Comparison of anal fistula treatment outcome – collagen plug vs advancement-flap (lambeau) surgery. A randomised prospective blinded multi-centre study

Perianal fistula is a common condition, with reported incidence of 5,6 pr 100.000 women and 12,3 pr 100.000 men and occurs most often between 20 – 40 years of age. The direct cause of the development of an anal fistula is often unclear but it commonly starts with an infected anal gland and may first present as a perianal abscess formation. Perianal fistulas may also arise as a complication in patients with Crohn´s disease. They seldom heal spontaneously or by medication and surgical intervention is often needed. Low trans sphincteric fistulas, involving less than 1/3 of the external sphincteric muscle, is often easily treated by fistulotomy with a high success-rate. High sphincteric fistulas still remain a challenge. Traditional surgical treatment can vary from long-term treatment with draining seton or instillation of fibrin glue, to major surgical debridement with extirpation of the fistula tract and a mucosal flap to cover the internal fistula opening (”advancement flap”) or other lambeau-techniques. All these techniques have disappointing success-rates. A new technique have been introduced were the fistula is treated with a bioabsorbable collagen plug (Cook Surgical, Inc., Bloomington, IN) and initial results are promising. The study is designed as a randomised prospective blinded multi centre trial and 148 patients will be included. Clinical examinations pre – and post operatively are supplemented with imaging techniques i.e. endo rectal ultrasound and pelvic MRI. In addition to the mandatory MRI sequences regulated in the study protocol two extra sequences, according to local clinical practise and including i. v. contrast, is added to the patients examined at CMIV The overall aim of the study is to evaluate if the anal plug technique is an alternative compared to the traditional advancement flap operation. From a visualization/ radiological point of view the aim is to evaluate the mandatory and added MR protocols with regard to diagnostic accuracy of anal fistulas, and compare it with the clinical, per operative and ultrasonography findings. Secondly, to apply and develop new visualization tools.

• Staff:

Bengt Norén , MD Radiologist		PI		CMIV, Radiology Department, US
Olof Hallböök , MD				Department of Surgery, US
Disa Kalman				Department of Surgery, US
Nils Dahlström , MD, PhD		Researcher		CMIV, Radiology Department, US
Johan Kihlberg , PhD-student		Researcher		CMIV, IMH, Radiology Department
Olof Dahlqvist Leinhard , PhD		Researcher		CMIV, IMH

• Former Staff:

• Project Description:

Clinical Aspect
Study design
The study is designed as a randomised prospective blinded multi centre trial (Akershus University Hospital, Norway; Sahlgrenska University Hospital /Østra, Sweden; Uppsala Academic Hospital, Sweden; Linköping Hospital, Sweden; Århus Hospital, Denmark), comparing traditional fistula operation with collagen plug as treatment in patients with anal fistulas that are not immediate treatable by laying open.
The study has been approved by the regional ethics committee in Linköping, Sweden.

Number of patients
About 30 patients are estimated included at each of the five contributing hospitals per year. The data collection should be satisfied within one to two years from starting date. With one year follow-up time, the study should be terminated and the results ready for publication within 3-4 years.
Inclusion criteria
• Patients with fistula involving > 1/3 of the external anal sphincter (not suited for direct fistulotomy)
• Single, continous fistula tract at time of inclusion (implies pre-treatment with seton)
• Patients with previous fistula surgery can be included (max. 1 lambeau or 1 plug)
• All patients included must be able to fill in an informed, written consent and to understand its implications and contents and to participate in the follow-up.
Exclusion criteria
• Fistula tract shorter than 2 cm
• Complex fistula tract system (branching of the fistula tract)
• Age < 18 years
• Pregnancy
• HIV-positivity
• Fistula caused by malignancy
• Tuberkulosis
• Hidrosadenitis suppurativa
• Pilonidal sinus disease
• No internal fistula opening found
• Unable/contra indications to go through MRI scanning
• Crohn´s disease
• Ulcerative proctitt

