|Year : 2020 | Volume
| Issue : 3 | Page : 461-466
Evaluating the role of topical tranexamic acid in cancers of the head-and-neck: A single-center randomized controlled trial
S Anand1, Vikrant Singh1, Pankaj Kumar Sahu2
1 Department of Surgery, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of ENT, Command Hospital (Air Force), Bengaluru, Karnataka, India
|Date of Submission||07-Jul-2020|
|Date of Decision||30-Jul-2020|
|Date of Acceptance||02-Aug-2020|
|Date of Web Publication||19-Sep-2020|
Department of Surgery, Armed Forces Medical College, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Closed suction drains can reduce the complications associated with neck dissection (ND) by facilitating the removal of bodily fluids from the operated site. A lower drain output helps in faster wound healing, thereby leading to early drain removal and better recovery. Topical application of tranexamic acid (TXA) to the raw area created by surgery has been shown to be beneficial in reducing the bleeding in cardiac, orthopedic, and endoscopic nasal surgeries.
Objectives: This study aimed at assessing whether the topical application of TXA after ND reduced the drain output, time to drain removal, and postoperative complications in patients undergoing surgery for head and neck cancers.
Materials and Methods: The present study was performed in a tertiary care teaching hospital in north India between August 2014 and December 2017. One hundred patients with head and neck cancer who underwent ND were randomized into two groups. Group 1 received 20 ml of 25 mg/ml topical TXA per neck after hemostasis, and Group 2 underwent routine neck closure. Primary end points included the daily drain output until postoperative day 5 and the day of drain removal. Age, lymph node yield, operative time, type of reconstruction, and postoperative complications till 30 days postoperatively were also recorded.
Results: The demographic and clinicopathological profiles were comparable between the two groups. Output from the neck drains was significantly lower in the TXA group compared to the standard closure group (208.29 ± 84.18 ml vs. 344.56 ± 110.93 ml; respectively, P < 0.0001). In addition, drain removal in the tranexamic acid group was done earlier than in the standard closure group (6.11 ± 1.20 days vs. 7.56 ± 1.42 days, respectively,P < 0.0001). Postoperative complications and requirement of secondary procedures were comparable between the two groups.
Conclusions: Topical TXA effectively reduces the postoperative drain output after ND in patients with head and neck cancer. It facilitates the early removal of the drain and helps in better recovery without any significant difference in the rate of postoperative complications.
Keywords: Head and neck cancer, neck dissection, neck drain, topical tranexamic acid
|How to cite this article:|
Anand S, Singh V, Sahu PK. Evaluating the role of topical tranexamic acid in cancers of the head-and-neck: A single-center randomized controlled trial. Cancer Res Stat Treat 2020;3:461-6
|How to cite this URL:|
Anand S, Singh V, Sahu PK. Evaluating the role of topical tranexamic acid in cancers of the head-and-neck: A single-center randomized controlled trial. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 21];3:461-6. Available from: https://www.crstonline.com/text.asp?2020/3/3/461/295547
| Introduction|| |
Neck dissection (ND) is a universally accepted procedure performed with the intent of staging and treatment for head and neck cancers. The common postoperative complications of ND include seroma, hematoma, surgical site infections (SSIs), and delayed wound healing. These complications can be reduced by using closed suction drains. Closed suction drains work by removing the bodily fluids and obliterating large dead space after ND. It is a common practice among surgeons to determine the time of removal of the drain based on the drain volume over a 24 hour period and a rate of ≤1 ml/h is the preferred standard for drain removal. Any means to reduce the drain output would aid in the better healing of the neck wound, thereby reducing the complication rates. Moreover, early removal of the neck drain would facilitate early discharge and better recovery.
