- Email: [email protected]
Prospective, randomized, controlled trial of tranexamic acid in patients who undergo head and neck procedures
Otolaryngology–Head and Neck Surgery (2008) 138, 762-767
ORIGINAL RESEARCH— HEAD AND NECK CANCER
Prospective, randomized, controlled trial of tranexamic acid in patients who undergo head and neck procedures Chih-Cheng Chen, MD, Chen-Chi Wang, MD, Ching-Ping Wang, MD, Tseng-Hsi Lin, MD, Whe-Dar Lin, PhD, and Shih-An Liu, MD, MHA, Taichung and Taipei, Taiwan OBJECTIVES: To determine if tranexamic acid could reduce the drainage duration after head and neck procedures. STUDY DESIGN: Prospective, randomized, controlled trial. METHODS: Patients who underwent head and neck operations were included. The study group was treated with tranexamic acid during the perioperative period whereas the control group received normal saline solution. Blood samples were also collected. RESULTS: The study and control groups consisted of 26 and 29 patients, respectively. Although there was a significant difference in the drainage amount between the two groups, (49.7 vs 88.8 mL, P ⫽ 0.041), no significant difference could be found in the drainage duration between the two groups (2.69 vs 3.07 days, P ⫽ 0.146). There was also no significant difference in the coagulation profiles between the two groups. CONCLUSION: We did not find a meaningful effect in reducing the drainage duration after head and neck procedures with the use of prophylactic tranexamic acid. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
H
ead and neck surgeons frequently use a drainage tube after head and neck operations to reduce hematoma or seroma formation.1 The drains are typically a closed vacuum system that removes any excess blood or tissue fluid and facilitates the approximation of the skin flaps. The duration of drainage tube placement is closely related to the length of hospital stay.2 Furthermore, prolonged drainage duration will increase the risk of surgical wound infections.3 Therefore, early removal of drainage tube is crucial in head and neck procedures. The factors related to the duration of drainage tube placement include: type of surgery,1 intraoperative bleeding,2 higher drainage output,4 and underlying disease of coagulation disorders. Tranexamic acid (TA) is a fibrinolytic inhibitor.5 It inhibits fibrinolysis by binding to the highaffinity lysine binding sites of plasminogen and plasmin, thus blocking the action of plasmin on fibrin.6 Several
prospective randomized clinical trials have proved its effectiveness in reducing intraoperative and postoperative bleeding in orthopedic and cardiovascular surgeries.7-9 However, few studies have addressed the use of TA in reducing postoperative bleeding and drainage duration in head and neck surgery. Therefore, the aim of this study was to investigate if TA could reduce postoperative bleeding and drainage duration after head and neck operations.
MATERIALS AND METHODS This study was conducted at Taichung Veterans General Hospital (TCVGH) from March 2006 to February 2007. This prospective, randomized, double-blind clinical trial was approved by the Institutional Review Board of TVCGH. Patients aged 20 to 80 years who were scheduled to undergo head and neck surgical procedures were eligible for this study. Patients with the following conditions were eliminated: allergy to TA, a history of hematologic disorders, advanced chronic renal insufficiency (creatinine ⬎2 mg/dL), undergoing anticoagulation therapy, previous radiation to the head and neck region, or who were reluctant to enroll in this protocol. After patients received detailed explanations about the protocol, they gave written informed consent. Basic data, laboratory study, and operation types, which included gender, age, prothrombin time (PT), activated partial thromboplastin time (aPTT), plasma fibrinogen, D-dimers, and perioperative blood loss, were obtained and recorded. Participants were randomized to the study group and the control group. The assignments were made according to a computer-generated randomization list.10 The drugs (tranexamic acid, 100 mg/mL, 4 ampules, 5 mL or saline solution, 20 mL) were placed in numbered dose packs by a person not involved with the surgical procedures and han-
Received December 20, 2007; revised February 20, 2008; accepted February 27, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.02.022
Chen et al
Prospective, randomized, controlled . . .
dled by anesthetist. Because a previous study pointed out that administration of TA at the end of operations failed to reduce the postoperative blood loss,11 we used a prophylactic antifibrinolytic protocol. The study group received one dose of preoperative TA (intravascular 10 mg/kg) before incision followed by continuous infusion of 1 mg/kg/hour during the operation.5,7 The control group received the same protocol except for the injection of normal saline solution instead of TA. The operations were performed by a single surgeon (SAL) and the postoperative dressing was similar between the two groups. The amount of drainage was recorded daily after the operation and the drainage tube was removed when the drainage amount was less than 10 mL during the previous 24 hours. The staff of both the operating room and the ward were blinded to the treatment, and the randomization code was not broken until the study was completed. As there were no previously published data about the difference in drainage duration between those who received TA and those who did not receive it in head and neck operations, we used the data of a previous study7 on another type of operation to estimate the sample size. The null hypothesis is that there is no clinically meaningful difference in drainage duration between those who did and those did not receive TA, and the alternative hypothesis is that the drainage duration of those who receive TA is shorter than that of those who do not receive TA. With a difference in postoperative bleeding of 294 mL between the two groups, the estimated sample size required to demonstrate a two-sided significance level of 0.05 with 80 percent power should be at least 20 subjects in each treatment arm.
