Single- versus two- layer intestinal anastomosis: a meta-analysis of randomized controlled trials

Background To compare single- with two- layer intestinal anastomosis after intestinal resection: a meta-analysis of randomized controlled trials. Methods Randomized controlled trials comparing single- with two-layer intestinal anastomosis were identified using a systematic search of Medline, Embase and the Cochrane Library Databases covering articles published from 1966 to 2004. Outcome of primary interest was postoperative leak. A risk ratio for trial outcomes and weighted pooled estimates for data were calculated. A fixed-effect model weighted using Mantel-Haenszel methods and a random-effect model using DerSimonian-Laird methods were employed. Results Six trials were analyzed, comprising 670 participants (single-layer group, n = 299; two-layer group, n = 371). Data on leaks were available from all included studies. Combined risk ratio using DerSimonian-Laird methods was 0.91 (95% CI = 0.49 to 1.69), and indicated no significant difference. Inter-study heterogeneity was significant (χ2 = 10.5, d.f. = 5, p = 0.06). Conclusion No evidence was found that two-layer intestinal anastomosis leads to fewer post-operative leaks than single layer. Considering duration of the anastomosis procedure and medical expenses, single-layer intestinal anastomosis appears to represent the optimal choice for most surgical situations.


Background
The basic principles of intestinal suture were established more than 100 years ago by Travers, Lembert and Halsted [1], and have since undergone little modification. Development of stapling instruments for intestinal anastomosis has added new dimensions to intestinal surgery. Two systematic reviews of randomized controlled trials (RCTs) comparing stapled with hand-sewn colorectal anastomo-sis found no difference between the two methods [2,3], but colorectal surgeons need to be familiar with both. Unsurprisingly, hand-suturing techniques were shown to display a longer learning curve than stapling [4]. One aspect of intestinal suturing technique that has remained controversial is the use of either one or two layers of sutures for anastomosis.
Historically, two-layer anastomosis using interrupted silk sutures for an outer inverted seromuscular layer and a running absorbable suture for a transmural inner layer has been standard for most surgical situations. Some recent reports have described single-layer continuous anastomosis using monofilament sutures as requiring less time and cost than any other method, without incurring any added risk of leakage [5][6][7][8]. Many surgeons probably now use single-layer suturing due to reductions in ischemia, tissue necrosis or narrowing of the lumen compared to the twolayer method.
While numerous RCTs have addressed this issue, no published reports have described meta-analysis of RCTs to date [9][10][11][12][13][14]. We therefore performed a meta-analysis of RCTs to assess efficacy and safety for single-and two-layer anastomosis after intestinal resection. This meta-analysis included studies clearly describing the following: 1) study design (randomized controlled trial); 2) main outcome (effectiveness of single-layer vs. twolayer intestinal anastomosis); 3) target population (patients needing intestinal resection); and 4) availability of leak data. Studies that were not RCTs were excluded from the analysis.

Data abstraction and quality assessment
Each investigator decided independently which reports should be included for analysis. Any disagreement was settled by consensus between all investigators. Data were extracted independently by two investigators (SS and YT), with any disagreements resolved by a final reviewer (YN).
Outcome of primary interest was risk of leakage related to intestinal anastomosis. Secondary outcomes comprised mortality, duration of anastomosis procedure, duration of total parenteral nutrition (TPN), length of hospital stay, risk of wound infection, and cost of sutures.
Quality of primary studies was evaluated as described by Jadad et al [15]. This method assesses description of randomization, appropriateness of randomization, descrip-tion of double-blinding, appropriateness of doubleblinding, and description of withdrawals and dropouts with scores of 0 or 1 for each. Minimum possible score was 0 and maximum was 5.

Statistical analysis
The fixed-effect model weighted using Mantel-Haenszel methods was used for pooling the risk ratio [16], followed by a test of homogeneity. Inter-study homogeneity was assessed using the χ 2 test (Q statistics) [17]. A homogeneity value of P < 0.10 was considered statistically significant. If the hypothesis of homogeneity was rejected, the random-effect model using DerSimonian-Laird methods was employed [18].
Meta-regression analyses were performed to explore sources of heterogeneity. Variables comprising year of publication, mean age of study participants, and percentage of male patients were examined for significant effects on risk of leak. In addition to that, informal graphical exploration using a L'Abbe plot was made and sensitivity analysis was performed [19,20]. And another sensitivity analysis was performed by excluding low quality studies (studies with 1 point on the Jadad scale) to assess the impact of study quality. We then performed the other analysis by including studies in which operations were only performed by consulting surgeons, staff surgeons, or residents with 5 years or more experience.
The potential for publication bias was examined using the funnel plot method [21], and the significance of differences was evaluated in accordance with the methods described by Begg and Egger [22,23]. A value of P < 0.10 for publication bias was considered statistically signifi-Flow of retrieval and inclusion of randomised controlled tri-als for meta-analysis Figure 1 Flow of retrieval and inclusion of randomised controlled trials for meta-analysis. RCT = randomized controlled trial.  All statistical analyses were performed using STATA statistical software version 8.1 (Stata Corporation, College Station, TX, USA). We used a user-written add-on Stata routine "metan", which was written by Bradburn et al. [24]. Results are expressed as mean with 95% confidence intervals (CIs). Values of P < 0.05 were considered statistically significant unless otherwise indicated. Figure 1 shows a summary profile of the search. A database search yielded 138 articles, and manual search of bibliographies in these articles yielded no additions. Of the 138 articles, 9 met all inclusion criteria. A further 3 studies that were considered to represent multiple publications were excluded. A total of 6 studies were therefore analyzed. Agreement between authors for selection of relevant articles was unanimous.

