 2017.
Topical application was used in only one study in this analysis (Jabalameli 2006). We considered this study to have unclear risk of bias for allocation concealment and blinding. We therefore cannot establish whether topical application of tranexamic acid leads to a reduction in blood loss.
No study reported on significant adverse effects with a follow‐up of 12 weeks. Our evidence is therefore limited to 24 hours of follow‐up after surgery. Evidence from eight included studies showed that, compared to placebo, tranexamic acid probably has little to no effect on the development of immediate significant adverse events (seizures or thromboembolism) within 24 hours of surgery, with no events in either group (moderate‐certainty evidence), but there is no evidence regarding the risk of serious adverse effects more than 24 hours after surgery. Considering the biochemical properties of tranexamic acid one would expect adverse events to occur fast in the case of a single dose of the medicine (day of surgery). Tranexamic acid prevents haemorrhage by inhibiting plasminogen (and so stabilising clot formation). The route of administration and metabolism play a significant role. About 90% of an intravenous dosage of this drug is excreted in the urine within 24 hours. The half‐life of the drug is two hours. If the drug is repeatedly administered then the drug will still be present in the body and active in the tissue for almost 24 hours. We feel that in this case, where all patients received tranexamic acid only on the day of surgery, a 12‐week follow‐up would probably not lead to more seizures or thromboembolism.
In the eight studies that we meta‐analysed for duration of surgery the results suggest that tranexamic acid probably results in a small difference in the duration of surgery compared to placebo (moderate‐certainty evidence). Subgroup analysis by age, route of administration, type of anaesthesia and use of pre‐ or intraoperative vasoconstrictors did not show a different direction of the overall treatment effect. Evidence of a difference in favour of tranexamic acid was noted in the subgroups: intravenous 5 mg/kg, intravenous 15 mg/kg, intravenous 25 mg/kg, intravenous 15 mg/kg plus 400 mL saline solution with 2 g tranexamic acid. Topical application was used in only two studies in this analysis (Baradaranfar 2017; El‐Ozairy 2021). We therefore cannot establish whether topical application of tranexamic acid influences the duration of surgery.
Completeness of surgery and surgical complications were only recorded in two small studies using intravenous tranexamic acid. Tranexamic acid probably neither increases nor decreases the incidence of incomplete surgery, with no events in either group (moderate‐certainty evidence) and likely results in little to no difference in surgical complications, again with no events in either group (moderate‐certainty evidence), although the numbers are too small to draw firm conclusions.
When we pooled six studies (two topical application and four intravenous application) we found that tranexamic acid may not change the likelihood of postoperative bleeding (placement of packing or revision surgery within two weeks of surgery) (low‐certainty evidence). The follow‐up in the included studies was limited to one to three days after surgery, instead of the aimed for two weeks follow‐up. Two events were recorded in the placebo group, compared to zero events in the tranexamic acid group.
Overall completeness and applicability of evidence
The 14 included studies in this review only addressed some of the review questions and the evidence is not complete.
The participants included in this review were both children and adults and form a representative sample, although few studies reported the extent of nasal disease, which could well influence outcomes such as duration of surgery and blood loss.
The included studies highlight the different delivery modalities used and dosing differences. With the currently available evidence we are not able to answer the question of whether there is any clear beneficial effect of intravenous administration over topical administration or vice versa; nor are we able to conclude whether there is a preferential dose of tranexamic acid. Based on subgroup analysis, the evidence with respect to surgical field bleeding score and duration of surgery suggests a benefit of intravenous application over topical application and that an intravenous dose > 500 mg for adults may be optimal (at least 5 mg/kg). However, due to the large heterogeneity in dosing (which leads to fewer options for pooling dosages), in combination with the small sample sizes, no clear conclusions can be drawn. We did not find a clear dose‐response relationship for either beneficial or harmful effects and other available literature did not provide more clarity (Abu‐Zaid 2022; Leverett 2022). In a large systematic review and meta‐analysis of 216 studies comprising 125,550 patients undergoing surgical procedures, no dose‐dependent association with thrombo‐embolic events was detected (Taeuber 2021).
For the primary outcome, bleeding score, it was unclear in four studies used in the meta‐analysis at what time point the bleeding score was calculated. For the other included studies the scores represent 10 to 30 minutes after the start of surgery or after the administration of tranexamic acid. Therefore we could not establish at which time point the most effect of tranexamic acid would be expected.
There was a lack of studies investigating completeness of surgery and surgical complications as outcome parameters. The evidence regarding adverse events is limited to 24 hours follow‐up postoperatively, which might be sufficient considering the specific adverse events of interest (seizures and thromboembolic events), however it would have been preferential to have a longer follow‐up after surgery. The same follow‐up duration was used for postoperative bleeding, which was not recorded for a follow‐up duration of two weeks in any of the studies. We feel that this is insufficient for this outcome.
Quality of the evidence
The evidence in this review (14 studies with a total of 942 participants) is not fully sufficient to allow robust conclusions to be drawn. The certainty of evidence for the outcomes assessed ranged from low to moderate. We downgraded the evidence for all outcomes mainly because of imprecision, indirectness or heterogeneity. See Table 1.
Potential biases in the review process
This review is based on a published protocol (Ravesloot 2017). There have been some changes to the search methods (see Differences between protocol and review). The search terms used should have identified all randomised controlled trials comparing the use of tranexamic acid during endoscopic sinus surgery to placebo (saline solution) or no tranexamic acid. The methodology of the review is unlikely to have introduced any bias into the review process.
We did decide to proceed with meta‐analysis even in the presence of statistical heterogeneity. We feel that there will always be clinical and methodological diversity in this area. We have quantified the level of heterogeneity in order to be able to interpret the impact on the meta‐analysis. We chose the random‐effects model for data synthesis in all analyses and additional fixed‐effect analysis if relevant.
For the surgical field bleeding score outcome we had to make some modifications to be able to perform meta‐analysis. We transformed N (%) or median and ranges into means (SD). We chose to use one measurement per study (highest time point after start of surgery), with a maximum of 30 minutes after surgery, to assess bleeding score because most studies reported within 30 minutes of surgery.
Agreements and disagreements with other studies or reviews
We are aware of two systematic reviews that have looked into the role of tranexamic acid in nasal surgery (Kim 2019; Pundir 2013). Pundir 2013 also included rhinoplasty and septoplasty and identified six of the studies included in our review (Alimian 2011; Athanasiadis 2007; Baradaranfar 2017; Jabalameli 2006; Langille 2013; Nuhi 2015). They concluded that intraoperative use of topical and intravenous tranexamic acid could significantly reduce estimated blood loss and improve surgical field quality, but highlighted that it would probably not reduce operation time. Kim 2019 included seven studies (Alimian 2011; Dongare 2018; El Shal 2015; Langille 2013; Nuhi 2015; Chhappola 2011; Moise 2010), five of which were also included in our review (Alimian 2011; Dongare 2018; El Shal 2015; Langille 2013; Nuhi 2015), and two of which we excluded (Chhappola 2011; Moise 2010). They concluded that the systemic administration of tranexamic acid could decrease operative time and intraoperative blood loss, and increase the satisfaction of surgeons. Both reviews drew conclusions within the limitations of the small number of studies available, the heterogeneity in the surgeries performed and the different dosing schemes used. The mainly low‐ and moderate‐certainty evidence in our review points in the same direction as these two reviews.
Authors' conclusions
Implications for practice.
There is moderate‐certainty evidence that topical or intravenous tranexamic acid probably reduces the surgical field bleeding score substantially within 30 minutes of the start of surgery or application of tranexamic acid. There is low‐certainty evidence that tranexamic acid may slightly reduce intraoperative blood loss. Whilst there is moderate‐certainty evidence that tranexamic acid probably does not lead to more immediate significant adverse events compared to placebo, there is no evidence regarding the risk of serious adverse events more than 24 hours after surgery.
There is moderate‐certainty evidence that tranexamic acid probably results in a small difference in the total duration of surgery. There is not enough evidence available to draw robust conclusions about incomplete surgery or surgical complications. There is low‐certainty evidence that tranexamic acid may not change postoperative bleeding within three days of surgery. Unfortunately, there is no evidence with respect to adverse events at a longer duration of follow‐up.
Implications for research.
Most included randomised controlled trials were performed after 2013, although two studies were performed in 2006 and 2007. This review has found evidence that there is a general benefit of tranexamic acid during endoscopic sinus surgery with respect to surgical field bleeding score, intraoperative blood loss and duration of surgery. Since there was a great deal of heterogeneity in the included studies the effect size cannot be estimated with high certainty. The only study that fully reported on important potential effect modifiers was Langille 2013. It is highly desirable for upcoming trials to report relevant baseline characteristics such as the severity of disease for which endoscopic sinus surgery is required, the extent of surgery, the surgical position of the patient and the surgical instruments used. More randomised controlled trials would be informative and should help to identify a preferable dose or route of administration of tranexamic acid. The main focus should be on surgical complications and adverse events, with a longer duration of follow‐up after surgery than in the current studies.
History
Protocol first published: Issue 11, 2017
Acknowledgements
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure, Cochrane Programme Grant or Cochrane Incentive funding to Cochrane ENT. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Evidence Synthesis Programme, NIHR, NHS or the Department of Health.
Editorial and peer reviewer contributions
Cochrane ENT supported the authors in the development of this review.
The following people conducted the editorial process for this article:
Sign‐off Editor (final editorial decision): Professor Martin Burton, Co‐ordinating Editor, Cochrane ENT.
Managing Editor (selected peer reviewers, collated peer reviewer comments, provided editorial guidance to authors, edited the article): Jenny Bellorini, Cochrane ENT.
Copy Editor (copy editing and production): Jenny Bellorini, Cochrane ENT.
Peer reviewers (provided comments and recommended an editorial decision): Professor Carl Philpott, Department of Medicine, Norwich Medical School, University of East Anglia (clinical/content review), Samuel MacKeith, Assistant Co‐ordinating Editor Cochrane ENT (clinical/content review), Adrian James, Editor Cochrane ENT (clinical/content review), Richard Harvey, Editor Cochrane ENT (clinical/content review), Richard Rosenfeld, Editor Cochrane ENT (clinical/content review), Jacqueline Coupe (consumer review), Brian Duncan (consumer review), Nuala Livingstone (methods review).
