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Efficacy of TachoSil® in preventing hemorrhage after loop electrosurgical excision procedure
European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 245–248
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Efficacy of TachoSil1 in preventing hemorrhage after loop electrosurgical excision procedure Jeong Jin Kim 1, Woo Young Kim 1, Doo Haeng Lee, Jun Hyeok Kang, Taejong Song *, Kyo Won Lee, Kye Hyun Kim 1 Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 February 2015 Received in revised form 26 August 2015 Accepted 3 September 2015
Study objective: To assess the utility of TachoSil for achieving hemostasis after loop electrosurgical excision procedure (LEEP). Design: Case–control study (Canadian Task Force Classification II-2). Setting: University hospital. Patients: One hundred seventy-three patients who underwent LEEP. Interventions: Patients were managed by LEEP with application of TachoSil (TachoSil group, n = 75) or without application of TachoSil (control group, n = 94). Measurements and main results: Patient characteristics (age, specimen depth, resection margin, LEEP histopathology, or use of TachoSil) except for parity were similar between the two study groups. Severe bleeding requiring any intervention developed in 14% of patients (24 of 169 patients), without any statistically significant difference between the two groups (11% in the TachoSil group vs. 17% in the control group; P = 0.274). On the logistic regression analysis, other potential clinico-pathologic parameters, including age, parity, specimen depth, involvement of the resection margin, and LEEP histopathology, were not correlated with severe bleeding after LEEP. Conclusion: The use of TachoSil may not reduce the incidence of severe bleeding after LEEP. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: LEEP Bleeding Hemorrhage TachoSil Fibrin sealant
Introduction Cervical intraepithelial neoplasia (CIN) is a common precancerous lesion in women of reproductive age [1]. Loop electrosurgical excision procedure (LEEP) is a procedure used in gynecology for diagnosis and treatment of cervical precancerous lesion (CIN II or III). This procedure has been widely performed because it can easily provide specimens for pathological examination, requires only local anesthesia, and has a high success rate and low major surgical morbidity [2]. In spite of these advantages, complications such as severe hemorrhage after LEEP may occur. These hemorrhages make the
patient undergo unnecessary follow-ups and additional procedures to stop the bleeding. Hence, several studies were performed for determining how to prevent hemorrhage after LEEP, using vasopressin, tranexamic acid, Monsel’s solution, or local hemostats [3–6]. Of the several local hemostats, TachoSil1 (Nycomed, Zurich, Switzerland), which is an equine-derived collagen sponge coated on one side with human fibrinogen and human thrombin, is indicated as supportive treatment in patients undergoing surgery to improve hemostasis and promote tissue sealing [7]. Although the application of TachoSil after LEEP is thought to be associated with a reduction in postoperative bleeding, there are no studies addressing this issue. Therefore, the aim of this study was to assess the utility of TachoSil for achieving hemostasis after LEEP. Materials and methods
* Corresponding author at: Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 110-746, Republic of Korea. Tel.: +82 2 2001 2582; fax: +82 2 2001 1102. E-mail address: [email protected] (T. Song). 1 These authors contributed equally to this paper. http://dx.doi.org/10.1016/j.ejogrb.2015.09.005 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Participants After obtaining approval of the Institutional Review Board, we retrospectively identified patients who underwent LEEP between
246
J.J. Kim et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 245–248
