Randomised controlled trial of n-butyl cyanoacrylate glue fixation versus suture fixation of mesh in laparoscopic totally extraperitoneal hernia repair.

BACKGROUND: We present a randomised control trial to compare suture fixation of the mesh with non-mechanical fixation using n-butyl cyanoacrylate (NBCA) glue for laparoscopic totally extraperitoneal (TEP) hernioplasty. PATIENTS AND METHODS: After a standard dissection for laparoscopic TEP hernioplasty, the mesh was fixed using sutures or NBCA glue to the Cooper's ligament as per the randomised allocation. The primary endpoints were recurrence at 24 months and chronic groin pain. The secondary endpoints were pain scores, analgesic requirement in the post-operative period and duration of surgery.
RESULTS: Group A consisting of suture fixation had 127 patients which included a total of 173 hernias while Group B consisting of NBCA had 124 patients including a total of 171 hernias. The patients' age, sex distribution, body mass indices and co-morbidities were comparable in both groups. No patient suffered any major intra-operative or post-operative complication or mortality. There were no conversions to open surgery in either of the groups. The operating time was similar in both the groups though there was a tendency toward a shorter surgery time in Group B. There was lesser consumption of analgesics in the immediate post-operative period in Group B but this did not reach statistical significance. Using visual analogue scale to measure pain, there was no difference in pain at 48 h; however, Group B patients complained of significantly less pain on day 7 as compared to Group A. Almost 98% of Group A patients and 99.2% of Group B patients completed 24 months of follow-up. There were no recurrences in either groups or was there any significant difference in chronic groin pain, in fact, none of the Group B patients complained of chronic groin pain.
CONCLUSION: Using NBCA glue to fix the mesh in laparoscopic TEP hernia repair is effective and associated with less pain on day 7 as compared to suture fixation of the mesh.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Since its inception in the early 1990s, laparoscopic groin hernia repair has evolved to become a mainstay in the treatment armamentarium of surgeons.[12] It is associated with less post-operative pain, faster recovery and earlier return to work.[2] In both the variants of laparoscopic groin hernia repair, the totally extraperitoneal (TEP) as well as the trans abdominal pre-peritoneal (TAPP) repairs, the mesh is traditionally fixed with tackers/staples or with sutures. Suture fixation is cost-effective as compared to tackers/staples but is technically difficult.[3] Mechanical mesh fixation in this manner has been associated with chronic post-operative groin pain, presumably due to nerve entrapment.[45] As an alternative, non-mechanical fixation with fibrin glue has been adopted.[67] A few of the drawbacks of fibrin glue are its high cost, weaker bonding, slow application and potential for causing allergenic reaction since it is of animal origin.[7] Use of cyanoacrylate glue for mesh fixation in laparoscopic hernia repair was first described in 1998.[8] However, there are no randomised controlled trials comparing n-butyl-cyanoacrylate (NBCA) glue fixation with any of the traditional methods of mesh fixation in laparoscopic hernia surgery. We have been performing suture fixation of mesh in laparoscopic hernia surgery since 2004. With this background, we carried out a randomised controlled trial comparing NBCA glue fixation of mesh in laparoscopic TEP hernioplasty with suture fixation.

PATIENTS AND METHODS

A randomised controlled trial was carried out between January 2009 and March 2012 to compare the two methods of mesh fixation in inguinal hernias. An approval of the Hospital Ethics Committee was obtained to carry out the study, and written consent of the patients was taken. The criteria for inclusion were:

Unilateral or bilateral inguinal hernia;

Age >18 years;

Fitness assessed for the administration of general anaesthesia and laparoscopic surgery.

The exclusion criteria were:

Patient unfit for general anaesthesia or laparoscopic surgery;

Large scrotal hernias;

Irreducible hernias;

Recurrent hernias;

Morbid obesity.