Appendices
Appendix 1. Search strategies
| CENTRAL (via CRS Web) | Cochrane ENT Register (via CRS Web) | Ovid MEDLINE | Ovid Embase |
| 1 MESH DESCRIPTOR Sinusitis EXPLODE ALL AND CENTRAL:TARGET 2 MESH DESCRIPTOR Rhinitis AND CENTRAL:TARGET 3 MESH DESCRIPTOR Rhinitis, Atrophic EXPLODE ALL AND CENTRAL:TARGET 4 MESH DESCRIPTOR Rhinitis, Vasomotor EXPLODE ALL AND CENTRAL:TARGET 5 MESH DESCRIPTOR Paranasal Sinus Diseases AND CENTRAL:TARGET 6 MESH DESCRIPTOR Paranasal Sinuses EXPLODE ALL AND CENTRAL:TARGET 7 (rhinosinusitis or nasosinusitis or pansinusitis or ethmoiditis or sphenoiditis):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 8 (kartagener* near syndrome*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 9 (inflamm* near sinus*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 10 ((maxilla* or frontal*) near sinus*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 12 MESH DESCRIPTOR Chronic Disease EXPLODE ALL AND CENTRAL:TARGET 13 MESH DESCRIPTOR Recurrence EXPLODE ALL AND CENTRAL:TARGET 14 (chronic or persis* or recurrent*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 15 #12 OR #13 OR #14 16 #11 AND #15 17 ((sinusitis or rhinitis) near (chronic or persis* or recurrent*)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 18 (CRSwNP or CRSsNP or ARS or RARS or ARR):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 19 #16 OR #17 OR #18 20 MESH DESCRIPTOR Nasal Polyps EXPLODE ALL AND CENTRAL:TARGET 21 MESH DESCRIPTOR Nose EXPLODE ALL AND CENTRAL:TARGET 22 MESH DESCRIPTOR Nose Diseases EXPLODE ALL AND CENTRAL:TARGET 23 #21 OR #22 24 MESH DESCRIPTOR Polyps EXPLODE ALL AND CENTRAL:TARGET 25 #23 AND #24 26 ((nose or nasal or rhino* or rhinitis or sinus* or sinonasal) near (papilloma* or polyp*)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 27 (rhinopolyp*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 28 #19 OR #20 OR #25 OR #26 OR #27 29 MESH DESCRIPTOR Endoscopy EXPLODE ALL AND CENTRAL:TARGET 30 MESH DESCRIPTOR Surgical Procedures, Operative EXPLODE ALL AND CENTRAL:TARGET 31 (surg*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 32 (endoscop* or uncinectomy or antrostomy or antrotomy or ethmoidectomy or sphenoidotomy):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 33 (sinus* near surg*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 34 (ess):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 35 #29 OR #30 OR #31 OR #32 OR #33 OR #34 36 #28 AND #35 37 MESH DESCRIPTOR Sinusitis EXPLODE ALL WITH QUALIFIER SU AND CENTRAL:TARGET 38 MESH DESCRIPTOR Paranasal Sinus Diseases WITH QUALIFIER SU AND CENTRAL:TARGET 39 MESH DESCRIPTOR Paranasal sinuses EXPLODE ALL WITH QUALIFIER SU AND CENTRAL:TARGET 40 MESH DESCRIPTOR Rhinitis EXPLODE ALL WITH QUALIFIER SU AND CENTRAL:TARGET 41 MESH DESCRIPTOR Nasal Polyps EXPLODE ALL WITH QUALIFIER SU AND CENTRAL:TARGET 42 (endoscop* near sinus* near surg*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 43 (sinonasal* and surg*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 44 (FESS):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 45 (((paranasal or nasal) near sinus*) and surg*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 46 #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 47 MESH DESCRIPTOR Antifibrinolytic Agents EXPLODE ALL AND CENTRAL:TARGET 48 (tranexamic or AMCHA or AMCA or Anvitoff or Cyclo‐F or Cyklokapron or Espercil or Exacyl or Femstrual or Lysteda or Spotof or Transamin* or Transcam* or TXA or Traxyl or Ugurol or "KABI 2161" or spotof or Amchafibrin* or Antifibrinolytic* or "Anti fibrinolytic*" or Anti‐fibrinolytic* or Antifibrinolysin* or Aminocaproic*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 49 (trans and (cyclohexanecarboxylic or "cyclohexane carboxylic")):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 50 (plasma near inhibitor*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 51 #47 OR #48 OR #49 OR #50 |
1 (trans and (cyclohexanecarboxylic or "cyclohexane carboxylic")):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER 2 (tranexamic or AMCHA or AMCA or Anvitoff or Cyclo‐F or Cyklokapron or Espercil or Exacyl or Femstrual or Lysteda or Spotof or Transamin* or Transcam* or TXA or Traxyl or Ugurol or "KABI 2161" or spotof or Amchafibrin* or Antifibrinolytic* or "Anti fibrinolytic*" or Anti‐fibrinolytic* or Antifibrinolysin* or Aminocaproic*):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER 3 (plasma near inhibitor*):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER 4 #1 OR #2 OR #352 #46 AND #51 |
1 exp Sinusitis/ 2 Rhinitis/ 3 exp Rhinitis, Atrophic/ 4 exp Rhinitis, Vasomotor/ 5 Paranasal Sinus Diseases/ 6 exp Paranasal Sinuses/ 7 (rhinosinusitis or nasosinusitis or pansinusitis or ethmoiditis or sphenoiditis).ab,ti. 8 (kartagener* adj6 syndrome*).ab,ti. 9 (inflamm* adj6 sinus*).ab,ti. 10 ((maxilla* or frontal*) adj6 sinus*).ab,ti. 11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 12 exp Chronic Disease/ 13 exp Recurrence/ 14 (chronic or persis* or recurrent*).ab,ti. 15 12 or 13 or 14 16 11 and 15 17 ((sinusitis or rhinitis) adj6 (chronic or persis* or recurrent*)).ab,ti. 18 (CRSwNP or CRSsNP or ARS or RARS or ARR).ab,ti. 19 16 or 17 or 18 20 exp Nasal Polyps/ 21 exp Nose/ 22 exp Nose Diseases/ 23 21 or 22 24 exp Polyps/ 25 23 and 24 26 ((nose or nasal or rhino* or rhinitis or sinus* or sinonasal) adj6 (papilloma* or polyp*)).ab,ti. 27 rhinopolyp*.ab,ti. 28 19 or 20 or 25 or 26 or 27 29 exp Endoscopy/ 30 exp Surgical Procedures, Operative/ 31 surg*.ab,ti. 32 (endoscop* or uncinectomy or antrostomy or antrotomy or ethmoidectomy or sphenoidotomy).ab,ti. 33 (sinus* adj6 surg*).ab,ti. 34 ess.ab,ti. 35 29 or 30 or 31 or 32 or 33 or 34 36 28 and 35 37 exp Sinusitis/su [SURGERY] 38 Paranasal Sinus Diseases/su [SURGERY] 39 exp Paranasal sinuses/su [SURGERY] 40 exp Rhinitis/su [SURGERY] 41 exp Nasal Polyps/su [SURGERY] 42 (endoscop* adj6 sinus* adj6 surg*).ab,ti. 43 (sinonasal* and surg*).ab,ti. 44 FESS.ab,ti. 45 (((paranasal or nasal) adj6 sinus*) and surg*).ab,ti. 46 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 47 exp Antifibrinolytic Agents/ 48 (tranexamic or AMCHA or AMCA or Anvitoff or Cyclo‐F or Cyklokapron or Espercil or Exacyl or Femstrual or Lysteda or Spotof or Transamin* or Transcam* or TXA or Traxyl or Ugurol or "KABI 2161" or spotof or Amchafibrin* or Antifibrinolytic* or "Anti fibrinolytic*" or Anti‐fibrinolytic* or Antifibrinolysin* or Aminocaproic*).ab,ti. 49 (trans and (cyclohexanecarboxylic or "cyclohexane carboxylic")).ab,ti. 50 (plasma adj6 inhibitor*).ab,ti. 51 47 or 48 or 49 or 50 52 46 and 51 |
1 exp sinusitis/ 2 rhinitis/ 3 exp atrophic rhinitis/ 4 exp vasomotor rhinitis/ 5 paranasal sinus disease/ 6 exp paranasal sinus/ 7 (rhinosinusitis or nasosinusitis or pansinusitis or ethmoiditis or sphenoiditis).ab,ti. 8 (kartagener* adj6 syndrome*).ab,ti. 9 (inflamm* adj6 sinus*).ab,ti. 10 ((maxilla* or frontal*) adj6 sinus*).ab,ti. 11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 12 exp chronic disease/ 13 exp recurrent disease/ 14 (chronic or persis* or recurrent*).ab,ti. 15 12 or 13 or 14 16 11 and 15 17 ((sinusitis or rhinitis) adj6 (chronic or persis* or recurrent*)).ab,ti. 18 (CRSwNP or CRSsNP or ARS or RARS or ARR).ab,ti. 19 16 or 17 or 18 20 exp nose polyp/ 21 exp nose/ 22 exp nose disease/ 23 21 or 22 24 exp polyp/ 25 23 and 24 26 ((nose or nasal or rhino* or rhinitis or sinus* or sinonasal) adj6 (papilloma* or polyp*)).ab,ti. 27 rhinopolyp*.ab,ti. 28 19 or 20 or 25 or 26 or 27 29 exp endoscopy/ 30 exp surgery/ 31 (endoscop* or uncinectomy or antrostomy or antrotomy or ethmoidectomy or sphenoidotomy).ab,ti. 32 surg*.ab,ti. 33 ess.ab,ti. 34 (sinus* adj6 surg*).ab,ti. 35 29 or 30 or 31 or 32 or 33 or 34 36 28 and 35 37 exp sinusitis/su [Surgery] 38 exp