From the Unit of General and Geriatric Surgery, School of Medicine, Department of Surgery, Second University of Naples, Italy

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1 Sutureless fixation with fibrin glue of lightweight mesh in open inguinal hernia repair: Effect on postoperative pain: A double-blind, randomized trial versus standard heavyweight mesh Silvestro Canonico, MD, Raffaella Benevento, MD, Giuseppe Perna, MD, Raffaella Guerniero, MD, Guido Sciaudone, MD, PhD, Gianluca Pellino, MD, Antonio Santoriello, MD, and Francesco Selvaggi, MD, EBSQ, Naples, Italy Background. Open inguinal hernia repair is associated with a low incidence of complications that can be influenced by the type of mesh and its method of fixation. Our aim was to investigate the frequency and severity of postoperative pain and other complications when lightweight, large-pore meshes, compared with heavyweight, small-pore meshes, are fixed with human fibrin glue (HFG) during open inguinal hernia repair. Methods. A cohort of 80 patients undergoing open inguinal repair were enrolled. Forty patients received a lightweight and large porous mesh and 40 a standard heavyweight mesh with small pores. In all patients, HFG was used for mesh fixation. Results. Patients who received lightweight, large-pore mesh reported less pain than those in the control group both postoperatively (2.8 ± 1.1 vs 4.9 ± 1.1; P =.0003) and at 1-month follow-up (1.7 ± 1.0 vs 3.1 ± 1.0; P =.0038), and took fewer analgesics. There was no difference in days off work/activity. No differences were observed concerning postoperative complications. After 6 months there was no difference in groin pain between groups. Conclusion. Patients who underwent open inguinal hernia repair with lightweight, large-pore mesh fixed with HFG experienced less pain throughout the first month after operation compared with those receiving standard mesh. (Surgery 2013;153: ) From the Unit of General and Geriatric Surgery, School of Medicine, Department of Surgery, Second University of Naples, Italy THE LICHTENSTEIN TECHNIQUE is a standard procedure for open inguinal repair and is associated with a low incidence of recurrence and complications. 1 Minor local complaints, such as discomfort and decreased abdominal wall mobility, are fairly frequent, but often they are tolerated by the patients because are temporary and reversible. In contrast, postoperative pain syndromes have a near 30% prevalence, and 12% of patients feel themselves to be restricted in their daily activities as a consequence of pain. 2 A systematic review of Accepted for publication June 8, Reprint requests: Silvestro Canonico, MD, Department of Surgery, University Hospital, Piazza Miraglia 5, Naples, Italy. silvestro.canonico@unina2.it /$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. prospective trials on mesh-based inguinal hernia repair measured outcome of pain at least 3 months postoperatively and reported that more than one quarter of the patients have moderate to severe pain, so that almost one third of patients have limitations in daily leisure activities. 3 Clinical studies have shown that these complications are influenced by the type of mesh and its method of fixation. 4-7 As regards the type of mesh, 2 major types of mesh prostheses are available currently, including so-called heavyweight meshes with small pores and the newer, lightweight meshes with large pores. Heavyweight meshes have a greater tensile strength and are stronger than lightweight meshes, 8 but they have an increased surface area and produce a more intense foreign body reaction. These heavyweight, small-pore meshes also tend to shrink more than lightweight meshes, and are stiffer. 9 Lightweight meshes seem to cause fewer 126 SURGERY

2 Surgery Volume 153, Number 1 Canonico et al 127 mesh-related problems, and patients report less pain and mesh awareness with these materials. 10 Conceptually, lightweight meshes are more flexible, both before and after tissue integration, which should improve physical properties, allowing a better activity profile after implantation. Conversely, implant rigidity of heavyweight mesh has led to greater complications and adverse events, such as pain and foreign body reaction. 11 With reference to mesh fixation, fibrin gluing has become increasingly accepted as an alternative method for mesh fixation in hernia repair. A recent study demonstrated that the use of human fibrin glue (HFG) in the Lichtenstein s inguinal hernia repair is accompanied by a decrease in postoperative pain and consequently is considered by some investigators as a better option over sutures for mesh fixation. 12 Investigations on a biomechanical model demonstrated that it is possible to achieve adequate fixation of lightweight, largepore meshes using fibrin glue with an optimum fibrin-mesh combination. 