Tranexamic acid (TXA) is an antifibrinolytic agent used for controlling surgical bleeding with a proven safety profile for oral and intravenous routes., When used topically, TXA has been shown to be beneficial in reducing the surgical ooze and bleeding in cardiac, orthopedic, and endoscopic nasal surgeries.,, It has also been shown to reduce seroma and hematoma formation in those who undergo breast surgery. Topical application of TXA provides a high-drug concentration at the site of the wound, is cost-effective, and free of any reported adverse effects or drug interactions.,,, An effective way for the topical application of TXA is to moisten the raw area with TXA at a concentration of 10–30 mg/ml., This way, a small quantity of the drug can be spread over a larger surface area, thus minimizing the systemic concentration. The aim of this study was to assess if the topical application of TXA after ND could reduce the wound drainage and rate of complications and facilitate the early removal of the drain in patients with histologically proven head and neck cancer. We tested this hypothesis in a prospective randomized controlled study on patients undergoing ND for staging and therapeutic purposes, by comparing the effects of topical TXA to that of the standard closure of the neck wound.
| Materials and Methods|| |
General study details
This single-center randomized controlled study was conducted at the malignant diseases' treatment center of an Armed Forces Hospital between August 2014 and December 2017. Ours is a tertiary care teaching hospital in north India, with facilities for surgical oncology and head and neck surgery. The study was approved by the Institutional Research and Ethics Committee (Project number 4961/2013, approved on August 22, 2013; Supplementary Appendix 1) and conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the International Committee of Medical Research Good Clinical Practice guidelines. All patients were counseled about the study, and written informed consent for participation in the study was obtained from them before randomization. There was no funding utilized for the study.
Patients in the age group of 18–80 years with an Eastern Cooperative Oncology Group performance status (PS) of 0–1 and histologically proven cancer of the head and neck subsites requiring ND as part of the comprehensive surgical management were included in the study. Patients with recurrent disease in the neck requiring re-operative ND, those who had received radiotherapy in the past, those with a history of any prior surgery to the neck, coagulopathy, or the usage of anticoagulants before surgery were excluded.
The primary outcomes were postoperative drain volume for the first five days and the day of removal of the drains. The secondary outcomes were the grade of surgical site infection (SSI), the formation of seroma or hematoma, skin flap necrosis, and secondary procedures for ND complications.
The study participants were assigned to two groups by the simple randomization using computer-generated numbers.
- Group 1: Test group where topical TXA was used at the end of the procedure and before placing the neck drains
- Group 2: Control group where standard closure of the neck over the drain was done without TXA application. Patients requiring bilateral ND were considered a single case. in the study.
A team of two surgeons, each with more than five years of experience operated on all the patients. All patients underwent ND using the standard incision, the modified Crile's incision. In cases with skin involvement at the primary site, the involved skin was incorporated with the incision keeping adequate margins. Dissection was done using standard monopolar and bipolar cautery settings. Various levels of lymph nodes were sent separately for the histopathological analysis. Intraoperative thoracic duct injury was ruled out using the standard Valsalva maneuver by anesthesiologists in all cases of left sided and bilateral ND. A total of 20 ml of TXA solution was prepared at a concentration of 25 mg/ml by adding one ampoule (5 ml) of TXA (100 mg/ml) to 15 ml of normal saline. After achieving complete hemostasis, 20 ml of TXA solution was sprayed on the operated field in the neck. For cases undergoing bilateral ND, 20 ml of TXA solution was sprayed on each side of the neck separately. Thereafter, standard closure of the neck was performed in two layers with one closed suction drain placed per neck. The drain was removed if the output was <20 ml/day for 2 consecutive days. The patients received standard perioperative antibiotics for not more than 72 hours (unless an infection was suspected) and thromboprophylaxis in the form of standard compression garments alone.
