THE TREATMENT OF CHRONIC ANAL FISSURES WITH FISSURE EXCISION AND BOTULINUM TOXIN TYPE A INJECTION (ISRCTN97413456)

THE TREATMENT OF CHRONIC ANAL FISSURES WITH FISSURE EXCISION AND BOTULINUM TOXIN TYPE A INJECTION (ISRCTN97413456) Tkalich O.V.1, Ponomarenko A.A.1, Fomenko O.Yu. 1, Arslanbekova K.I.2, Khryukin R.Yu.1, Misikov V.K.3, Mudrov A.A.1,2, Zharkov E.E.1 1 Ryzhikh National Medical Research Centre for Coloproctology of the Ministry of Health of Russia, Moscow, Russia (director – professor, academician of the RAS Yu.A. Shelygin) 2 Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare of the Russian Federation, Moscow, Russia 3 Moscow Regional Research and Clinical Institute («MRRCI») Moscow, Russia (director – professor, MD, doctor of medicine sciences D.Yu. Semenov)


INTRODUCTION
Chronic anal fissure is a linear ulcerative defect of the anal canal that occurs due to trauma and further permanent spasm of the internal sphincter, leading to ischemia of the anoderm. Due to the fact that the occurrence of a defect in the anal canal forms a pathogenetic circle, including an intense pain syndrome and spasm of the sphincter, its relaxation is a mandatory for any method of chronic anal fissure treatment. The 'golden' standard for the elimination of spasm of the internal sphincter in world practice is a lateral subcutaneous sphincterotomy. The disadvantage of this method is the development of anal incontinence in some patients, which incidence is 8-30% [1][2][3][4][5]. In this regard, the search for the most optimal methods of relaxation of the anal sphincter, which do not lead to its irreversible damage, is currently continuing. In 1992, Sohn N. et al. proposed the anal sphincter pneumatic balloon dilatation [6]. Despite experimental studies by Li L. et al. indicating damage to the neuromuscular structures and the microcirculatory network of the anal sphincter in pneumatic balloon dilatation, the use of this method can reduce the incidence of anal incontinence to 12.5% in the early and 0% in the long-term postoperative follow-up [7]. However, it is quite obvious that it is possible to completely eliminate the risk of anal incontinence only in the absence of mechanical lesion on the anal sphincter. Thus, it was decided to conduct a prospective randomized trial, the purpose of which is to improve the results of treatment of chronic anal fissure.

PATIENTS AND METHODS
The prospective, single-center, randomized study involving 80 patients with chronic anal fissure with sphincter spasm was performed in January 2017 -May 2019. Patients were randomized into groups by random number generation using a computer program. The main group consisted of 40 patients who underwent relaxation of the internal sphincter with botulinum toxin type A; the control group consisted of 40 patients who underwent pneumatic balloon dilatation of the anal sphincter according to the standard method.
The design was developed on the basis of a previous pilot study [8] (Fig. 1). The primary end point of the study is to achieve significant differences in the incidence of anal incontinence on day 30 of the postoperative period. Secondary end points: the intensity of the pain syndrome after surgery; the incidence and structure of postoperative complications; the incidence and severity of weakening of the anal sphincter as per the Wexner scale on day 60; the duration of transitory postoperative incontinence; indicators of the continence according to profilometry before surgery and in the postoperative period on days 7 and 60; the incidence and time of wound healing. All patients included in the study underwent profilometry: before the surgery, on the 7 th and 60 th days after the surgery. Before surgery and daily afterwards, the patients assessed the pain syndrome using VAS. On the 60 th day, the results were evaluated, and the patients underwent anoscopy. For two months after the surgery, taking painkillers was assessed. The patients in the main group after fissure excision were injected with botulinum toxin type A, free of complexing proteins, at 3 and 9 o'clock with 5 units of the drug (a total of 10 units) using an insulin 100-division syringe. The patients in the control group underwent fissure excision and pneumatic balloon dilatation of the anal sphincter according to the standard method [9]. In the future, for various reasons, 28 patients were excluded from the study. Twenty-eight patients of the main and 24 patients of the control groups met the Protocol and passed all tests, which allowed to reach the primary point of the study. The groups were homogenous in the basic clinical characteristics (Table 1).