13 In our prospective, randomized, double-blind study, newer lightweight and heavyweight meshes both fixed with HFG were compared in open inguinal hernia repair. The purpose of this study was to investigate the frequency and severity of postoperative pain and other complications when lightweight, large-pore meshes, compared with heavyweight, small-pore meshes, are fixed with HFG during open inguinal hernia repair. MATERIALS AND METHODS This was a prospective, double-blind, randomized study of patients undergoing anterior, open surgery for primary unilateral inguinal hernia. Our primary endpoint was decrease in postoperative pain by means of a lightweight mesh fixed with HFG; our secondary endpoint was evaluating the incidence of other postoperative complications. Patients received either heavyweight, small-pore mesh (Prolene mesh, Ethicon Inc, Somerville, NJ) or lightweight, large-pore mesh (Evolution P3EM, Di.pro sas, Torino, Italy). Evolution mesh is polypropylene monofilament mesh with a mean weight of 48 g/m 2, a porosity of 88%, and a thickness of 0.46 mm. The patients were blinded to which mesh they received. Patients were randomized at the time of operation (1:1 ratio). The mesh was fixed with HFG in all the patients. Inclusion criteria were age over 18 years, body mass index of #35 kg/m 2, and uncomplicated primary inguinal hernia suitable for operative repair. Exclusion criteria included large hernias (class M3 or L3 according to the European Hernia Society Classification 14 ), bilateral hernias, concurrent diabetes, immunologic or psychiatric disorders, and hypersensitivity to aprotinin. Patients taking anti-inflammatory drugs preoperatively for management of pain were excluded. All patients were required to provide informed consent, and ethical committee approval was obtained. All operations were performed by experienced surgeons. Operative technique. The following standardized procedures were implemented. The inguinal canal was dissected and the hernial sac managed according to the Lichtenstein technique. The ilioinguinal nerve, the iliohypogastric nerve, and the genital branch of the genitofemoral nerve were preserved in all patients. The mesh was positioned on the inguinal floor, overlying the pubic tubercle for a minimum of 1.5 cm, then the mesh was glued to the inguinal ligament and the internal oblique muscle with HFG (Tissucol/Tisseel; Baxter Healthcare, Deerfield, IL). The glue was prepared from 4 components: Human pooled fibrinogen ( mg/ml), aprotinin (3,000 kallidinogenase inactivator U/mL), human thrombin (500 U/mL), and calcium chloride (40 mmol/ml). Components were mixed during the operation to form fibrin and applied under the mesh by a spraying device; this technique ensured an even and complete covering of the inguinal floor. Less than 0.5 ml of adhesive was required to complete the entire procedure. The prosthesis was compressed over the glue against the inguinal floor for 2 minutes. Lateral to the exit of the spermatic cord, from the internal ring, the upper arm of the mesh, which had been split for the spermatic cord, was flipped over the lower one and they were joined with 1 polypropylene stitch. After suturing the external oblique aponeurosis and subcutaneous space, the skin was closed with a subcuticular absorbable suture (3/0 Monocryl; Ethicon Inc). Operation details, including duration of the operation, were noted immediately after the operation was completed. Analgesics were not routinely administrated postoperatively; these were only given if necessary to relieve postoperative pain. Endpoint definition. Postoperative pain was the primary outcome endpoint of the study. A visual analog scale was used to assess pain intensity on a scale of 0 (no pain) to 10 (unbearable pain). Pain was assessed by observers who were blinded to which mesh the patient received. The frequency of postoperative hemorrhagic complications (hematoma or ecchymosis) in the inguinal region was the secondary outcome measure. Hematoma was defined when a blood collection exceeding 5 3 2cm