paranasal sinus/su [Surgery] 39 paranasal sinus disease/su [Surgery] 40 exp rhinitis/su [Surgery] 41 exp nose polyp/su [Surgery] 42 (endoscop* adj6 sinus* adj6 surg*).ab,ti. 43 (sinonasal* and surg*).ab,ti. 44 FESS.ab,ti. 45 (((paranasal or nasal) adj6 sinus*) and surg*).ab,ti. 46 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 47 exp antifibrinolytic agent/ 48 (tranexamic or AMCHA or AMCA or Anvitoff or Cyclo‐F or Cyklokapron or Espercil or Exacyl or Femstrual or Lysteda or Spotof or Transamin* or Transcam* or TXA or Traxyl or Ugurol or "KABI 2161" or spotof or Amchafibrin* or Antifibrinolytic* or "Anti fibrinolytic*" or Anti‐fibrinolytic* or Antifibrinolysin* or Aminocaproic*).ab,ti. 49 (trans and (cyclohexanecarboxylic or "cyclohexane carboxylic")).ab,ti. 50 (plasma adj6 inhibitor*).ab,ti. 51 47 or 48 or 49 or 50 52 46 and 51 53 (random* or factorial* or placebo* or assign* or allocat* or crossover*).tw. 54 (control* adj group*).tw. 55 (trial* and (control* or comparative)).tw. 56 ((blind* or mask*) and (single or double or triple or treble)).tw. 57 (treatment adj arm*).tw. 58 (control* adj group*).tw. 59 (phase adj (III or three)).tw. 60 (versus or vs).tw. 61 rct.tw. 62 crossover procedure/ 63 double blind procedure/ 64 single blind procedure/ 65 randomization/ 66 placebo/ 67 exp clinical trial/ 68 parallel design/ 69 Latin square design/ 70 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 71 exp ANIMAL/ or exp NONHUMAN/ or exp ANIMAL EXPERIMENT/ or exp ANIMAL MODEL/ 72 exp human/ 73 71 not 72 74 70 not 73 75 52 and 74 |
| Web of Science (Web of Knowledge | ClinicalTrials.gov | ICTRP | Other |
| #1 TOPIC: (rhinosinusitis or nasosinusitis or pansinusitis or ethmoiditis or sphenoiditis) #2 TOPIC: (kartagener* near/6 syndrome*) #3 TOPIC: (inflamm* near/6 sinus*) #4 TOPIC: (((maxilla* or frontal*) near/6 sinus*)) #5 #4 OR #3 OR #2 OR #1 #6 TOPIC: (chronic or persis* or recurrent*) #7 #6 AND #5 #8 TOPIC: ((sinusitis or rhinitis) near/6 (chronic or persis* or recurrent*)) #9 TOPIC: (CRSwNP or CRSsNP or ARS or RARS or ARR) #10 TOPIC: ((nose or nasal or rhino* or rhinitis or sinus* or sinonasal) near/6 (papilloma* or polyp*)) #11 TOPIC: (rhinopolyp*) #12 #11 OR #10 OR #9 OR #8 OR #7 #13 TOPIC: (endoscop* or uncinectomy or antrostomy or antrotomy or ethmoidectomy or sphenoidotomy or surg*) #14 TOPIC: (sinus* near/6 surg*) #15 TOPIC: (ess) #16 #15 OR #14 OR #13 #17 #16 AND #12 #18 TOPIC: ((endoscop* near/6 sinus* near/6 surg*)) #19 TOPIC: (sinonasal* and surg*) #20 TOPIC: (FESS) #21 TOPIC: ((((paranasal or nasal) NEAR/6 sinus*) and surg*)) #22 #21 OR #20 OR #19 OR #18 OR #17 #23 TOPIC: ((tranexamic or AMCHA or AMCA or Anvitoff or Cyclo‐F or Cyklokapron or Espercil or Exacyl or Femstrual or Lysteda or Spotof or Transamin* or Transcam* or TXA or Traxyl or Ugurol or "KABI 2161" or spotof or Amchafibrin* or Antifibrinolytic* or "Anti fibrinolytic*" or Anti‐fibrinolytic* or Antifibrinolysin* or Aminocaproic*)) #24 TOPIC: ((trans and (cyclohexanecarboxylic or "cyclohexane carboxylic"))) #25 TOPIC: (plasma near/6 inhibitor*) #26 #25 OR #24 OR #23 #27 #26 AND #22 |
via CRS Web 1 (trans and (cyclohexanecarboxylic or "cyclohexane carboxylic")) AND ALL:CRSTYPE AND CENTRAL:TARGET 2 (tranexamic or AMCHA or AMCA or Anvitoff or Cyclo‐F or Cyklokapron or Espercil or Exacyl or Femstrual or Lysteda or Spotof or Transamin* or Transcam* or TXA or Traxyl or Ugurol or "KABI 2161" or spotof or Amchafibrin* or Antifibrinolytic* or "Anti fibrinolytic*" or Anti‐fibrinolytic* or Antifibrinolysin* or Aminocaproic*) AND ALL:CRSTYPE AND CENTRAL:TARGET 3 (plasma near inhibitor*) AND ALL:CRSTYPE AND CENTRAL:TARGET 4 #1 OR #2 OR #3 AND ALL:CRSTYPE AND CENTRAL:TARGET 5 (nct*):AU AND CENTRAL:TARGET 6 (nct*):SID,SN AND STUDY:CRSTYPE AND CENTRAL:TARGET 7 #5 OR #6 AND ALL:CRSTYPE AND CENTRAL:TARGET 8 #4 AND #7 AND ALL:CRSTYPE AND CENTRAL:TARGET via www.clinicaltrials.gov (tranexamic OR Antifibrinolytic OR "Anti fibrinolytic" OR AMCHA OR AMCA OR Anvitoff OR Cyclo‐F OR Cyklokapron OR Espercil OR Exacyl OR Femstrual OR Lysteda OR Spotof OR Transamin OR transmins OR Antifibrinolysin* OR Aminocaproic* OR TXA OR Traxyl OR Ugurol OR "KABI 2161" OR spotof OR Amchafibrin* OR (trans AND cyclohexanecarboxylic) OR (trans AND "cyclohexane carboxylic" OR Antifibrinolytics) OR “plasma inhipitor”) AND (fess OR (sinus AND surgery) OR ESS OR (nose AND surgery) OR (nasal AND surgery) OR (paranasal AND surgery) OR rhinitis OR rhinosinusitis OR sinusitis OR crs OR crswnp OR crssnp OR (nasal polyp) OR (sinonasal AND surgery)) Study Type: Interventional |
tranexamic* AND sinus* OR tranexamic* AND nasal OR tranexamic* AND nose OR tranexamic* AND paranasal OR tranexamic* AND rhinitis OR tranexamic* AND rhino* OR tranexamic* AND sinonasal OR tranexamic* AND FESS OR tranexamic* AND ESS OR tranexamic* AND CRS* OR Antifibrinolytic* AND sinus* OR Antifibrinoly* AND nasal OR Antifibrinoly* AND nose OR Antifibrinoly* AND paranasal OR Antifibrinoly* AND rhinitis OR Antifibrinoly* AND rhino* OR Antifibrinoly* AND sinonasal OR Antifibrinoly* AND FESS OR Antifibrinoly* AND ESS OR Antifibrinoly* AND CRS* OR “Anti fibrinoly*” AND sinus* OR “Anti fibrinoly*” AND nasal OR “Anti fibrinoly*” AND nose OR “Anti fibrinoly*” AND paranasal OR “Anti fibrinoly*” AND rhinitis OR “Anti fibrinoly*” AND rhino* OR “Anti fibrinoly*” AND sinonasal OR “Anti fibrinoly*” AND FESS OR “Anti fibrinoly*” AND ESS OR “Anti fibrinoly*” AND CRS* OR Antiplasmin** AND sinus* OR Antiplasmin* AND nasal OR Antiplasmin* AND nose OR Antiplasmin* AND paranasal OR Antiplasmin* AND rhinitis OR Antiplasmin* AND rhino* OR Antiplasmin* AND sinonasal OR Antiplasmin* AND FESS OR Antiplasmin* AND ESS OR Antiplasmin* AND CRS* |
LILACS TW:tranexamic* OR TW:Antifibrinoly* OR (TW:"plasma inhibitor*") OR TW:Antiplasmin* AND Controlled Clinical Trial CNKI (via Google Scholar) site:en.cnki.com.cn (tranexamic OR Antifibrinolytic AND Antifibrinolytics OR “plasma inhipitor”) (fess OR (sinus surgery) OR ESS OR (nasal surgery) OR (paranasal surgery) OR rhinitis OR rhinosinusitis OR sinusitis OR (nasal polyp) OR (sinonasal surgery)) |
Appendix 2. Summary of data collection
We extracted the following information using a data collection form.
General information: publication type, year, country, author contact details.
Study eligibility: type of study, participants, types of interventions, comparisons and outcomes.
Study methods: design, unit of allocation, start and end dates, duration of participation, ethical approval, funding, possible conflicts of interest.
-
Participants: population description, setting, inclusion and exclusion criteria, method of recruitment, informed consent, total number randomised, clusters (if applicable), baseline imbalances, withdrawals and exclusions, age, sex, race/ethnicity, severity of illness, comorbidities, other relevant sociodemographics, measured and reported subgroups, confounders:
application of anti‐Trendelenburg position (degrees?);
anaesthetic and vasoconstrictive agents administrated to prepare surgical field;
administration of total intravenous anaesthesia or inhalational agents;
mean arterial pressure;
surgical instruments applied (traditional, microdebrider);
presence of polyps, active infection and fungal rhinosinusitis.
Intervention and comparison groups: tranexamic acid and comparison type, number randomised to group, duration of treatment, timing, delivery, dosage, providers, co‐interventions, economic information, resource requirements, integrity of delivery, compliance.
Outcomes: type of outcome, time points measured, time points reported, unit of measurement, scale, assumed risk estimate, power.
Funding sources.
Declarations of interest.
Risk of bias assessment: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, other bias.
