ORIGINAL ARTICLE
Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection: a randomized, double-blind, controlled, prospective study Su Young Kim, MD, Jun-Won Chung, MD, PhD, Dong Kyun Park, MD, PhD, Kwang An Kwon, MD, PhD, Kyoung Oh Kim, MD, PhD, Yoon Jae Kim, MD, PhD Incheon, Korea
Background and Aims: Endoscopic submucosal dissection (ESD) is commonly performed under air insufflation and is often accompanied by abdominal discomfort. CO2 is absorbed more rapidly by the body than is air; however, the use of CO2 insufflation in ESD remains controversial. This randomized, double-blind, controlled, prospective study was designed to assess the efficacy of CO2 versus air insufflation in gastric ESD. Methods: Between May 2012 and August 2014, a total of 110 patients with gastric tumors were randomly assigned to the CO2 insufflation (CO2 group, n Z 54) or air insufflation group (air group, n Z 56). Abdominal pain after ESD was chronologically recorded via visual analog scale (VAS) scores. Secondary outcome measurements were adverse events, abdominal circumference, amount of sedatives prescribed, and use of analgesics. Results: Neither the baseline patient characteristics nor the mean procedural time differed between the groups. The VAS score for abdominal pain was 35.2 in the CO2 insufflation group versus 48.5 in the air insufflation group 1 hour after ESD (P Z .026), 27.8 versus 42.5 three hours after ESD (P Z .007), 18.4 versus 34.8 six hours after ESD (P Z .001), and 9.2 versus 21.9 one day after ESD (P < .001). Changes in abdominal circumference, the amounts of sedative drugs taken, and the adverse events did not differ between the groups. However, the air insufflation group required more analgesics than did the CO2 insufflation group (CO2 group, 22.0% [11/50]; air group, 42.3% [22/52]; P Z .028). Conclusions: CO2 insufflation during gastric ESD significantly reduced abdominal pain and analgesic usage compared with air insufflation. (Clinical trial registration number: NCT01579071.) (Gastrointest Endosc 2015;:1-7.)
Endoscopic submucosal dissection (ESD) is a new treatment for early stage cancer of the digestive tract.1 Insufflation is required during ESD to allow adequate visualization of the gut lumen. To date, it has been standard practice to Abbreviations: ESD, endoscopic submucosal dissection; RCT, randomized controlled trial; VAS, visual analog scale. DISCLOSURE: All authors disclosed no financial relationships relevant to this article. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.05.043 Received February 15, 2015. Accepted May 25, 2015. Current affiliations: Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, South Korea. Reprint requests: Jun-Won Chung, MD, PhD, Assistant Professor, Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, Korea.
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insufflate the lumen with room air. However, a high volume of insufflated gas can distend the gut, causing postprocedural pain and discomfort.2 Unlike air, CO2 is rapidly absorbed by the intestinal mucosa and subsequently expired via the lung, possibly decreasing the duration of bowel distension.3 In several studies, CO2 insufflation reduced procedurerelated pain and discomfort.2,4-9 CO2 insufflation also would be expected to help maintain a stable hemodynamic state and respiration during ESD because CO2 insufflation may restrict the increase in inner pressure of the GI tract as a result of quick absorption into the bloodstream.3,10-12 Pneumoperitoneum or mediastinal emphysema resulting from CO2 insufflation also may disappear quickly because leaking CO2 in the peritoneal cavity or mediastinum is rapidly absorbed into the bloodstream.3,10-12 The safety of CO2 insufflation during ESD has been demonstrated in several studies.13,14 As an alternative to air, CO2 has been insufflated effectively during colorectal and esophageal Volume
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection
ESD.13,15,16 Although many studies on the efficacy of CO2 insufflation during endoscopy have thus appeared, trials of the efficacy of such insufflation during gastric ESD are few in number. To the best of our knowledge, only a single relevant randomized controlled trial (RCT) has been performed.17 Thus, we conducted a prospective, doubleblind, RCT to assess the efficacy of CO2 insufflation in patients undergoing gastric ESD.
