Preservation of the azygos vein versus ligation of the azygos vein during primary surgical repair of congenital esophageal atresia
Abstract
Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess the benefits and harms of preservation of the azygos vein versus ligation of the azygos vein during primary surgical repair of congenital esophageal atresia.
Background
Description of the condition
Definition and classification
Esophageal atresia is one of the most common life‐threatening congenital malformations. It is generally defined as an interruption in the continuity of the esophagus with or without fistula to the trachea or bronchi (Spitz 2007).
Various classification systems for esophageal atresia exist based on the presence and type of fistula. The most commonly used classification systems for esophageal atresia were suggested by Vogt 1929 and Gross 1953, dividing the malformation into six or five subtypes, respectively. Despite many anatomical variations, most children (approximately 85%) have esophageal atresia with a distal tracheoesophageal fistula (Gross type C) (Gross 1953; Kluth 1976; Spitz 2007).
Epidemiology
International surveillance programs and recent observational studies (from China, Europe, and the USA) have found an overall prevalence of esophageal atresia of 2.4 per 10,000 births, with regional differences ranging from 0.2 to 4.6 per 10,000 (Lupo 2017; Nassar 2012; Oddsberg 2012; Pedersen 2012; Schmedding 2021; Wittekindt 2019; Zhou 2020). Although there is variation in the reported prevalence, several European studies suggest that the prevalence appears to be stable over time (Cassina 2016; Oddsberg 2010; Pedersen 2012). The malformation is most common in males, with a male: female ratio of 1:0.74 (Pedersen 2012).
Diagnosis, etiology and associated malformations
At birth, the child presents with typical drooling of saliva, inability to swallow, choking, coughing, cyanotic attacks (skin appearing blue due to poor circulation or inadequate blood oxygenation), and possibly a distended abdomen, depending on the type of fistula (Höllwarth 2020). The diagnosis is then usually made by the inability to pass a feeding tube into the stomach, followed by a plain X‐ray of the thorax/abdomen (Höllwarth 2020; Morini 2020). Most children with esophageal atresia are diagnosed after birth, although prenatal diagnostics have improved from 26% to 36% over the last 30 years (Pedersen 2012). The postnatal diagnosis occurs at birth in 83.4% of children with esophageal atresia, within the first week in 15.4% of the children, and after the first week of life in only 1.2% of children (Pedersen 2012).
The exact etiology is still obscure (Felix 2009; Harmon 2012). As most cases occur sporadically, the etiology is likely to be multifactorial, involving multiple genes and complex gene‐environment interactions (Felix 2009 Harmon 2012). Observational studies suggest that risk factors may include infectious diseases, teratogens (e.g., thalidomide), statins, alcohol, smoking, contraceptive pills, hormones, maternal diabetes, high maternal age, and assisted pregnancy (Felix 2009; Källén 2010; Oddsberg 2010).
As it is an early organogenesis defect, people with esophageal atresia have a high frequency of associated anomalies (40 to 80%) (Oddsberg 2012; Pedersen 2012; Sfeir 2013; Stoll 2009; van Heurn 2002). Recent observational studies have found that esophageal atresia was isolated in 45 to 53% of cases, 32 to 47% had multiple anomalies, and 23.7% had an association or a syndrome (Pedersen 2012; Stoll 2017). The most commonly associated anomalies are congenital heart defects (23 to 29% of children with esophageal atresia), other gastrointestinal anomalies (16 to 21%), urinary tract anomalies (15 to 16%), and limb anomalies (13 to 14%) (Pedersen 2012; Stoll 2017). Up to 10% of people with esophageal atresia have a nonrandom VACTERL association involving a spectrum of abnormalities (vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb) (Pedersen 2012; Stoll 2017). Other associations that may include esophageal atresia are the CHARGE association, Feingold syndrome, Anophthalmia‐Esophageal‐Genital (AEG) syndrome, PallisterHall syndrome, Opitz G syndrome, X‐linked Opitz syndrome, Edwards syndrome, Downs syndrome, and other chromosomal or non‐chromosomal syndromes (Brosens 2014; Pedersen 2012; Spitz 2007; Stoll 2017).