Medical records of the patients were accessed to obtain the details for age, histopathology (tumor size, number of lymph nodes harvested, and number of lymph nodes positive for metastasis), operation time, blood loss, postoperative complications within 30 days, and any procedural complications during TXA instillation. The assessor of the drain output was blinded to the randomization and measured the drain volumes independent of the primary surgeons. The drain output was recorded for all the patients on a daily basis until the 5th postoperative day. In patients who underwent bilateral ND, the drain output for each neck was recorded separately. Similarly, the day of removal of the drain from each neck was noted separately. Complications after ND, namely, SSI graded according to the Clavien-Dindo classification, seroma, hematoma, and skin flap necrosis were recorded. Any secondary procedure performed for the management of complications was noted. The lymph node yield in the ND and the lymph node positivity based on the histopathology were noted for all the cases.
Sample size calculation
Based on the current literature on the quantitative analysis of drainage after ND, the average duration of drains remaining in the place was estimated to be 4.7 ± 1.5 days. A 30% difference in the duration of drains between the intervention and standard groups was considered clinically significant. We estimated the required sample size to be 96 NDs with 48 in each group to detect a difference of 0.3, with a significance level of 0.05 and a power of 0.8. To counter unforeseen events, we included 100 consecutive patients in our study.
The demographic, clinicopathological, and drain-related variables were organized, evaluated, and statistically analyzed using the SPSS® version 22.0 software (IBM Corporation, Armonk, NY). The data on categorical variables are shown as numbers (n) and percentage (%) of cases, and continuous variables are presented as mean ± standard deviation. The intergroup statistical comparison of the categorical variables was done using the Chi-square or Fisher's exact test, as appropriate. The comparison of the continuous variables was done using the independent sample t-test. All the study hypotheses were formulated using the two-tailed alternatives against each null hypothesis, and P < 0.05 was considered statistically significant.
| Results|| |
One hundred consecutive patients fulfilling the eligibility criteria were enrolled over a period of 40 months. One patient developed chyle leak because of the thoracic duct injury and was excluded from the study, leaving 99 patients (51 in the test group and 48 in the control group) for the analysis [Figure 1]. One patient in the test group succumbed to acute coronary syndrome on day 14 after the surgery. As his drain-related variables were recorded as per the study protocol until the removal of drain, he was not excluded from the study. The data variables of the two groups are summarized in [Table 1]. All the variables in the two groups were comparable, and the differences were not statistically significant (all P > 0.05).
The data related to the drain output are summarized in [Figure 2] and [Figure 3] and [Table 2]. The mean neck drain output in the TXA group (208.29 ± 84.18 ml) was significantly lower than that in the standard closure group (344.56 ± 110.93 ml), P < 0.0001. The mean number of days until the removal of the drain was also significantly lower in the TXA group than in the standard closure group (6.11 ± 1.20 days vs. 7.56 ± 1.42 days, respectively, P < 0.0001).
|Figure 2: Box-whisker plot showing inter-group distribution of the drain output following neck dissection. Group 1 indicates the patients who received topical tranexamic acid, and Group 2 consisted of patients who underwent standard neck closure without the use of tranexamic acid.|
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|Figure 3: Inter-group distribution of mean neck drain output (Group 1 - Tranexamic group, Group 2 - standard hemostasis and closure without tranexamic acid)|
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The postoperative complications recorded are summarized in [Table 3]. The incidence of the recorded complications, namely SSI, flap necrosis, and hematoma and seroma formation were not significantly different between the two groups. The need for secondary procedures to manage the complications was also comparable between the two groups. Topical TXA was tolerated well by all patients in the test group, and no adverse effects were recorded.
| Discussion|| |
Our study showed that the topical application of TXA to moisten the raw surface after ND in patients with head and neck cancer reduced the postoperative fluid drain output and facilitated early drain removal with no significant increase in the surgical complications.
Surgeries for head and neck cancers involve various ND procedures. ND is classified as radical, modified radical, or selective, and each of these procedures lead to different types of raw surface areas or wounds. Therefore, it is challenging to design a study for ND procedures that result in inequivalent wound surfaces, aimed at determining the efficiency of an intervention to reduce the drain volumes and the duration of drain retention. Reducing the drain volume for facilitating early drain removal post-ND in patients with head and neck cancers is an issue that has not been well addressed in the medical literature.