STATISTICAL ANALYSIS This study used descriptive statistics for general data presentation. Comparisons of nominal or ordinal variables between the two groups were analyzed by the Chi-square test. In addition, two-tailed Student’s t test was used when the variables fulfilled the presumption of normal distribution whereas the Mann-Whitney U test was used when the variables were not normally distributed. Finally, stepwise multiple regression for correlation between drainage duration and all other variables was applied. All statistics were calculated by SPSS for Windows version 10.1 (SPSS Inc, Chicago, IL). Statistical significance was considered as P ⬍ 0.05.
RESULTS A total of 62 patients were enrolled in this study. Two patients asked to withdraw from the trial during the hospitalization. Three patients left the operating room without using drainage tube. One patient developed wound infection
763
Figure 1
Participants’ flow chart.
2 days after the operation, and the drainage tube was removed immediately. One patient had a poorly functioning drainage tube soon after operation (air leakage from wound). The drainage tube was cut outside the neck and used as a penrose drain. After these seven patients withdrew, 55 patients remained in the trial. The participants’ flow chart is listed in Figure 1. The average age of participants was 48.0 years (⫾ 13.9 years). The study group and control group consisted of 26 and 29 patients, respectively. Males and females were equally distributed in the two groups. No obvious difference was noted in the demographic data between the two groups. The operation types included modified radical neck dissection (n ⫽ 16, 29.1%), hemithyroidectomy (n ⫽ 20, 36.4%), and superficial parotidectomy (n ⫽ 19, 34.5%). The detailed descriptive data are presented in Table 1. Although the drainage amount was significantly lower in the study group (49.7 ⫾ 32.6 versus 88.8 ⫾ 89.8 mL, P ⫽ 0.041), no significant difference could be found in the drainage duration between groups (2.69 ⫾ 0.68 versus 3.07 ⫾ 1.13 days, P ⫽ 0.146). The mean difference between the two groups in drainage amount was 39.1 mL with 95 percent confidence interval ranging from 1.7 to 76.5 mL; the mean difference between the two groups in drainage duration was 0.38 day with 95% confidence interval ranging from – 0.14 to 0.89. No patients developed symptoms or signs suggestive of thromboembolic complications such as deep vein thrombosis during hospitalization. As one of the factors associated with drainage duration is surgical type, we stratified the patients according to the surgical procedures. We found that the drainage amount and
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Otolaryngology–Head and Neck Surgery, Vol 138, No 6, June 2008
Table 1 Comparison of demographic data and surgical related records between two groups
Variables Age (years) Body mass index (kg/M2) Gender Female Male Operation type Modified radical neck dissection Hemithyroidectomy Superficial parotidectomy Operation duration (hours) Perioperative bleeding (mL) Drainage amount (mL) Drainage duration (days) Hospitalization (days)
Study group (n ⫽ 26)
Control group (n ⫽ 29)
Number of patients (%) or mean ⫾ SD
Number of patients (%) or mean ⫾ SD
49.8 ⫾ 13.0 24.8 ⫾ 3.7
46.4 ⫾ 14.8 24.1 ⫾ 4.2
11 (42.3%) 15 (57.7%)
13 (44.8%) 16 (55.2%)
6 (23.0%) 10 (38.5%) 10 (38.5%) 0.7 128.5 32.6 0.68 0.80
10 (34.5%) 10 (34.5%) 9 (31.0%) 0.8 120.3 89.9 1.13 1.26
P value 0.372 0.495 0.851 0.725
2.7 86.5 49.7 2.69 4.81
⫾ ⫾ ⫾ ⫾ ⫾
2.7 115.5 88.8 3.07 5.31
⫾ ⫾ ⫾ ⫾ ⫾
0.731 0.392 0.041* 0.146 0.087
*Statistical significance.
duration were both lower in study group regardless of the surgical type (Fig 2). In addition, perioperative bleeding was significantly correlated with drainage duration (Pearson correlation coefficient: 0.299, P ⫽ 0.027). Due to some technological reasons (inadequate specimen, coagulated specimen, or staff forgot to obtain specimens), only 41 (74.5%) patients had sufficient laboratory data for analysis. The study and control group consisted of 20 and 21 patients, respectively. The detailed data are presented in Table 2 with the format of mean ⫾ standard deviation. There was no significant difference in the coagulation profiles between the two groups. The results of the stepwise multiple regression analysis of drainage duration based on study group and operative duration are shown in Table 3. Shortened operation time and TA treatment were contributing factors in early removal of drainage tube. However, the R2 value of the stepwise multiple regression analysis was only 0.168. Operation duration and TA treatment group contributed 13.5, 3.3 percent of the drainage duration variance, respectively.