August 2013 and October 2014 from the tumor registry of the Kangbuk Samsung Hospital. Patients who did not receive followup care, who underwent additional hysterectomy within a month of LEEP, or in whom another hemostatic agents except for TachoSil was used, were excluded from the analysis. Demographic data, Papanicolaou (Pap) smear history, colposcopy results, human papilloma virus test results, pathology results, treatment, and follow-up data were abstracted from medical records. Study protocol All surgical procedures were performed in a standardized manner. Just before the procedure, a second-generation cephalosporin was intravenously injected to prevent infection. Under local or general anesthesia, a speculum was inserted into the vagina and the cervix was grasped with a Tenaculum forceps or Allis forceps. The electrosurgical generator used was Force-FXTM (Valleylab, Boulder, CO, USA) and the loop electrodes (Valleylab) were also used. The size of the loop was dependent on the extent of the lesion. The electrical power for the electrode was set at 80 W. After completion of the excision, control of bleeding was achieved using a 5-mm ball electrode with a pure coagulation frequency. At the discretion of the surgeon, TachoSil was applied over the cervical wound during LEEP, according to the manufacturer’s protocol. Briefly, prior to TachoSil application, surgeons cleansed the area to be treated to remove disinfectants and other fluids, and confirmed no active bleeding from the site for TachoSil application. Then, surgeons applied the yellow, active side of the patch to the cervical wound, held in place with gentle pressure on the white, inactive side of TachoSil for at least three minutes, and left TachoSil in place once it adhered to the cervical wound. In some cases, vaginal gauze packing was performed to control invisible bleeding. All patients were scheduled for follow-up at 1 and 4 weeks after LEEP to counsel them on histopathology reports and treatment decision-making, and to inquire about their symptoms and complications. Outcome measures The primary outcome was postoperative complications such as vaginal bleeding or cervical infection. Complications were defined as adverse events arising within 4 weeks of surgery. Vaginal bleeding was classified into two categories according to the severity and timing. Early (within 24 h) and delayed (after 24 h) postoperative bleeding was considered to be severe if hemostatic interventions, including chemical cautery, electrocautery, cervical suturing, or vaginal packing, were required. In contrast, uncomplicated bleeding was defined as postoperative vaginal bleeding that did not require any intervention. Postoperative cervical infection was defined when the use of additional antibiotics for the treatment of purulent vaginal discharge, cervicitis, endometritis, and pelvic inflammatory disease was necessary. Statistical analysis For comparative analysis, patients were classified into two groups based on the use of TachoSil during LEEP. Data are presented as the mean standard deviation (SD) or median (range) for quantitative variables and frequency (percentage) for qualitative variables. The baseline clinical characteristics and study outcomes between the two study groups were compared using the Student’s t test or Mann–Whitney test for continuous variables and the x2 test or Fisher’s exact test for categorical variables, as appropriate. Logistic regression model was used to identify the clinicopathologic factors for severe bleeding after LEEP. A P-value of less than 0.05 was considered to be statistically significant. Statistical analyses were
performed with SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA).
Results Of the 173 patients who underwent LEEP during the study period, we excluded 4 patients who did not receive follow-up care at our institution, who underwent additional hysterectomy within 4 weeks based on their LEEP findings, or who received application of another local hemostat (Tisseel; Baxter Healthcare, Deerfield, IL, USA). Thus, 169 patients were included in the final analysis; 75 patients in whom TachoSil was applied during LEEP (44%; TachoSil group) and 94 patients in whom TachoSil was not applied during LEEP (56%; control group). Demographic characteristics of patients in the two study groups are presented in Table 1. Mean age of patients at the time of surgery was 42.7 10.8 years, with no statistically significant difference between the two groups. The proportion of nulliparous women was significantly higher in the TachoSil group than in the control group (46% vs. 27%; P = 0.014). Other demographic data including Pap smear results, LEEP histopathology, resection margin involvement, and specimen depth were similar between the two study groups. Although HPV test was not performed in 38 patients (22.5%) because of patient’s concern of medical cost, surgeon’s decision, or missing data, high-risk human papilloma virus infection was similar between the two study groups. Table 2 shows all complications arising within 4 weeks after LEEP. Severe bleeding requiring any intervention developed in 14% of the total population (24 of 169 patients), with no statistically significant difference between the two groups (11% in the TachoSil Table 1 Baseline characteristics.
