Background
Incisional hernia (IH) is the most frequently seen long term complication in surgery causing much morbidity and even mortality in patients [
1‐
4]. Despite studies on the optimal closing technique for laparotomies, the risk for IH after midline incision remains about 11-20% [
5,
6]. In the Netherlands alone about 4000 IH operations are performed each year. Incisional hernia surgery is, in fact, a re-operation to relieve symptoms caused by this common complication and the results of repair are often disappointing [
7,
8].
Patient-related risk factors for incisional hernia after a laparotomy, like obesity, steroid use, malnutrition, smoking, abdominal aortic aneurysm (AAA), and connective tissue disorders are known [
7,
9‐
13]. Despite this knowledge a sufficient method for prevention, has not been developed yet. Most research in the field of incisional hernia surgery has been performed to prevent recurrence after repair. The closure technique of midline incisions has grosso modo remained unchanged since many decades and primarily consists of suturing the linea alba. Interest in prevention of incisional hernias with the aid of synthetic mesh is growing and small, yet promising studies have now been published [
14‐
25].
One specific group of high-risk patients are patients with an AAA. Aortic aneurysm is considered to be related to a type of connective tissue disorder. The connective tissue in these patients is thought to be compromised, playing an important role in the pathogenesis of an aneurysmal distension of the aorta. Healing of the midline fascia after laparotomy may be compromised due to formation of collagen with insufficient strength. Sutures can tear through the fascia and defects can develop in the abdominal wall. The relationship between aortic aneurysm and other abdominal wall hernias, like inguinal hernias, has been reported [
26‐
28]. Retrospective and prospective studies have shown an average risk for incisional hernia after AAA repair of about 30% (Table
1) [
9,
26,
28‐
34].
Table 1
Publications concerning risk for incisional hernia after aortic aneurysm repair with midline incision with a minimum of 2 years follow-up
| 2005 | 50 months | RCT | 20 | 22 | 90,9 |
| 2004 | 36 months | Prospective | 14 | 61 | 22,9 |
| 2004 | 63 months | Prospective | 32 | 197 | 16,2 |
| 2003 | 33 months | Prospective | 50 | 177 | 28,2 |
| 2002 | 42 months | Case series | 49 | 140 | 35 |
| 2001 | 49 months | Prospective | 16 | 51 | 31,4 |
| 1998 | 36 months | Retrospective | 18 | 58 | 31,0 |
| 1996 | 24 months | Case series | 13 | 34 | 38,2 |
| 1988 | 38 months | Retrospective | 10 | 27 | 37,0 |
Another high risk group is the group of obese patients [
5]. Patients with a BMI of 30 or more have a high risk of developing an incisional hernia after midline incision, with an incidence of 22% after 12 months [
5,
13]. Most recent literature is showing us that even a BMI of more than 27 gives a 20% risk for developing an incisional hernia after midline laparotomy [
35]. Considering only 50% of incisional hernia will be clinically evident in the first 12 months, the total incidence is likely to be above 30%. It is known from the study of Burger et al. that an extensive follow up time of up to 10 years is needed to evaluate outcome in hernia surgery [
7]. A tailored approach might be necessary, since hernia formation is multifactorial. Thus, the above mentioned high-risk group of patients with obesity and aneurysmal disease can benefit most from prevention.
Some small studies have been performed to evaluate the effect and safety of primary laparotomy wound closure with the aid of prosthetic mesh (Table
2) [
14‐
25]. These studies show a very low risk for incisional hernia and a low infection rate, even when used in contaminated area’s, as seen in colostomy surgery. However, no high quality and adequately powered randomized controlled trial has been performed to evaluate the impact of prophylactic mesh augmentation for prevention of incisional hernia in high risk patients. This is the reason that the
PRImary
Mesh Closure of
Abdominal Midline Wound (PRIMA) trial is being conducted.