Randomising
Randomising to treatment with fistula plug or advancement flap surgery is done by opening sealed envelopes, with 5 envelopes per block. The randomisation will be done in the operating room, when the final preoperative anal examination with the patient in general anesthesia is performed by the surgeon, to ensure an adequate choice of treatment strategy.
Procedure
Preoperatively
The patient is invited to an outpatient preoperative assessment and clinical examination. Fill-in forms to the patient are provided with the invitation. These are incontinence score, pain score and quality of life score.
In the preoperative encounter, the patient and the fistula is assessed according to normal clinical standards. In addition, a preoperative assessment scheme is filled in by the surgeon.
Informed, written consent is collected. Preoperative MRI of the fistula tract is ordered.
Operation/surgery
A mini-enema is taken in the morning on the day of the surgery. The operation is performed in loco-regional anesthesia or general anesthesia by a proctologist. Prophylactic antibiotics are given perioperatively. Each hospital may do this according to their routine, but equally in both groups. The procedure will be performed with the patient in the position preferred by the surgeon. The randomisation is performed after the initial examination with the patient under anesthesia. The patient is not informed about the outcome of the randomisation.

Anorectal Advancement Flap
Conventional surgery will be performed according to previously employed and established procedures, i.e. by the advancement flap technique: Careful excision of the fistula tract, leaving the external fistula opening open to heal from the depth and outwards. The internal fistula opening is covered by a mobilised musculo-mucosal flap with appropriate blood-supply. The flap is pulled in the caudad direction and cover the internal fistula opening with sufficient side margins, but without tissue tension. The flap is fixed with absorbable suture (Figure 3).
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Fig. 3 Anorectal advancement flap
Anal Fistula Plug
Introduction of the Anal Fistula Plug will be according to the recommendations from (http://www.cookbiotech.com/products/surgisis_afp/index.html). The internal fistula opening is identified (draining seton removed), followed by cleansing of the fistula tract with hydrogenperoxide or sterile salt water. Further manipulation of the fistula tract is not indicated when employing the fistula plug. A suture is fixed to the end of the plug. An introducer is lead from the external to the internal fistula opening and the suture attached to the plug is grasped. Then the plug is pulled into the fistula tract, tail first. The suture is pulled until the plug safely blocks the internal opening and is well fit in the tract itself. Any surplus of the plug is trimmed off. The plug is fixed at the internal opening by resorbable sutures. This suture should also close the internal opening to the anal canal, while the external opening is left open to allow secretion/drainage. (Fig. 3). According to our study protocol we apply only one plug in the fistula tract.


Fig 4. Plug placement and suture


Postoperatively
The patient leaves the hospital with prescription on pain killers, prophylactic antibiotics, stool softener and laxatives. The patient is instructed not to do straining physical exercise for at least three weeks postoperatively. The surgeon fills in the study’s operation form.


Evaluation/Treatment results

Healing of fistula is defined as
1. Total absence of secretion
2. Only a dry scar at external fistula opening
3. Absence of deep infection/cavities

If not all the three criteria are satisfied, the fistula will be defined as persistent.
Follow up/evaluation
The patients will be followed up for 1 year, with clinical encounter/examination after 3 and 12 months, respectively. The 12 months follow-up assessments will be performed by an independent proctologist, so that neither the physician nor the patient knows what kind of treatment was employed. MR control imaging is performed after one year. At both follow-up meetings the patients fill in incontinence score, pain score and quality of life score. The surgeon fills in the follow-up scheme.
Pain-score
The patients will report degree of pain in a Visual Analogue Scale from 0 – 10 by increasing pain. In addition, two questions about pain frequency and effect on daily activities are provided.

Continence-score
Fecal continence is evaluated pre- and postoperatively by Vaizey score (16). The Vaizey score describes the type of incontinence (gas, fluid, solid) and frequency (all scores from 0-4) and additional questions about change in life style (0-4), need of pads or plug (0-2), need of constipating medicines (0-2) and ability to postpone defecation (0-4). The Total Vaizey score span from 0 (fully continent) to 24 (total incontinence).

Quality of life
Quality of life will be measured by the well established SF-36 questionnaire, that maps the patient´s physical and emotional restrains due to their disease, at a given time.

End points
Primary parameters
1. Anorectal fistula closing rate

Sekundary parameters
1. Continence as evaluated by the Vaizey score
2. Post-operative pain
3. Fistula specific symptom score
4. Quality of life
5. Patient´s global assessment of the operation (scale 1 through 4)

Analysis of results
The following statistical tests will be employed in evaluating the results: For the dichotome end points: The chi square test for dichotome end points. The Wilcoxon Mann–Whitney test for quantitative end points. All P values presented will be 2-sided. Statistical analyses will be performed using the computer software program SPSS v 11.5 for Windows.