The lifetime risk of developing gastric cancer in the United States is 0.9%. It is estimated that 26,370 new cases of gastric cancer were diagnosed in 2016 alone, and that 10,730 people died of it [1]. Worldwide, it is the third highest leading cause of cancer-related death [2]. Early gastric carcinoma in the United States accounts for about 20% of the total cases of gastric cancer [3].

Endoscopic submucosal dissection (ESD) helps in both the staging and treatment of early gastric carcinoma. It is a well-established technique for en bloc removal of gastrointestinal (GI) epithelial lesions [4-10]. However, this procedure is technically demanding and time consuming. Extensive gas insufflation is required to maintain optimal visualization during the procedure. Compared with standard air insufflation, carbon dioxide (CO₂) insufflation has been found to be safe and effective in various studies [11-16]. CO₂ is absorbed 160 times more rapidly than nitrogen and 13 times more rapidly than oxygen across the intestine into the blood. Hence, it is easily excreted by the lungs [17]. Our aim was to evaluate the safety and efficacy of CO₂ insufflation in terms of maximal end-tidal CO₂ during the procedure, procedure length, and incidence of adverse events as compared with air insufflation in gastric ESD.

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement for reporting meta-analysis and systemic reviews, as recommended by the Cochrane Collaboration, was used for this meta-analysis (Fig. 1) [18]. We included all relevant studies published up to November 2016. Medline, Embase, Cochrane library, and clinicaltrials.gov databases were used to identify the studies. The search was conducted using four broad themes. For the theme of carbon dioxide, the all field terms “carbon dioxide” and “CO₂” were used. For the theme of air, the all field terms “air” and “room air” were used. For the theme gastric cancer, all field terms “gastric”, “stomach”, “early gastric carcinoma”, “gastric carcinoma”, and “gastric tumor” were used. For endoscopic submucosal dissection, the all field terms “endoscopic submucosal dissection”, “ESD”, “endoscopic treatment”, and “endoscopic procedure” were used. The results were combined using the Boolean operator “AND”.

All results were reviewed. No language restrictions were used and all necessary measures to prevent data duplication were taken. Two different investigators (RB and SU) conducted the search and excluded the studies that did not meet the inclusion criteria. Relevant data extracted by the two investigators was corroborated by two other investigators (JK and SKS). A fifth investigator was consulted whenever any issue arose (TSM). The eligibility criteria for the included studies relied on previously published guidelines for systematic reviews and was based on the PICO framework; P (population–patients with early gastric cancer undergoing ESD), I (interventions–CO₂ insufflation), C (comparative interventions–control group, air insufflation), and O (outcomes–procedure-related primary or secondary adverse events including post-procedural pain and discomfort and pulmonary dysfunction) [19]. Studies that did not compare CO₂ insufflation with air were excluded [11,20-22]. A total of four randomized control trials (RCTs) met the inclusion criteria [23-26]. Three of them had been published in peer-reviewed journals [24-26], and one was a published abstract [23]. The quality of each study was evaluated by two investigators (BKG and GB) using the Delphi consensus criteria for RCTs (Table 1) [27].

From all the selected studies, we extracted the baseline study details: the type of study, mean patient age, history of smoking, FEV1 (%), tumor size, resection size, mean procedural size and histological type, and adverse events (Table 2). Six outcomes were measured: procedural length, maximal end-tidal CO₂, maximal post-operative pain, post-procedural hemorrhage, perforation, and overall adverse events (Table 3). Overall adverse events included post-procedural hemorrhage, bowel perforation, aspiration pneumonia, Mallory-Weiss tear, paroxysmal atrial fibrillation, and other adverse events (such as fever, and stricture with dysphagia) (Table 3). The outcomes were calculated with Review Manager (RevMan, version 5.3 for Windows; The Cochrane Collaborations, The Nordic Cochrane Centre, Copenhagen, Denmark, 2014). Analysis was performed by the Mantel-Haenszel test using RevMan. Mean difference (MD) was calculated for continuous variables, whereas the odds ratio (OR) was calculated for categorical variables using a confidence interval (CI) of 95%. Heterogeneity was calculated using I². A randomized model was used because low heterogeneity is typically a major problem in small sample size reviews [28]. A p-value of <0.05 was considered significant. Mean values were estimated from the median using a modified Hozo’s formula [26,29]. The characteristics of the trials evaluated during the study are presented in Table 4.

A total of 391 patients were included in the four RCTs. The severity of abdominal pain was measured using a 100-mm visual analog scale (VAS) [30]. Maximal post-operative pain was significantly lower in the CO₂ insufflation group compared with the air group (MD, -7.41; 95% CI, -13.6–-1.21; p=0.02; Fig. 2). However, procedural time (MD, 5.97; CI, -0.77–12.72; p=0.08; Fig. 3) and maximal end-tidal CO₂ (MD, -0.14; CI, -2.04–1.76; p=0.88; Fig. 4) were not significantly different. A total of 125 adverse events (post-procedural hemorrhage, perforation, aspiration pneumonia, Mallory-Weiss tear, paroxysmal atrial fibrillation, and others) were reported (Table 3). No death was reported in any of the studies. The total number of post-procedural hemorrhages and perforations was 30 and 11, respectively. The difference in post-procedural hemorrhage between the two groups was not significant (OR, 0.51; 95% CI, 0.22–1.19; p=0.12; Fig. 5). Similarly, no significant difference in the rate of perforation was found (OR, 0.39; 95% CI, 0.10–1.57; p=0.19; Fig. 6). Statistical significance was also calculated for overall adverse events. The incidence of overall adverse events was significantly lower in the CO₂ group (OR, 0.51; CI 0.32–0.84; p=0.007; Fig. 7). The study by Takada et al. uniquely reported Mallory-Weiss tear as a separate category, and its occurrence was significantly lower in the CO₂ group compared to the air insufflation group (p=0.013) [26].