Age (years) <50 years 50 years Parity Nulliparous Parous Pap smear results ASCUS or LSIL HSIL or ASC-H Cancer Others High-risk HPV infectiona Positive Negative LEEP histopathology CIN2 CIN3 Cancer Resection margin involvement Positive Negative Not evaluated Specimen depth Shallow (<10 mm) Deep (10 mm)
TachoSil group (n = 75)
Control group (n = 94)
P-value
61 (81%) 14 (19%)
68 (72%) 26 (28%)
0.204
34 (46%) 40 (54%)
25 (27%) 69 (73%)
24 36 3 6
43 41 2 5
0.014
0.375 (35%) (52%) (4%) (9%)
(47%) (45%) (2%) (6%) 0.718
62 (95%) 3 (5%)
61 (92%) 5 (8%)
40 (53%) 32 (43%) 3 (4%)
51 (54%) 32 (34%) 11 (12%)
10 (13%) 60 (80%) 5 (7%)
19 (20%) 69 (73%) 6 (6%)
49 (79%) 13 (21%)
54 (67%) 27 (33%)
0.154
0.566
0.133
Pap, Papanicolaou; ASCUS, atypical squamous cells of undetermined significance; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; ASC-H, atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion; HPV, human papilloma virus; LEEP, loop electrosurgical excision procedure; CIN, cervical intraepithelial neoplasia. Data are expressed as the means standard deviation, medians (range), or frequencies (percentages), as appropriate. a HPV tests were performed in 65 patients (87%) in the TachoSil group and 66 patients (70%) in the control group by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), Hybird Capture 2 TM (Diagene, Gaithersburg, MD, USA), or oligonucleotide microarray (HPV-DNA chip).
J.J. Kim et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 245–248 Table 2 All complications arising within 4 weeks after LEEP.
Uncomplicated bleeding Cervical infection Severe bleeding requiring intervention Timing of severe bleeding Early bleeding Delayed bleeding Intervention method for severe bleeding Chemical cautery Electrocautery Hemostatic suture Vaginal gauze packing
TachoSil group (n = 75)
Control group (n = 94)
P-value
2 (3%) 0 8 (11%)
2 (2%) 1 (1%) 16 (17%)
>0.999 >0.999 0.274 0.526
0 8 (100%)
3 (19%) 13 (81%)
4 (50%) 4 (50%) 0 0
10 (63%) 4 (25%) 0 2 (13%)
0.428
group vs. 17% in the control group; P = 0.274). The intervention methods were chemical cautery (in 14 patients, 58%), followed by electrocautery (in 8 patients, 33%), and vaginal gauze packing (in 2 patients, 8%). Cervical infection developed in only one case (0.6%). Associations of clinicopathologic parameters with severe bleeding after LEEP are described in Table 3. On the logistic regression analysis, all potential clinico-pathologic parameters, including age, parity, specimen depth, involvement of the resection margin, and LEEP histopathology were not correlated with severe bleeding after LEEP. Discussion In this comparative study, we found that the application of TachoSil on the conization site was not effective in decreasing severe hemorrhage in patients who underwent LEEP. We also found that severe bleeding developed in 14% of the total population (24 of 169 patients) and bleeding in most of the cases (92%) was controlled by chemical cautery and electrocautery. To the best of our knowledge, this is the first study to determine the efficacy of TachoSil in preventing hemorrhage after LEEP. Because the application of TachoSil was thought to be associated with a reduction in postoperative bleeding, we used TachoSil while performing LEEP at the discretion of the surgeon between August 2013 and October 2014. However, we did not identify any clinicopathologic factors, including the use of TachoSil, which were associated with severe bleeding after LEEP on the logistic regression model. The main reason for this seems to Table 3 Associations of clinicopathologic parameters with severe bleeding after LEEP. Variable
N (%)
Univariate OR
Age <50 years 50 years Parity Nulliparous Parous Specimen depth 10 mm <10 mm Resection margin Positive Negative LEEP histopathology CIN2 CIN3 or cancer Use of TachoSil Yes No
P-value 0.868
129 (76%) 40 (24%)
1.088 1
59 (35%) 109 (65%)
