All of the surgeons were trained at the reference center. To further ensure the quality of surgery, standard LIFT and LIFT-plug operating procedures were predefined and given to all surgeons before the start of the trial. All hospitals provided at least 3 videos of the LIFT and LIFT-plug procedures to the reference center before the study commenced. The center could enter the study only after the videos were approved by the study group.
All of the patients followed liquid diets and underwent bowel preparation with polyethylene glycol or magnesium sulfate on the day before surgery. Lumbar or sacral canal anesthesia was administered at the discretion of the anesthetist. A single dose of an antibiotic [most often, cefoxitin (2 g iv) for all patients not allergic to beta-lactam antibiotics] was administrated prophylactically 30 to 60 minutes before surgery. After lumbar or sacral canal anesthesia, the patient was placed in the prone jack-knife or lithotomy position based on the position of the external opening.
The LIFT-plug procedure was performed according to the description previously introduced by our group.14 In brief, the fistula tract and internal opening were identified with a metal fistula probe or saline injection using a syringe from the external opening. A 1.5 to 2.0 cm curvilinear incision was made in the intersphincteric groove overlying the fistula tract. The probe placed within the tract facilitated identification of the fistula tract within this space. After dissection of the fistula tract, the probe was removed. The intersphincteric tract was divided with a right angle clamp at the point where the tract passed into the internal sphincter, and the fistula opening in the internal sphincter was sutured transversely with a figure-of-eight 3/0 absorbable suture. Then, the intersphincteric tract was divided at the point near the external sphincter and submitted for pathologic examination. The fistula tract running from the external sphincter to the external opening was left open, and infected granulation tissue was gently curetted, followed by irrigation with a metronidazole saline solution. A portion of the fistula tract was excised from either end within the intersphincteric space. One porcine small-intestine submucosa extracellular matrix plug (Shaanxi Reshine Biotech Co. Ltd., Shaanxi, People's Republic of China) was soaked in saline for 5 to 10 minutes, and then placed into the intersphincteric groove and pulled through the curetted tract to the external opening. The plug was secured with a figure-of-eight 3/0 absorbable suture to the fistula opening in the external sphincter and ligated. Excess plug protruding from the external opening was trimmed flush with the skin without fixation. The wound was loosely closed with 2 to 3 interrupted 3/0 absorbable sutures.
The LIFT procedure was performed as initially described by Rojanasakul et al.8 The curvilinear incision and dissection of the intersphincteric tract were made as in the LIFT-plug technique. After the tract was isolated, the tract was doubly ligated and suture-ligated with absorbable sutures as close as possible to the lateral margin of the internal anal sphincter and the medial margin of the external anal sphincter. The tract was then divided between the 2 sutures. A portion of the fistula tract was excised after ligation of either end within the intersphincteric space. The medial ligature was very close to the internal opening, and nearly obliterated the internal opening. The external opening was then enlarged to allow adequate drainage. The internal and external sphincters were then re-approximated, and the skin was closed loosely with interrupted 3/0 absorbable suture.
Intravenous cefoxitin was administered for 1 day after surgery. The wound dressings were changed daily. Patients fasted for 1 day postoperatively, followed by a liquid diet, then a regular diet. All patients were discharged 3 to 5 days postoperatively. Patients were advised to maintain smooth bowel movements, clean the anus with warm salt water after defecation, and avoid anal contractions, sitz baths, strenuous activity, sexual activity, exercise, and lifting weights for the first 2 weeks postoperatively.
After discharge, follow-up assessments were performed during clinic visits or by telephone interview weekly for 4 weeks, and followed at 6 weeks, 3 months, and 6 months at each hospital by the treating surgeons and/or investigators. Data on healing time, recurrence, and pre- and postoperative pain [visual analog scale (VAS)] and other associated morbidities were collected from all available outpatient department visits or telephone interviews. Pre- and postoperative anal function was assessed by a questionnaire (Wexner incontinence scale) during the 6-month follow-up period. Successful clinical healing of the fistula was defined as complete wound healing and closure of all external openings in combination with the absence of symptoms at any time during follow-up. Our primary outcome measures were success rate and healing time within 6 months. The secondary outcome measures were recurrence rate, morbidity, postoperative pain, and incontinence rate.
The sample size was calculated based on the primary healing rate with 180 days of follow-up as the main variable. Specifically, we expected the rate in LIFT group to be 82.2%,12 and the rate in the LIFT-plug procedure group to be 95%.14 Accepting an α error of 0.05% and a β error of 0.20 (2-sided), we calculated that 93 patients per arm were needed to detect a difference of 11.8%. Assuming a 15% dropout rate, approximately 107 patients per group were required. Thus, we enrolled 120 patients per arm, which exceeded the sample size requirement.