Prognosis
Untreated, the child succumbs to starvation, infections, and respiratory complication (Höllwarth 2020; Spitz 2007). Survival thus depends on surgical correction. If surgery is delayed, prolonged total parenteral nutrition or gastrostomy can be necessary (Patel 2002). Esophageal atresia is still associated with increased mortality (Cassina 2016; Choudhury 1999; Lilja 2008; Schmedding 2021; Sfeir 2013; Zimmer 2019). The mortality rate for newborns with isolated esophageal atresia ranges from 4.3% to 8.1% (Pedersen 2012; Zhou 2020). The mortality rate increases with the presence of associated abnormalities: to 13.5% in children with VACTERL association, 23 to 36% for newborns with heart defects, and 88.5% for children with Edwards syndrome (Pedersen 2012; Wittekindt 2019; Zhou 2020). The influences of major cardiac and chromosomal anomalies are among the most important predictors of death and complications, which warrants the need for echocardiography examination and genetic testing in people with esophageal atresia (Cassina 2016; Choudhury 1999; Pedersen 2012; Tan 2019).
Even after surgical correction, there is an increased mortality risk (Tan 2019). In a recent study of 650 people with esophageal atresia in Australia, 22 (3.8%) died after discharge from the hospital (Tan 2019). Similar findings were reported in another study, with 17 (7.1%) late deaths, defined as death occurring more than 30 days after birth out of 240 people (Choudhury 1999). These late deaths were primarily due to respiratory compromise, including sudden infant death, aspiration, tracheomalacia (a condition in which the cartilage of the trachea is misshapen, leading to airway collapse), and reactive airway disease (Choudhury 1999; Tan 2019).
Complications
Early complications
Common complications during the postoperative period include esophageal anastomosis leak, fistula recurrence, anastomotic strictures, respiratory complications, and infections (Acher 2016; Harmsen 2017; Nurminen 2019; Rayyan 2015). Anastomotic leaks occur in 5% to 17% of children undergoing surgery (Allin 2014; Chittmittrapap 1992; Zimmer 2019), representing one of the most common serious complications. Anastomotic leakage into the mediastinum can result from the small, friable lower segment, use of prosthetic materials, anastomotic tension, ischemia of the esophageal ends, sepsis, and relatively long distance between the upper and lower esophageal segment (Lal 2018; Teague 2016; Upadhyaya 2007). Major leaks are rare and usually manifest with acute deterioration associated with pneumothorax and sepsis, which may require emergency chest tube decompression or surgical intervention (Chittmittrapap 1992).
Recurrent fistula can be life‐threatening and is experienced by about 3% to 9% of people with esophageal atresia (Allin 2014; Smithers 2017; Zimmer 2019). Treatment by endoscopic injection of glue, trichloroacetic acid, thermal ablation, or an open surgical intervention can be used for occlusion (Meier 2007; Richter 2008).
Late complications
Despite advancements in preoperative, operative, and postoperative management, the overall burden of comorbidities and long‐term complications influences quality of life in both children and their parents, notably in children with tracheal and esophageal complications (Ijsselstijn 2013; Legrand 2012; Rozensztrauch 2019; Sistonen 2011; Witt 2019a; Witt 2019b). After surgical repair, children are at risk of late complications such as strictures of the anastomotic region, gastroesophageal reflux, esophagitis, tracheomalacia, feeding difficulties, pulmonary symptoms, and developmental challenges (Acher 2016; Harmsen 2017; Morini 2018; Nurminen 2019; Rayyan 2015).
Reported rates of esophageal strictures vary from 25% to 75%, occurring early postsurgically or later in childhood (Allin 2014; Friedmacher 2017; Koivusalo 2013; Zimmer 2019). This makes strictures the main complication after surgical repair of esophageal atresia (Zimmer 2019).
Children with esophageal atresia have an inherent disorder in esophageal motility and peristalsis, leading to feeding difficulties such as delayed esophageal clearance, gastroesophageal reflux, and dysphagia (Faure 2017 Sistonen 2010). Symptoms of feeding difficulties have been reported in up to 80% of people with esophageal atresia in follow‐up studies (Acher 2016; Gibreel 2017). A recent review demonstrated that 22% to 63% of children with esophageal atresia are affected by gastroesophageal reflux (Krishnan 2016). The esophageal repair plays a significant role in the etiology of reflux that may displace the gastroesophageal junction upward due to esophageal shortening (Krishnan 2016). Other possible etiologies for feeding difficulties include delayed feeding skills and behavioral factors, esophageal strictures, tracheomalacia due to malformation of the cartilage, or abnormal gastric function (Duvoisin 2017; Mahoney 2016; Puntis 1990).