DISCUSSION One of the most important concerns that head and neck surgeons have when visiting the patients after the surgical procedures is the drainage amount. If the drainage amount remains high, the removal of drainage tube will be postponed. Delayed drainage removal not only prolongs the hospitalization but also increases the risk of developing surgical wound infection.3 Therefore, several strategies have been proposed to reduce the perioperative and postop-
erative bleeding including: identifying patients at risk, pharmacologic intervention,12 meticulous surgical techniques,13 cell salvage, and acute hemodilution.14 Benoni et al11 in their studies about the timing of TA administration found that giving TA at the end of operations failed to reduce the postoperative blood loss.11 Protocol for postoperative administration is TA 10 mg/kg body weight intravenously at the end of the operation. The administration was repeated 3 hours later. Protocol for preoperative administration (from the same authors’ previous work) is TA 10 mg/kg body weight (maximum 1g) in a slow (5 to 10 minutes) intravenous injection immediately before the operation starts.15 However, the authors11 compared the results with their previous work.15 There was significant difference between two groups (preoperative vs postoperative administration) in drainage amount (199 mL vs 440 mL) yet no difference in perioperative blood loss (561 mL vs 550 mL). Nevertheless, no data of operative time were reported in the preoperative administration group. Patel et al4 in their study about factors associated with prolonged wound drainage found that increased volume of drain output was an independent risk factor for prolonged wound drainage. However, the results of current study showed that although the usage of TA could decrease the postoperation drainage amount after head and neck procedures, it could not shorten the drainage duration. The reason might be that there are different drainage amounts in diverse surgical fields. The average perioperative blood loss in cardiac and orthopedic surgeries ranged from 488 to 1099 mL7-9 whereas that of the current study was 102 mL. The coagulation factors can either be loss from bleeding or dilution from the infused fluids during operation.12 As the
Chen et al
Prospective, randomized, controlled . . .
Figure 2 The drainage amount and duration of two groups stratified according to the operation types. Symbols (□, Q) represent mean values; error bars represent one standard deviation.
average perioperative blood loss in head and neck operations is not as much as that in cardiac or orthopedic surgeries, TA treatment in head and neck procedures may not be as efficacious as that in cardiac or orthopedic procedures. A comparable finding was also reported by Orpen et al.16 Another reason might be due to the timing of drainage tube removal. If the threshold of removing drainage tube was higher (eg, 20 cc/24 hours), maybe there will be a difference between the two groups. In the current study, we found that a significant factor associated with the drainage duration is the operation time. It is easy to understand that a surgical procedure that required a longer period is likely to have extended dissection and more perioperative bleeding. As a result, more postoperative drainage is expected. However, the R2 value of the operation duration in the multiple regression model contributed only 13.5 percent of the drainage duration variance. Therefore, most of the drainage duration variance was attributable to other factors.
765 Horrow et al17 in their study about the dose-response relationship of TA found that the D-dimer concentration of the placebo group was significantly higher than that of the control group. D-dimer is also known as fragment D-dimer. It is produced only after a clot has formed and is in the process of being broken down. Measuring of D-dimer is to detect thrombotic diseases and conditions such as deep vein thrombosis, pulmonary embolism, or disseminated intravascular coagulation. We included D-dimer measurement only because previous studies included that item and we want to compare our data with previous works. Nevertheless, the result showed no significant difference between two groups. This might be due to the different population. They recruited patients who were receiving anticoagulation therapy and scheduled to undergo cardiac surgeries whereas our patients never received anticoagulation therapy. In addition, our study found no significant difference in coagulation profiles after head and neck procedures between the two groups. Similar results have been reported in other studies.18,19 Benoni et al20 found that TA diminished the Ddimer level significantly in blood from the wounds when compared with that of the control group. They also found that the fibrinolytic activity seemed to be more stimulated in blood from the wound than from peripheral blood. This could be the reason why there was no significant difference in coagulation profiles from peripheral blood between the two groups in our study. There were some limitations in this study. First, the population size was small as our sample estimation in recruiting participants was based on an expected greater total blood loss such as was found in the orthopedic surgery. Large 95 percent confidence intervals were noted in the differences of drainage amount and duration between the two groups, raising the possibility of a type 2 error (false negative conclusion). Second, not all of our participants obtained adequate laboratory data due to inadequate specimen, coagulated specimen or because staff forgot to obtain specimens and bias might thus exist. Third, the drainage output after a head and neck procedure could be due to blood or serous discharges. TA pharmacologically affects the breakdown of fibrinogen and would probably not affect the production of serous discharge. Last, we chose three head and neck procedures instead of a single procedure as was used in other studies on TA. Consequently, a confounding effect might be present.