The patients were distributed into two groups based on computer-generated random numbers: Group A, wherein the mesh was fixed with sutures. Group B, wherein the mesh was fixed with NBCA glue. The patients were blinded regarding their group allocation. The flow of patients is depicted in Figure 1. The primary endpoints were recurrence at 24 months and chronic groin pain. The secondary endpoints were pain scores and analgesic requirement in the post-operative period and duration of surgery. Randomisation was done by computer-generated random numbers by an independent operator and group allocation was concealed in a sealed envelope that was opened in the operation theatre and the surgeon was then informed of it.

Figure 1

Flow diagram of patients

All the patients were operated by a single surgeon who had already performed >500 laparoscopic hernia repairs. The technique of surgery is described as follows:

The infra-umbilical extra-peritoneal space was entered by a sub-umbilical vertical skin incision followed by a transverse paramedian incision on the ipsilateral anterior rectus sheath for unilateral hernias or the right anterior rectus sheath for bilateral hernias. The creation of extraperitoneal space, placement of two 5 mm trocars, dissection and reduction of hernia sac and placement of polypropelene mesh (Bard Mesh, Bard India Healthcare Pvt Ltd., Mumbai, India) was done in a standardised manner.[3] The mesh was trimmed down to 12 cm × 15 cm from its original 15 cm ×15 cm size. The mesh was then fixed according to the group allocation of the patient. The surgeon was informed of the technique of fixation at this point. For Group A patients, the mesh was fixed to the ipsilateral Cooper's ligament with a single stitch of 2-0 polyglactin 910. In Group B, a sterile disposable lumbar puncture needle of 20 gauge size was introduced percutaneously through the midline about 3 cm above the pubic symphysis and directed caudally. The needle tip was held in place if necessary by grasping it with a needle holder. Then, 0.5 ml of NBCA glue (Endocryl, Samarth Pharmaceuticals, India) was sprayed onto the mesh and the ipsilateral Cooper's ligament. The mesh was held pressed at the spraying point with the tip of the needle holder for 60 s. In cases of bilateral hernias, 0.5 ml of glue was used in a similar fashion for each mesh.

Post-operatively, the patients were mobilised and allowed liquids orally after 2 h. Soft diet was allowed after 4 h. All the patients were administered ceftriaxone 1 g in the peri-operative period. One dose of non-steroidal analgesic (injection diclofenac 50 mg) was given per-operative and this was repeated after 12 h. Thereafter, analgesics (diclofenac 50 mg + paracetamol 500 mg tablets) were provided on demand only. Patients were discharged after 48 h. The patients were asked to rate their pain on a visual analogue scale (VAS) on the 1st, 2nd and 7th post-operative days. Patients were called for follow-up at 7 days, 1-month, 6 months, 12 months and 24 months. At each follow-up, clinical history was elicited for pain, groin discomfort or swelling and recurrence. Chronic groin pain was defined as discomfort in the groin region on the operative side persisting beyond 6 months.

The statistical analysis was carried out with statistical software (SPSS 11.0, IBM Corporation, Chicago, IL, USA) by a person blinded to the method of mesh fixation in the patient. To test the significance of the difference between continuous data, the P test was applied at 95% confidence levels while for discrete data, Pearson's Chi-square test was applied at 95% confidence levels.

RESULTS

Between January 2009 and March 2012, a total of 251 patients were included in the study. As per randomisation, 127 patients were placed in Group A (suture fixation) and 124 in Group B (glue fixation). The age ranged from 20 to 72 years. The patient characteristics are summarised in Table 1. All the patients were operated under general anaesthesia.

Table 1

Patient characteristics

We actively pursue early post-operative mobilisation for our patients. All patients were made to sit up in bed under supervision of the ward doctor about 2 h after being shifted to ward. After a further 5-10 min, they were made to walk around and allowed clear fluids orally. All liquids were allowed after a further 30 min if the patients did not experience any nausea, and the patients could consume soft diet after 4 h. Full diet was resumed after 12 h. Significant nausea precluded this approach in 2 patients belonging to Group A and 1 patient belonging to Group B. In these patients, liquids orally were resumed by 6-8 h, soft diet after 12 h and full diet after 24 h. The operative time, measured from skin incision to closure was less for unilateral as well as bilateral hernias in Group B. At 95% levels of confidence, the P = 0.56 for unilateral hernias and 0.61 for bilateral hernias. The per-operative findings are summarised in Table 2.