Figure 1. Study design
So, there were no significant differences in the intensity of pain after defecation and during the day between the groups. Analgesics were required by 27 of 28 patients after botulinum toxin type A injection and by 23 of 24 patients after anal sphincter pneumatic balloon dilatation.
The median duration of taking analgesics in the group of botulinum toxin type A was 7 (4; 14), and in the control group of pneumatic balloon dilatation -8 days (4; 16) (p=0.87). There were no significant differences in the number of patients taking analgesics after surgery (Fig. 3). On days 7 and 60, both groups showed a significant decrease in the maximal pressure in the anal canal at rest compared with the preoperative data (main group p=0.0003; controls p=0.002). At the same time, there were no significant differences in maximal rest anal pressure between the groups (on 7 th day p=0.32; on 60 th day p=0.21) (Fig. 4). There were also no significant differences in the distribution of patients by the level of maximal rest anal pressure on the 7 th and 60 th days of the postoperative period (Table 2). Both in the main and in the control groups there was a significant decrease in the rest anal pressure on the 7 th and 60 th days of the postoperative period compared with the indicators before the surgery (p<0.0001 for both groups). As in the case of maximal rest anal pressure, the average pressure in the postoperative period did not differ significantly between the groups, (on 7 th day, p=0.19; on 60 th day, p=0.08) (Fig. 5).
Between the main and control groups there were no significant differences in the distribution of patients by the level of mean rest anal pressure on the 7 th and 60 th days after surgery (Table 3). Thus, on the 60 th day, spasm of the internal anal sphincter remained in 11 (21%) patients: in 8 patients after administration of botulinum toxin type A, and in 3 patients after pneumatic balloon dilatation, p=0.36.
The anal pressure with a voluntary contraction looked somewhat different. Both in the main and in the control groups, a statistically significant decrease in the maximal anal rest pressure was detected only on 7 th day (p=0.0002 and p<0.0001, respectively), while by 60 th it returned to the baseline in both groups (Fig. 6). There were no significant differences in the value of this data between the groups in the postoperative period, (on 7 th day, p=0.2; on 60 th day, p=0.15) ( Table 4).
In contrast to the maximal pressure, the analysis of the mean anal pressure with a voluntary contraction showed that its significant decrease on the 7 th day of the postoperative period is observed only after the anal sphincter pneumatic balloon dilatation (p<0.0001). After injection of botulinum toxin type A,   the mean anal pressure with voluntary contraction remains at the baseline level on the 7 th and 60 th days after surgery (p=0.66) (Fig. 7). At the same time, the distribution of patients by the level of this indicator on the 7 th and 60 th days of the postoperative period did not differ significantly between the groups ( Table 5).
The groups were comparable in the complications rate (perianal skin hematomas, external hemorrhoid thrombosis, urinary retention, long-term non-healing wounds) (p=0.76) ( Table 6). Postoperative anal incontinence on 30 th day was noted by 6 (21%) patients of the main group, while in the control group in 18 (75%) people (p=0.0002).
The median score on the Wexler scale after botulinum toxin administration was 3 (2; 4) points, after pneu-  Logistic regression was performed to identify factors that affect the development of transitory anal incon-tinence on the 30 th day of the postoperative period (Table 8).
On 60 th day, the transitory anal incontinence was noted by 3 (10.7%) patients of the main group and by 10 (41%) patients of the control group (p=0.02).