0.887 1
40 (28%) 103 (72%)
1 0.908
29 (18%) 129 (82%)
1 0.926
91 (54%) 73 (46%)
0.661 1
75 (44%) 94 (56%)
1 1.718
247
be that TachoSil was not effective in preventing delayed bleeding (after 24 h of LEEP). The other reason may be that although TachoSil was effective, our sample size was too small to detect meaningful differences. Therefore, additional studies with a large sample size should be performed. The direct medical cost for LEEP was about $150 under the Korean National Health Insurance that covers 100% of the population (97% have health insurance and 3% are covered by medical aid). If TachoSil is used in LEEP, direct medical cost increase to more than $380. Therefore, we do not recommend the routine use of TachoSil for preventing severe hemorrhage after LEEP based on our results and medical cost. There are several methods in the literature for preventing severe hemorrhage after a cervical procedure. Lee et al. conducted a randomized trial of vasopressin in patients undergoing laser vaporization of the cervix [3]. They concluded that there was no significant difference in the risk of troublesome bleeding between women who received vasopressin and placebo [3]. Doyle et al. reported that an application of Monsel’s solution after LEEP appeared to reduce the duration of postoperative vaginal bleeding, even though it did not significantly prevent severe complications [3]. In accordance with the findings of previous studies [3,5] our results showed that the application of TachoSil after LEEP did not significantly reduce the incidence of postoperative vaginal bleeding. In contrast, according to the study by Kim et al., the use of Tisseel reduced the incidence of severe post-operative hemorrhage after LEEP [6]. Among the total 169 cases, postoperative infection developed in only one case (0.6%), and thus the incidence of cervical infection was lower than the reported incidence (0.8–14.4%) [8–10]. Purulent vaginal discharge with cervical inflammation was observed in one patient at 1 week after surgery. The patient was successfully treated for the infection with oral antibiotics without requiring any surgical or radiologic intervention (Clavien-Dindo grade 2). Although postoperative symptoms following LEEP including vaginal discharge, vaginal spotting, and lower abdominal discomfort were commonly observed, these symptoms were mostly mild and they spontaneously resolved without the need for intervention. Other serious complications were not observed during the follow-up of 4 weeks. Our study has several limitations. First, this study was a retrospective comparative study without a randomization process and had an unequal number of patients in each group. Second, there was no objective tool for bleeding assessment such as change in the hemoglobin level. Third, although all surgeries were performed using a standard surgical protocol, inter-surgeon variability in the operative technique was not totally avoidable. In conclusion, the use of TachoSil did not reduce the incidence of severe bleeding after LEEP. However, our findings may not be generalized, because this study is a retrospective review of a small, non-randomized population. Therefore, additional randomized controlled trials with large sample size are necessary to confirm the results of this study.
0.792
0.863
0.897
0.361
0.243
References [1] Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489–98. [2] Wright Jr TC, Gagnon S, Richart RM, Ferenczy A. Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol 1992;79:173–8. [3] Lee ET, Ozumba EN, Bevan JR. A randomized trial of Citanest with Octapressin for relief of pain associated with laser vaporization of the cervix. Br J Obstet Gynaecol 1986;93:967–9. [4] Rybo G, Westerberg H. The effect of tranexamic acid (AMCA) on postoperative bleeding after conization. Acta Obstet Gynecol Scand 1972;51:347–50.
