Single-Layer or Double-Layer Intestinal Anastomosis: A Systematic Review of Randomized Controlled Trials

Several malignant and benign indications may necessitate bowel resection. Despite the emergence of newer techniques, the hand-sewn technique remains popular for the reestablishment of intestinal continuity after resection. This method can achieve anastomosis in one or two layers. Some studies have suggested that the single-layer technique has several potential benefits compared to its rivals while simultaneously maintaining a comparable efficacy and safety profile. Previous reviews have failed to recommend either of these methods over the other due to a lack of high-quality evidence. This review aims to establish which technique provides the best outcomes by reviewing recent relevant trials and comparing both methods. We conducted a systematic review of randomized controlled trials (RCTs) using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. A database search of PubMed, Google Scholar, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) ultimately returned nine randomized trials published between 2003 and 2023 comparing single-layer intestinal anastomosis (SLIA) and double-layer intestinal anastomosis (DLIA) that fit the inclusion criteria. Overall, results show a dearth of robust trials, and the included studies displayed variable eligibility criteria and materials used for anastomosis. The available evidence, however, does suggest that neither technique is inferior in terms of preventing post-operative complications, but SLIA is less expensive and quicker to perform. The evidence is, however, limited, and further high-quality research is needed.


Introduction And Background
The establishment of principles for bowel anastomosis marked a remarkable feat for the surgeon, enabling the re-establishment of bowel continuity after resection.Since then, little has changed, and the time-tested hand-sewn technique remains a popular option even in the face of emerging new technologies such as stapling devices and anastomotic rings [1].It is affordable and widely available, and the vast majority of surgeons share a common familiarity with the technique.Furthermore, as studies have failed to demonstrate the superiority of the newer emerging methods [1][2][3] and anastomotic leaks (AL) remain a dreaded complication [4], surgeons have often reverted to reliable hand-sewn anastomosis when faced with challenging high-risk surgery [5].It is, however, whether to use the single-layer or double-layer approach for hand-sewn anastomosis that remains the source of debate.
The original two-layer approach, or double-layer intestinal anastomosis (DLIA), has historically been considered the conventional approach [1].It typically consists of an inner layer of absorbable sutures, followed by a seromuscular layer of non-absorbable sutures.Some authors have suggested that long durations of surgery and higher costs of surgery have shifted emphasis towards the alternate option, singlelayer intestinal anastomosis (SLIA) [3,5], which provides a potentially simpler, less expensive, and less timeconsuming alternative that requires only a single layer of interrupted or continuous sutures [5].
The feared potential complication, regardless of technique, is the AL, which unfortunately complicates up to 5% of intestinal anastomosis.When it occurs, it increases morbidity and mortality and is associated with prolonged stays in hospitals and increased healthcare costs [4].Theoretically, SLIA is associated with less tissue handling [6], and there is a lower likelihood of tissue strangulation as suture tension is more evenly distributed around the gut wall, thereby producing less ischemia and perhaps fewer anastomotic leaks [7,8].However, previous reviews and meta-analyses have not been able to confidently establish such a difference.
A 2012 Cochrane review concluded that although SLIA showed promise of faster surgeries with a similar complication profile as DLIA, the quality of evidence comparing both techniques was suboptimal [6].Following the authors' recommendation that further, more robust research was required, multiple newer trials have attempted to compare both approaches [9].However, no reviews have accounted for these trials, leaving this important clinical question mostly unanswered.Our aim was to perform a systematic review of recent randomized controlled trials (RCTs), comparing the safety and efficacy of both techniques with a view to developing recommendations to guide practice and further research.

Review Methods
We performed a systematic review of randomized control trials (RCTs) using the guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist (PRISMA) [10].We have chosen to include only RCTs as this represents the best quality evidence to guide treatment.Without proper randomization, researchers may preferentially allocate patients to a particular treatment arm of a trial depending on presentation, with the implication that more high-risk patients may undergo a particular procedure.Similar issues arise from retrospective reviews [11].