CONCLUSION We did not find a meaningful effect in the reduction of the drainage duration after head and neck procedures with the use of prophylactic TA. However, TA can reduce the drainage amount after head and neck operations. Therefore, patients who undergo extensive dissection that may involve massive postoperative oozing are more suitable for TA treatment. Nevertheless, further investigation with a larger
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Otolaryngology–Head and Neck Surgery, Vol 138, No 6, June 2008
Table 2 Coagulation profiles of studied population according to subgroups
Variables Platelet count (1000 mm3) Preoperative Perioperative Postoperative Prothrombin time (seconds) Preoperative Perioperative Postoperative INR* Preoperative Perioperative Postoperative Partial prothrombin time (seconds) Preoperative Perioperative Postoperative Plasma fibrinogen (mg/dl) Preoperative Perioperative Postoperative D-dimer (mg/ml) Preoperative Perioperative Postoperative
Study group (n ⫽ 20)
Control group (n ⫽ 21)
mean ⫾ SD
mean ⫾ SD
P value
272.9 ⫾ 76.1 262.7 ⫾ 69.2 258.3 ⫾ 69.2
272.3 ⫾ 84.9 269.1 ⫾ 79.4 286.5 ⫾ 97.1
0.982 0.782 0.293
12.2 ⫾ 1.1 12.6 ⫾ 0.8 12.3 ⫾ 1.0
12.0 ⫾ 0.8 12.2 ⫾ 0.8 12.2 ⫾ 1.0
0.264 0.224 0.589
1.03 ⫾ 0.11 1.06 ⫾ 0.14 1.03 ⫾ 0.15
1.00 ⫾ 0.07 1.01 ⫾ 0.12 1.00 ⫾ 0.16
0.363 0.246 0.569
28.3 ⫾ 2.0 28.6 ⫾ 2.7 27.8 ⫾ 3.1
30.0 ⫾ 3.7 30.2 ⫾ 3.1 29.5 ⫾ 3.7
0.086 0.092 0.123
308.9 ⫾ 117.5 299.3 ⫾ 90.0 344.9 ⫾ 135.6
316.3 ⫾ 103.1 327.6 ⫾ 93.3 335.2 ⫾ 100.0
0.830 0.329 0.263
0.41 ⫾ 0.34 0.35 ⫾ 0.26 0.94 ⫾ 1.99
0.44 ⫾ 0.38 0.71 ⫾ 1.35 1.01 ⫾ 1.17
0.795 0.261 0.886
*INR, International Normalized Ratio.
population may be needed to clarify the relationship between TA and postoperative bleeding after major head and neck surgeries.
ACKNOWLEDGEMENTS This study was supported by a grant from Taichung Veterans General Hospital (TCVGH-957001A) Taichung, Taiwan, Republic of China. The authors thank Ms Hui-Ching Ho for statistical software processing.
AUTHOR INFORMATION From the Department of Otolaryngology (Drs Chen, C-C Wang, C-P Wang, and Liu) and Hematology Division, Department of Internal Medicine (Dr T-H Lin), Taichung Veterans General Hospital, Taichung, Taiwan; and Faculty of Medicine (Drs C-C Wang, C-P Wang, and Liu), School of Medicine, National Yang-Ming University, Taipei; and the Department of Information Technology (Dr W-D Lin), Overseas Chinese Institute of Technology, Taichung, Taiwan. Corresponding author: Shih-An Liu, No. 160, Sec 3. Taichung Harbor Road, Taichung, Taiwan. 40705. E-mail address: [email protected].
Table 3 Factors that affect drainage duration based on stepwise multiple regression analysis
Operation time (hours) Tranexamic acid treatment group
Coefficient
95% Confidence interval
R2 value
p value
0.480 –0.344
0.149 ⬃ 0.811 –0.824 ⬃ 0.137
0.135 0.033
0.005 0.157
Chen et al
Prospective, randomized, controlled . . .
AUTHOR CONTRIBUTIONS Chih-Cheng Chen, manuscript draft; Chen-Chi Wang, study design; Ching-Ping Wang, data collection; Tseng-Hsi Lin, study design; WheDar Lin, statistical process; Shih-An Liu, study design.
FINANCIAL DISCLOSURE None.
REFERENCES 1. Williams J, Toews D, Prince M. Survey of the use of suction drains in head and neck surgery and analysis of their biomechanical properties. J Otolaryngol 2003;32:16 –22. 2. Urquhart AC, Berg RL. Neck dissections: predicting postoperative drainage. Laryngoscope 2002;112:1294 – 8. 3. Vilar-Compte D, Jacquemin B, Robles-Vidal C, et al. Surgical site infections in breast surgery: case-control study. World J Surg 2004; 28:242– 6. 4. Patel VP, Walsh M, Sehgal B, et al. Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty. J Bone Joint Surg Am 2007;89:33– 8. 5. Porte RJ, Leebeek FWG. Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002;62: 2193–211. 6. Neilipovitz DT. Tranexamic acid for major spinal surgery. Eur Spine J 2004;13(Suppl.1):S62–5. 7. Zabeeda D, Medalion B, Sverdlov M, et al. Tranexamic acid reduces bleeding and the need for blood transfusion in primary myocardial revascularization. Ann Thorac Surg 2002;74:733– 8. 8. Yamasaki S, Masuhara K, Fuji T. Tranexamic acid reduces blood loss after cementless total hip arthroplasty: prospective randomized study in 40 cases. Int Orthop 2004;28:69 –73.