PATIENTS AND METHODS Patients All patients provided written informed consent before gastric ESD. Between May 2012 and August 2014, all consecutive patients undergoing gastric ESD at the Gil Medical Center were screened. The exclusion criteria were as follows: chronic obstructive pulmonary disease with retention of CO2, heart failure with dyspnea, an inability to complete the relevant questionnaire, and refusal to participate. We informed all patients of our aims, methods, and the possible side effects and obtained signed written consents from all. The study was approved by the Institutional Review Board of the Gil Medical Center (IRB No. GIRBA 2681-2012) and was registered in the clinical trial database at http://www. clinicaltrials.gov (NCT01579071).
Blinding and endoscopic procedure This was a single-center, double-blind, prospective, RCT. Participants were allocated randomly to either the CO2 insufflation (CO2) or air insufflation (air) group, by using a randomization schedule generated by using http:// www.randomization.com by an investigator not involved in the work. All endoscopists, patients, and recovery room nurses were blinded to the gas used. A nursing assistant operated the CO2 device (“on” and “off”) as dictated by the randomization. The gas equipment was hidden from the endoscopist by draping and was retained in the endoscopy unit even when not in use. ESD was performed with the aid of a GIF-Q260 or GIFQ260J endoscope (Olympus Medical Systems Corp, Tokyo, Japan); a transparent hood (D-201-10704; Olympus Medical Systems Corp) was attached to the tip of either endoscope. A water-jet junction or a hand-made external water channel was used during ESD, which featured the use of flex, an insulation-tipped knife (IT2; Olympus Medical Systems Corp, Tokyo, Japan), and dual knives. Sodium hyaluronate (Endo-MucoUp 20, BMI Korea Corp, Uiwang, Korea) was locally injected into the submucosa. The electrocautery unit (VIO 300 D; ERBE, Tübingen, Germany) was operated in the endo-cut mode (effect 2; cut duration 2; cut interval 2) running the 40 W swift-coagulation option. All ESD procedures were performed by 5 endoscopists, each of whom had at least 5 years of experience in therapeutic GI endoscopy. All procedures were performed on an inpatient basis. 2 GASTROINTESTINAL ENDOSCOPY Volume
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CO2 insufflation and intraprocedural management CO2 was administered with the aid of a commercial CO2-efficient endoscopic insufflator (Colosence Pro-500; Miraemedics Inc, Sung Nam, Korea) connected to a CO2 bottle. Oxygen saturation, blood pressure, and heart rate were monitored constantly. A combination of propofol and midazolam (given as an intravenous bolus) was used for sedation. After an appropriate sedation level had been attained, continuous drip infusion (1-5 mg/kg/h) of propofol, via a syringe pump, was used to preserve sedation. The volume of oxygen inhaled and the rate of intracellular fluid infusion were increased if cardiopulmonary repression developed, and the rate of propofol infusion was reduced under such circumstances. The target sedation level was moderate to deep. Clinical sedation states were defined by using the practice guidelines of the American Society of Anesthesiologists Task Force.18
Postprocedural management All patients fasted on the day of ESD and the following day. Chest and abdominal radiographs were obtained immediately after ESD and perforations sought. Laboratory tests were run before ESD and on day 1 thereafter. After ESD, analgesics (tramadol; Tridol, Yuhan Corporation, Seoul, Korea; or diclofenac; Dicknol, Myungmoon Pharmaceuticals, Seoul, Korea) were prescribed if any patient complained of severe pain. The day after the procedure, follow-up upper GI endoscopy was performed to search for post-ESD lesions. If any procedural adverse event developed, endoscopic treatment was performed.
Study endpoints and outcome measurements The primary endpoint of the study was the severity of abdominal pain, as recorded on a 100-mm visual analog scale (VAS) 1 hour after ESD. The 100-mm VAS ranged from “no pain” on the left to “pain as bad as it could be” on the right. Abdominal pain estimates were taken 1, 3, 6, and 24 hours after ESD. The secondary endpoints were abdominal distention (waist circumference was measured at the start of the procedure and immediately thereafter by using a tape measure), the amounts of sedative drugs (propofol and midazolam) and analgesics prescribed, and adverse events.