As in any endoscopic procedure, adequate gastric distention is required for the safe advancement of the scope and adequate visualization of the mucosa during ESD. Although it is universally available, ambient air is poorly absorbed by the GI tract, causing excessive post-operative distention of the bowel lumen and consequent pain and discomfort [31]. On the contrary, CO₂ is absorbed approximately 160 times faster than nitrogen (a major gaseous ingredient of ambient air) into gut mucosa and is rapidly exhaled through the lungs, resulting in reduced gut distention. This leads to significantly less post-procedural pain and discomfort, and improved recovery times, which has been proven in multiple previous studies on GI endoscopy [13,15,31-34]. To the best of our knowledge, this is the first review comparing CO₂ to air insufflation in gastric ESD. Our analysis of 391 patients showed significantly less post-operative pain in the CO₂ insufflation group, which is attributable to the shorter duration of bowel distention. Pain associated with the procedure was analyzed in three of the four trials [23-25]. Kim et al. and Tanioka et al. showed that there were significantly lower mean pain scores in the CO₂ group compared with the air insufflation group (p=0.028 and p=0.04, respectively) [23,24]. As a result, patients in the air insufflation group requested more analgesics for pain control. This finding has been corroborated by other studies and meta-analyses done on sigmoidoscopy, colonoscopy, double-balloon enteroscopy, and endoscopic retrograde cholangiopancreatography [12,13,15,31,33-39]. However, the study by Maeda et al. [25] showed no significant difference in pain levels between the two groups. We believe this is due to the strong analgesic effect of pentazocine, which was used in both groups in that study. Otherwise, significant discomfort can be expected in the air insufflation group, in which a mean of 1,037 mL of residual gas in the GI tract was observed post-operatively compared with that of 643 mL in the CO₂ group (p<0.001).

The other important consideration in this study was the procedure time, which was not significantly different between the two groups. The implications of this finding are three-fold. First, it shows that the type of gas used does not influence the length of the procedure. Second, the endoscopists in both groups were equally skilled. This finding is substantiated by the fact that all the procedures were performed by endoscopists with years of experience in therapeutic GI endoscopy at high-volume tertiary care centers. Third, the comparison of end-tidal CO₂ between the two groups increases in reliability as a result. The end-tidal CO₂ increased significantly from baseline in both groups in the study by Takada et al. [26]; however, our study failed to show a difference in maximal end-tidal CO₂ between the two groups. This result is in accordance with previous data on the safety of CO₂ in various GI endoscopic procedures [14,40,41]. However, most of those studies did not include patients with significant pulmonary dysfunction. On the other hand, some other studies conducted on patients with pulmonary dysfunction also failed to show significant CO₂ retention, acidosis, or narcosis, and CO₂ was found to be safe in terms of adverse event risks and hospital stay. In those studies, the only significant correlation that was found was between the length of the procedure and an elevation in end-tidal CO₂ [22]. In fact, CO₂ insufflation has been found to be safe even in patients with obstructive ventilatory disturbances in various gastric and non-gastric ESD studies [11,42]. Moreover, end-tidal CO₂ remained within acceptable limits even in the context of prolonged procedure time in those studies [21,40]. In general, there is a paucity of data demonstrating CO₂ retention in patients with pulmonary dysfunction in ESD.

In terms of adverse events, the rate of procedure-related hemorrhage and bowel perforation did not reach a statistically significant level between the two groups since only four trials were included in the study. Additionally, all studies were conducted in high-volume medical centers by experts in their field, which naturally led to a lower rate of adverse events. However, the overall adverse event rate was significantly lower in the CO₂ insufflation group. In the study by Takada et al. [26], CO₂ insufflation was shown to confer the benefit of reducing the risk of Mallory-Weiss tears (p=0.013). Again, this is due to the more rapid absorption of CO₂ compared with air, which resulted in a significantly lower overall adverse event rate in the CO₂ group in our study. Although no life-threatening adverse events were reported in our study, air insufflation is known to cause adverse events such as perforation, tension pneumothorax, air embolism, mediastinal emphysema, and abdominal compartment syndrome during endoscopic procedures [43-46]. CO₂ insufflation would be advantageous in such situations, as it is more rapidly absorbed into the blood and cleared by the lungs. Our study had a few limitations. The main limiting factor of our study is the low number of included studies due to the small number of published RCTs. Additionally, the studies did not include patients with significant pulmonary dysfunction.

In conclusion, CO₂ insufflation appears to be safe and effective for gastric ESD. It significantly decreases post-procedural pain and discomfort and neither prolongs the procedure time, nor significantly increases end-tidal CO₂. Lastly, fewer overall adverse events were observed in the CO₂ insufflation group during ESD.