Search Sources and Strategies
An electronic search of the following databases was carried out: PubMed, Google

Screening
The identified articles were collected and transferred to the reference management tool, Mendeley.The screening was carried out by two researchers working independently.Duplicates were first identified and removed.Then we screened the titles and abstracts, followed by full-text screening.Disagreements were resolved in consultation with a third researcher.

Eligibility Criteria
Only RCTs published between 2003 and 2023 and available in English were included.In order to meet the inclusion criteria, studies must compare the single-layer with the double-layered hand-sewn anastomotic techniques to establish gastrointestinal continuity.Studies comparing stapling devices with hand-sewn techniques, non-RCT studies such as retrospective studies, and those that involved anastomosis of extraintestinal gastrointestinal structures such as pancreatic duct surgeries and esophageal studies were excluded.Grey literature, non-human studies, and ex-vivo studies were all removed.

Data Extraction
Two authors independently retrieved selected data using an Excel spreadsheet that was tested on the first two studies, then edited and standardized to extract data from the remaining trials.Conflicts were reconciled by a consensus among all the investigators.Data extracted included the study title, dates of the trials, population, sample size, inclusion and exclusion criteria used, and surgical techniques and sutures used.The occurrence of postoperative AL will be considered the primary outcome, as it is the most feared complication.Secondary outcomes include length of hospital stay, presence of stenosis or intestinal obstruction, cost of anastomosis, time taken to perform anastomosis (duration of anastomosis), and mortality.

Risk of Bias Assessment
All included studies were RCTs and were assessed using the revised Cochrane risk-bias tool for randomized trials (ROB2) by two reviewers working separately.Risk is assessed across five domains, namely, randomization, deviations from intended outcomes, missing outcome data, measurement of the outcome, and selection of the reported results [11].Harmonization of the reviewers' assessment was done, and where there were differences in the assessment of bias in any domain, arbitration was provided by a third researcher.
Where some information necessary to fully assess the risk of bias was missing, this was classified as 'some concerns'.Trials with concerns in more than two domains were ranked as having an overall high risk of bias if the concerns significantly reduced confidence in the results.

Results
A total of 932 papers were identified by the initial search.Using Mendeley, 620 duplicates were removed.Screening of titles and abstracts excluded a further 270 articles.One potential article had to be removed as full texts were unavailable for review.This meant that 42 studies underwent full-text assessment, at which point we excluded a further 32 articles, leaving a finalized number of nine articles.The PRISMA flow diagram showing the process of scrutinizing the identified articles is presented in Figure 1.

Characteristics of Included Trials
All researchers unanimously agreed that the nine trials included met the set-out inclusion criteria.The earliest trial started recruitment in 2004, while the earliest publication was a different trial in 2013.The sample size range was 50 to 250 patients.
Criteria for inclusion and exclusion, age, and outcomes assessed varied between trials.Only two studies included children; one study included only children aged four months to 14 years [12], whereas in another trial, the lower age limit was set at 12 years [13].Some trials excluded patients with anemia [3,14], or those requiring anastomosis to peculiar sites such as gastric and duodenal [3,5,12,13], as well as rectal anastomosis [3,5,13], or middle and distal rectal anastomosis [15].Table 1 summarizes the characteristics of the included studies.According to this study, SLIA had better outcomes for mean duration of anastomosis and cost of surgery while maintaining comparable efficacy in preventing anastomotic leaks as DLIA.

Study
Despite being one of the studies with the largest sample size, we judged the potential for bias to be high as an alternative allotment method was used for patient allocation.

Surgical Technique
Seven of the included trials provided detailed accounts of the surgical techniques used.The approach and materials for achieving either type of anastomosis varied slightly between the trials.In performing SLIA, researchers used either continuous sutures, interrupted sutures, or both.Other variations included the size of sutures and absorbable versus non-absorbable sutures, which are summarized in Table 2.