Sample size and statistical analysis The required sample size was estimated via prospective power analysis. Sample size calculation was based on between-group VAS score differences 1 hour after the procedure. By using data available at the time of study planning,4,5,8,19,20 we estimated that the air group would have a mean VAS score of 40 mm and the CO2 group a mean score of 20 mm. Thus, each group had to include 45 www.giejournal.org
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection
Figure 1. Patient flow chart.
patients to afford a 90% power of detection of such a difference at a 2-sided significance level of 5%. Assuming that some dropouts would occur, the recruitment goal was at least 50 patients per group All data were collected prospectively and entered into SPSS software (version 12.0; SPSS Inc, Chicago, Ill). The t test was used to compare between-group means of continuous variables, and the chi-square test (or the Fisher exact test) was used to compare between-group categorical variables. Mean standard deviation (SD) were calculated, and a P value < .05 was considered to reflect statistical significance.
RESULTS Patients Between May 2012 and August 2014, a total of 117 patients underwent gastric ESD at the Department of Gastroenterology, Gil Medical Center, Gachon University. Allocation of patients to study groups and the reasons for exclusion are shown in Figure 1. Seven patients were excluded, and thus 110 patients were assigned randomly to receive either type of insufflation. Those who did not complete questionnaires (n Z 8) were excluded from final analyses, finally leaving 102 included in the analyses, of whom 50 received CO2 (CO2 group) and 52 air (air group) insufflation. Patient characteristics are shown in Table 1. No significant between-group difference was evident in terms of age, sex, abdominal surgery history, procedure time, location of lesion, size of resected lesion, or pathology result. www.giejournal.org
After-procedure pain assessment Patients in the CO2 group had lower pain scores at all times. Figure 2 shows the significant between-group differences in 100-mm VAS scores at 1, 3, 6, and 24 hours after ESD (CO2 group vs air group; before ESD: 2.0 8.3 vs 1.9 8.4; P Z .963; 1 hour: 35.2 30.3 vs 48.5 29.0; P Z .026; 3 hours: 27.8 25.1 vs 42.5 28.4; P Z .007; 6 hours: 18.4 19.0 vs 34.8 28.2; P Z .001; and 24 hours: 9.2 13.1 vs 21.9 20.1, P < .001). The pain line approached the baseline level (no pain) 24 hours after ESD in the CO2 group. Figure 3 shows the proportions of patients with scores of 0 (no pain) in the 2 treatment groups at each time point. More patients in the CO2 group reported no pain at all times. The between-group difference was significant both 1 hour (20% vs 3.8%; P Z .011) and 24 hours after ESD (54% vs 25%; P Z .003).
Secondary outcomes Secondary outcomes are shown in Table 2. The mean increase in abdominal distension was somewhat greater in the air than the CO2 group; however, this did not attain statistical significance (þ 0.9 cm vs þ 1.5 cm; P Z .164). The amounts of sedatives required did not differ between the 2 groups (CO2 group vs air group; propofol: 363.0 186.3 mg vs 377.1 209.0 mg; P Z .720; midazolam: 2.6 1.5 mg vs 3.2 1.3 mg; P Z .064). The percentages of patients requesting analgesics were 22.0% (11/50) in the CO2 group and 42.3% (22/52) in the air group (P Z .028). Procedure-related adverse events are listed in Table 2. Nine patients in the CO2 group and 15 in the air group Volume
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TABLE 1. Patient characteristics Variable
CO2 group
Air group
P value
Total no. of patients
50
52
Age, mean SD, y
61.8 9.5
62.0 7.5
.925
Sex, male/female
34/16
38/14
.574
BMI, mean, kg/m2
24.2
24.3
.862
12 (24.0)
15 (28.8)
.579
History of smoking, no. (%) History of alcohol, no. (%)
18 (36.0)
28 (53.8)
.070
Hypertension, no. (%)
15 (30.0)
20 (38.5)
.368
Diabetes mellitus, no. (%)
10 (20.0)
10 (19.2)
.922
2 (4.0)
2 (3.8)
.968
Pulmonary disease history*, no. (%) Cardiovascular disease historyy, no. (%)
2 (4.0)
1 (1.9)
.535
Abdominal surgery historyz, no. (%)
6 (12.0)
10 (19.2)
.315
Current analgesic taking, no. (%)
1 (2)
0 (0)
.305
Procedure time, mean SD, min
48.8 26.9
48.6 31.1
.972
Location
.871
Antrum
24
27
Body
17
16
Angle
6
7
Cardia
2
2
Fundus
1
0
Tumor size, mean SD, mm
13.7 7.0
16.7 9.9
.088
Resection size, mean SD, mm
32.2 8.3
35.1 10.3
.126
Adenoma
25
27
Adenocarcinoma
24
21
Signet ring cell carcinoma
1
2
Otherx
0
2
Histology
.774
SD, Standard deviation; BMI, body mass index. *Pulmonary disease history of 4 cases all had old tuberculosis scar. yCardiovascular disease history of 3 cases all had angina pectoris. zAbdominal surgeries include appendectomy, cholecystectomy, hysterectomy, cesarean section, subtotal colectomy. xOthers included GI stromal tumor, heterotopic pancreas.