Table 2
Publications concerning incisional hernia prevention with the aid of prosthetic mesh
| 2011 | Prospective | 95 | 15/50 | 2/45 | 24 months | Polypropylene | Sublay |
O. H. Llaguna et al. [ 15] | 2011 | Prospective | 134 | 11/62 | 1/44 | 17 months | Biological | Intraperitoneal |
| 2010 | RCT | 85 | 16/43 | 5/37 | 36 months | Polypropylene | Sublay |
G. Currò et al. | 2010 | Prospective | 50 | 8/25 | 1/25 | 12 months | Polypropylene | Sublay |
M. P. Hidalgo et al. | 2010 | Cohort | 72 | - | 0/72 | 46 months | Polypropylene | Onlay |
O. H. El-Khadrawy et al. [ 19] | 2009 | RCT | 40 | 1/20 | 3/20 | 36 months | Polypropylene | Preperitonial |
G. Hebert et al. | 2009 | Cohort | 16 | - | 1/16 | 6 months | Mix | Sublay |
J. Strzelczyk et al. [ 21] | 2006 | RCT | 74 | 8/38 | 0/36 | 28 months | Polypropylene | Sublay |
| 2007 | Cohort | 39 | - | 1/28 | 48 months | Polypropylene | Sublay |
C. Gutierrez de la Pena et al. [ 23] | 2003 | RCT | 88 | 5/44 | 0/44 | 36 months | Polypropylene | Onlay |
J. Strzelczyk et al. [ 24] | 2002 | Prospective | 60 | 9/48 | 0/12 | 12 months | Polypropylene | Sublay |
| 1998 | RCT | 288 | 41/144 | 33/144 | 29 months | Vicryl | Intraperitoneal |
Objective
The objective of this study is to evaluate the effectiveness of incisional hernia prevention in patients after laparotomy for aortic aneurysm and in obese patients with a BMI of more than 27. A double blind randomized controlled trial will compare the commonly used technique of running suture to closure with the aid of a prosthetic mesh.
-
The primary outcome measure will be incisional hernia occurrence 2 years postoperatively.
-
Secondary outcome measures will cover relevant postoperative complications, post-operative pain and quality of life.
Methods/design
Trial design
The trial is a double blinded randomized controlled international multi centre trial comparing traditional closure with running slowly absorbable suture to closure with the aid of prosthetic mesh. A total of 11 centers have agreed to participate in the trial which are located in three different countries (The Netherlands, Germany and Austria). A total number of 460 patients will be included. Patients will be randomized in three groups per-operatively to either receive primary closure, or mesh supported closure either in a sublay or onlay position. Patients will be kept unaware of the procedure until the endpoint of the trial was assessed. Outpatient clinic controls will be done by surgeons or surgical residents blinded for the procedure. Results will be stratificated by center and operation indication.
Participants
Patients meeting the inclusion criteria scheduled for elective laparotomy will be asked to participate in the study. After ample information has been given, patients will be asked for informed consent.
Exclusion criteria
-
Age < 18 years
-
Inclusion in other trials with interference of the primary endpoint
-
Life expectancy less than 24 months (as estimated by the treating physician)
-
Pregnant women
-
Immune suppression therapy within 2 weeks before surgery
-
Bovine allergy
Registration and randomization procedure
Patients who are scheduled for operation and who have given informed consent will be registered by contacting the trial coordinator using the telephone or using the online inclusion randomization system. Included patient are registrated in an online data base (designed and managed by HOVON data center, Rotterdam, the Netherlands) called TOP (Trial Online Process; see
http://www.primatrial.nl). The patient name code, date of birth, name of caller, name of responsible physician, sex and eligible criteria will be registered. Every participating institution has its own login code.
Randomisation will take place at the end of the scheduled operation before closing the abdomen in the operating room by contacting the trial coordinator using the telephone or using the online inclusion randomization system. The patient will stay in the randomization group on an intention to treat principle.
Intervention
Patients will be randomized for three different closing techniques (1A: primary suture closure of the midline fascia, 2B onlay mesh supported closure and 3C sublay mesh supported closure). Both mesh techniques are extensively used in incisional hernia surgery. However, a powered randomized comparison of these two techniques has not been performed. Infection rates in these trials seem low, even in the presence of open bowel [
36‐
41]. Because the study population will not be operated for an incisional hernia, which necessitates extended dissection of the abdominal wall in a previously operated area, infection rates are expected to be lower than the rates mentioned in the literature. Intra-peritoneal placement has not been considered given the high risk for adhesions between viscera and mesh [
42].