767 9. Camarasa MA, Olle G, Serra-Prat M, et al. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. Br J Anaesth 2006;96:576 – 82. 10. Su HY, Ding DC, Chen DC, et al. Prospective randomized comparison of single-dose versus 1-day cefazolin for prophylaxis in gynecologic surgery. Acta Obstet Gynecol Scand 2005;84:384 –9. 11. Benoni G, Lethagen S, Nilsson P, et al. Tranexamic acid, given at the end of the operation, does not reduce postoperative blood loss in hip arthroplasty. Acta Orthop Scand 2000;71:250 – 4. 12. Koh MBC, Hunt BJ. The management of peri-operative bleeding. Blood Rev 2003;17:179 – 85. 13. Dalloglio MF, Srougi M, Antunes AA, et al. An improved technique for controlling bleeding during simple retropubic prostatectomy: a randomized controlled study. BJU Int 2006;98:384 –7. 14. Fergusson D, Blair A, Henry D, et al. Technologies to minimize blood transfustion in cardiac and orthopedic surgery: results of a practice variation survey in nine countries. International Study of Peri-operative Transfusion (ISPOT) Investigators. Int J Technol Assess Health Care 1999;15:717–28. 15. Benoni G, Bjorkman S, Fredin H. Application of pharmacokinetic data from healthy volunteers for the prediction of plasma concentrations of traexamic acid in surgical patients. Clin Drug Invest 1995;10:280 –7. 16. Orpen NM, Little C, Walker G, et al. Tranexamic acid reduces early post-operative blood loss after total knee arthroplasty: a prospective randomized controlled trial of 29 patients. Knee 2006;13:106 –10. 17. Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relationship of tranexamic acid. Anesthesiology 1995;82:383–92. 18. Armellin G, Casella S, Guzzinati S, et al. Tranexamic acid in aortic valve replacement. J Cardiothorac Vasc Anesth 2001;15:331–5. 19. Casati V, Sandrelli L, Speziali G, et al. Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: a prospective, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 2002;123:1084 –91. 20. Benoni G, Lethagen S, Fredin H. The effect of tranexamic acid on local and plasma fibrinolysis during total knee arthroplasty. Thromb Res 1997;85:195–206.
ORIGINAL RESEARCH— HEAD AND NECK CANCER
Prospective, randomized, controlled trial of tranexamic acid in patients who undergo head and neck procedures Chih-Cheng Chen, MD, Chen-Chi Wang, MD, Ching-Ping Wang, MD, Tseng-Hsi Lin, MD, Whe-Dar Lin, PhD, and Shih-An Liu, MD, MHA, Taichung and Taipei, Taiwan OBJECTIVES: To determine if tranexamic acid could reduce the drainage duration after head and neck procedures. STUDY DESIGN: Prospective, randomized, controlled trial. METHODS: Patients who underwent head and neck operations were included. The study group was treated with tranexamic acid during the perioperative period whereas the control group received normal saline solution. Blood samples were also collected. RESULTS: The study and control groups consisted of 26 and 29 patients, respectively. Although there was a significant difference in the drainage amount between the two groups, (49.7 vs 88.8 mL, P ⫽ 0.041), no significant difference could be found in the drainage duration between the two groups (2.69 vs 3.07 days, P ⫽ 0.146). There was also no significant difference in the coagulation profiles between the two groups. CONCLUSION: We did not find a meaningful effect in reducing the drainage duration after head and neck procedures with the use of prophylactic tranexamic acid. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
H
ead and neck surgeons frequently use a drainage tube after head and neck operations to reduce hematoma or seroma formation.1 The drains are typically a closed vacuum system that removes any excess blood or tissue fluid and facilitates the approximation of the skin flaps. The duration of drainage tube placement is closely related to the length of hospital stay.2 Furthermore, prolonged drainage duration will increase the risk of surgical wound infections.3 Therefore, early removal of drainage tube is crucial in head and neck procedures. The factors related to the duration of drainage tube placement include: type of surgery,1 intraoperative bleeding,2 higher drainage output,4 and underlying disease of coagulation disorders. Tranexamic acid (TA) is a fibrinolytic inhibitor.5 It inhibits fibrinolysis by binding to the highaffinity lysine binding sites of plasminogen and plasmin, thus blocking the action of plasmin on fibrin.6 Several
prospective randomized clinical trials have proved its effectiveness in reducing intraoperative and postoperative bleeding in orthopedic and cardiovascular surgeries.7-9 However, few studies have addressed the use of TA in reducing postoperative bleeding and drainage duration in head and neck surgery. Therefore, the aim of this study was to investigate if TA could reduce postoperative bleeding and drainage duration after head and neck operations.
MATERIALS AND METHODS This study was conducted at Taichung Veterans General Hospital (TCVGH) from March 2006 to February 2007. This prospective, randomized, double-blind clinical trial was approved by the Institutional Review Board of TVCGH. Patients aged 20 to 80 years who were scheduled to undergo head and neck surgical procedures were eligible for this study. Patients with the following conditions were eliminated: allergy to TA, a history of hematologic disorders, advanced chronic renal insufficiency (creatinine ⬎2 mg/dL), undergoing anticoagulation therapy, previous radiation to the head and neck region, or who were reluctant to enroll in this protocol. After patients received detailed explanations about the protocol, they gave written informed consent. Basic data, laboratory study, and operation types, which included gender, age, prothrombin time (PT), activated partial thromboplastin time (aPTT), plasma fibrinogen, D-dimers, and perioperative blood loss, were obtained and recorded. Participants were randomized to the study group and the control group. The assignments were made according to a computer-generated randomization list.10 The drugs (tranexamic acid, 100 mg/mL, 4 ampules, 5 mL or saline solution, 20 mL) were placed in numbered dose packs by a person not involved with the surgical procedures and han-
Received December 20, 2007; revised February 20, 2008; accepted February 27, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.02.022
Chen et al
Prospective, randomized, controlled . . .