experienced adverse events (P Z .197); all were postprocedural hemorrhages. No serious cardiopulmonary adverse events occurred. All patients recovered after endoscopic hemostasis.
DISCUSSION This prospective, double-blind, RCT revealed that CO2 insufflation during gastric ESD reduced postprocedural abdominal pain compared with air insufflation. The pain levels were significantly lower at 1, 3, and 6 hours, and even at 1 day after the procedure. The proportions of CO2 group patients with VAS scores of 0 were higher, compared with the air group, up to 24 hours after the procedures. Many previous studies, meta-analyses, and a review have shown that patients undergoing CO2 insufflation have less postprocedural pain than do those 4 GASTROINTESTINAL ENDOSCOPY Volume
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undergoing air insufflation; the procedures evaluated include sigmoidoscopy, colonoscopy, double-balloon enteroscopy, and ERCP.2,4,5,7,9,12,20-27 This is because CO2 is rapidly absorbed from the GI tract into the blood, with subsequent pulmonary excretion.4,5,22 A few RCTs have suggested that CO2 insufflation did not reduce procedure-related pain measured by using VASs.28-30 However, only a few studies have evaluated CO2 insufflation during endoscopic resection. Most studies did not focus on procedure-related pain but rather on safety and feasibility.13,14,31 A PubMed search yielded only one study exploring the efficacy of CO2 insufflation during gastric ESD.17 In that study, Maeda et al17 found that the GI tract contained less gas after CO2 insufflation, but no between-group difference in either postprocedural pain or discomfort was noted. To the best of our knowledge, this result of the present study is the second RCT to compare CO2 and air www.giejournal.org
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection
Figure 2. Time-dependent changes in 100-mm visual analog scale scores after endoscopic submucosal dissection in the CO2 and air groups. Values are the mean standard deviation. VAS, visual analog scale; ESD, endoscopic submucosal dissection.
Figure 3. Percentages of patients who were pain-free (score of 0 on the visual analog scale) after endoscopic submucosal dissection, showing statistically significant differences between 2 time points. ESD, endoscopic submucosal dissection.