Appraisal of Studies
We used the revised Cochrane risk-of-bias tool for randomized trials (RoB2) to assess the risk of bias in each of the selected trials [11].
The trials showed varying degrees of limitations.One trial sought only to measure the length of hospital stay [12], but it is not clear whether the assessors were knowledgeable of the assigned intervention and if they oversaw discharging the patients, thereby raising concerns of potential bias in measuring outcomes.The alternating technique of allocation used in Garude et al. [13] and Shah et al. [17] undermines the randomization process as the patient's recruitment may be affected by the recruiter's or participants' knowledge of the sequence.Singh et al. used the Chit and Box method for randomization, but poor concealment may give the researchers knowledge of the sequence [18].No information as to randomization was provided by Moeen et al. beyond stating that their patients were randomly allocated [16].
Given that neither Singh et al. nor Moeen et al. provided a definition for anastomotic leaks used in their studies [16,18], we were concerned that different diagnostic criteria may have been applied to different patients as it is possible for researchers to define anastomotic leaks differently [19].
Furthermore, we did not find prospectively registered pre-trial protocols for some of the studies.Questions were therefore raised as regards the choice of outcomes reported or omitted, especially for those trials where only a few parameters were analyzed with the exclusion of others [12,16,17].
The risk of bias in each domain of each trial is summarized in Figure 2. Figure 3 shows the proportion of studies classified as low-risk, with some concerns and a high risk of bias in each domain.

FIGURE 2: Revised risk of bias (ROB 2) appraisal of included trials
Applying the revised risk of bias tool to appraise the included trials [3,5,12-18]

Anastomotic Leaks
Eight out of nine included trials assessed for anastomotic leaks.The four best-quality studies reported no statistical differences between the techniques.Only the study by Mooen et al. showed significantly lower rates of anastomotic leaks in the SLIA intervention arm [16].This study, however, was judged to have a high risk of bias.The proportion of patients with anastomotic leaks in each intervention arm is shown in Figure 4.

Duration of Anastomosis and Cost of Materials
Six different trials compared SLIA and DLIA in terms of the duration taken to achieve anastomosis.The mean duration ranged from 9.50 minutes to 19.7 minutes for SLIA and 19.50 to 30.00 minutes for DLIA.SLIA was significantly shorter in duration in all studies, including three with a low risk of bias [3,14,15].Both studies that analyzed cost, one with low risk and the other with high risk of bias, determined that SLIA was significantly cheaper than DLIA [3,13].

Stenosis
No studies demonstrated a significant difference in rates of stenosis between the techniques.
The study by Herrle et al. showed two cases of stenosis among the SLIA group and no cases among the patients who had DLIA.This relationship was, however, not statistically significant [15].

Length of Hospital Stay and Mortality
The majority of good-quality studies showed no difference in length of hospital stay following either intervention, except for Kar et al., where patients who had SLIA were discharged at significantly faster rates than those who received DLIA (p<0.001) [3].This finding was corroborated by Ahmad et al., who demonstrated similar findings in the pediatric population, albeit in a lower-rated trial [12].
Similarly, no studies showed any significant difference in rates of mortality.
Table 3 shows the quantitative results from each of the included studies.Table 4 summarizes the primary and secondary outcomes and the quality of the supporting evidence for each outcome.Seven studies -Four good quality trials [3,5,14,15], one moderate quality trial [18], and two low quality trials [13,16] suggested that rates of anastomotic leaks were comparable.One low quality trial [16] found SLIA to be the safer option.No trials suggested that DLIA was better than SLIA in preventing anastomotic leaks.

Time to achieve anastomosis 6
All six studies found SLIA to be the quicker option to perform including three good quality - [3,14,15], one moderate quality - [18], and two poor quality trials [13,17].

Cost comparison 2
Both studies: one good quality [3], and one low quality [13], found SLIA to be the cheaper option.