3 128 Canonico et al Surgery January 2013 Table I. Baseline demographic and clinical characteristics in inguinal hernia patients Group A (n = 40) Group B (n = 40) P value Total (n = 80) Mean age, yr (±SD) 63 (±12) 66 (±10) > (±11) Males, n (%) 36 (90) 32 (80) (88) Mean BMI (±SD), kg/m 2 25 (±3) 27 (±1) (±3) Risk factors for hernia, n (%) Smoking 14 (35) 16 (40) (37) COPD 4 (10) 8 (20) (15) Chronic constipation 17 (42) 8 (20) (31) Prostatism 5 (12) 4 (10) >.99 9 (11) Right/left hernia, n (%).16 Right 19 (47) 12 (30) 31 (39) Left 21 (52) 28 (70) 49 (61) Pain intensity, mean VAS score (±SD) 3.5 (±2.2) 1.9 (±0.8) (±2.1) Spinal column pain, n (%) 6 (15) 8 (20) (17) BMI, Body mass index; COPD, chronic obstructive pulmonary disease; SD, standard deviation; VAS, visual analog scale on a scale of 1 (no pain) to 10 (unbearable pain). was diagnosed by immediate postoperative screening by ultrasonography. Subcutaneous ecchymosis was defined clinically when it was >50 cm 2. Postoperative assessment was followed by assessments at 1 week, 1 month, and 6 months. A diagnostic/therapeutic checklist was used by evaluators at each follow-up visit. Statistical analysis. Hypothesizing a decrease in pain of 50% by means of lightweight, large-pore mesh we needed to study 40 pairs of subjects to be able to reject the null hypothesis that this response difference is zero with probability (power) 0.8, with a type I error probability associated with this test of this null hypothesis of Results are expressed as or mean ± SD unless otherwise indicated. Differences in means and medians between subgroups were compared using the Mann Whitney U test. Comparisons between categorical variables were analyzed using the Fisher s Exact test. Data were analyzed using the SPSS statistical package (SPSS for MS Windows, version 17.0, Chicago, IL). RESULTS From May 2009 to December 2009, 80 patients undergoing open inguinal repair were enrolled. Forty patients received a lightweight, large-pore mesh (group A) and 40 a standard heavyweight, small-pore mesh (group B). In all patients HFG was used for mesh fixation. The cohort of 80 patients had a mean age of 64 years (SD ± 11; range, 31 80) and 44 (88%) were male. Baseline demographics and clinical characteristics of 2 groups are given in Table I. Patients in group A tended to be less overweight, slightly younger, and in more pain than those in the control group, but these differences were not significant. Over half (54%) of patients were workers or active pensioners. Using the European Hernia Classification system, 16 inguinal hernias (20%) were graded as L1, 40 (50%) as L2, 13 (16%) as M1, and 11 (14%) as M2. Mean operating time was 55 ± 15 minutes; 57 patients (71%) had spinal anesthesia, 20 (25%) had local anesthesia, and 3 (4%) had general anesthesia. No complications occurred in the immediate postoperative period in 32 of 40 patients (80%) in the lightweight, large-pore mesh group and 28 of 40 (70%) of those in the heavyweight, small-pore mesh group (Table II). When evaluated at 1 week, hematoma was observed in 1 patient in group B; ecchymoses were observed in 7 patients in the lightweight, large-pore mesh group and in 4 patients in group B. Patients who had received lightweight, large-pore mesh reported less pain than those in group B (2.8 ± 1.1 vs 4.9 ± 1.1; P =.0003). Relative to baseline (3.5 ± 2.2), there was a decrease in postoperative pain (2.8 ± 1.1) in patients who received lightweight, largepore mesh; more pain was reported in group B subjects (4.9 ± 1.1) relative to baseline (1.9 ± 0.8; Tables I and II). One month after operation, there were no recurrences or surgical site infections. Patients who received lightweight, large-pore mesh reported less pain than those in group B (1.7 ± 1.0 vs 3.1 ± 1.0; P =.0038), and received fewer analgesics. Patients in the lightweight, large-pore mesh group tended to have fewer days off work/activity than those in the group B (8.8 ± 2.6 vs 11.0 ± 3.7; P =.0926). Hematoma was evident in no patients and ecchymosis was evident in only 1 patient in group B. After

4 Surgery Volume 153, Number 1 Canonico et al 129 Table II. One-week and 1-month follow-up data in patients after inguinal hernia repair Postoperative 1 month Group A (n = 40) Group B (n = 40) P value Total (n = 80) Group A (n = 40) Group B (n = 40) P value Total (n = 80) Pain intensity, mean VAS 2.8 (±1.1) 4.9 (±1.1) (±1.4) 1.7 (±1.0) 3.1 (±1.0) (±1.2) score (±SD) Analgesics, number of patients (%) 0 (0) 15 (37) < (30) 0 (0) 7 (17) (14) Objective examination, n (%) No complication 32 (80) 28 (70) (75) 40 (100) 37 (93) (96) Hematoma 0 (0) 1 (3) >.99 1 (1) 0 (0) 0 (0) 0 (0) Ecchymosis 7 (18) 4 (10) (14) 0 (0) 1 (3) >.99 1 (1) Other complications, n (%) 3 (7) 6 (15).48 9 (11) 0 (0) 2 (5).49 2 (3) SD, Standard deviation; VAS, visual analog scale on a scale of 1 (no pain) to 10 (unbearable pain). 6 months, there were no recurrences or other complications. Also in this follow-up, there was no difference in pain between the 2 groups. DISCUSSION The ideal mesh should become integrated into the abdominal wall based on a maximum of biocompatibility, be without serious long-term complications such as recurrence, infection, or chronic pain, and have optimal handling characteristics for an easy, comfortable, and safe hernia repair. 