insufflation during gastric ESD. Our data differ from those of a 2013 Japanese study17 for several reasons. First, in the cited work, pain levels were very low in both groups, rendering it difficult to compare them. In our present work, postprocedural pain was evident in both groups, allowing comparisons to be made. Second, the cited work used propofol and pentazocine as sedative drugs, but we used only propofol and midazolam. Midazolam is a weaker analgesic than pentazocine.32,33 Pentazocine is a drug of the benzomorphan class of opioids used to treat moderate to severe pain. It is known to have a strong analgesic effect. In addition, pentazocine is reported to provide analgesia about 4 hours.32 Pentazocine was not used for the patients www.giejournal.org
in the present study. Thus, unlike in the cited work, the effects of sedative drugs on pain were minimal in our present work, rendering the effects of CO2 insufflation more apparent. Finally, the present study’s patient age was almost 10 years younger than that of the prior study’s patient’s age. Compared to elder patients, it is considered that younger patients have higher pain sensitivity and express pain actively to a medical team. For these reasons, it would have affected the measurement of postprocedure pain. We sought to assess objectively the extent of abdominal distension after procedures by measuring the change in waist circumference. Compared with the air group, waist Volume
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TABLE 2. Analysis of secondary outcomes
CO2 group
Air group
P value
Before ESD
85.4 12.0
85.6 7.6
.912
After ESD
86.2 12.0
87.1 7.7
.402
0.9 1.6
1.5 2.7
.164
Propofol
363.0 186.3
377.1 209.0
.720
Midazolam
2.6 1.5
3.2 1.3
.064
11 (22.0)
22 (42.3)
.028
9 (18.0)
15 (28.8)
.197
0
0
N/A
Variable Abdominal circumference, mean SD, cm
Increase in waist circumference Dose of sedative drugs, mean SD, mg
Analgesics used, no. of patients, no. (%) Adverse events, no. (%) Postprocedure hemorrhage Perforation Emphysema
0
0
N/A
Pneumonia
0
0
N/A
Death
0
0
N/A
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to endoscopic treatment as adverse events. The safety of CO2 as a substitute for air, during insufflation, has been confirmed in many endoscopic procedures.2,4,5,20,22,37 No pulmonary adverse event or CO2 retention has been reported after CO2 insufflation in patients without pulmonary problems, and even in unselected populations. Air insufflation is associated with certain uncommon but grave adverse events of endoscopic procedures, including perforation, tension pneumothorax, air embolism, and abdominal compartment syndrome.38-40 CO2 insufflation would be expected to limit such adverse events, because CO2 is more rapidly absorbed from the gut into the bloodstream than is air, thus limiting any increase in intraabdominal pressure. Our study had the following limitations. First, it was conducted at a single center. Second, intravenous sedation was not standardized. However, the use of CO2 during gastric ESD affords significant advantages compared with air insufflation. Postprocedural pain and the need for analgesics were reduced in the CO2 insufflation group. Thus, CO2 rather than air insufflation is recommended during gastric ESD.
ESD, Endoscopic submucosal dissection; SD, standard deviation; N/A, not applicable.
REFERENCES
circumference increased less in the CO2 group, but statistical significance was not attained. In previous studies, bowel gas and flatus levels were measured either radiographically or by recording changes in abdominal circumference.17,22,23,34,35 Residual gas volumes (assessed via colonoscopy) were less in groups undergoing CO2 insufflation,34,35 as was bowel distension as measured by abdominal radiography.22,23 However, we measured only the change in abdominal circumference, which is an indirect indicator of residual gas. This may explain the betweenstudy differences observed. In previous studies, a lower dose of sedative drugs was required when endoscopic procedures were done under CO2 rather than air insufflation.9,16 In our present study, we used two sedative drugs, midazolam and propofol. Although the depth of sedation was not strictly controlled, the amounts of sedative drugs used were similar in both groups. Therefore, measurement of postprocedural pain would have been affected similarly by the sedatives in each group. The numbers of patients requiring postprocedural analgesics were compared. Analgesics were given on patient demand, and the air group requested more analgesics than did the CO2 group, showing that severe pain was rare in the latter group. The frequency of adverse events (all postprocedural hemorrhages) associated with gastric ESD in the present study was 23.5% but did not differ between the groups. We experienced more side effects than did previous studies17,36 because we considered both nonbleeding visible vessels and actively bleeding vessels subjected 6 GASTROINTESTINAL ENDOSCOPY Volume