Table 2

Pre-operative findings

A total of three patients developed urinary retention in the immediate post-operative period. All three patients were elderly (age >65 years) and were already taking treatment for prostatism in the form of tamsulosin 0.4 mg at night. They required a single catheterisation and then were able to void spontaneously. All the patients could be discharged after 48 h. The patients were asked to record the intensity of pain on the VAS after 48 h, prior to discharge and then again at 7 days. The immediate and early post-operative findings are summarised in Table 3. History was also elicited regarding the total number of tablets of the oral analgesics that were consumed. The χ2 value for this test was equal to 0.59 at 95% levels of confidence with lower mean consumption of analgesics in Group B.

Table 3

Immediate and early post-operative findings

All the patients were actively followed-up with reminders given to them using short messaging service, mobile phone calls, emails or regular telephone calls. This ensured a high level of compliance with 125 cases in Group A (98.4%) and 123 cases in Group B (99.2%) completing 2 years follow-up. The three defaulters were unable to complete as they were expatriates. The late post-operative sequelae are described in Table 4. A total of 19 patients developed local seroma that was diagnosed clinically. The patients were reassured, and all the seromas resolved spontaneously by 6 months. One patient in Group A developed a hematoma which was diagnosed by ultrasound. No active intervention was required, and the finding resolved by 12 months. While there was no difference in the pain scores on day 2; by 7 days, Group B patients were having significantly less pain than Group A patients.

Table 4

Late post-operative sequelae

DISCUSSION

N-butyl cyanoacrylate is a butyl polymer of cyanoacrylate, an acrylic resin, which undergoes an exothermic reaction in the presence of water to form a bond in about 5 s that finalizes in about a minute. Hence, the mesh has to be held against the underlying tissue after applying NBCA for this period. Among the different polymers of cyanoacrylate, the butyl polymer forms the stronger bond.

Fixation of the mesh in laparoscopic hernia surgery is a critical step of the procedure. It is known to lead significant complications like injuries of vascular structures or nerves in the region.[910] Of the inguinal nerves prone to injury during laparoscopic repair of groin hernia, viz., the genitofemoral nerve, the iliohypogastric nerve, the ilioinguinal nerve and the lateral cutaneous nerve of the thigh, the latter is the most commonly injured, reportedly in 0.1-10% of surgeries.[11] Overall, post-operative neuralgia has been reported in literature in a range of 0.5-14%.[1213] Chronic suprapubic or pelvic pain has also been reported after TAPP repair.[14]

Problems associated with mesh fixation have also prompted an approach to non-fixation of the mesh, with the surgeon relying on adequate dissection of the extraperitoneal space and the large size of the mesh to prevent its displacement.[1516] Preliminary reports indicate that non-fixation does not lead to an increased incidence of recurrence in certain selected hernias while being associated with a reduced incidence of chronic groin pain.[17] However, this method is not universally accepted, and there have been fears that displacement or distortion of the mesh could lead to an increased incidence of hernia recurrence in the long-term.[18]

Due to these shortcomings of tacker/staple fixation, researchers have adopted non-mechanical fixation of the mesh using various adhesive materials.[14] As compared to tackers, fibrin glue has been found by some investigators to be cheaper and associated with a reduced incidence of neuralgic pain and chronic groin pain.[1119] However, its cost-effectiveness vis-à-vis tackers is controversial as other studies have reported fibrin glue to be as costly[20] or even costlier than tackers.[21] We used to perform suture fixation of the mesh using polyglactin 910. This has been shown to be associated with lower pain, lower incidence of neuralgia, reduced analgesic consumption, and lower costs.[22]