Statistical analysis was performed using SPSS for Windows (version 16.0; SPSS, Inc, Chicago, IL). Continuous variables (eg, age, intraoperative blood loss, and operative time) are presented as the median and range or mean and SD. Success rate analysis was performed using the Kaplan-Meier method with the log-rank test. Differences between groups were compared using chi-square analysis or the Fisher exact test for categorical data. Continuous variables were compared using the Student t test or Mann-Whitney U test. Changes in VAS scores between the 2 groups from baseline to day 180 were assessed using repeated measures analysis of variance. All P values reported were 2-sided with values of <0.05 considered statistically significant.
Between March 2011 and May 2014, a total of 239 consecutive patients were enrolled in the trial. After exclusions (1 patient was excluded because of a high glucose level in each group, 1 patient was lost to follow-up in the LIFT group, and 1 patient was excluded due to a lack of full preoperative laboratory data in the LIFT-plug group), 235 patients were randomly included in the analysis with 117 in the LIFT-plug group and 118 in the LIFT-group. There were no differences in age, sex, body mass index, comorbidities, smoking, or alcohol consumption between the 2 groups. The comorbidities included coronary atherosclerotic heart disease, hypertension, diabetes mellitus, colon polyps, and hepatitis B. One patient (0.9%) had undergone a previous fistulectomy, and 1 patient had a fistulotomy in the LIFT-plug group. Two patients (1.7%) had received a previous cutting seton in the LIFT group. All patient characteristics are shown in Table 2.
In addition, there were no differences in the fistula anatomy or intraoperative blood loss between the 2 groups. The LIFT procedure showed shorter operative time than the LIFT-plug procedure (26.7 min vs 28.5 min, P = 0.03).
The postoperative pain was assessed by using the VAS scores. As shown in Figure 2, the VAS scores at baseline were similar, and after a rapid increase on day 1 and a rapid decrease the following days, a significant difference was noted between the 2 groups (P for time trend <0.001). Although the changes in VAS scores from baseline to day 180 differed by group (P = 0.01 for time-by-group interaction), the difference in VAS scores across all time points was not statistically significant between the groups (P = 0.13 for overall comparison). Two patients required oral tramadol analgesics, and 1 patient required oral oxycodone acetaminophen for up to 5 days postoperatively in the LIFT-plug group. In the LIFT group, 2 patients received oral nonsteroidal anti-inflammatory drugs for up to 14 and 21 days, and 3 patients used oral tramadol for up to 5 days.
There were no significant differences in the pre- and postoperative Wexner scores between the 2 groups. Neither the LIFT-plug nor LIFT group exhibited a worsening trend in the preoperative baseline scores. Two patients reported worse continence in each group 5 days postoperatively (1 patient had worsening Wexner scores from 0 to 4 and 1 patient had a Wexner score change from 3 to 4 in the LIFT-plug group; and 1 patient had worsening Wexner scores from 1 to 4 and 1 patient had a Wexner score change from 0 to 3 in the LIFT group), and 1 patient had worsening of the baseline Wexner scores from 0 to 1 after the LIFT procedure 6 months postoperatively.
The median follow-up time was 180 days (range, 174–211 d) in the LIFT-plug group and 180 days (range, 173–212 d) in the LIFT group. There was no documented postoperative mortality. No intra- or postoperative complications were observed in the LIFT group. Two patients (1.7%) in the LIFT-plug group developed postoperative complications. A wound infection was detected in 1 patient at the follow-up on postoperative day 5. A perianal abscess was reported in 1 patient 18 days postoperatively that was successfully treated with operative drainage.
There were 7 failures in the LIFT-plug group and 19 failures in the LIFT group during the follow-up. Based on Kaplan-Meier estimation method and the log-rank test, healing rate was significantly higher in LIFT-plug group than in LIFT group [94.0% (95% confidence interval 89.7%–98.3%) vs 83.9% (95% confidence interval 77.2%–90.6%), log-rank test P < 0.001] at 6 months postoperatively (Fig. 3). The median healing time was 22 days (range, 12–45 d) in the LIFT-plug group and 30 days (range, 14–90 d) in the LIFT group (P < 0.001). No recurrence existed within the follow-up period of 6 months.
Our study demonstrated that the LIFT-plug technique is associated with a significantly higher success rate than the LIFT procedure without any recurrences in patients with transphincteric anal fistulas over a median follow-up period of 6 months. Madbouly et al15 performed a prospective randomized trial for high transsphincteric anal fistulas, and reported a 74.3% successful rate in patients who underwent the LIFT procedure after 1 year of follow-up, which was similar with mucosal advancement flaps (65.7%). In one retrospective study comparing the LIFT against mucosal advancement flaps, the LIFT technique had a significantly lower success rate (62.5% vs 93.5%, P = 0.006).16 A systematic review assessed a total of 19 original reports involving the LIFT procedure, and suggested that LIFT is a safe procedure that provides a mean healing of 70.6% (432 of 612) with no reports of impairment of sphincter function, which was in agreement with our LIFT results.17 Indeed, our study has one of the largest numbers of patients who have undergone the LIFT procedure. Furthermore, there was no study that has been undertaken to compare the LIFT-plug procedure with the LIFT procedure.