Description of the intervention
Treatment of the esophageal atresia consists of surgical reconstruction of the continuity of the esophagus. This is achieved by performing an end‐to‐end anastomosis between the esophageal segments and, if present, ligation and division of the fistula (Höllwarth 2020). With increasing overall treatment success, the goal of surgical management of esophageal atresia has shifted from pure survival towards minimizing postoperative morbidity (Dingemann 2020).
Different surgical techniques may be used, and the choice of operative approach depends on the specific type of esophageal atresia, the occurrence of associated anomalies, expertise present, and the clinical state of the newborn (Lal 2013). An international survey investigation showed considerable variability in surgical practice and postoperative management among hospitals and institutes (Lal 2013). There is thus no consensus on the best surgical approach; open or thoracoscopic techniques are equally used, but the use of the thoracoscopic approach seems to be increasing (Dingemann 2020; Lal 2013). The thoracoscopic approach is less invasive, and preliminary studies have shown that it seems to be as effective as open surgery in terms of operating time, postoperative care, leaks, and strictures (Borruto 2012; Lal 2013).
Treatment of children with long‐gap esophageal atresia is considered more challenging and requires staged repair (Foker 1997). Management of long‐gap esophageal atresia includes esophageal myotomy (circular or spiral), lengthening or traction techniques, esophagus replacement by gastric transposition, or intestinal interposition (Baird 2019; Bairdain 2015; Foker 1997). To allow for growth of the esophageal pouches, delayed repair (six weeks to months) is, therefore, often a part of the strategy, prompting the need for prolonged parental nutrition or gastrostomy (Patel 2002).
Regardless of the surgical approach taken, the azygos vein is traditionally divided early during surgery to facilitate dissection of the anatomical structure and to ease identification of the vagus nerve, the distal esophagus pouch, and the fistula (Harmon 2012; Spitz 2007). However, in recent years, it has been hypothesized that preservation of the azygos vein might maintain mediastinal venous drainage and thereby decrease the number of postoperative complications, including anastomotic leakage (Cui 2020; Sharma 2007).
The azygos vein drains a considerable amount of deoxygenated blood from the esophagus, the posterior wall of the thorax, and the abdomen towards the superior vena cava vein (Grays 2015). The anatomy of the azygos vein can be variable, but it usually starts at the level of the lumbar vertebrae and unites the ascending lumbar veins with the right subcostal veins. As it ascends in the thorax running to the right of the esophagus, it is joined by the intercostal veins, the hemiazygos vein, and the bronchial veins, before arching over the right main bronchus to join the superior cava vein (Grays 2015). Importantly, the azygos vein also drains the esophageal veins of the thoracic part of the esophagus, as these veins only to a lesser extent drain into the intercostal and bronchial veins (Grays 2015).
How the intervention might work
As the azygos is a major draining vein for the esophageal and bronchial veins, as well as the viscera within the mediastinum (Grays 2015), its preservation during surgery might have beneficial effects on postsurgical venous drainage, and thereby decrease postoperative congestion and tissue edema (Cui 2020). This may ultimately promote healing, as the diffusion of oxygen and other nutrients improves in the absence of congestion and tissue edema formation (Scallan 2010). This, in turn, has been hypothesized to decrease the risk of anastomotic leak, esophageal stricture, and potentially even decrease the risk of tracheal and pulmonary complications (Sharma 2007; Upadhyaya 2007). Furthermore, the preservation of the azygos vein has been proposed to prevent fistula recurrence by being interposed between the anastomosis and the fistula stump, thereby using the vein to physically separate the two structures (Patkowsk 2009).
Ligation of the vein provides easy access, which might decrease the risk of damaging the nerves and blood vessels during the surgical repair (Morrow 2020). Consequently, the choice of surgical approach towards the azygos vein may influence both short‐term and long‐term complications and morbidity (Cui 2020).