To the best of our knowledge, ours is the first study to establish the role of topical TXA after ND in patients with head and neck cancer. Erişen et al. and Saito et al. reported that the drain volume decreased until postoperative day 5 with an average drain retention time of 4.7 ± 1.5 days and 6.1 ± 1.3 days, respectively. Our study has shown an overall reduction in the drain volume during the first 5 postoperative days with instillation of topical TXA after ND (208.29 ± 84.18 in the TXA groups vs. 344.56 ± 110.93 in the standard closure group, P <0.0001). Although the mean duration of drain retention was longer in our study than that reported previously, there was a clear difference in the mean duration of drain retention of 1.45 days between the two groups, favoring the topical application of TXA [Table 2].
Intravenous TXA has been evaluated for perioperative blood loss in patients undergoing surgery for head and neck cancers with contradictory results. While Das etal. reported that intravenous TXA reduced intraoperative blood loss and perioperative transfusion requirement, Kulkarni etal. in their study concluded that intravenous TXA neither significantly reduced perioperative blood loss nor the need for transfusion of red blood cells in patients undergoing surgery for head and neck cancers. Kulkarni etal. further hypothesized that fibrinolytic activity is more pronounced in the surgical wound than in the peripheral blood in these patients, and hence, the site of action of TXA is likely to be limited to the surgical field, thereby strengthening the case for its topical application.
The results of our study are relevant to the current practice among surgeons. The optimal time for drain removal according to the drain volume after ND varies from 10 to 15 ml to ≤50 ml in a 24 hour period. Patients, at times, would otherwise be ready for discharge before the drain volume met the criteria for the removal. Routine discharge of patients with a drain in place, if appropriate is challenging in our setting, as our patients live several hours away from any medical establishment, and follow-up for drain volume measurement and its removal is often difficult. Early drain removal decreases patient discomfort and improves mobilization, further reducing the length of hospital stay. Even a single-day reduction in hospital stay could save health-care costs, improve patient mobilization and decrease patient discomfort. It would help in improving the patient flow by enabling bed availability for the following day elective admission. TXA is inexpensive, and the entire procedure of topical application takes only few additional minutes and is favorable in the cost-benefit analysis.
The study, however, has several limitations. First, we included patients with heterogeneous indications for ND, where the primary site resections and the variety of flaps used for reconstruction could have influenced the drain volume. Saito et al. observed in their study that modified radical ND, longer operative time, use of pedicle flaps, and higher operative blood loss were significantly correlated with higher drain volumes after ND. As these factors were comparable in the intervention and control groups in our study, and TXA was instilled only on the raw area left after ND; thus, we believe that these confounders had little effect on our results. Second, the surgeons performing the procedures were not blinded to the randomization during the surgery or enrollment. However, a team of two surgeons operated on all the patients, and the assessor of drain-related variables was blinded to the randomization. The assessor acted independent of the surgeons for drain measurement and removal to limit the potential bias. Third, the wound surfaces after ND were not identical, and the use of 20 ml of 25 mg/ml of TXA is somewhat arbitrary. There is little information on the concentration of topical TXA needed for local anti-fibrinolytic activity; the concentration ranges from 10 to 30 mg/ml in cardiac surgeries to 100 mg/ml in endoscopic sinus surgeries. We opted for the concentration of 25 mg/ml to provide enough volume to moisten a large surface area after ND, while preventing its systemic absorption.
Tranexamic acid is inexpensive. The procedure of topical application of TXA is easily adoptable and is cost-effective, simple, and takes only few additional minutes during the surgery without any significant adverse effect. Our results could encourage further studies to validate the role of TXA post-ND in patients with head and neck cancer. If conclusively proven beneficial through larger multicenter studies this simple step could have a significant impact on the postoperative recovery of patients with operable head and neck cancers.
| Conclusions|| |
Topical application of TXA is effective in reducing the fluid output from the neck drains after ND without any effect on the complication rates. It also facilitates earlier removal of the drains from the neck. The safety profile of TXA, its ease of application, its cost-effectiveness, and the potential to reduce the length of hospital stay make it widely adoptable.