The mesh will be fixed to the fascia structures with fibrin sealant (Tissucol DUO 500 2,0 ml (Baxter Deutschland GmbH, Unterschließheim, Germany) in order to avoid sutures subcutaneously, to prevent the production of seroma and to simplify the procedure [
43]. Nowadays fibrin sealants are occasionally used in inguinal hernia surgery [
44‐
46]. The mesh will be fixed adequately with fibrin sealant to the ventral part of linea alba and posterior rectus sheath. The Optilene Mesh LP, 6 × 35 cm, B. Braun Aesculap AG, Tuttlingen, Germany, will be used as it was shown to have an optimal fixation with fibrin sealant and to provide good tensile strength [
47].
Only the first operations of each center will be supervised by one of the PRIMA trial research fellows. If during operation an incisional hernia was discovered the patient was excluded from the trial, as the interest of this study was incisional hernia prevention, not repair. All centers were familiar with the 4:1 suture length to wound length ratio concept although not measured. As the focus of the trial was on the effect of primary mesh augmentation versus common day practice closure, no measurements of the suture closure were done.
Group A. Primary closure of the midline
The midline fascia will be closed in all three groups with a running slowly absorbable suture (MonoPlus, USP 1, Needle HRT48, 150 cm loop, B.Braun Aesculap, Tuttlingen, Germany). The ratio of suture length to wound length of 4:1 is recommended (but not measured). Subcutaneous tissue and skin are closed in a fashion preferred by the surgeon.
Mesh supported closure
Group B. Onlay mesh supported closure
First, the midline will be closed as indicated in group A.
The Optilene Mesh LP will be positioned on the primary closed midline fascia with an overlap of 3 cm at each side. The mesh will then be fixed with fibrin sealant (5 ml). The fibrin sealent will be applied on the entire surface of the mesh, and in one shot having permanent contact between the mesh and the tip of the joining piece. Immediately after application of the fibrin sealant, the mesh will be smoothed with the back of a forceps to get a good fixation of the mesh on the entire surface and especially on the suture line. If present, it is also possible to use spray fixation using the EASYSPRAY system, Deutschland GmbH, Unterschließheim, Germany. When laparotomy is larger then 25 cm use 2 applicators of Tissucol (10 ml). Subcutaneous tissue and skin are closed in a fashion preferred by the surgeon.
Group C. Sublay mesh supported closure
A space will be created between both posterior rectus sheaths and the rectus muscle. Both posterior rectus sheath edges are sutured using a running slowly absorbable suture,(Monoplus, USP1, Needle HRT48, 150 cm, B. Braun Aesculap AG, Tuttlingen, Germany). A suture length to wound length ratio of 4:1 was recommended (not measured). The Optilene Mesh LP will then be placed between the posterior rectus sheath and the rectus muscle with an overlap of 3 cm at each side and fixed with fibrin sealant (5 ml). The fibrin sealent will be applied on the entire surface of the mesh, in one shot having permanent contact between the mesh and the tip of the joining piece. Immediately after application of the fibrin sealant, the mesh will be smoothed with the back of a forceps to get a good fixation of the mesh on the entire surface and especially on the suture line. If present, it is also possible to use spray fixation using the EASYSPRAY system, Deutschland GmbH, Unterschließheim, Germany. When laparotomy is >25 cm use 2 applicators of Tissucol (10 ml). The midline anterior rectus sheath will be closed using a running slowly absorbable suture (Monoplus, USP1, Needle HRT48, 150 cm, B. Braun Aesculap AG, Tuttlingen, Germany), covering the mesh. A suture length to wound length ratio of 4:1 was recommended (not measured). Subcutaneous tissue and skin will be closed in a fashion preferred by the surgeon.
Postoperative treatment
Wound drainage will not be routinely applied. Seromas do not have to be punctured or drained, but can be left untreated to resolve spontaneously.
Implementation
Pre-operative data
-
Date of birth
-
Length and weight
-
Smoking history (current smoker ( Y or N )
-
Medical history (COPD, diabetes, cardiac disease)
-
Preoperative Radiotherapy or chemotherapy
-
Preoperative corticosteroids
-
Postoperative corticosteroids
-
Previous abdominal operations
-
Other abdominal hernias (inguinal, umbilical, epigastric hernias)
-
ASA class
-
Width of linea alba (when pre-operative C.T. imaging is available)
-
Size of aneurysm and location
-
Epidural catheter
Operation data
-
Type of operation
-
Type and length of prosthesis
-
Volume of fibrin sealant applied
-
Length of incision
-
Blood loss
-
Operation time
-
Antibiotic prophylaxis
-
Suture material
-
Drains and location
-
Thrombosis prophylaxis
-
Pain medication
-
Complications (intestinal lesions, bleeding, other)
Ultrasound examination
At 6 and 24 months ultrasound imaging will be performed to examine the midline for any asymptomatic clinically not detectable incisional hernias. This will provide valuable information about the onset of an incisional hernia. Size and location of all incisional hernias noted radiographically will be registered, as well as complaints presented by the patients. Endpoint of this study will be at 2 years follow up. At this follow-up the presence of a hernia will be investigated by physical examination and ultrasound imaging.