Why it is important to do this review
In the last decade, randomized clinical trials have begun to study the strengths and limitations of preservation of the azygos vein during primary surgical repair of esophageal atresia (Cui 2020; Rashid 2012; Zimmer 2019).
We have not identified any previous systematic review that assesses the effects of preservation of the azygos vein versus ligation of the azygos vein during primary surgical repair of esophageal atresia. No consensus on the topic was achieved in the current guidelines from the European Reference Network for rare Inherited and Congenital (digestive and gastrointestinal) Anomalies (ERNICA) (Dingemann 2020). A systematic Cochrane Review with meta‐analyses of randomized clinical trials on the topic is warranted; it may aid in achieving consensus and potentially help to improve treatment in the future.
Objectives
To assess the benefits and harms of preservation of the azygos vein versus ligation of the azygos vein during primary surgical repair of congenital esophageal atresia.
Methods
Criteria for considering studies for this review
Types of studies
We will only include randomized clinical trials, irrespective of publication type, publications status, and language. We will include trials with parallel and cluster designs.
Types of participants
We will include participants less than three months of age with congenital esophageal atresia undergoing primary repair/surgery (as defined by trialists).
Types of interventions
The intervention group will have preservation of the azygos vein in children whilst undergoing surgery for esophageal atresia (as defined by trialists).
The control group will receive ligation of the azygos vein in children whilst undergoing surgery for esophageal atresia (as defined by trialists).
Types of outcome measures
Primary outcomes
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All‐cause mortality.
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Proportion of participants with one or more serious adverse event. We will define a serious adverse event as any untoward medical occurrence that resulted in death, was life‐threatening, jeopardized the participant, was persistent, led to significant disability, hospitalization, or prolonged hospitalization (ICH‐GCP 2016). We expect the reporting of serious adverse events in many trials to be heterogeneous and not strictly according to the recommendations regarding good clinical practice from The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH‐GCP) (ICH‐GCP 2016). Therefore, we will include the event as a serious adverse event if the trial authors either 1) use the term 'serious adverse event' but do not refer to ICH‐GCP, or 2) report the proportion of participants with an event we consider to fulfil the ICH‐GCP definition (e.g. anastomosis leakage or esophageal stricture). If a trial reports several of such events, we will choose the event with the highest proportion reported in each trial to avoid double‐counting (Korang 2021a; Korang 2021b).
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Proportion of participants with anastomosis leakage (as defined by trialists).
Secondary outcomes
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Proportion of participants with sepsis or mediastinitis.
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Proportion of participants with esophageal stricture (as defined by trialist).
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Proportion of participants with recurrent tracheoesophageal fistula.
If the trials report multiple time points, we will use the time point at maximum follow‐up as our primary time point of interest for all outcomes.
Search methods for identification of studies
Electronic searches
We will search for studies using methods described in the Cochrane Handbook of Systematic Reviews for Interventions (Lefebvre 2021).
We will search the following databases from the inception of each database to the date of search and place no restrictions on the language of publication.
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Cochrane Gut Group Specialized Register
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Cochrane Central Register of Controlled Trials (CENTRAL) (via Ovid Evidence‐Based Medicine Reviews Database (EBMR), from inception; Appendix 1)
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MEDLINE (via Ovid, from 1946; Appendix 2)
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Embase (via Ovid, from 1984; Appendix 3
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CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCO, from 1984; Appendix 4)
A Cochrane Gut Information Specialist developed the search strategies. We will not apply an RCT filter in MEDLINE and Embase as the yield from preliminary testing showed fewer than 500 citations in each database (Lefebvre 2021).
To identify unpublished trials, we will search clinical trial registers: ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/).
Searching other resources
We will check the reference lists of all primary studies and review articles for additional references. We will contact experts in the field to identify additional unpublished materials. We will search for errata or retractions from included studies published in full text on PubMed (www.ncbi.nlm.nih.gov/pubmed), and report the date on which we searched this in the review.
Data collection and analysis
Selection of studies
Two review authors (SKK, SH) will independently screen titles and abstracts identified as a result of the search, and assess these for inclusion.