Financial support and sponsorship
No funding was obtained for the study. The Armed Forces hospitals provide comprehensive health care to serving and retired armed forces personnel and their dependents free of cost. Tranexamic acid is used widely in our clinical practice and is easily available in our medical stores. Since our patients are entitled to treatment, no additional funds were allocated for the study and it was completed with the available resources in our hospital.
Conflicts of interest
The authors declare that no conflict of interest.
| Supplementary Appendix|| |
Supplementary Appendix 1: Approved study protocol
Research Proposal - Department of Surgical Oncology – CH (CC) Lucknow No-4961/2013.
Evaluation of topical tranexamic acid after neck dissection in patients undergoing surgery for Head and Neck cancers.
| Principal Investigator|| |
Dr. S Anand
| Other Investigators|| |
1. Dr. P.K. Sahu
2. Dr. Vikrant Singh (Assessor)
| AIM/Hypothesis|| |
This is a single-blinded randomized controlled study to establish the role of topical tranexamic acid (TXA) after neck dissection in patients undergoing surgery for head and neck cancer. The aim of this study is to investigate if topical TXA application helps in reduction in drain output and facilitates early removal of drain in patients undergoing neck dissection (ND). The other objectives of this study would be to determine the incidence of surgical site infections (SSIs), hematoma formation, seroma formation and secondary procedures due to skin flap complications.
| Introduction|| |
Neck dissection (ND) in head and neck cancers is routinely done for staging and therapeutic indications. ND leaves a large dead space with potential fluid collection and little scope for spontaneous absorption. Use of drains to avoid the complications of such large collections has been traditionally accepted. However, heterogeneity exists in the optimal time of drain removal exists. A routine practice is to remove the drain when daily drainage volume falls below 20–25 ml. This study aims to determine whether instillation of topical tranexamic acid after ND decreases the drain output and time to drain removal.
Possible influence on clinical practice
With improved surgical techniques and better understanding of the surgical anatomy, ND has become safer and standardized. However, in resource-constrained setting like India, patients after ND are kept in hospital until drains are removed for a variety of reasons. Finding decreased drain output and early removal of drain with topical tranexamic acid in safe manner would change drain management strategies after surgery for head and neck cancer. In addition, it will improve patient comfort and mobilization. A prospective, randomized controlled study is a good method to evaluate the possible role of topical tranexamic acid for early drain removal by limiting bias and confounding variables. Though the role of topical tranexamic acid is established in endoscopic sinus surgeries, cardiac surgeries and orthopedic surgeries, no clinical study has been performed on this topic; thus, our proposal is new and the findings of the study might be potentially relevant.
| Subjects and Methods|| |
All adult patients (age group 18–80 years) with good Performance Status (PS-0 and PS-1) with histologically proven head and neck cancer subsites requiring ND as part of comprehensive curative management will be consecutively enrolled. The patients will be randomized using computer generated tables, to one of two groups; Group 1 – Instillation of 20 ml of TXA solution prepared by adding one ampoule (5 mL) of TXA (100 mg/ml) to 15 mL of normal saline, after complete hemostasis per one neck and standard closure of the neck with drains placed. In cases of bilateral ND, 20 mL of TXA solution will be sprayed separately on each side. Group 2 – Only standard closure of the neck after hemostasis with drains. Drains will be removed once the output is below 20 ml/day on two consecutive days. Exclusion criteria will be unwilling patients, recurrent cancers, postradiotherapy patients, history of surgery or coagulopathy in the past or use of anti-coagulants prior to surgery. Also patients in whom re-exploration for flap complications is done in the immediate postoperative period till 7 days, will be excluded.