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[5] Doyle M, Warwick A, Redman C, Hillier C, Chenoy R, O’Brien S. Does application of Monsel’s solution after loop diathermy excision of the transformation zone reduce post operative discharge? Results of a prospective randomised controlled trial. Br J Obstet Gynaecol 1992;99:1023–4. [6] Kim K, Park SI, Kim BJ, Kim MH, Choi SC, Ryu SY, et al. Efficacy of fibrin sealant in reducing hemorrhage after a loop electrosurgical excision procedure. Gynecol Obstet Invest 2012;74:1–5. [7] Rickenbacher A, Breitenstein S, Lesurtel M, Frilling A. Efficacy of TachoSil a fibrin-based haemostat in different fields of surgery – a systematic review. Expert Opin Biol Ther 2009;9:897–907.
[8] Sutthichon P, Kietpeerakool C. Perioperative complications of an outpatient loop electrosurgical excision procedure: a review of 857 consecutive cases. Asian Pac J Allergy Immunol 2009;10:351–4. [9] Prendiville W, Cullimore J, Norman S. Large loop excision of the transformation zone (LLETZ). A new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynaecol 1989;96:1054–60. [10] Mitchell MF, Tortolero-Luna G, Cook E, Whittaker L, Rhodes-Morris H, Silva E. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Obstet Gynecol 1998;92:737–44.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Efficacy of TachoSil1 in preventing hemorrhage after loop electrosurgical excision procedure Jeong Jin Kim 1, Woo Young Kim 1, Doo Haeng Lee, Jun Hyeok Kang, Taejong Song *, Kyo Won Lee, Kye Hyun Kim 1 Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 February 2015 Received in revised form 26 August 2015 Accepted 3 September 2015
Study objective: To assess the utility of TachoSil for achieving hemostasis after loop electrosurgical excision procedure (LEEP). Design: Case–control study (Canadian Task Force Classification II-2). Setting: University hospital. Patients: One hundred seventy-three patients who underwent LEEP. Interventions: Patients were managed by LEEP with application of TachoSil (TachoSil group, n = 75) or without application of TachoSil (control group, n = 94). Measurements and main results: Patient characteristics (age, specimen depth, resection margin, LEEP histopathology, or use of TachoSil) except for parity were similar between the two study groups. Severe bleeding requiring any intervention developed in 14% of patients (24 of 169 patients), without any statistically significant difference between the two groups (11% in the TachoSil group vs. 17% in the control group; P = 0.274). On the logistic regression analysis, other potential clinico-pathologic parameters, including age, parity, specimen depth, involvement of the resection margin, and LEEP histopathology, were not correlated with severe bleeding after LEEP. Conclusion: The use of TachoSil may not reduce the incidence of severe bleeding after LEEP. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: LEEP Bleeding Hemorrhage TachoSil Fibrin sealant
Introduction Cervical intraepithelial neoplasia (CIN) is a common precancerous lesion in women of reproductive age [1]. Loop electrosurgical excision procedure (LEEP) is a procedure used in gynecology for diagnosis and treatment of cervical precancerous lesion (CIN II or III). This procedure has been widely performed because it can easily provide specimens for pathological examination, requires only local anesthesia, and has a high success rate and low major surgical morbidity [2]. In spite of these advantages, complications such as severe hemorrhage after LEEP may occur. These hemorrhages make the
patient undergo unnecessary follow-ups and additional procedures to stop the bleeding. Hence, several studies were performed for determining how to prevent hemorrhage after LEEP, using vasopressin, tranexamic acid, Monsel’s solution, or local hemostats [3–6]. Of the several local hemostats, TachoSil1 (Nycomed, Zurich, Switzerland), which is an equine-derived collagen sponge coated on one side with human fibrinogen and human thrombin, is indicated as supportive treatment in patients undergoing surgery to improve hemostasis and promote tissue sealing [7]. Although the application of TachoSil after LEEP is thought to be associated with a reduction in postoperative bleeding, there are no studies addressing this issue. Therefore, the aim of this study was to assess the utility of TachoSil for achieving hemostasis after LEEP. Materials and methods