The use of cyanoacrylate glue in open Lichtenstein repair was reported in 1993[23] followed by mesh fixation in laparoscopic hernia repair using NBCA glue.[8] After the initial reports, this method did not gain much acceptance possibly due to the tendency of NBCA glue to solidify immediately on contact with organic matter and fears about its cytotoxicity.[24] The latter concern was ill-founded owing to the long documented use of over 30 years of this chemical in the treatment of gastric fundic varices, where it is injected intravariceally or peri-variceally.[25] Its biocompatibility, toxicological safety, and tolerance was demonstrated by Kukleta et al. in both in vitro studies and in vivo implantation studies on animals.[26] This fact led to several authors using NBCA glue for mesh fixation in open Lichtenstein hernia instead of suture fixation.[27] This background encouraged us to carry out this randomised trial of NBCA glue fixation in laparoscopic TEP hernioplasty.

Though our operative times for unilateral as well as bilateral hernias were less in NBCA fixation than suture fixation, the difference did not reach statistical significance. Similarly, though analgesic consumption was not statistically different in the immediate post-operative period in Group B as compared to Group A. However, when we compared the VAS scores, the difference reached statistical significance favouring Group B. In non-randomised comparison, NBCA fixation has been associated with reduced groin pain, both acute and chronic, equivalent recurrence rates, decreased incidence of hematoma and lower cost as compared to tacker fixation.[28] NBCA glue fixation of the mesh was associated with decreased pain levels, shorter hospital stay, rapid resumption of all physical activities, earlier return to work and high levels of patient satisfaction.[2627] None of our patients in either of the groups reported chronic groin pain.

One of the reasons for recurrence could be displacement of the medial edge of the mesh is the fixation has been inadequate. One of the concerns with the use of fibrin glue is its low adhesiveness. In vitro study has shown that fibrin glue has an adhesive strength of 64.3 N while cyanoacrylate has adhesive strength of 105.4 N.[29]

This adequate fixation is attested to absence of recurrence on completion of 24 months of follow-up in our study.

Concerns have been raised about cyanoacrylate glue adhering to surgical instruments, making it difficult to treat them.[20] However, we found that any glue residue on the needle holder used to hold the mesh in position was easily cleaned by a vigorous rub with gauze piece soaked in spirit. Others have found acetone to be as effective.[26]

Though we did not include cost-effectiveness as one of the study parameters, 0.5 ml NBCA costs about Rs. 450/-, which is almost same as the cost of a foil of polyglactin 910 while the tacker costs about Rs. 22,000/- in India. So it is evident that use of either NBCA glue or suture for mesh fixation is going to be much more cost-effective than the use of tackers.

There are several drawbacks in our study, the chief one being power of the study. If we simply consider recurrence as a primary end-point, to show a 50% benefit over mechanical fixation, we would need a total sample size of 1800 patients, far in excess of the 251 that we accrued. Similarly, for a primary endpoint of chronic groin pain, if we consider 10% to be the average incidence of post-operative chronic groin pain (as per data available) and want to show a benefit of a similar magnitude, we would need about 450 patients in each arm. In addition, 2 years follow-up may not be sufficient to detect all recurrences as it is estimated that only 50% of eventual total recurrences are manifest by 2 years.[2] In addition, we have demonstrated the effectiveness of NBCA glue fixation in only one variant of laparoscopic groin hernia repair, viz., TEP repair. A trial needs to be conducted for TAPP hernia repairs too. Since the overall incidence of chronic groin pain and recurrence rate after laparoscopic groin hernia is low, a large, multi-centre trial would be able to finally settle all these questions.

CONCLUSION

This randomised controlled trial shows, in TEP hernia repair, NBCA glue fixation is associated with lower pain score on the 7th day. Though there is a trend toward lesser analgesic consumption in the immediate post-operative period and lower operating times, these did not reach statistical significance in our study. However, NBCA glue fixation is much less costly than a tacker, and it is easier to apply than suturing the mesh and so, should be much more easily adoptable by general surgeons everywhere.