dled by anesthetist. Because a previous study pointed out that administration of TA at the end of operations failed to reduce the postoperative blood loss,11 we used a prophylactic antifibrinolytic protocol. The study group received one dose of preoperative TA (intravascular 10 mg/kg) before incision followed by continuous infusion of 1 mg/kg/hour during the operation.5,7 The control group received the same protocol except for the injection of normal saline solution instead of TA. The operations were performed by a single surgeon (SAL) and the postoperative dressing was similar between the two groups. The amount of drainage was recorded daily after the operation and the drainage tube was removed when the drainage amount was less than 10 mL during the previous 24 hours. The staff of both the operating room and the ward were blinded to the treatment, and the randomization code was not broken until the study was completed. As there were no previously published data about the difference in drainage duration between those who received TA and those who did not receive it in head and neck operations, we used the data of a previous study7 on another type of operation to estimate the sample size. The null hypothesis is that there is no clinically meaningful difference in drainage duration between those who did and those did not receive TA, and the alternative hypothesis is that the drainage duration of those who receive TA is shorter than that of those who do not receive TA. With a difference in postoperative bleeding of 294 mL between the two groups, the estimated sample size required to demonstrate a two-sided significance level of 0.05 with 80 percent power should be at least 20 subjects in each treatment arm.
STATISTICAL ANALYSIS This study used descriptive statistics for general data presentation. Comparisons of nominal or ordinal variables between the two groups were analyzed by the Chi-square test. In addition, two-tailed Student’s t test was used when the variables fulfilled the presumption of normal distribution whereas the Mann-Whitney U test was used when the variables were not normally distributed. Finally, stepwise multiple regression for correlation between drainage duration and all other variables was applied. All statistics were calculated by SPSS for Windows version 10.1 (SPSS Inc, Chicago, IL). Statistical significance was considered as P ⬍ 0.05.
RESULTS A total of 62 patients were enrolled in this study. Two patients asked to withdraw from the trial during the hospitalization. Three patients left the operating room without using drainage tube. One patient developed wound infection
763
Figure 1
Participants’ flow chart.
2 days after the operation, and the drainage tube was removed immediately. One patient had a poorly functioning drainage tube soon after operation (air leakage from wound). The drainage tube was cut outside the neck and used as a penrose drain. After these seven patients withdrew, 55 patients remained in the trial. The participants’ flow chart is listed in Figure 1. The average age of participants was 48.0 years (⫾ 13.9 years). The study group and control group consisted of 26 and 29 patients, respectively. Males and females were equally distributed in the two groups. No obvious difference was noted in the demographic data between the two groups. The operation types included modified radical neck dissection (n ⫽ 16, 29.1%), hemithyroidectomy (n ⫽ 20, 36.4%), and superficial parotidectomy (n ⫽ 19, 34.5%). The detailed descriptive data are presented in Table 1. Although the drainage amount was significantly lower in the study group (49.7 ⫾ 32.6 versus 88.8 ⫾ 89.8 mL, P ⫽ 0.041), no significant difference could be found in the drainage duration between groups (2.69 ⫾ 0.68 versus 3.07 ⫾ 1.13 days, P ⫽ 0.146). The mean difference between the two groups in drainage amount was 39.1 mL with 95 percent confidence interval ranging from 1.7 to 76.5 mL; the mean difference between the two groups in drainage duration was 0.38 day with 95% confidence interval ranging from – 0.14 to 0.89. No patients developed symptoms or signs suggestive of thromboembolic complications such as deep vein thrombosis during hospitalization. As one of the factors associated with drainage duration is surgical type, we stratified the patients according to the surgical procedures. We found that the drainage amount and
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Otolaryngology–Head and Neck Surgery, Vol 138, No 6, June 2008
Table 1 Comparison of demographic data and surgical related records between two groups
Variables Age (years) Body mass index (kg/M2) Gender Female Male Operation type Modified radical neck dissection Hemithyroidectomy Superficial parotidectomy Operation duration (hours) Perioperative bleeding (mL) Drainage amount (mL) Drainage duration (days) Hospitalization (days)
Study group (n ⫽ 26)
Control group (n ⫽ 29)
Number of patients (%) or mean ⫾ SD
Number of patients (%) or mean ⫾ SD
49.8 ⫾ 13.0 24.8 ⫾ 3.7
46.4 ⫾ 14.8 24.1 ⫾ 4.2
11 (42.3%) 15 (57.7%)
13 (44.8%) 16 (55.2%)
6 (23.0%) 10 (38.5%) 10 (38.5%) 0.7 128.5 32.6 0.68 0.80
10 (34.5%) 10 (34.5%) 9 (31.0%) 0.8 120.3 89.9 1.13 1.26
P value 0.372 0.495 0.851 0.725
2.7 86.5 49.7 2.69 4.81
⫾ ⫾ ⫾ ⫾ ⫾
2.7 115.5 88.8 3.07 5.31
⫾ ⫾ ⫾ ⫾ ⫾
0.731 0.392 0.041* 0.146 0.087
*Statistical significance.