* Corresponding author at: Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 110-746, Republic of Korea. Tel.: +82 2 2001 2582; fax: +82 2 2001 1102. E-mail address: [email protected] (T. Song). 1 These authors contributed equally to this paper. http://dx.doi.org/10.1016/j.ejogrb.2015.09.005 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Participants After obtaining approval of the Institutional Review Board, we retrospectively identified patients who underwent LEEP between
246
J.J. Kim et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 245–248
August 2013 and October 2014 from the tumor registry of the Kangbuk Samsung Hospital. Patients who did not receive followup care, who underwent additional hysterectomy within a month of LEEP, or in whom another hemostatic agents except for TachoSil was used, were excluded from the analysis. Demographic data, Papanicolaou (Pap) smear history, colposcopy results, human papilloma virus test results, pathology results, treatment, and follow-up data were abstracted from medical records. Study protocol All surgical procedures were performed in a standardized manner. Just before the procedure, a second-generation cephalosporin was intravenously injected to prevent infection. Under local or general anesthesia, a speculum was inserted into the vagina and the cervix was grasped with a Tenaculum forceps or Allis forceps. The electrosurgical generator used was Force-FXTM (Valleylab, Boulder, CO, USA) and the loop electrodes (Valleylab) were also used. The size of the loop was dependent on the extent of the lesion. The electrical power for the electrode was set at 80 W. After completion of the excision, control of bleeding was achieved using a 5-mm ball electrode with a pure coagulation frequency. At the discretion of the surgeon, TachoSil was applied over the cervical wound during LEEP, according to the manufacturer’s protocol. Briefly, prior to TachoSil application, surgeons cleansed the area to be treated to remove disinfectants and other fluids, and confirmed no active bleeding from the site for TachoSil application. Then, surgeons applied the yellow, active side of the patch to the cervical wound, held in place with gentle pressure on the white, inactive side of TachoSil for at least three minutes, and left TachoSil in place once it adhered to the cervical wound. In some cases, vaginal gauze packing was performed to control invisible bleeding. All patients were scheduled for follow-up at 1 and 4 weeks after LEEP to counsel them on histopathology reports and treatment decision-making, and to inquire about their symptoms and complications. Outcome measures The primary outcome was postoperative complications such as vaginal bleeding or cervical infection. Complications were defined as adverse events arising within 4 weeks of surgery. Vaginal bleeding was classified into two categories according to the severity and timing. Early (within 24 h) and delayed (after 24 h) postoperative bleeding was considered to be severe if hemostatic interventions, including chemical cautery, electrocautery, cervical suturing, or vaginal packing, were required. In contrast, uncomplicated bleeding was defined as postoperative vaginal bleeding that did not require any intervention. Postoperative cervical infection was defined when the use of additional antibiotics for the treatment of purulent vaginal discharge, cervicitis, endometritis, and pelvic inflammatory disease was necessary. Statistical analysis For comparative analysis, patients were classified into two groups based on the use of TachoSil during LEEP. Data are presented as the mean standard deviation (SD) or median (range) for quantitative variables and frequency (percentage) for qualitative variables. The baseline clinical characteristics and study outcomes between the two study groups were compared using the Student’s t test or Mann–Whitney test for continuous variables and the x2 test or Fisher’s exact test for categorical variables, as appropriate. Logistic regression model was used to identify the clinicopathologic factors for severe bleeding after LEEP. A P-value of less than 0.05 was considered to be statistically significant. Statistical analyses were
performed with SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA).