Length of hospital stay 7
Five studies including three good quality trial [5,4,15], one moderate quality [18], and one poor quality trial [13] showed comparable results between both interventions.Two trials, a good quality trial [15], and a moderate quality trial [18] found significantly shorter duration of hospital stay among SLIA patients.DLIA was the better option in none of the included studies.

Stenosis 2
Both studies found comparable values.One was a good quality trial [15].

Mortality 6
All studies found mortality rates to be comparable.This included four high quality trials [5,14,15], one moderate quality [18] and one low-quality study [17].No studies found significantly lower rates of deaths with either intervention.

Discussion
The potential benefits of SLIA continue to drive research to establish its safety and efficacy in comparison to DLIA.This review summarizes the last 20 years of randomized trials on this topic, including nine studies and a total of 984 patients.In our review, most studies took place in India (six) and Pakistan (two), in contrast to previous reviews that were dominated by European trials [6].Stapled anastomosis offers an alternative that may reduce both the interest and the recruiting power of studies comparing handsewn techniques as the popularity of staplers increases.Paradoxically, retrospective and prospective studies have shown that surgeons will preferentially perform hand-sewn techniques on patients with a perceived higher burden of disease, especially in acute care settings.Interestingly, despite this surgeon-derived bias, failure rates are equivalent [20] or doubled when stapling is done [21].It therefore remains relevant to establish a universal first-choice technique for hand-sewn anastomosis.The interest in this topic among global researchers is crucial, as findings from more developed countries may not always be universally applicable [22].
Many of the studies in this review excluded anastomosis involving the stomach [3,5,12,13,15,17], the duodenum [3,5,12,13,17], and/or the entire rectum [5,13,17], or part of the rectum [15].This was done to increase homogeneity as the stomach is more vascular and less likely to bleed [5], the duodenum and the rectum may be difficult to fully mobilize [5], and the rectum has a higher risk of leaks.It is also becoming increasingly popular to use stapled anastomosis for the rectum [15].Unsurprisingly, trials that did not exclude the rectum had the highest overall rates of anastomotic leaks [14,16,18].Excluding rectal anastomosis may have also limited the recruiting power of the trials.Future trials should include high-risk anastomosis and analyze the best technique to use in such cases.No good-quality studies have been done on children, and most trials have excluded the elderly population.Age, systemic conditions, and immunocompromise have been thought to affect the occurrence of anastomotic leaks.Similarly, modifiable factors such as smoking, alcohol use, and obesity are known to affect healing.These trials did not test for the impact of these factors on gastrointestinal healing.
We also noticed a relative variability in techniques among the studies.In performing single-layer anastomosis, some centers described an interrupted technique, while others chose a continuous technique for anastomosis, and yet others used both.Continuous technique may take less time and fewer sutures, but again, high-quality evidence is lacking.However, it is not obvious that using continuous and/or interrupted sutures introduces significant heterogeneity, as both techniques have demonstrated clinical equipoise [23].
The preferred use of continuous sutures for single-layer anastomosis among surgeons appears to be from a technical and time-saving point of view rather than proven superior efficacy.
Eight studies were included that assessed anastomotic leaks.As in previous systematic reviews [1,6], we found that SLIA and DLIA had comparable rates of anastomotic leaks in most trials.Only the article by Moeen et al. reported a significant difference between the techniques, with SLIA having a lower incidence of leaks [16].Although this was one of the larger trials with 200 participants, it ultimately showed an overall high risk of bias.The best available evidence therefore suggests that rates of anastomotic leaks are similar.
Previous reviews have shown that SLIA tests are better than DLIA in terms of the duration of anastomosis and the cost of surgery.We included six studies, including three good-quality trials, that assessed the time taken to establish anastomosis.In all the studies, the single layer took significantly less time in our review [3,14,15].The surgeon must delineate layers of the intestine before applying sutures to each layer in the double-layer technique, and this technique is thought to require higher technical skill [6].Similarly, two studies analyzed the cost of suture materials, and in both cases, DLIA was the significantly more expensive option [3,13].The vast majority of studies used a different suture material for each of the layers in their double-layer anastomosis [3,5,13,17,18], which means that surgeons inevitably must expend an extra suture when performing the DLIA.Herrle et al. used PDS sutures for both the seromuscular and inner layers of their double-layer anastomosis, but this study did not compare the costs of surgery [15].
It is documented that surgical trials are notoriously difficult to conduct [9], and it may be difficult to answer these questions in any single surgical trial.Issues with sample size, blinding, and measurement outcome have been known to plague the quality of surgical trials.Recruiting patients who have presented in emergency situations may not always be practical; there may be issues with patient preference or uncommon conditions; and apparently, only a third of surgery trial patients can be adequately blinded [24,25].The population size in our review ranged from 50 to 252 patients, which is only slightly higher than what had been tested in the Cochrane review in 2012 [6].The research by Herrle et al., which was the largest multicenter trial included, calculated a sample size of 768 but eventually had to settle for 252 due to slow uptake over eight years across four centers.This multi-center trial also reported difficulties keeping surgeons motivated to recruit patients in all the centers involved [15].Poor randomization reduced the quality of various studies, especially where the alternating allocation technique was used, which means that the sequence may be predictable.Interestingly, some of the larger studies were compromised by issues of randomization and a lack of pre-trial protocols and definitions [16].Given the challenges with blinding and sample recruitment, future researchers should emphasize good randomization, concealment, harmonization of interventions, and published pre-trial protocols to improve the quality of the evidence.
It would likely require a large multi-center study, meticulously designed and standardized, to adequately test this hypothesis [9,15].Such a trial should crossmatch for systemic conditions and lifestyle choices that may affect the development of anastomotic leaks, the location of anastomosis along the intestine, suture materials, and continuous versus interrupted suture techniques.Until such a trial is concluded, however, the evidence has remained consistently limited but has consistently suggested that SLIA and DLIA have comparable outcomes.