Author (ref.) Year Inclusion criteria Exclusion criteria
Irvin (9) 1973 Resection with end-to-end anastomosis of the small or large intestine NR Everett (10) 1975 Elective resection of the large bowel and end-to-end colorectal anastomosis colo-anal anastomosis, extra-peritoneal anastomosis Goligher (11) 1977 High and low colorectal anastomosis following resection for carcinoma NR Maurya (12) 1984 With bowel resection and end to end anastomosis only NR Ordorica (13) 1998 Pediatric, aged between 1 month and 16 years duodenum, rectum, enteroplasty or proximal stoma Burch (14) 2000 Requiring intestinal anastomosis duodenum, rectum/surgeon's technical concerns NR = not reported

Exploring sources of heterogeneity and sensitivity analysis
Meta-regression revealed that neither year of publication, mean age of study participants, nor percentage of male patients were related to risk of leak. From the graphical exploration using a L'Abbe plot [ Fig. 3

Discussion
The present study assessed the efficacy and safety of singleand two-layer anastomosis after intestinal resection. The main finding of the study was that there is no evidence of a difference in terms of risk of leak but that there is insufficient evidence to rule out a modest but potentially important difference. Sensitivity analysis excluding the study by Goligher et al. suggested it as the source of heterogeneity. In their trial, techniques of vertical mattress sutures in the posterior two-thirds of the circumferences and Lembert sutures of horizontal mattress type in the anterior third of the bowel circumference were performed in single-layer group and reported the highest risk of leaks (45%). One possible explanation of this high rate of leaks may be their inclusion criteria, high and low colorectal anastomosis. On this subject, they described "We are quite unable to explain the difference between Everett's results and ours" in their report [11]. This suture technique is not common in intestinal anastomosis in the present day. Although various endpoints can be used to assess efficacy and safety of intestinal anastomosis, risk of leak after operation occupies the greatest attention among surgeons. Because there is no difference in the main outcome between two techniques, choices in clinical practice should be made after taking into account the results of other outcomes such as mortality, duration of anastomosis procedure, duration of TPN, length of hospital stay, risk of wound infection, and cost of sutures. Arithmetical means of these endpoints suggests that the single-layer method offers almost the same or better results than the two-layer method.
None of the studies except Ordorica et al. met the requirements for appropriateness of double-blinding. In the study by Ordorica et al., neither the physician performing the assessments nor the pediatric patient knew the type of anastomosis. However, assessing outcomes under blinding is virtually impossible in surgical trials. We therefore regarded studies with a Jadad score of 3 as high-quality studies.

Limitations
There are several limitations in current study. First, the study by Goligher et al. had a substantial influence on the combined risk ratio. However, the main conclusion of a lack of evidence for an advantage of two-layer over singlelayer anastomosis is unaffected, as the result of a sensitivity analysis excluding this study was more favourable to single-layer. Secondly, the quality of individual RCTs included in our analysis was not necessarily high, mainly due to a lack of blinding. This is, however, inevitable in most surgical trials. Thirdly, there were differences in inclusion criteria, definition of the term "leak" and suture techniques for studies included for meta-analysis. Exclusion criteria among studies also varied. Lastly, the total number of patients included for this meta-analysis might not have been sufficient to identify small differences between the two techniques. However, no significant differences in methods were identified. Future RCTs may yield different conclusions from meta-analysis. Despite these limitations, we believe that this meta-analytic overview provides the current best information in making clinical decision to choose a surgical suture techniques.

Conclusion
The current meta-analysis clarified that two-layer intestinal anastomosis offers no definite advantage over singlelayer anastomosis in terms of postoperative leak. Considering duration of the anastomosis procedure and medical expenses, single-layer intestinal anastomosis may prove the optimal choice in most surgical situations. participated in the design of the study and performed the data abstraction and statistical analysis. YN participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.