duration were both lower in study group regardless of the surgical type (Fig 2). In addition, perioperative bleeding was significantly correlated with drainage duration (Pearson correlation coefficient: 0.299, P ⫽ 0.027). Due to some technological reasons (inadequate specimen, coagulated specimen, or staff forgot to obtain specimens), only 41 (74.5%) patients had sufficient laboratory data for analysis. The study and control group consisted of 20 and 21 patients, respectively. The detailed data are presented in Table 2 with the format of mean ⫾ standard deviation. There was no significant difference in the coagulation profiles between the two groups. The results of the stepwise multiple regression analysis of drainage duration based on study group and operative duration are shown in Table 3. Shortened operation time and TA treatment were contributing factors in early removal of drainage tube. However, the R2 value of the stepwise multiple regression analysis was only 0.168. Operation duration and TA treatment group contributed 13.5, 3.3 percent of the drainage duration variance, respectively.
DISCUSSION One of the most important concerns that head and neck surgeons have when visiting the patients after the surgical procedures is the drainage amount. If the drainage amount remains high, the removal of drainage tube will be postponed. Delayed drainage removal not only prolongs the hospitalization but also increases the risk of developing surgical wound infection.3 Therefore, several strategies have been proposed to reduce the perioperative and postop-
erative bleeding including: identifying patients at risk, pharmacologic intervention,12 meticulous surgical techniques,13 cell salvage, and acute hemodilution.14 Benoni et al11 in their studies about the timing of TA administration found that giving TA at the end of operations failed to reduce the postoperative blood loss.11 Protocol for postoperative administration is TA 10 mg/kg body weight intravenously at the end of the operation. The administration was repeated 3 hours later. Protocol for preoperative administration (from the same authors’ previous work) is TA 10 mg/kg body weight (maximum 1g) in a slow (5 to 10 minutes) intravenous injection immediately before the operation starts.15 However, the authors11 compared the results with their previous work.15 There was significant difference between two groups (preoperative vs postoperative administration) in drainage amount (199 mL vs 440 mL) yet no difference in perioperative blood loss (561 mL vs 550 mL). Nevertheless, no data of operative time were reported in the preoperative administration group. Patel et al4 in their study about factors associated with prolonged wound drainage found that increased volume of drain output was an independent risk factor for prolonged wound drainage. However, the results of current study showed that although the usage of TA could decrease the postoperation drainage amount after head and neck procedures, it could not shorten the drainage duration. The reason might be that there are different drainage amounts in diverse surgical fields. The average perioperative blood loss in cardiac and orthopedic surgeries ranged from 488 to 1099 mL7-9 whereas that of the current study was 102 mL. The coagulation factors can either be loss from bleeding or dilution from the infused fluids during operation.12 As the
Chen et al
Prospective, randomized, controlled . . .
Figure 2 The drainage amount and duration of two groups stratified according to the operation types. Symbols (□, Q) represent mean values; error bars represent one standard deviation.
average perioperative blood loss in head and neck operations is not as much as that in cardiac or orthopedic surgeries, TA treatment in head and neck procedures may not be as efficacious as that in cardiac or orthopedic procedures. A comparable finding was also reported by Orpen et al.16 Another reason might be due to the timing of drainage tube removal. If the threshold of removing drainage tube was higher (eg, 20 cc/24 hours), maybe there will be a difference between the two groups. In the current study, we found that a significant factor associated with the drainage duration is the operation time. It is easy to understand that a surgical procedure that required a longer period is likely to have extended dissection and more perioperative bleeding. As a result, more postoperative drainage is expected. However, the R2 value of the operation duration in the multiple regression model contributed only 13.5 percent of the drainage duration variance. Therefore, most of the drainage duration variance was attributable to other factors.
765 Horrow et al17 in their study about the dose-response relationship of TA found that the D-dimer concentration of the placebo group was significantly higher than that of the control group. D-dimer is also known as fragment D-dimer. It is produced only after a clot has formed and is in the process of being broken down. Measuring of D-dimer is to detect thrombotic diseases and conditions such as deep vein thrombosis, pulmonary embolism, or disseminated intravascular coagulation. We included D-dimer measurement only because previous studies included that item and we want to compare our data with previous works. Nevertheless, the result showed no significant difference between two groups. This might be due to the different population. They recruited patients who were receiving anticoagulation therapy and scheduled to undergo cardiac surgeries whereas our patients never received anticoagulation therapy. In addition, our study found no significant difference in coagulation profiles after head and neck procedures between the two groups. Similar results have been reported in other studies.18,19 Benoni et al20 found that TA diminished the Ddimer level significantly in blood from the wounds when compared with that of the control group. They also found that the fibrinolytic activity seemed to be more stimulated in blood from the wound than from peripheral blood. This could be the reason why there was no significant difference in coagulation profiles from peripheral blood between the two groups in our study. There were some limitations in this study. First, the population size was small as our sample estimation in recruiting participants was based on an expected greater total blood loss such as was found in the orthopedic surgery. Large 95 percent confidence intervals were noted in the differences of drainage amount and duration between the two groups, raising the possibility of a type 2 error (false negative conclusion). Second, not all of our participants obtained adequate laboratory data due to inadequate specimen, coagulated specimen or because staff forgot to obtain specimens and bias might thus exist. Third, the drainage output after a head and neck procedure could be due to blood or serous discharges. TA pharmacologically affects the breakdown of fibrinogen and would probably not affect the production of serous discharge. Last, we chose three head and neck procedures instead of a single procedure as was used in other studies on TA. Consequently, a confounding effect might be present.