Results Of the 173 patients who underwent LEEP during the study period, we excluded 4 patients who did not receive follow-up care at our institution, who underwent additional hysterectomy within 4 weeks based on their LEEP findings, or who received application of another local hemostat (Tisseel; Baxter Healthcare, Deerfield, IL, USA). Thus, 169 patients were included in the final analysis; 75 patients in whom TachoSil was applied during LEEP (44%; TachoSil group) and 94 patients in whom TachoSil was not applied during LEEP (56%; control group). Demographic characteristics of patients in the two study groups are presented in Table 1. Mean age of patients at the time of surgery was 42.7 10.8 years, with no statistically significant difference between the two groups. The proportion of nulliparous women was significantly higher in the TachoSil group than in the control group (46% vs. 27%; P = 0.014). Other demographic data including Pap smear results, LEEP histopathology, resection margin involvement, and specimen depth were similar between the two study groups. Although HPV test was not performed in 38 patients (22.5%) because of patient’s concern of medical cost, surgeon’s decision, or missing data, high-risk human papilloma virus infection was similar between the two study groups. Table 2 shows all complications arising within 4 weeks after LEEP. Severe bleeding requiring any intervention developed in 14% of the total population (24 of 169 patients), with no statistically significant difference between the two groups (11% in the TachoSil Table 1 Baseline characteristics.
Age (years) <50 years 50 years Parity Nulliparous Parous Pap smear results ASCUS or LSIL HSIL or ASC-H Cancer Others High-risk HPV infectiona Positive Negative LEEP histopathology CIN2 CIN3 Cancer Resection margin involvement Positive Negative Not evaluated Specimen depth Shallow (<10 mm) Deep (10 mm)
TachoSil group (n = 75)
Control group (n = 94)
P-value
61 (81%) 14 (19%)
68 (72%) 26 (28%)
0.204
34 (46%) 40 (54%)
25 (27%) 69 (73%)
24 36 3 6
43 41 2 5
0.014
0.375 (35%) (52%) (4%) (9%)
(47%) (45%) (2%) (6%) 0.718
62 (95%) 3 (5%)
61 (92%) 5 (8%)
40 (53%) 32 (43%) 3 (4%)
51 (54%) 32 (34%) 11 (12%)
10 (13%) 60 (80%) 5 (7%)
19 (20%) 69 (73%) 6 (6%)
49 (79%) 13 (21%)
54 (67%) 27 (33%)
0.154
0.566
0.133
Pap, Papanicolaou; ASCUS, atypical squamous cells of undetermined significance; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; ASC-H, atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion; HPV, human papilloma virus; LEEP, loop electrosurgical excision procedure; CIN, cervical intraepithelial neoplasia. Data are expressed as the means standard deviation, medians (range), or frequencies (percentages), as appropriate. a HPV tests were performed in 65 patients (87%) in the TachoSil group and 66 patients (70%) in the control group by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), Hybird Capture 2 TM (Diagene, Gaithersburg, MD, USA), or oligonucleotide microarray (HPV-DNA chip).
J.J. Kim et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 194 (2015) 245–248 Table 2 All complications arising within 4 weeks after LEEP.
Uncomplicated bleeding Cervical infection Severe bleeding requiring intervention Timing of severe bleeding Early bleeding Delayed bleeding Intervention method for severe bleeding Chemical cautery Electrocautery Hemostatic suture Vaginal gauze packing
TachoSil group (n = 75)
Control group (n = 94)
P-value
2 (3%) 0 8 (11%)
2 (2%) 1 (1%) 16 (17%)
>0.999 >0.999 0.274 0.526
0 8 (100%)
3 (19%) 13 (81%)
4 (50%) 4 (50%) 0 0
10 (63%) 4 (25%) 0 2 (13%)
0.428
group vs. 17% in the control group; P = 0.274). The intervention methods were chemical cautery (in 14 patients, 58%), followed by electrocautery (in 8 patients, 33%), and vaginal gauze packing (in 2 patients, 8%). Cervical infection developed in only one case (0.6%). Associations of clinicopathologic parameters with severe bleeding after LEEP are described in Table 3. On the logistic regression analysis, all potential clinico-pathologic parameters, including age, parity, specimen depth, involvement of the resection margin, and LEEP histopathology were not correlated with severe bleeding after LEEP. Discussion In this comparative study, we found that the application of TachoSil on the conization site was not effective in decreasing severe hemorrhage in patients who underwent LEEP. We also found that severe bleeding developed in 