Conclusions
The current data, albeit problematic, suggests that performing the more expensive and potentially timeconsuming DLIA offers no significant advantages over SLIA.The level of evidence on this topic has always been poor, and research over the last few years has done little to change that.At least until better evidence is available, SLIA may be considered first-line for intestinal anastomosis given better technical, time, and economic considerations.Further research should develop a recorded pre-trial protocol that is consistently followed, address issues with randomization, and aim to compare both techniques in low-risk and high-risk scenarios.
analysis, and helped in designing tables and figures.Hafsa Ashraf and Adiprasad Bodapati performed an additional literature search for the discussion sections, synthesizing other closely related ideas, such as problems with RCTs in surgery.These ideas were used for comparison in the discussions.They also independently proofread and made corrections to the manuscripts before finalization.Ayesha Hanif prepared part of the abstract, helped streamline the inclusion and exclusion criteria, and carried out the final editing of the paper.Without the supervision of our mentor, Safeera Khan, we would not have been able to complete this research.She had a role in the conceptualization, study design, and methodology; read and approved outcome measures; performed quality appraisals of the studies; and provided arbitration where necessary.The final article was read and approved for publication by all authors.

FIGURE 1 :
FIGURE 1: PRISMA flow diagram for literature search and selection PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis, n: number of studies SLIA had a significantly shorter duration for establishment of anastomosis and post-operative hospital stay compared to those with DLIA.Other parameters were comparable.The randomization method was good, the study is limited by small sample size.were found in any of the outcomes measured in this study.only study that focused specifically on anastomosis in the paediatric population.Unfortunately, it only tested for length of hospital stay and rates of AL were not analyzed here.DLIA group was found to have spent significantly longer hospital days than SLIA group.The authors, however, did not specify if the surgical team in charge of discharging the patient were blinded or aware of the interventions the patients had received.This could lead to a bias in potentially discharging patients from one treatment arm quicker.