11,15 Modern biomaterials, including polymers, are physically and chemically inert and stable, nonimmunogenic, and nontoxic; however, in vivo they trigger a wide variety of adverse responses, including inflammation and fibrosis. Therefore, it is not fully clear why inert and nonimmunogenic materials induce a foreign body reaction, even if it is widely accepted that the aim of this process is to isolate the foreign body or biomaterial from the host tissues by forming an artificial outside world at the site of implantation. 16 Before the introduction of the lightweight, large-pore meshes, biocompatibility of meshes was regarded generally as excellent; however, the foreign body reaction depends not only on the polymer, but also the surface area in contact with the host tissues. The surface area depends on textile properties of the mesh, such as the pore size or the diameter and number of fibers used. The lightweight, large-pore meshes have less surface area than the heavyweight mesh group; consequently, the foreign body reaction in the lightweight mesh group is decreased markedly. In addition to this decreased chronic inflammatory reaction, the fibrotic reaction around the mesh in total as well as around each single mesh fiber is greatly reduced. 15 For ventral hernia repair, pore size has been discussed extensively. The heavyweight, microporous meshes have a lesser risk of tissue-to-mesh adhesion, but carry a risk of encapsulation and foreign body reaction, resulting in decreased integration. Conversely, lightweight, macroporous mesh results in better tissue in-growth and lesser foreign body reaction, but may lead to a greater risk of adhesions. 17 A larger pore size also provides optimal flexibility for improved physical properties, allowing a better activity profile postoperatively, but decreases the memory of the mesh, which is important for handling during the procedure. 11 Two recent, prospective studies demonstrated that implantation of a lightweight mesh fixed by glue is a highly effective option for preventing chronic pain and decreasing postoperative pain both in open and laparoscopic hernia repair when compared with suture fixation. 18,19 Mesh fixation with HFG is an alternative in young patients with chronic groin pain owing to impalpable hernia. 20 Moreover, HFG is also effective in preventing local hemorrhagic complications after herniorrhaphy in patients with concurrent coagulation disorders, thereby decreasing the costs of prolonged hospitalization related to such complications. 12 Our study suggests that the patients submitted to open inguinal hernia repair with lightweight, large-pore mesh fixed with HFG experienced significantly less pain throughout the month after hernia repair compared with those receiving heavyweight, small-pore mesh. Postoperative pain is an upcoming issue in the field of hernia repair and will probably become the most important topic to be discussed and addressed by the responsible surgeons. Clinical trials report high percentages of patients with chronic pain after hernia repair, including mesh repair. In

5 130 Canonico et al Surgery January study, all mesh modifications with small pores had unacceptably high rates of chronic pain, in particular all the heavyweight polypropylene meshes. 21 In contrast, Post et al 22 reported that the use of lightweight mesh for Lichtenstein inguinal repair was associated with significantly less pain on exercise 6 months after the operation. In another randomized trial, patients who had lightweight mesh for their Lichtenstein repair had less pain on examination, less pain on rising from lying to sitting, fewer miscellaneous groin problems, and felt the mesh less than patients with heavyweight, small-pore mesh. 23 In our study, pain was not different after 6 months in patients who received lightweight, large-pore mesh compared with heavyweight, small-pore mesh both fixed with HFG. In our opinion, this result can be related to the early foreign body reaction of lightweight mesh, that is more and more decreased when HFG is used for its fixation, whereas the different meshes are alike in late reaction. There were some limitations to our study, primarily related to the duration of follow-up and evaluation of chronic pain. Consequently, further study in larger cohorts with greater follow-up are needed to clarify the promising role of lightweight, large-pore mesh fixed with HFG as a strategy to decrease postoperative pain in patients operated on for inguinal hernia. REFERENCES 1. Amid PK. Lichtenstein tension-free hernioplasty: its inception, evolution, and principles. Hernia 2004;8: Bay-Nielsen M, Perkins FM, Kehlet H. Pain and functional impairment 1 year after inguinal herniorrhaphy: a nationwide questionnaire study. Ann Surg 2001;233: Nienhuijs S, Staal E, Strobbe L, Rosman C, Groenwoud H, Bleichrodt R. 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