Outpatient follow-up
The follow-up schedule is displayed in Table
3. During visits the following information will be gathered.
-
Outpatient clinic visit at 1, 3, 12 and 24 months
-
○ Incisional hernia
-
○ Wound infection
-
○ Seroma formation
-
○ Other wound problems
-
○ Inguinal hernia
-
Ultrasound at 6 and 24 months
-
VAS score at 1 month
-
VAS scores and Quality of Life forms preoperatively ( day of operation or the day before) and at 3, 12 and 24 months
Table 3
Follow up schedule
Pre-operative | X | X | | X | |
1 month | | | X | X | |
3 months | X | X | X | X | X at 6 months |
12 months | X | X | X | X | |
24 months | X | X | X | X | X |
Economical evaluation
Cost effectiveness will be calculated after 2 years. The direct costs, admissions, operation costs, costs of materials and treatment of complications and incisional hernias, will be calculated. Quality Adjusted Life Years will be calculated.
An incisional hernia correction costs Є3777,-. When 100 patients are operated with the aid of a mesh insertion we estimate to prevent 15 incisional hernias (=Є56.655,-). One hundred meshes cost approximately Є30.000,-. We would save Є26.655,- if all incisional hernias are repaired. We did not include all extra costs as for example visits to the general practitioner, but these will be included in our final analysis.
Statistical analysis
Three comparisons will be made leading to pair-wise comparison at alpha = 0.017 (=0.05/3) according to Bonferroni’s correction for multiple testing. Assuming a 30% rate of incisional hernia in group A, and about 10% in both groups B and C, for a power of 90% comparing group A versus group B and C, 92 patients are required in group A and 164 in groups B and C. Allowing for some dropouts, 100 will be included in the control group and 180 in each experimental group.
It is expected that differences between groups B and C can only be demonstrated with a very large number. Therefore it was decided to set the objective to showing “non inferiority” for onlay (group C) versus sublay (group B). Setting the non-inferiority margin at 10%, the power to show non-inferiority regarding the incidence rate of incisional hernia will be greater than 80%.
For the comparison of both experimental groups with the control group, Kaplan-Meier curves will be constructed and the log-rank tests will be performed. These logrank tests will be done with stratification by center and operation indication.
For the comparison of both experimental groups B and C, the cumulative 2-years probability will be calculated with the one-sided 98.3% confidence interval for the difference. Analysis will be done according to the intention-to-treat principle in comparing group A with groups B and C. For the comparison of groups B and C a per-protocol analysis will be the primary analysis.
Comparison of VAS and QOL scales between groups will be done using Repeated Measures Anova (SAS PROC MIXED) with baseline value, age, gender, operation indication and center as covariates.
The following putative risk factors regarding incisional hernia (smoking, infection, diabetes, corticosteroids) will be evaluated using Cox-regression.
Serious Adverse Event (SAE) reporting & Monitoring
A SAE will be reported to the Dutch Department for Human Research (Centrale Commissie Mensgebonden Onderzoek), Baxter and Braun within 24 hours.
Requirements for SAE reporting will be:
1.
(Prolonged) Hospitalisation (difined as a longer stay in the hospital than normally expected caused by a postoperative complication)
Once a year, data from each center will be monitored. In compliance with GCP guidelines, monitors will verify data collected on data collection forms against source documents. Source documents are defined as any original records or data related to the trial or to subject treatment or medical history. Source documents include: original hospital, clinical, and office charts, laboratory notes, subject diaries or evaluation checklists, pharmacy records, recorded data from automated instruments, transcriptions (certified to be accurate after verification), magnetic media, or x-rays.