Data and analysis: comparison, outcome, subgroup, time points, results, number of missing participants, reason missing, number of participants moved from another group, reason for move, unit of analysis, statistical method.
Other information: key conclusions of the study, references to other relevant studies.
Data and analyses
Comparison 1. Tranexamic acid versus placebo (saline solution or sterile water).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Surgical field bleeding score (during surgery) | 13 | 772 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.87 [‐1.23, ‐0.51] |
| 1.2 Surgical field bleeding score by age (during surgery or within 30 minutes after surgery) | 12 | 739 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.07 [‐1.68, ‐0.46] |
| 1.2.1 Adults (≥ 18 years of age) | 11 | 639 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐1.76, ‐0.37] |
| 1.2.2 Children | 1 | 100 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.12 [‐1.55, ‐0.70] |
| 1.3 Surgical field bleeding score by administration route (during surgery or within 30 minutes after surgery) | 13 | 772 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.96 [‐1.30, ‐0.63] |
| 1.3.1 Topical application | 4 | 196 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.80 [‐1.52, ‐0.08] |
| 1.3.2 Intravenous administration | 9 | 516 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.90 [‐1.16, ‐0.63] |
| 1.3.3 Combined administration | 1 | 60 | Std. Mean Difference (IV, Random, 95% CI) | ‐2.87 [‐3.61, ‐2.14] |
| 1.4 Surgical field bleeding score by dosage (during surgery or within 30 minutes after surgery) | 13 | 772 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐1.33, ‐0.63] |
| 1.4.1 IV 10 mg/kg | 3 | 174 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.10 [‐1.42, ‐0.78] |
| 1.4.2 IV 25 mg/kg | 1 | 100 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.12 [‐1.55, ‐0.70] |
| 1.4.3 IV 500 mg | 1 | 10 | Std. Mean Difference (IV, Random, 95% CI) | 0.50 [‐0.77, 1.77] |
| 1.4.4 IV 15 mg/kg + infusion 1 mg/kg/hour | 1 | 28 | Std. Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.74, 0.74] |
| 1.4.5 IV 15 mg/kg | 2 | 120 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.41, ‐0.41] |
| 1.4.6 Topical 1000 mg | 1 | 56 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐1.54, ‐0.42] |
| 1.4.7 Topical 100 mg or 1000 mg | 1 | 20 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.52 [‐1.42, 0.37] |
| 1.4.8 Topical 2000 mg in 400 mL saline | 2 | 120 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐2.58, 0.77] |
| 1.4.9 IV 5 mg/kg or 15 mg/kg | 1 | 84 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.99 [‐1.47, ‐0.51] |
| 1.4.10 IV 15 mg/kg and topical 2000 mg in 400 mL saline | 1 | 60 | Std. Mean Difference (IV, Random, 95% CI) | ‐3.04 [‐3.79, ‐2.28] |
| 1.5 Surgical field bleeding score by type of anaesthesia (during surgery or within 30 minutes after surgery) | 11 | 722 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.89 [‐1.28, ‐0.50] |
| 1.5.1 Total intravenous anaesthesia (TIVA) | 3 | 200 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.20, ‐0.62] |
| 1.5.2 Inhalational anaesthesia | 5 | 318 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.92 [‐1.76, ‐0.08] |
| 1.5.3 Combined anaesthesia | 3 | 204 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐1.41, ‐0.07] |
| 1.6 Surgical field bleeding score and use of vasoconstrictive agents (during surgery or within 30 minutes after surgery) | 10 | 635 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.00 [‐1.39, ‐0.61] |
| 1.6.1 Use of pre‐operative or perioperative vasoconstrictors | 8 | 464 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.97 [‐1.49, ‐0.44] |
| 1.6.2 No use of pre‐operative or perioperative vasoconstrictors | 2 | 171 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.02 [‐1.35, ‐0.70] |
| 1.7 Surgical field bleeding score (during surgery) excluding small sized studies | 9 | 654 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐1.46, ‐0.66] |
| 1.8 Surgical field bleeding score (during surgery) using fixed‐effect model | 13 | 772 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.97 [‐1.12, ‐0.81] |
| 1.9 Intraoperative blood loss (mL) | 12 | 802 | Mean Difference (IV, Random, 95% CI) | ‐70.32 [‐92.28, ‐48.35] |
| 1.10 Intraoperative blood loss (mL) by age | 11 | 772 | Mean Difference (IV, Random, 95% CI) | ‐74.45 [‐97.99, ‐50.91] |
| 1.10.1 Adult patients ≥ 18 years of age | 10 | 672 | Mean Difference (IV, Random, 95% CI) | ‐76.95 [‐106.97, ‐46.92] |
| 1.10.2 Children | 1 | 100 | Mean Difference (IV, Random, 95% CI) | ‐51.00 [‐59.27, ‐42.73] |
| 1.11 Intraoperative blood loss by administration route | 12 | 802 | Mean Difference (IV, Random, 95% CI) | ‐70.33 [‐92.29, ‐48.37] |
| 1.11.1 Topical application | 1 | 56 | Mean Difference (IV, Random, 95% CI) | ‐55.10 [‐64.54, ‐45.66] |
| 1.11.2 Intravenous administration | 11 | 746 | Mean Difference (IV, Random, 95% CI) | ‐71.84 [‐98.36, ‐45.33] |
| 1.12 Intraoperative blood loss by dosage | 12 | 827 | Mean Difference (IV, Random, 95% CI) | ‐66.40 [‐85.28, ‐47.51] |
| 1.12.1 IV 10 mg/kg | 3 | 174 | Mean Difference (IV, Random, 95% CI) | ‐110.64 [‐194.01, ‐27.26] |
| 1.12.2 IV 25 mg/kg | 1 | 100 | Mean Difference (IV, Random, 95% CI) | ‐51.00 [‐59.27, ‐42.73] |
| 1.12.3 IV 500 mg | 1 | 10 | Mean Difference (IV, Random, 95% CI) | ‐50.00 [‐165.12, 65.12] |
| 1.12.4 IV 15 mg/kg | 4 | 343 | Mean Difference (IV, Random, 95% CI) | ‐56.53 [‐81.08, ‐31.97] |
| 1.12.5 IV 15 mg/kg + 1 mg/kg/hour | 1 | 28 | Mean Difference (IV, Random, 95% CI) | ‐85.00 [‐192.95, 22.95] |
| 1.12.6 Topical 1000 mg | 1 | 56 | Mean Difference (IV, Random, 95% CI) | ‐55.10 [‐64.54, ‐45.66] |
| 1.12.7 Topical 2000 mg in 400 mL saline solution | 1 | 60 | Mean Difference (IV, Random, 95% CI) | ‐18.50 [‐123.83, 86.83] |
| 1.12.8 IV 5 mg/kg | 1 | 56 | Mean Difference (IV, Random, 95% CI) | ‐21.54 [‐26.77, ‐16.31] |
| 1.13 Intraoperative blood loss by type of anaesthesia | 10 | 602 | Mean Difference (IV, Random, 95% CI) | ‐73.38 [‐98.98, ‐47.78] |
| 1.13.1 Total intravenous anaesthesia | 3 | 200 | Mean Difference (IV, Random, 95% CI) | ‐79.46 [‐139.51, ‐19.41] |
| 1.13.2 Inhalational anaesthesia | 4 | 198 | Mean Difference (IV, Random, 95% CI) | ‐93.06 [‐179.34, ‐6.77] |
| 1.13.3 Combined anaesthesia | 3 | 204 | Mean Difference (IV, Random, 95% CI) | ‐33.62 [‐39.44, ‐27.81] |
| 1.14 Intraoperative blood loss and use of vasoconstrictive agents | 10 | 544 | Mean Difference (IV, Random, 95% CI) | ‐53.81 [‐68.73, ‐38.90] |
| 1.14.1 Use of perioperative or pre‐operative vasoconstrictive agents | 8 | 404 | Mean Difference (IV, Random, 95% CI) | ‐51.38 [‐57.20, ‐45.55] |
| 1.14.2 No use of perioperative or pre‐operative vasoconstrictive agents | 2 | 140 | Mean Difference (IV, Random, 95% CI) | ‐79.26 [‐172.50, 13.98] |
| 1.15 Intraoperative blood loss (mL) excluding small sized studies | 9 | 704 | Mean Difference (IV, Random, 95% CI) | ‐73.28 [‐97.98, ‐48.59] |
| 1.16 Intraoperative blood loss (mL) using fixed‐effect model | 12 | 802 | Mean Difference (IV, Fixed, 95% CI) | ‐51.03 [‐54.95, ‐47.12] |
| 1.17 Significant adverse events (seizures, thromboembolism within 12 weeks of surgery) | 8 | 664 | Risk Difference (M‐H, Random, 95% CI) | 0.00 [‐0.02, 0.02] |
| 1.18 Duration of surgery (minutes) | 10 | 666 | Mean Difference (IV, Random, 95% CI) | ‐13.04 [‐19.27, ‐6.81] |
| 1.19 Duration of surgery (minutes) by route of administration | 10 | 726 | Mean Difference (IV, Random, 95% CI) | ‐13.59 [‐19.28, ‐7.90] |
| 1.19.1 Intravenous administration | 9 | 546 | Mean Difference (IV, Random, 95% CI) | ‐13.69 [‐20.05, ‐7.33] |
| 1.19.2 Topical application | 2 | 120 | Mean Difference (IV, Random, 95% CI) | ‐7.14 [‐20.67, 6.39] |
| 1.19.3 Combined administration | 1 | 60 | Mean Difference (IV, Random, 95% CI) | ‐22.50 [‐37.67, ‐7.33] |
| 1.20 Duration of surgery by dosage (minutes) | 10 | 754 | Mean Difference (IV, Random, 95% CI) | ‐15.82 [‐24.19, ‐7.45] |
| 1.20.1 IV 10 mg/kg | 2 | 144 | Mean Difference (IV, Random, 95% CI) | ‐16.58 [‐34.27, 1.11] |
| 1.20.2 IV 25 mg/kg | 1 | 100 | Mean Difference (IV, Random, 95% CI) | ‐51.00 [‐59.27, ‐42.73] |
| 1.20.3 IV 500 mg | 1 | 10 | Mean Difference (IV, Random, 95% CI) | 62.40 [1.57, 123.23] |
| 1.20.4 IV 15 mg/kg + 1 mg/kg/hour | 1 | 28 | Mean Difference (IV, Random, 95% CI) | ‐85.00 [‐192.95, 22.95] |
| 1.20.5 IV 15 mg/kg | 4 | 236 | Mean Difference (IV, Random, 95% CI) | ‐11.59 [‐15.71, ‐7.47] |
| 1.20.6 Topical 2000 mg in 400 mL saline solution | 2 | 120 | Mean Difference (IV, Random, 95% CI) | ‐7.14 [‐20.67, 6.40] |
| 1.20.7 IV 15 mg/kg diluted in 20 mL saline and irrigation fluid 400 mL saline solution with 2 g TXA | 1 | 60 | Mean Difference (IV, Random, 95% CI) | ‐22.50 [‐37.67, ‐7.33] |
| 1.20.8 IV 5 mg/kg | 1 | 56 | Mean Difference (IV, Random, 95% CI) | ‐8.03 [‐13.49, ‐2.57] |
| 1.21 Duration of surgery by type of anaesthesia (minutes) | 10 | 666 | Mean Difference (IV, Random, 95% CI) | ‐27.98 [‐48.38, ‐7.58] |
| 1.21.1 Total intravenous anaesthesia | 2 | 144 | Mean Difference (IV, Random, 95% CI) | ‐7.88 [‐16.30, 0.55] |
| 1.21.2 Inhalational anaesthesia | 5 | 318 | Mean Difference (IV, Random, 95% CI) | ‐52.19 [‐106.14, 1.76] |
| 1.21.3 Combined anaesthesia | 3 | 204 | Mean Difference (IV, Random, 95% CI) | ‐9.79 [‐13.49, ‐6.10] |
| 1.22 Duration of surgery and use of vasoconstrictive agents (minutes) | 9 | 606 | Mean Difference (IV, Random, 95% CI) | ‐11.51 [‐16.90, ‐6.12] |
| 1.22.1 Use of perioperative or pre‐operative vasoconstrictive agents | 7 | 438 | Mean Difference (IV, Random, 95% CI) | ‐11.62 [‐19.55, ‐3.70] |
| 1.22.2 No use of perioperative or pre‐operative vasoconstrictive agents | 2 | 168 | Mean Difference (IV, Random, 95% CI) | ‐10.52 [‐15.19, ‐5.84] |
| 1.23 Duration of surgery by age (minutes) | 10 | 666 | Mean Difference (IV, Random, 95% CI) | ‐13.05 [‐19.30, ‐6.80] |
| 1.23.1 Adults > 18 years of age | 9 | 566 | Mean Difference (IV, Random, 95% CI) | ‐11.40 [‐18.86, ‐3.93] |
| 1.23.2 Children | 1 | 100 | Mean Difference (IV, Random, 95% CI) | ‐20.40 [‐25.46, ‐15.34] |
| 1.24 Duration of surgery (minutes) excluding small sized studies | 7 | 568 | Mean Difference (IV, Random, 95% CI) | ‐15.42 [‐21.74, ‐9.10] |
| 1.25 Duration of surgery (minutes) using fixed‐effect model | 10 | 666 | Mean Difference (IV, Fixed, 95% CI) | ‐17.15 [‐19.32, ‐14.99] |
| 1.26 Incomplete surgery | 2 | 58 | Risk Difference (M‐H, Random, 95% CI) | 0.00 [‐0.09, 0.09] |
| 1.27 Surgical complications | 2 | 58 | Risk Difference (M‐H, Random, 95% CI) | 0.00 [‐0.09, 0.09] |