DISCUSSION
Almost all contemporary methods of treatment of anal fissure are comparable in their effect on the pain syndrome, the need for painkillers, the nature and postoperative complications rate, as well as a number of other indicators taken into account when conducting research. When evaluating the immediate results of treatment,    98 the main discussion revolves around two parameters: the wound healing rate and anal incontinence rate.
The method of treatment of chronic anal fissure, which allows to improve one of them, most often leads to the deterioration of the other and vice versa, whereas the sphincterotomy is the 'golden' mean.
In the study methods are homogenous in the intensity of pain syndrome, the need for painkillers, the effect on the internal anal sphincter function, the wound healing rate. Unexpected was the fact that the wound healing rate after pneumatic balloon dilatation is lower than after sphincterotomy and is comparable to the same after the injection of botulinum toxin type A (p=0.76). On 60 th day after the surgery, the anal fissure healed in 18 (64%) patients of the botulinum toxin type A group and in 17 (71%) of the pneumatic balloon dilatation group (p=0.76). We think, that the main reason for this outcome is a worth vascularization in the postoperative wound area and the addition of a specific wound infection in some patients. It is not possible to explain it completely this only by the presence of spasm of the internal sphincter, since it was detected only in 50% of the patients of the main and 14% of the control group (p=0.3) with non-healing wounds. This assumption is supported by the fact that of the 8 patients of the main group and 3 patients of the control group (p=0.052), who according to the functional tests on the 60 th day failed to eliminate the spasm of the internal anal sphincter, the wound did not heal in 5 patients in the main group and in 1 patient in the control group. In the remaining 5 patients (3 -in the main and 2 -in the control group) the anal wound healed despite the persisting spasm of the sphincter.
The above data allowed us to change the approach to treatment of patients with non-healing wounds.
As the first stage of treatment, all the patients were prescribed ointments containing recombinant epithelial growth factor. This approach, despite the persisting spasm of the sphincter, led to the healing of postoperative wounds in 3 patients of the main group and 1 patient of the control group within 2 weeks. Re-operation was required only for one patient with sphincter spasm, who was administered botulinum toxin type A in an increased dosage of up to 40 units without fissure excision, which allowed to eliminate the increased tone of the internal sphincter. Another patient developed a posterior transsphincteric anal fistula, but no spasm of the internal sphincter was detected according to profilometry. This patient underwent fistulectomy. In both cases, it was possible to achieve postoperative wound healing within 2 months. In patients with wound infection without spasm of the sphincter, further inclusion in the treatment regimen of antibacterial therapy, taking into account the sensitivity of the microbs, allowed to achieve healing. Thus, the ways to improve the effectiveness of treatment we see in elimination of internal anal sphincter spasm, including in the treatment drugs that affect healing processes, plastic closure of the wound defect after fissure excision (V-Y closure). However, these assumptions require further studies. Despite the fact that the groups did not differ in the postoperative morbidity, transitory anal incontinence was signifi- cantly more often observed after performing pneumatic balloon dilatation. Given that the groups were comparable in terms of the main risk factors for the postoperative anal incontinence [10], this can be explained by the greater invasiveness of the pneumatic balloon dilatation [1,7,11]. According to the logistic regression, the development of transitory postoperative anal incontinence is associated only with the method of relaxation of the internal anal sphincter. The chances of its development in patients who underwent the fissure excision with pneumatic balloon dilatation, on the 30 th day 11 times higher than after the injection of botulinum toxin type A, OR 11  p=0.0002, and on the 60 th day -6 times, OR 6 (1.4-25) p=0.015. The value of other factors are not significant. Obviously, pneumatic balloon dilatation has a more significant effect on the external sphincter function, which is indirectly confirmed by the results of functional tests. Thus, a significant decrease in the mean anal pressure with voluntary contraction was observed only in the control group.

CONCLUSION
The use of botulinum toxin type A after excision of the anal fissure is similar to pneumatic balloon dilatation efficacy (the intensity of pain, the need for analgesics, the rate and time of wound healing) but has a less pronounced adverse effect on the function of the external sphincter of the rectum and reduces the anal incontinence rate after surgery.