Ethics
Before centers could participate in this trial, approval was obtained from the local medical ethics committee (Medische Ethische Toetsings Commissie, Erasmus MC). Patients will be extensively informed about the research project and can only participate after giving informed consent. Patients will always be permitted to withdraw from the study without providing further reasons. This will have no consequences for further treatment. Data of these patients will be evaluated in the final analysis. This trial was registered at Clinical trial.gov under NCT00761475.
History and current status
After Ethical approval was obtained the trial started including patients in the middle of 2009. Initially the intake of patients was rather slow. This was attributed to the the low number of participating hospitals, the continued increase of laparoscopy and endovascular treatment, and the inclusion criteria of BMI >30. After the publication of Seiler et al. the BMI inclusion criteria were lowered from 30 to 27 [
35]. The BMI amendment and the inclusion of additional participating hospitals made it possible to include more patients per month. Currently the trial is in the final stage of the inclusion of patients. It is estimated that the last patients will be seen in the outpatient clinic in the beginning of 2015. Around this time the final results will be subjected to peer-review for publication.
Acknowledgements
PRIMA Trialist Group
C.W. Burger, Department of Gynecology, Erasmus MC, Rotterdam, The Netherlands
H.J. Verhagen, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands
D. de Jong, Department of Gynecology, Erasmus MC, Rotterdam, The Netherlands
P.J. Klitsie, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands
E.G. Pierik, Department of Surgery, Isala Clinics, Zwolle, The Netherlands
S.S. Lases Department of Surgery, Isala Klinieken, Zwolle, The Netherlands
A.C. van der Ham Department of Surgery, Sint Franciscus Gasthuis, Rotterdam, The Netherlands
J.J. Harlaar Department of Surgery, Sint Franciscus Gasthuis, Rotterdam, The Netherlands
J.A. Charbon Department of Surgery, Maxima MC, Veldhoven, The Netherlands
B. Leenders Department of Surgery, Maxima MC, Veldhoven, The Netherlands
I. Dawson Department of Surgery, IJsseland ziekenhuis,Cappele aan de IJssel, The Netherlands
M. van den Berg Department of Surgery, Scheper ziekenhuis, Emmen, The Netherlands
N.J. Harlaar Department of Surgery, Scheper ziekenhuis, Emmen, The Netherlands
C.M Seiler Department of Surgery, Sinsheim Klinikum, Sinsheim, Germany
M.W Buchler Department of Surgery, Universitätsklinikum Heidelberg, Heidelberg, Germany
M.K Diener Department of Surgery, Universitätsklinikum Heidelberg, Heidelberg, Germany
C. Schuhmacher Department of Surgery, Ludwig-Maximilians-Universität München, München, Germany
A.L Mihaljevic Department of Surgery, Ludwig-Maximilians-Universität München, München, Germany
J.R. Izbicki Department of Surgery Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
A. Kutup Department of Surgery Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
P. Neuhaus Department of Surgery, Universitätsmedizin Berlin: Charité, Berlin, Germany
P. Fikatas Department of Surgery, Universitätsmedizin Berlin: Charité, Berlin, Germany
M. Golling Department of Surgery, Diakonie-Klinikum Schwäbisch Hall, Schwäbisch Hall, Germany
D. Laux Department of Surgery, Diakonie-Klinikum Schwäbisch Hall, Schwäbisch Hall, Germany
R. Fortelny Department of Surgery, Allgemeines Krankenhaus der Stadt Wien,Vienna, Germany
C. May, Department of Surgery, Allgemeines Krankenhaus der Stadt Wien,Vienna, Germany
Competing interests
This study was supported by B. Braun Aesculap GmbH, Tuttlingen, Germany and Baxter Deutschland GmbH, Unterschließheim, Germany. None of these sponsors were involved in the design, conduct or analysis of the study. Disclosure: The authors declare no other conflict of interest.
Authors’ contributions
JN drafted the original protocol and wrote the protocol manuscript, HHE drafted following procotol amendments and was involged in patient inclusion and data gathering, LT drafted following procotol amendments and was involved in patient inclusion and data gathering, WCJH is the trial statistician and performed the power analysis and was responsible for the trial methodology, GJK was involved in writing of the first manuscript and all following amendments, JJis initiator and creator of the PRIMA trial and was involved in writing of the first manuscript and all following amendments, J. F. Lange is initiator and creator of the PRIMA trial and was involved in writing of the first manuscript and all following amendments, PRIMA Trialist group were all responsible for including patients, organizing and conducting follow-up. All authors read and approved the final manuscript.