| 1.28 Postoperative bleeding (place of packing or revision surgery within 14 days of surgery) | 6 | 404 | Risk Difference (M‐H, Random, 95% CI) | ‐0.01 [‐0.03, 0.02] |
| 1.29 Postoperative bleeding (place of packing or revision surgery within 14 days of surgery) using fixed‐effect model | 6 | 404 | Risk Difference (M‐H, Fixed, 95% CI) | ‐0.01 [‐0.04, 0.02] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Alimian 2011.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment only once during surgery and a 3‐day follow‐up | |
| Participants |
Location: Iran, 1 site Setting of recruitment: Department of Anesthesiology, Rasul Akram Hospital, Teheran University of Medical Science, Teheran, Iran Study dates: June 2008 to February 2009 Sample size: 84 Number randomised: 84 Participant (baseline) characteristics:
Inclusion criteria: patients aged 19 to 64 years scheduled for endoscopic sinus surgery for CRS Exclusion criteria: patients receiving anticoagulants or having a bleeding diathesis |
|
| Interventions |
Tranexamic acid (N = 42): intravenous bolus of 10 mg/kg TXA after induction of TIVA Placebo (N = 42): intravenous bolus of 0.1 mL/kg sterile water after induction of TIVA Additional interventions: TIVA and all patients underwent ESS |
|
| Outcomes |
Primary outcome:
Secondary outcomes:
Other outcomes reported by the study:
|
|
| Funding sources | Departmental sources only | |
| Declarations of interest | None declared | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: hospital pharmacy randomised by using a table of random numbers. Probably done and not visible for study personnel. |
| Allocation concealment (selection bias) | Low risk | Comment: patients and medical personnel were unaware of the table with random numbers |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: only the pharmacy was aware of the allocation. After the allocation and during the surgery no medical personnel involved in the care of the patient were aware of the study assignment. It is not reported how long the blinding was after surgery. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: surgeons were outcome assessors and they were adequately blinded. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no patients dropped out of the study. |
| Selective reporting (reporting bias) | Low risk | Comment: there is a trial registration available and all outcomes are reported. |
| Other bias | Unclear risk | No obvious further issues. |
Athanasiadis 2007.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial, with unclear follow‐up | |
| Participants |
Location: Australia, 1 site Setting of recruitment: Department of Otorhinolaryngology, Head and Neck Surgery, The Queen Elizabeth Hospital, University of Adelaide, Australia Study dates: January to December 2005 Sample size: 20 Number randomised: 20 Participant (baseline) characteristics:
Inclusion criteria: patients aged > 18 years scheduled for ESS involving complete sphenoidectomy and frontal recess clearance for CRS Exclusion criteria: patients with asymmetric disease, known allergy to antifibrinolytics, pregnancy or breastfeeding, bleeding diathesis, anticoagulant medication |
|
| Interventions |
Tranexamic acid 100 mg one nostril (N = 10): 100 mg TXA applied during surgery Tranexamic acid 1000 mg one nostril (N = 10): 1000 mg TXA applied during surgery Placebo contralateral nostril (N = 20): not mentioned what agent was applied Additional interventions: unclear |
|
| Outcomes |
Outcomes (primary and secondary not specifically reported)
|
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "by computer randomisation" |
| Allocation concealment (selection bias) | Low risk | Quote: "to a code in a sealed envelope" |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "The surgical team and the independent observer thus were blinded as to which agent the patient was receiving". The study is reported to be double‐blind. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The surgical team and the independent observer thus were blinded as to which agent the patient was receiving" |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no exclusions reported. All included patients were analysed. Both grading scales are reported as mentioned in the 'Aims' section. |
| Selective reporting (reporting bias) | Low risk | Comment: all outcomes are reported. |
| Other bias | Unclear risk | Comment: no other obvious issues. |
Baradaranfar 2017.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment during surgery and follow‐up for the length of hospitalisation | |
| Participants |
Location: Iran, 1 site Setting of recruitment: Otorhinolaryngology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran Study dates: unclear Sample size: 60 Number randomised: 60 Participant (baseline) characteristics:
Inclusion criteria: CRSwNP patients who did not respond to medical treatment and were candidates for ESS Exclusion criteria: previous sinus or nasal surgery, underlying disease with increased risk of thrombosis (hypercoagulable states) such as Factor V Leiden, antiphospholipid syndrome, heparin‐induced thrombocytopenia, cancer, pregnancy, high blood pressure (systolic > 140 mmHg and/or diastolic > 90 mmHg), contraindications for the use of tranexamic acid (active clot inside arteries), and patient unwillingness or participation in other similar clinical trials |
|
| Interventions |
Tranexamic acid (n = 30): 2 g in 400 mL saline solution rinsed during surgery whenever the field became obscured Placebo (n = 30): normal saline solution 400 mL rinsed during surgery whenever the field became obscured Additional interventions: TIVA/inhalational N20, all patients underwent ESS and received systemic prednisone 1 mg/kg for 5 days before surgery. Epinephrine 1/2000‐soaked pledges were used when there was excessive bleeding during surgery as preferred by surgeon. |
|
| Outcomes |
Primary outcome:
Secondary outcomes:
Other outcomes reported by the study:
|
|
| Funding sources | Study supported by a grant from Shahid Sadoughi University of Medical Sciences,Yazd, Iran | |
| Declarations of interest | None declared | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomly divided" |
| Allocation concealment (selection bias) | High risk | Quote: "using a random number table" |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: the surgical team were unaware which solution was used for each patient. However, it is unclear who prepared the solutions and how they were presented. Unclear if anaesthesia team was blinded (and if mean blood loss was estimated by them). |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: unclear who assessed mean total blood loss during surgery. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no patients dropped out of the study. |
| Selective reporting (reporting bias) | High risk | Comment: the total amount of irrigation fluid used in each patient during surgery is also unclear. |
| Other bias | Unclear risk | No further obvious issues. |
Dongare 2018.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment once during surgery | |
| Participants |
Location: India, probably 1 site Setting of recruitment: Department of Anaesthesia and Critical Care, probably in the General Hospital, Pune, Maharashtra, India Study dates: unclear Sample size: 60 Number randomised: 60 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions | Tranexamic acid (N = 30): pre‐medication with tranexamic acid 15 mg/kg as a slow intravenous bolus Placebo (N = 30): 10 mL normal saline as intravenous bolus | |
| Outcomes |
Outcomes (primary and secondary not specifically reported)
|
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: randomisation was done with a random number table. |
| Allocation concealment (selection bias) | Unclear risk | Comment: unclear how the allocated treatment remained concealed. The authors did not provide this information. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: a blinded observer applied the contents of the syringes to the patients. It is unclear if the syringes were identical in colour/appearance. It is not specifically reported that patients were blinded to the treatment, but this is plausible. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: the surgeons were blinded to treatment and performed the measurement of the bleeding score. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no missing patients or exclusions, and all patients were analysed in the allocated group. |
| Selective reporting (reporting bias) | High risk | Comment: no study protocol or statistical analysis plan available. Bleeding score was not reported at 60 minutes, although measured, with no reason provided. Only 15, 30, 45 minutes were reported (significant results). |
| Other bias | Unclear risk | Comment: patients were followed up for thrombotic events until discharge. This period of time probably was variable for patients; the study does not specifically mention this. |
Eldaba 2013.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment once during surgery | |
| Participants |
Location: Egypt, 1 site Setting of recruitment: Department of Anesthesia and Surgical Intensive Care, Tanta University, Tanta, Egypt Study dates: unclear Sample size: 100 Number randomised: 100 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
Tranexamic acid (N = 50): IV 25 mg/kg diluted in 10 mL saline solution after induction of anaesthesia Placebo (N = 50): IV 10 mL of normal saline solution after induction of anaesthesia |
|
| Outcomes |
Outcomes (primary and secondary not specifically reported)
|
|
| Funding sources | Not reported | |
| Declarations of interest | None declared | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: randomisation by computer‐based random number generator |
| Allocation concealment (selection bias) | Low risk | Comment: assignment entered in sealed envelopes. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "anesthesiologists, operating personnel, and study staff were blind as to treatment groups". "A blinded chief nurse who did not participate in the study protocol or data collection prepared the syringes". No statement is made about patient blinding. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: study staff were blinded. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no missing patients, all were analysed. |
| Selective reporting (reporting bias) | Low risk | Comment: no study protocol available, however all measurements reported in the methods section were reported. |
| Other bias | Unclear risk | No further obvious issues. |
El‐Ozairy 2021.