Our study showed that the median healing time was 22 days in the LIFT-plug group, which was faster than 30 days in the LIFT group, with a median follow-up of 6 months. Since Rojanasakul et al8 reported a mean healing time of 4 weeks for the LIFT technique, several studies have shown a wide range of healing time from 26.6 days to 8 weeks.12,13,15,18,19 Tan et al16 reported a retrospective study of 93 patients who underwent LIFT with a median healing time of 4 weeks (range, 1–12 wk). The median healing time in the Ooi et al's13 study in which the LIFT technique was used for complex crytoglandular anal fistulas was 6 weeks. A recent review, including 18 studies between 2003 and 2009, suggested that the mean healing time was 5.5 weeks for the LIFT technique.1 In the current study, the median healing time for the LIFT group was 30 days, which was similar to previous studies.1,13,16 We propose that the addition of a bioprosthetic plug to the LIFT technique might accelerate fistula healing.
Two prospective randomized trials suggested that LIFT has the advantage of less postoperative pain compared with mucosal advancement flap.11,15 Bleier et al20 reported a total of 39 patients who underwent LIFT during a 17-month period; only 1 patient (2.6%) presented with persistent anal pain, which necessitated an examination under anesthesia and was unremarkable. Until now, no prospective studies have compared the postoperative pain score between LIFT-plug and LIFT. We expected the postoperative pain scores in the LIFT-plug group may be higher than the LIFT group because of the additional procedure. In contrast to our expectation, the pain scores were nearly the same as the LIFT-plug group for overall comparisons between groups across all time points, and there was no meaningful management difference for the patients. Early and rapid revascularization of the implanted biological plug is thought to enhance resistance to contamination,21,22 which might partly decrease the early postoperative pain scores in the LIFT-plug group.
The ideal surgical management to treat anal fistulas is to cure the disease without any risk of fecal incontinence. In the current study, the continence did not show a worsening trend of the preoperative baseline scores in both groups. Furthermore, there were no differences in incontinence scores between the 2 groups; thus, both the LIFT-plug and LIFT techniques were effective sphincter-conserving approach for the treatment of transsphincteric anal fistulas. LIFT has gained popularity due to its high success rate and preservation of continence. Most subsequent studies have shown no postoperative impairment of continence.13,15,20,23 In a systematic review that included 29 articles, 183 patients were formally assessed for continence, of whom only 11 (6%) had a minor disturbance.24 Other reviews also suggested that LIFT is a feasible and effective surgical technique with a low impact on fecal continence.25,26 As a variation of the LIFT technique, LIFT-plug in the present study was also a good option for maintaining continence in the management of transsphincteric anal fistulas.
It has been suggested that inserting a draining seton for 8 to 12 weeks preoperatively to promote maturation of the fistula tract around the seton reduces infection and makes it easier to perform LIFT with impressive outcomes11; however, there were only 2 patients who had received draining setons before the LIFT procedure in our study. Tsunoda et al18 and Aboulian et al27 suggested that a drainage seton did not have a protective effect on fistula recurrence, and believed no seton insertions were required before the LIFT procedure. It is still not clear if there is any advantage in the use of seton drainage before the LIFT procedure.24
Both LIFT-plug and LIFT procedures were safe in the current study. We observed no intra- or postoperative complications in the LIFT group, and only one wound infection and one perianal abscess in the LIFT-plug group. In a systematic review of 435 patients, only 8 (1.8%) had postoperative complications, as follows: purulent discharge, superficial persistent wound dehiscence, anal fissure, persistent anal pain, thrombosed hemorrhoids, and secondary bleeding.25 All of the complications were treated successfully with no reported case of new onset or worsening incontinence.25
Nevertheless, there were some limitations to this study. The main limitation was the length of follow-up, which was only 6 months. It has been suggested that the recurrence rate of complex anal fistulas increases over time with longer follow-up.3 Further studies are warranted to determine the long-term outcome of the LIFT-plug and LIFT procedures. A further limitation was the methodology used to define the main outcome. Although this trial was intended to be prospective and blinded, the fact that the treating surgeon-determined outcome might introduce some degree of possible observer bias.
This multicenter prospective randomized study includes the management of transsphincteric anal fistulas. The study supports that both the LIFT and LIFT-plug procedures are simple and safe procedures, which have high healing rate with no risk of incontinence; however, LIFT-plug has the advantage of a higher healing rate, less healing time, and a lower early postoperative pain score.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
bioprosthetic anal fistula plug; ligation of intersphincteric fistula tract; ligation of intersphincteric fistula tract-plug; transsphincteric anal fistula