We will retrieve selected full‐text study reports/publications, and two review authors (SKK, SH) will independently screen the full‐text papers to identify trials for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, consult a third review author (ULT). We will exclude duplicates and collate multiple reports of the same study, so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009), and 'Characteristics of excluded studies' table. We will not impose any language or publication restrictions.
Data extraction and management
We will use a data collection form to record study characteristics and outcome data, which we will pilot on at least one study in the review. One review author (SKK or SH) will extract trial characteristics from included trials. We will extract the following trial characteristics.
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Methods: trial design, total duration of trial, number of trial centers and location, trial setting, withdrawals, and date of trial.
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Participants: number of participants, mean age, age range, sex, presence of other anomalies, diagnostic criteria, type of esophageal atresia (Pinheiro 2012), inclusion criteria, and exclusion criteria.
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Interventions: intervention and comparison.
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Outcomes: primary and secondary outcomes specified and collected, and time points reported.
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Notes: funding for trial, and notable conflicts of interest of trial authors.
Two review authors (SKK, SH) will independently extract outcome data from included trials. We will note in the 'Characteristics of included studies' table if a study does not report outcome data in a usable way. We will resolve disagreements by consensus or by consulting a third review author (ULT). One review author (SKK) will enter data into Review Manager software (Review Manager 2020). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (SH) will spot‐check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
We will undertake risk of bias (RoB) assessments according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021; RoB 2 2019). Two review authors (SKK and SH) will each independently assess the risk of bias in the included trials. In case of disagreements, a third author (JCJ) will arbitrate.
We will assess the effect of assignment to the intervention, using RoB 2 (Higgins 2021). Therefore, we will perform analysis based on the intention‐to‐treat (ITT) principle, which includes all randomized participants irrespective of the interventions that participants actually received.
We will use the following domains to assess the trial methodology for individually randomized trials (Higgins 2021; Sterne 2019 b; Appendix 5):
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bias arising from the randomization process;
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bias due to deviations from intended interventions;
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bias due to missing outcome data;
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bias in measurement of the outcome; and
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bias in selection of the reported result.
For trials that allocated clusters of individuals, we will include an additional domain specific to that trial design (Eldridge 2016), i.e. bias arising from the timing of identification or recruitment of individual participants within clusters.
We will use the most recently developed Rob 2 Excel toolto manage the RoB 2 assessments.
Overall risk of bias
The overall rating assigns one of three levels of judgement:
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low risk of bias: the trial is judged to be at low risk of bias for all domains for this result;
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some concerns: the trial is judged to raise some concerns in at least one domain for this result, but is not at high risk of bias for any of the remaining domains;
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high risk of bias: the trial is judged to be at high risk of bias in at least one domain for this result, or the study is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result.
Judging a result to be at a particular level of risk of bias for an individual domain implies that the result has an overall risk of bias that is at least this severe.
We will assess the domains ‘bias due to missing outcome data', 'bias in measurement of the outcome', and ‘bias in selection of the reported result' for all of our outcomes.
We will store our RoB 2 evaluation data on local secure computers and provide the links to our evaluation data with the publication of the review. We plan to use the web app 'robvis' to generate a traffic‐light plot of our RoB 2 assessments (Sterne 2019 a).
The risk of bias assessments will feed into one domain of the GRADE approach for assessing the certainty of a body of evidence.
Measures of treatment effect
We will enter the outcome data for each trial into the data tables in Review Manager 5.4.1 to calculate the treatment effects (Review Manager 2020).
We will calculate risk ratios (RRs) with 97.5% confidence intervals (CI) for dichotomous outcomes. We do not have any continuous outcomes.
Unit of analysis issues
The unit of analysis will be the children participating in the individually‐randomized trials.
We will analyze cluster‐randomized trials according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). If results do not control for clustering, we will contact trialists to request an estimate of the intracluster correlation coefficient (ICC). If we are unable to obtain an ICC from the trialists, we will calculate the ICC using design effects (Killip 2004).
Where a single trial reports multiple intervention groups, we will include only those relevant for our review intervention groups. If there are two experimental intervention groups of interest to our review and a common control intervention group in the same trial that are both relevant to the same meta‐analysis, we will halve the control group to avoid double‐counting while adding data to the meta‐analysis.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Where this is not possible, and we think the missing data could introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by conducting a sensitivity analysis.