| Study characteristics | ||
| Methods | Randomised, controlled, double‐blind trial with treatment during surgery | |
| Participants |
Location: Egypt, 1 site Setting of recruitment: Department of Otorhinolaryngology at Ain Shams University Hospital, Cairo, Egypt Study dates: June 2019 to January 2020 Sample size: 120 Number randomised: 120 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
Tranexamic acid (N = 90): either TXA IV 15 mg/kg diluted in 20 mL saline over 30 minutes or irrigation fluid 400 mL saline solution with 2 g TXA, or both Placebo (N = 30): IV 20 mL of saline solution over 30 minutes and irrigation fluid 400 mL of saline solution Other interventions: All patients were instructed to take oral prednisone 1 mg/kg 5 days before surgery to reduce inflammation. Upon admission, all patients were pre‐medicated with IV midazolam 0.05 mg/kg, ranitidine 50 mg and dexamethasone 10 mg, 15 minutes prior to surgery. |
|
| Outcomes |
Primary outcome
Effectiveness of local, IV and combined use of TXA in improving the surgical field quality during FESS Secondary outcomes Total fentanyl and esmolol consumption, operative time, recovery time and postoperative complications |
|
| Funding sources | Not reported | |
| Declarations of interest | None of the authors have any conflicts of interest to declare | |
| Notes | We contacted the corresponding author with a request to provide means and standard deviations (SDs) for the intervention groups for missing clinically relevant outcomes. The authors contacted did not provide us with these data. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: randomisation is mentioned ‐ use of a computer‐generated list. No further details are provided. |
| Allocation concealment (selection bias) | Low risk | Comment: it is unclear how the interventions were allocated exactly and who created the computer‐generated list, however the drugs were prepared by a pharmacist and only had the patient number on them (not the name of the drugs). |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: study was double‐blinded. A pharmacist prepared the drugs. Anaesthesiologist and surgeon were blinded to the study group. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: surgeon was blinded to study group. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: outcomes reported for all randomised patients. No patients lost to follow‐up. |
| Selective reporting (reporting bias) | Low risk | Comment: all outcomes (pre‐specified in the clinical trials register) were reported. |
| Other bias | Unclear risk | No other issues identified. |
El Shal 2015.
| Study characteristics | ||
| Methods | Three‐arm, parallel‐group randomised controlled trial with treatment once during surgery and 24 hours follow‐up | |
| Participants |
Location: Egypt, 1 site Setting of recruitment: Department of Anesthesia, Faculty of Medicine, Cairo University, Egypt Study dates: unclear Sample size: 90 Number randomised: 90 Participant (baseline) characteristics:
Inclusion criteria: patients aged from 18 to 50 years and undergoing FESS for chronic sinusitis; ASA I and II Exclusion criteria:
|
|
| Interventions |
Tranexamic acid (N = 30): IV 10 mg/kg diluted in 100 mL saline solution after induction of anaesthesia EACA (N = 30): IV epsilon aminocaproic acid (EACA) 100 mg/kg diluted in 100 mL normal saline solution after induction of anaesthesia Placebo (N = 30): IV 100 mL normal saline solution after induction of anaesthesia Additional interventions: total inhalational anaesthesia and all patients underwent ESS |
|
| Outcomes |
Outcomes (primary and secondary not specifically reported)
|
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | The trial is a 3‐arm treatment arm comparing 2 antifibrinolytic agents and placebo. For the purposes of this review the EACA group was not included. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: parallel‐group randomised controlled trial. |
| Allocation concealment (selection bias) | Low risk | Comment: randomisation was done by means of computer‐generated codes. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: the anaesthesiologists, surgeons and patients were blinded to study drugs and an anaesthesiologist not involved in the study prepared the infusion drugs before induction of anaesthesia. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: unlikely that the blinding could have been broken. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no missing outcome data. |
| Selective reporting (reporting bias) | Low risk | Comment: no trial protocol available, however in the methods section pre‐specified outcome parameters. |
| Other bias | Unclear risk | No obvious further issues. |
Jabalameli 2006.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment once during surgery | |
| Participants |
Location: Iran, 1 site Setting of recruitment: Department of Anesthesiology and Intensive Care, Alzahra General Hospital, Isfahan University of Medical Sciences, Isfahan, Iran Study dates: unclear Sample size: 56 Number randomised: 56 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria: Medications affecting coagulation system, history of thromboembolic events, disseminated intravascular coagulopathy, haemophilia, hypersensitivity to drugs and normal renal function |
|
| Interventions |
Tranexamic acid (N = 26): topical 1000 mg diluted in 20 mL saline once during surgery Placebo (N = 30): topical 20 mL normal saline solution once during surgery Additional interventions: total intravenous anaesthesia and all patients underwent ESS |
|
| Outcomes |
Outcomes (primary and secondary not specifically reported)
|
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "... and then they were randomly assigned to TA (n=26) and placebo groups (n=30)" |
| Allocation concealment (selection bias) | Unclear risk | Comment: no information about how randomisation was performed or by whom. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: no information about who was blinded. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: unclear if surgeon could have known randomisation ‐ there is no information. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: all randomised participants were analysed. |
| Selective reporting (reporting bias) | Low risk | Comment: no trial protocol, however outcome of interest is fully reported. |
| Other bias | Unclear risk | Comment: no further obvious issues. |
Langille 2013.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment during surgery | |
| Participants |
Location: Canada, 1 site Setting of recruitment: Division of Otolaryngology – Head and Neck Surgery, University of Alberta, Edmonton, AB, Canada Study dates: March 2010 to November 2011 Sample size: 28 Number randomised: 28 Participant (baseline) characteristics:
Lund Mackay Score (median, SD): TXA 11 (1.9), placebo 10 (2.7)
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
Tranexamic acid (N = 14): IV bolus 15 mg/kg + infusion 1 mg/kg/hour in 100 mL saline Placebo (N = 14): IV equivalent amount of normal saline solution Additional interventions: inhalational anaesthesia and all patients underwent ESS |
|
| Outcomes |
Primary outcome
Secondary outcomes
Other outcomes reported: data on acetylsalicylic acid and oral steroid use |
|
| Funding sources | Not reported | |
| Declarations of interest | None to declare | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: parallel‐group randomised controlled trial with block randomisation. |
| Allocation concealment (selection bias) | Low risk | Quote: "the randomisation scheme was not revealed until data had been collected from all patients" |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: the study was double‐blinded. Only 1 study investigator knew the randomisation and was responsible for preparing tranexamic acid solution and normal saline solution. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: two blinded investigators were involved in outcome assessment. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: all randomised participants were analysed. |
| Selective reporting (reporting bias) | Low risk | Comment: all outcomes are reported. |
| Other bias | Unclear risk | No further obvious issues. |
Nuhi 2015.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment once on the day of surgery | |
| Participants |
Location: Iran, 1 site Setting of recruitment: Department of Otorhinolaryngology, Shahid Beheshti University of Medical Sciences, Taleghani Hospital, Tehran, Iran Study dates: 2009 to 2011 Sample size: 170 Number randomised: 170 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
Tranexamic acid (N = 100): IV 15 mg/kg once on the day of surgery Placebo (N = 70): IV normal saline, unclear dose Additional interventions: all patients underwent ESS |
|
| Outcomes |
Outcomes (primary and secondary not specifically reported)
|
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | We contacted the corresponding author with a request to provide means and standard deviations (SDs) for the intervention groups for missing clinically relevant outcomes. The authors contacted did not provide us with these data. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: parallel‐group randomised controlled trial. |
| Allocation concealment (selection bias) | Unclear risk | Quote: "sequential numbers". |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "Both participants and study staff (site investigators and trial coordinating center staff) were blinded to treatment allocation." |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: attending anaesthesiologist and the surgeon estimated blood loss and surgical field grading. It is unknown if these are considered part of the study staff, but most likely they were blinded. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no missing outcome data. |
| Selective reporting (reporting bias) | High risk | Comment: surgical field bleeding score is reported inadequately so that it could not be used for (meta)‐analysis. |
| Other bias | Unclear risk | Comment: no further obvious issues. |
Padhy 2019.