14% of the total population (24 of 169 patients) and bleeding in most of the cases (92%) was controlled by chemical cautery and electrocautery. To the best of our knowledge, this is the first study to determine the efficacy of TachoSil in preventing hemorrhage after LEEP. Because the application of TachoSil was thought to be associated with a reduction in postoperative bleeding, we used TachoSil while performing LEEP at the discretion of the surgeon between August 2013 and October 2014. However, we did not identify any clinicopathologic factors, including the use of TachoSil, which were associated with severe bleeding after LEEP on the logistic regression model. The main reason for this seems to Table 3 Associations of clinicopathologic parameters with severe bleeding after LEEP. Variable
N (%)
Univariate OR
Age <50 years 50 years Parity Nulliparous Parous Specimen depth 10 mm <10 mm Resection margin Positive Negative LEEP histopathology CIN2 CIN3 or cancer Use of TachoSil Yes No
P-value 0.868
129 (76%) 40 (24%)
1.088 1
59 (35%) 109 (65%)
0.887 1
40 (28%) 103 (72%)
1 0.908
29 (18%) 129 (82%)
1 0.926
91 (54%) 73 (46%)
0.661 1
75 (44%) 94 (56%)
1 1.718
247
be that TachoSil was not effective in preventing delayed bleeding (after 24 h of LEEP). The other reason may be that although TachoSil was effective, our sample size was too small to detect meaningful differences. Therefore, additional studies with a large sample size should be performed. The direct medical cost for LEEP was about $150 under the Korean National Health Insurance that covers 100% of the population (97% have health insurance and 3% are covered by medical aid). If TachoSil is used in LEEP, direct medical cost increase to more than $380. Therefore, we do not recommend the routine use of TachoSil for preventing severe hemorrhage after LEEP based on our results and medical cost. There are several methods in the literature for preventing severe hemorrhage after a cervical procedure. Lee et al. conducted a randomized trial of vasopressin in patients undergoing laser vaporization of the cervix [3]. They concluded that there was no significant difference in the risk of troublesome bleeding between women who received vasopressin and placebo [3]. Doyle et al. reported that an application of Monsel’s solution after LEEP appeared to reduce the duration of postoperative vaginal bleeding, even though it did not significantly prevent severe complications [3]. In accordance with the findings of previous studies [3,5] our results showed that the application of TachoSil after LEEP did not significantly reduce the incidence of postoperative vaginal bleeding. In contrast, according to the study by Kim et al., the use of Tisseel reduced the incidence of severe post-operative hemorrhage after LEEP [6]. Among the total 169 cases, postoperative infection developed in only one case (0.6%), and thus the incidence of cervical infection was lower than the reported incidence (0.8–14.4%) [8–10]. Purulent vaginal discharge with cervical inflammation was observed in one patient at 1 week after surgery. The patient was successfully treated for the infection with oral antibiotics without requiring any surgical or radiologic intervention (Clavien-Dindo grade 2). Although postoperative symptoms following LEEP including vaginal discharge, vaginal spotting, and lower abdominal discomfort were commonly observed, these symptoms were mostly mild and they spontaneously resolved without the need for intervention. Other serious complications were not observed during the follow-up of 4 weeks. Our study has several limitations. First, this study was a retrospective comparative study without a randomization process and had an unequal number of patients in each group. Second, there was no objective tool for bleeding assessment such as change in the hemoglobin level. Third, although all surgeries were performed using a standard surgical protocol, inter-surgeon variability in the operative technique was not totally avoidable. In conclusion, the use of TachoSil did not reduce the incidence of severe bleeding after LEEP. However, our findings may not be generalized, because this study is a retrospective review of a small, non-randomized population. Therefore, additional randomized controlled trials with large sample size are necessary to confirm the results of this study.
0.792
0.863
0.897
0.361
0.243
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