The procedure and postoperative care will be standardized as follows: All patients will be operated by a team of two surgeons, both with experience in treatment of head and neck cancers. Standard incisions will be used for ND and standard monopolar and bipolar cautery settings will be used for dissection. Various levels of lymph nodes will be dissected separately and sent for histopathological examination separately. Intraoperative thoracic duct injury will be ruled out before closure of neck by Valsalva maneuver given by anesthesiologists. One 14 French closed–vacuum suction drain will be used per neck after complete hemostasis. All neck wounds will be closed with 3-0 vicryl, 4-0 Monocryl, and 5-0 fast absorbing sutures. All patients will receive standardized postoperative orders including inpatient antibiotics and mechanical DVT prophylaxis. The assessor will be blinded for randomization and he would note the daily drainage output and remove the drains as per protocol independent of other investigators. All patients will receive standardized postoperative instructions including wound care. A standardized physical exam will be performed on all patients every day of inpatient stay by the primary investigator and on postoperative appointments till 30 days after surgery to evaluate for clinical evidence of SSIs graded by Clavien-Dindo classification, seroma, hematomas and decision for requirement of secondary procedures.
The primary outcome of this study will be the comparison of daily drainage output for the first 5 postoperative days from each neck and day of removal of drains between the groups. Secondary outcomes will be comparison of SSIs, seroma and hematoma formation and incidence of secondary procedures due to wound complications, between the groups.
The study will be conducted at the Departments of Surgical Oncology and Head and Neck surgery of Command Hospital (Central Command) Lucknow and all patients will be screened by the principal investigator.
The assessor will be blinded to the randomization group of the patients.
Current literature on the quantitative analysis of the drainage after ND estimates the average duration of the drains remaining in place to be 4.7 ± 1.5 days. (Erişen L, Yircali G, Mescigoglu A, Basut O, Coşkun H. Quantitative analysis of the drainage after ND. Otolaryngol Head Neck Surg. 2000; 123 (5):603-606). We estimate the necessary sample size to be 96 NDs with 48 in each group to detect a 30% decrease rates in the duration of drains with a 0.05 significance level and 0.8 power. We plan to accrue 100 consecutive patients who qualify for our inclusion and exclusion criteria for this study. The statistical comparison of categorical variables will be made using Chi-square test or Fisher's exact test as appropriate. Comparison of continuous variables will be done using independent sample “t” test and P < 0.05 will be considered significant.
Standardization of surgery will be obtained by following the procedure technique described in subjects and methods. The procedure and postoperative care will be standardized as much as possible. All necks will be closed with 3-0 vicryl, 4-0 Monocryl and 5-0 fast absorbing sutures. All patients will receive standardized postoperative orders including inpatient antibiotics not to exceed 72 h (unless an infection is suspected) and DVT prophylaxis in the form of mechanical pumps while on ventilator and TED stockings later on.
All specimen will be examined by a single onco-pathologist and the pathology reports will document the following:
- Primary site and the T staging
- Total number of lymph nodes dissected
- Total number of lymph nodes positive for metastases.
Training of personnel required for this study (e.g., subspecialists, assessor etc.):
None: Subspecialists required for this study are already party of the multidisciplinary oncology team. No special procedure which involves additional training is required.
Support staff available for study completion:
Yes. Within our resources we will complete the study.
Consenting, data & sample collection, and regulatory issues:
Consenting, data and sample collection: Dr Vikrant Singh
Regulatory: Dr S Anand.
| Funding|| |
Injection Tranexamic acid is readily available in our medical stores and patients accrued will be entitled to it without any additional cost to patient. Support is in place from the Departments of Surgery and Head and Neck Surgery to carry out initial enrollment and data collection. No separate funding is required.
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- Erişen L, Yircali G, Mescigoglu A, Basut O, Coşkun H. Quantitative analysis of the drainage after neck dissection. Otolaryngol Head Neck Surg 2000;123:603-6.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]