| Study characteristics | ||
| Methods | Randomised controlled trial with treatment once during surgery | |
| Participants |
Location: Department of Otolaryngology ‐ Head and Neck Surgery, Command Hospital (Eastern Command), Kolkata, tertiary care centre, 1 site Setting of recruitment: Department of Otolaryngology ‐ Head and Neck Surgery, Command Hospital (Eastern Command), Kolkata Study dates: January 2017 to June 2018 Sample size: 30 Number randomised: 30 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
Tranexamic acid (N = 15): IV 10 mg/kg after induction of anaesthesia Placebo (N = 15): IV normal saline Additional interventions: all patients underwent ESS. All patients received prednisolone 1 mg/kg daily pre‐operatively for 5 days plus IV amoxycillin‐clavulanic acid 1200 mg twice daily was given the first 48 hours in all patients. |
|
| Outcomes |
Outcomes (primary and secondary not reported separately)
|
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: randomised controlled trial. |
| Allocation concealment (selection bias) | Low risk | Comment: the authors used a computer‐based random number table. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: the surgeon was not aware of which patient received the intervention. The anaesthesiologist was not blinded. There is no statement about patient blinding. |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Comment: the surgeon was blinded and performed the surgical field scoring. The anaesthesiologist was not blinded and performed the total blood loss calculation after the surgery. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: all randomised patients were analysed. |
| Selective reporting (reporting bias) | Low risk | Comment: all outcomes are reported. |
| Other bias | High risk | Comment: adequate baseline characteristics are missing. |
Pannerselvam 2019.
| Study characteristics | ||
| Methods | Randomised, double‐blind clinical trial with treatment once short before surgery | |
| Participants |
Location: Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India, probably 1 site Setting of recruitment: unclear Study dates: January 2013 to December 2013 Sample size: 84 Number randomised: 84 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
Group A tranexamic acid (N = 28): IV 15 mg/kg 20 minutes prior to surgery Group B tranexamic acid (N = 28): IV 5 mg/kg 20 minutes prior to surgery Group C placebo (N = 28): IV normal saline Additional interventions: all patients underwent ESS |
|
| Outcomes |
Outcomes Primary
Secondary
|
|
| Funding sources | Not reported | |
| Declarations of interest | Not reported | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: patients were randomised by computer‐generated block randomisation. |
| Allocation concealment (selection bias) | Low risk | Comment: central allocation by computer. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: anaesthesiologists, surgeons, nurses and other staff were blinded to study protocol. Independent anaesthesiologist prepared study treatment. No statement is made about patient blinding. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: study staff was reported to be adequately blinded, but who assessed the primary and secondary outcome parameters remains unclear |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: all randomised patients were analysed. |
| Selective reporting (reporting bias) | Low risk | Comment: predefined primary and secondary outcome parameters were reported. |
| Other bias | Unclear risk | No other obvious issues. |
Quiroga 2018.
| Study characteristics | ||
| Methods | Parallel‐group randomised controlled trial with treatment once during surgery | |
| Participants |
Location: Philippines, 1 site Setting of recruitment: Department of Otorhinolaryngology Head and Neck Surgery, Quirino Memorial Medical Center Quezon City, Philippines Study dates: September 2016 to August 2017 Sample size: 10 Number randomised: 10 Participant (baseline) characteristics:
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
Tranexamic acid (N = 5): IV 500 mg of tranexamic acid per 5 mL 1 hour prior to surgery Placebo (N = 5): IV normal saline solution 1 hour prior to surgery Additional interventions: general anaesthesia and all patients underwent FESS |
|
| Outcomes |
Outcomes (primary and secondary not specifically reported)
Other outcomes reported:
|
|
| Funding sources | Not reported | |
| Declarations of interest | None declared | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "double‐blind, randomized, placebo‐controlled trial" |
| Allocation concealment (selection bias) | High risk | Quote: "... randomized using simple random sampling. They were asked to pick a folded paper with written number from a bowl. Those who picked the paper with “odd” numbers were assigned to the treatment group". |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "The surgeons and anesthesiologists were blinded to treatment allocation". The study was reported to be double‐blinded. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The surgeons and anesthesiologists were blinded to treatment allocation". One person who was not included in surgery prepared the medications. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: all randomised participants were analysed. |
| Selective reporting (reporting bias) | Low risk | Comment: all outcomes are reported. |
| Other bias | Unclear risk | No further obvious issues. |
Yang 2021.
| Study characteristics | ||
| Methods | Randomised, controlled, double‐blind trial with treatment during surgery | |
| Participants |
Location: China, 1 site Setting of recruitment: Department of Otorhinolaryngology at Beijing Tongren Hospital, Beijing, China Study dates: unclear Sample size: 60 Number randomised: 60 Participant (baseline) characteristics
Inclusion criteria:
Exclusion criteria:
|
|
| Interventions |
TXA (N = 30): intravenous drip of TXA 15 mg/kg in 100 mL normal saline over 30 minutes Placebo (N = 30): 100 mL of normal saline only over 30 minutes |
|
| Outcomes |
Primary outcome:
Boezaart grading scale Secondary outcomes: Total blood loss, operation time, bleeding rate, postoperative complications (including nausea, vomiting, anaphylaxis, visual impairment, seizure, venous thromboembolism (VTE) and postoperative intervention for excessive fresh bleeding in the first 24 hours after the operation) |
|
| Funding sources | This study was supported by Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support | |
| Declarations of interest | No conflicts of interest | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: randomisation by a computer‐generated random number list |
| Allocation concealment (selection bias) | Low risk | Comment: the computer‐generated random number list was performed by IBM SPSS Statistics 26.0 and allocation was sealed in an envelope by one researcher not involved in the treatment/surgery. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: allocation for each participant was sealed in an envelope by one researcher who was blinded to the surgeons, patients, anaesthesiologists and recorders. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: outcome assessors were blinded. Primary outcome was assessed by a surgically trained researcher (who was blinded to the group allocation). All surgeries were performed by 2 experienced surgeons. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: no patients were lost to follow‐up. |
| Selective reporting (reporting bias) | Low risk | Comment: all outcomes were reported. |
| Other bias | Unclear risk | The study appears to be free of other sources of bias. |
aPTT: activated partial thromboplastin time ASA: American Society of Anesthesiologists BMI: body mass index CRS: chronic rhinosinusitis CRSsNP: chronic rhinosinusitis without nasal polyps CRSwNP: chronic rhinosinusitis with nasal polyps EACA: epsilon aminocaproic acid ESS: endoscopic sinus surgery FESS: functional endoscopic sinus surgery INR: international normalised ratio IQR: interquartile range IV: intravenous NSAIDs: non‐steroidal anti‐inflammatory drugs SD: standard deviation TIVA: total intravenous anaesthesia TXA: tranexamic acid
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Abbasi 2012 | ALLOCATION: randomised PARTICIPANTS: patients with chronic rhinosinusitis undergoing endoscopic sinus surgery INTERVENTIONS: patients received tranexamic acid in both treatment groups |
| Athanasiadis 2009 | ALLOCATION: not randomised |
| Beule 2010 | ALLOCATION: not randomised |
| Chhappola 2011 | ALLOCATION: randomised PARTICIPANTS: patients undergoing different endoscopic nasal surgeries (ESS, septoplasty, excision of nasal mass) |
| IRCT201203242963N7 2012 | ALLOCATION: randomised
PARTICIPANTS: candidates for endoscopic sinus surgery INTERVENTIONS: 2 different dosages of tranexamic acid, no control group |
| IRCT2015062021436N2 | ALLOCATION: randomised
PARTICIPANTS: patients with chronic rhinosinusitis undergoing endoscopic sinus surgery INTERVENTIONS: patients received tranexamic acid in both treatment groups |
| IRCT2015092824241N1 | ALLOCATION: randomised PARTICIPANTS: patients undergoing open rhinoplasty |
| Jahanshahi 2014 | ALLOCATION: randomised
PARTICIPANTS: patients with chronic rhinosinusitis undergoing endoscopic sinus surgery INTERVENTIONS: patients received tranexamic acid or phenylephrine soaked pledgets |
| Kulkarni 2018 | ALLOCATION: randomised
PARTICIPANTS: patients with chronic rhinosinusitis undergoing endoscopic sinus surgery INTERVENTIONS: patients received tranexamic acid or ethamsylate |
| Kurozumi 1977 | ALLOCATION: not randomised; cross‐over trial |
| NCT00671281 | Study got cancelled |
| Shehata 2014 | ALLOCATION: not randomised |
| Yaniv 2006 | ALLOCATION: not randomised |
ESS: endoscopic sinus surgery
Characteristics of studies awaiting classification [ordered by study ID]
32971 2018.
| Methods | Double‐blind clinical trial on 56 patients with chronic rhinosinusitis requiring endoscopic sinus surgery |
| Participants | Patients with chronic rhinosinusitis that did not respond to drug therapy |
| Interventions | Intervention: a mesh soaked in a mixture of phenylephrine 0.05% volume and tranexamic acid at a dose of 15 mg/kg for 10 minutes placed in the nose Control group: a mesh soaked in phenylephrine |
| Outcomes | Bleeding during surgery; quality of surgical field |
| Notes | Unable to retrieve paper |
Amal Das 2012 CRSSTD‐7068696.
| Methods | 30 patients subjected to endoscopic sinus surgery and randomised within‐patient to topical intervention one side and control other side |
| Participants | Bilateral sphenoethmoidal disease |
| Interventions | Intervention: 5 mL (100 mg/mL) of tranexamic acid spray Comparison: normal saline spray |
| Outcomes | Bleeding was documented using Boezaart’s and Wormald’s surgical field grading scales |
| Notes | Unable to retrieve paper |
IRCT2012111411455N1 2013 CRSSTD‐7068603.