We will use intention‐to‐treat data if the original report contains such data. If the report does not include such data, we will not impute missing values for any outcomes in our primary analysis, but we will assess the effects of missing data in our two sensitivity analyses (see Sensitivity analysis).
Assessment of heterogeneity
We will visually inspect forest plots to assess signs of heterogeneity and explore possible heterogeneity in our prespecified subgroup analyses. We will also inspect study characteristics across trials to identify clinical heterogeneity. We will assess the presence of statistical heterogeneity using the Chi² test (threshold P < 0.10) and measure the quantities of heterogeneity using the I² statistic (Higgins 2002; Higgins 2003). If we detect moderate or high heterogeneity, we plan to explore the possible causes (for example, differences in study design, participants, interventions or completeness of outcome assessments). Ultimately, we may decide that a meta‐analysis should be avoided (Deeks 2021).
Assessment of reporting biases
We will use a funnel plot to assess publication bias if we include 10 or more trials. We will visually inspect funnel plots to assess the risk of bias, and test asymmetry with the Harbord test (Harbord 2006).
Data synthesis
We will pool data from studies we judge to be clinically homogeneous using Review Manager software or STATA (Review Manager 2020; STATA 2019). If more than one study provides usable data in any single comparison, we will perform a meta‐analysis.
Meta‐analysis
We will undertake this meta‐analysis according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021). We will use Review Manager 5.4.1 or STATA (Review Manager 2020; STATA 2019).
We will assess our intervention effects with both random‐effects meta‐analyses (DerSimonian 1986), and fixed‐effect meta‐analyses (DeMets 1987). We will use the more conservative point estimate of the two. The more conservative point estimate is the estimate closest to zero effect (Jakobsen 2014). We use three primary outcomes and, therefore, we will consider a P value of 0.025 or less as the threshold for statistical significance (Jakobsen 2014).
If pooling is not possible, we will describe the results of the individual trials narratively.
Subgroup analysis and investigation of heterogeneity
We plan to conduct the following subgroup analyses.
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Trials at low risk of bias compared to trials at high risk of bias.
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We will pool trials assessed to have 'some concerns' with trials assessed to be at 'high risk'.
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This subgroup is planned because high risk of bias trials and trials with 'some concerns' usually overestimate positive intervention effects and underestimate negative effects (Gluud 2006; Kjaergard 2001; Savović 2012; Savović 2018; Schulz 1995; Wood 2008).
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Trials at high or uncertain risks of vested interests compared to trials at low risk of vested interests.
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This subgroup will assess for‐profit bias (Lundh 2017).
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Trials including newborns with isolated esophageal atresia compared to trials including newborns with additional congenital malformation.
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Trials including participants with different types of esophageal atresia (Pinheiro 2012).
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Trials including participants with different types of preoperative risk factors according to the Waterston classification (Pinheiro 2012).
If trials include a mix of the different types of esophageal atresia, we will contact the authors to request separate data for the relevant groups of participants for subgroup analyses three to five.
Sensitivity analysis
To assess the potential impact of missing data, we will perform two sensitivity analyses on the primary outcomes.
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‘Best‐worst‐case’ scenario: we will assume that all participants lost to follow‐up in the experimental group survived, had no serious adverse event, and had no anastomosis leakage. We will assume that all of those with missing outcomes in the control group died, had a serious adverse event, and had anastomosis leakage.
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'Worst‐best‐case’ scenario: we will assume that all participants lost to follow‐up in the experimental group died, had a serious adverse event, and had anastomosis leakage. We will assume that all those participants lost to follow‐up in the control group survived, had no serious adverse event, and had no anastomosis leakage. We will present the results of both scenarios in our review.
Summary of findings and assessment of the certainty of the evidence
We will create a summary of findings table reporting our primary outcomes: all‐cause mortality, serious adverse events, and anastomosis leakage; and the secondary outcomes sepsis or mediastinitis, esophageal stricture, and recurrent tracheoesophageal fistula. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We will use methods and recommendations described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021), using GRADEproGDT software (GRADEpro GDT). We will justify all decisions to downgrade or upgrade the certainty of studies, report our rationale in footnotes, and make comments to aid the reader's understanding of the review where necessary.