CONCLUSION We did not find a meaningful effect in the reduction of the drainage duration after head and neck procedures with the use of prophylactic TA. However, TA can reduce the drainage amount after head and neck operations. Therefore, patients who undergo extensive dissection that may involve massive postoperative oozing are more suitable for TA treatment. Nevertheless, further investigation with a larger
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Otolaryngology–Head and Neck Surgery, Vol 138, No 6, June 2008
Table 2 Coagulation profiles of studied population according to subgroups
Variables Platelet count (1000 mm3) Preoperative Perioperative Postoperative Prothrombin time (seconds) Preoperative Perioperative Postoperative INR* Preoperative Perioperative Postoperative Partial prothrombin time (seconds) Preoperative Perioperative Postoperative Plasma fibrinogen (mg/dl) Preoperative Perioperative Postoperative D-dimer (mg/ml) Preoperative Perioperative Postoperative
Study group (n ⫽ 20)
Control group (n ⫽ 21)
mean ⫾ SD
mean ⫾ SD
P value
272.9 ⫾ 76.1 262.7 ⫾ 69.2 258.3 ⫾ 69.2
272.3 ⫾ 84.9 269.1 ⫾ 79.4 286.5 ⫾ 97.1
0.982 0.782 0.293
12.2 ⫾ 1.1 12.6 ⫾ 0.8 12.3 ⫾ 1.0
12.0 ⫾ 0.8 12.2 ⫾ 0.8 12.2 ⫾ 1.0
0.264 0.224 0.589
1.03 ⫾ 0.11 1.06 ⫾ 0.14 1.03 ⫾ 0.15
1.00 ⫾ 0.07 1.01 ⫾ 0.12 1.00 ⫾ 0.16
0.363 0.246 0.569
28.3 ⫾ 2.0 28.6 ⫾ 2.7 27.8 ⫾ 3.1
30.0 ⫾ 3.7 30.2 ⫾ 3.1 29.5 ⫾ 3.7
0.086 0.092 0.123
308.9 ⫾ 117.5 299.3 ⫾ 90.0 344.9 ⫾ 135.6
316.3 ⫾ 103.1 327.6 ⫾ 93.3 335.2 ⫾ 100.0
0.830 0.329 0.263
0.41 ⫾ 0.34 0.35 ⫾ 0.26 0.94 ⫾ 1.99
0.44 ⫾ 0.38 0.71 ⫾ 1.35 1.01 ⫾ 1.17
0.795 0.261 0.886
*INR, International Normalized Ratio.
population may be needed to clarify the relationship between TA and postoperative bleeding after major head and neck surgeries.
ACKNOWLEDGEMENTS This study was supported by a grant from Taichung Veterans General Hospital (TCVGH-957001A) Taichung, Taiwan, Republic of China. The authors thank Ms Hui-Ching Ho for statistical software processing.
AUTHOR INFORMATION From the Department of Otolaryngology (Drs Chen, C-C Wang, C-P Wang, and Liu) and Hematology Division, Department of Internal Medicine (Dr T-H Lin), Taichung Veterans General Hospital, Taichung, Taiwan; and Faculty of Medicine (Drs C-C Wang, C-P Wang, and Liu), School of Medicine, National Yang-Ming University, Taipei; and the Department of Information Technology (Dr W-D Lin), Overseas Chinese Institute of Technology, Taichung, Taiwan. Corresponding author: Shih-An Liu, No. 160, Sec 3. Taichung Harbor Road, Taichung, Taiwan. 40705. E-mail address: [email protected].
Table 3 Factors that affect drainage duration based on stepwise multiple regression analysis
Operation time (hours) Tranexamic acid treatment group
Coefficient
95% Confidence interval
R2 value
p value
0.480 –0.344
0.149 ⬃ 0.811 –0.824 ⬃ 0.137
0.135 0.033
0.005 0.157
Chen et al
Prospective, randomized, controlled . . .
AUTHOR CONTRIBUTIONS Chih-Cheng Chen, manuscript draft; Chen-Chi Wang, study design; Ching-Ping Wang, data collection; Tseng-Hsi Lin, study design; WheDar Lin, statistical process; Shih-An Liu, study design.
FINANCIAL DISCLOSURE None.
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