| Methods | Double‐blind randomised controlled trial in 66 patients |
| Participants | 16‐ to 40‐year olds ASA class 1 with chronic sinusitis and candidates for surgery |
| Interventions | Intervention group: 10 mg/kg tranexamic acid Control group: 50 cc normal saline infusion |
| Outcomes | Intraoperative bleeding, intraoperative pressure |
| Notes | No full‐text paper found |
IRCT2013012911822N3 2013 CRSSTD‐7068595.
| Methods | Double‐blinded randomised controlled trial in 70 patients that underwent nasal surgery |
| Participants | 18‐ to 65‐year olds undergoing nasal surgery |
| Interventions | Intervention: 500 mg intravenous tranexamic acid mixed up in 500 mL lactated Ringer's solution with concentration 1 mg/mL and maximum infusion rate 100 mg/min and maximum dosage 15 mg/kg Control group: lactated Ringer's solution as maintenance therapy |
| Outcomes | Primary outcomes: (a) quality of surgical field every 20 minutes during surgery using Boezaart scale; (b) determine blood volume accumulated in the suction chamber after operation; (c) changes haemoglobin and haematocrit 6 hours after surgery; (d) satisfaction of surgeon at end of operation Secondary outcomes: measurement of (a) seizures; (b) nausea; (c) vomiting; (d) and impaired colour vision 24 hours after surgery |
| Notes | No full‐text paper found |
IRCT2014031016924N1 2016 CRSSTD‐7068683.
| Methods | Randomised (unblinded) clinical trial in 90 patients |
| Participants | 90 patients ages 15 to 75 years; ASA class 1 and 2 |
| Interventions | 3 groups of N = 30 Group 1: 1 g oral tranexamic acid 2 hours before surgery Group 2: 1 mg/kg/day oral prednisolone for 5 days Group 3: no drug |
| Outcomes | Quality of the surgery zone and volume of bleeding at the end of surgery |
| Notes | No full‐text paper found |
Kurozumi 1976.
| Methods | Double‐blind comparative study using a cross‐over design |
| Participants | 63 patients with sinusitis in which lesions were almost the same on both sides |
| Interventions | Intervention: tranexamic acid on one side of the nose Control: placebo on one side of the nose |
| Outcomes | Total and per minute bleeding amount |
| Notes | Unable to retrieve paper |
Moise 2010.
| Methods | Prospective, double‐blinded, randomised clinical trial |
| Participants | 60 patients admitted to the ENT Department for FESS treatment for chronic rhinosinusitis |
| Interventions | Intervention: 10 mg/kg tranexamic acid in 10 mL saline solution with 2 administrations: before induction and before nasal pack removal Control: 10 mL saline solution with 2 administrations: before induction and before nasal pack removal |
| Outcomes | Intraoperative bleeding, nasal pack bleeding, blood coughed up, vomiting, preoperative, postoperative and after nasal pack removal haemoglobin |
| Notes | Unable to retrieve paper |
ASA: American Society of Anesthesiologists FESS: functional endoscopic sinus surgery
Characteristics of ongoing studies [ordered by study ID]
IRCT20180730040640N1.
| Study name | 'The effect of topical tranexamic acid on bleeding reduction during functional endoscopic sinus surgery in choronic rhinosinousitis patient' |
| Methods | Double‐blind randomised controlled trial |
| Participants | TXA: 56 patients requiring chronic rhinosinusitis Placebo: 56 patients Inclusion criteria:
Exclusion criteria:
|
| Interventions | Intervention 1: a mesh soaked in a mixture of phenylephrine 0.05% vol and tranexamic acid at a dose of 15 mg/kg for 10 minutes will be placed in the nose (nasal cavity) of the patient by an operating room technician, then it will get extracted and operation (procedure) will begin Intervention 2: a mesh soaked in a solution of 0.05% vol of phenylephrine for 10 minutes will be placed in the nose (nasal cavity) of the patient by an operating room technician, then the mesh will get extracted and operation (procedure) will begin |
| Outcomes |
Primary outcome Bleeding during surgery (time point: at the 15th, 30th and 45th minute after intervention) Method of measurement: Boezaart scale Secondary outcome Bleeding volume (time point: every 15 minutes after start of surgery) Method of measurement: suction device |
| Starting date | 23 September 2018 |
| Contact information | Allahkaram Akhlaghi Units 16, Block 1, Fatemeh Zahra pension, Moallem square, Siraf Ave 7517933755 Boushehr Iran (Islamic Republic of) Akhlaghidr@gmail.com |
| Notes | — |
NCT03965767.
| Study name | 'Does the combined use of local and intravenous tranexamic acid offer better surgical field quality during functional endoscopic sinus surgery? A placebo‐controlled clinical trial' |
| Methods | Parallel‐group randomised controlled trial |
| Participants | Each treatment group: 30 patients Inclusion criteria
Exclusion criteria
|
| Interventions |
Group I: patients will receive an intravenous dose of 15 mg/kg‐1 of tranexamic acid in a 10 mL syringe. The irrigation fluid will be 400 mL of normal saline Group II: patients will receive an intravenous dose of 10 mL normal saline in a 10 mL syringe. Irrigation fluid will be 400 mL of normal saline with 2 g of tranexamic acid added to it. If more irrigation is needed, normal saline will be used. Group III: patients will receive an intravenous dose of 15 mg/kg‐1 of tranexamic acid in a 10 mL syringe. Irrigation fluid will be 400 mL of normal saline with 2 g of tranexamic acid added to it. If more irrigation is needed, normal saline will be used. Group IV (control): patients will receive intravenous dose of 10 mL normal saline in 10 mL syringe. The irrigation fluid will be 400 mL of normal saline. |
| Outcomes |
Primary outcome Bleeding during surgery (time frame: time of surgery) Surgeon satisfaction |
| Starting date | 25 April 2019 |
| Contact information | Ossama Mady, Faculty of Medicine Ain Shams University, MD 01117341201 ext 202; omady84@gmail.com; Cairo, Egypt |
| Notes | — |
NCT04754230.
| Study name | 'Effect of tranexamic acid on postoperative bleeding following sinus and nasal surgery' |
| Methods | Parallel randomised clinical trial |
| Participants | Sample size: n = 250 Inclusion criteria:
Exclusion criteria:
|
| Interventions | Intervention: 1000 mg IV tranexamic acid Comparator: normal saline solution |
| Outcomes |
Primary outcome:
Secondary outcomes:
|
| Starting date | 17 June 2021 |
| Contact information | Principal Investigator: Zara M. Patel, MD, Stanford University, California, United States, 94305 |
| Notes | — |
NCT04905901.
| Study name | 'Nebulized tranexamic acid in sinus surgery' |
| Methods | Parallel‐group randomised controlled trial |
| Participants |
Site: Egypt, 1 site Sample size: N = 90 (30 patients in each group) Inclusion criteria:
Exclusion criteria:
|
| Interventions |
TXA group 1: nebulised tranexamic acid 500 mg 15 minutes before operation TXA group 2: nebulised tranexamic acid 1 g 15 minutes before operation Comparator group 3: normal saline nebulisation 15 minutes before operation |
| Outcomes |
Primary outcome:
Secondary outcomes:
|
| Starting date | 6 May 2021 |
| Contact information | Contact: Omar Soliman Email: omarmakram347@yahoo.com |
| Notes | — |
TCTR20210531005.
| Study name | 'Effect of local injection of tranexamic acid on surgical field during functional endoscopic sinus surgery in patients with chronic rhinosinusitis: a prospective randomized controlled trial' |
| Methods | Parallel‐group randomised controlled trial |
| Participants | Sample size: N = 47 Inclusion criteria:
Exclusion criteria:
|
| Interventions |
TXA: injection of 250 mg/5 mL Comparator: normal saline solution injection |
| Outcomes |
Primary outcome:
Secondary outcomes:
|
| Starting date | 1 July 2021 |
| Contact information | Kshidej Bongsabhikul Department of Otolaryngology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270, Rama VI Road, Toong Phaya Thai, Ratchathewi 10400 Bangkok Thailand Telephone: 0993546456 Email: kshidej@gmail.com Affiliation: Faculty of Medicine, Mahidol University |
| Notes | — |
ASA: American Society of Anesthesiologists FESS: functional endoscopic sinus surgery INR: international normalised ratio IV: intravenous PTT: partial thromboplastin time TXA: tranexamic acid
Differences between protocol and review
We adapted the sources to search from those listed in the Methods section of the protocol (Ravesloot 2017) for the search run for the review. We did not search the following resources:
PubMed (as a top up to searches in Ovid MEDLINE);
EBSCO CINAHL (1982 to date);
Ovid CAB abstracts (1910 to date);
KoreaMed (search to date);
IndMed (search to date);
PakMediNet (search to date);
ISRCTN, www.isrctn.com (search to date);
Google (search to date).
We decided to report all outcomes in the summary of findings table, instead of the four outcomes selected in the protocol.
Following methodological feedback, we have made some edits in Types of outcome measures to clarify our time points of interest and prioritisation of scoring systems for the surgical field bleeding score primary outcome. We have also defined our pre‐planned subgroups as primary and secondary subgroups.
Contributions of authors
Drafting the protocol: MJL Ravesloot, E Lourijsen, V Pundir, WJ Fokkens. Obtaining copies of studies: E Lourijsen, K Avdeeva. Selecting which studies to include: E Lourijsen, K Avdeeva, KL Gan. Extracting data from studies: E Lourijsen, K Avdeeva. Assessing risk of bias: E Lourijsen, K Avdeeva. Entering data into RevMan: E Lourijsen. Carrying out the analysis: E Lourijsen, K Avdeeva, WJ Fokkens. Interpreting the analysis: E Lourijsen, K Avdeeva, WJ Fokkens. Drafting the final review: E Lourijsen, WJ Fokkens. Updating the review: E Lourijsen, K Avdeeva, WJ Fokkens.
Sources of support
Internal sources
-
Amsterdam Medical Research BV, Netherlands
Salary
External sources
-
National Institute for Health Research, UK
Infrastructure funding for Cochrane ENT
Declarations of interest
E Lourijsen: none known. K Avdeeva: none known. V Pundir: none known. KL Gan: none known. WJ Fokkens: none known.
New
References
References to studies included in this review
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NCT04905901 {published data only}
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