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection: a randomized, double-blind, controlled, prospective study Su Young Kim, MD, Jun-Won Chung, MD, PhD, Dong Kyun Park, MD, PhD, Kwang An Kwon, MD, PhD, Kyoung Oh Kim, MD, PhD, Yoon Jae Kim, MD, PhD Incheon, Korea
Background and Aims: Endoscopic submucosal dissection (ESD) is commonly performed under air insufflation and is often accompanied by abdominal discomfort. CO2 is absorbed more rapidly by the body than is air; however, the use of CO2 insufflation in ESD remains controversial. This randomized, double-blind, controlled, prospective study was designed to assess the efficacy of CO2 versus air insufflation in gastric ESD. Methods: Between May 2012 and August 2014, a total of 110 patients with gastric tumors were randomly assigned to the CO2 insufflation (CO2 group, n Z 54) or air insufflation group (air group, n Z 56). Abdominal pain after ESD was chronologically recorded via visual analog scale (VAS) scores. Secondary outcome measurements were adverse events, abdominal circumference, amount of sedatives prescribed, and use of analgesics. Results: Neither the baseline patient characteristics nor the mean procedural time differed between the groups. The VAS score for abdominal pain was 35.2 in the CO2 insufflation group versus 48.5 in the air insufflation group 1 hour after ESD (P Z .026), 27.8 versus 42.5 three hours after ESD (P Z .007), 18.4 versus 34.8 six hours after ESD (P Z .001), and 9.2 versus 21.9 one day after ESD (P < .001). Changes in abdominal circumference, the amounts of sedative drugs taken, and the adverse events did not differ between the groups. However, the air insufflation group required more analgesics than did the CO2 insufflation group (CO2 group, 22.0% [11/50]; air group, 42.3% [22/52]; P Z .028). Conclusions: CO2 insufflation during gastric ESD significantly reduced abdominal pain and analgesic usage compared with air insufflation. (Clinical trial registration number: NCT01579071.) (Gastrointest Endosc 2015;:1-7.)
Endoscopic submucosal dissection (ESD) is a new treatment for early stage cancer of the digestive tract.1 Insufflation is required during ESD to allow adequate visualization of the gut lumen. To date, it has been standard practice to Abbreviations: ESD, endoscopic submucosal dissection; RCT, randomized controlled trial; VAS, visual analog scale. DISCLOSURE: All authors disclosed no financial relationships relevant to this article. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.05.043 Received February 15, 2015. Accepted May 25, 2015. Current affiliations: Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, South Korea. Reprint requests: Jun-Won Chung, MD, PhD, Assistant Professor, Division of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, Korea.
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insufflate the lumen with room air. However, a high volume of insufflated gas can distend the gut, causing postprocedural pain and discomfort.2 Unlike air, CO2 is rapidly absorbed by the intestinal mucosa and subsequently expired via the lung, possibly decreasing the duration of bowel distension.3 In several studies, CO2 insufflation reduced procedurerelated pain and discomfort.2,4-9 CO2 insufflation also would be expected to help maintain a stable hemodynamic state and respiration during ESD because CO2 insufflation may restrict the increase in inner pressure of the GI tract as a result of quick absorption into the bloodstream.3,10-12 Pneumoperitoneum or mediastinal emphysema resulting from CO2 insufflation also may disappear quickly because leaking CO2 in the peritoneal cavity or mediastinum is rapidly absorbed into the bloodstream.3,10-12 The safety of CO2 insufflation during ESD has been demonstrated in several studies.13,14 As an alternative to air, CO2 has been insufflated effectively during colorectal and esophageal Volume
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection
ESD.13,15,16 Although many studies on the efficacy of CO2 insufflation during endoscopy have thus appeared, trials of the efficacy of such insufflation during gastric ESD are few in number. To the best of our knowledge, only a single relevant randomized controlled trial (RCT) has been performed.17 Thus, we conducted a prospective, doubleblind, RCT to assess the efficacy of CO2 insufflation in patients undergoing gastric ESD.
PATIENTS AND METHODS Patients All patients provided written informed consent before gastric ESD. Between May 2012 and August 2014, all consecutive patients undergoing gastric ESD at the Gil Medical Center were screened. The exclusion criteria were as follows: chronic obstructive pulmonary disease with retention of CO2, heart failure with dyspnea, an inability to complete the relevant questionnaire, and refusal to participate. We informed all patients of our aims, methods, and the possible side effects and obtained signed written consents from all. The study was approved by the Institutional Review Board of the Gil Medical Center (IRB No. GIRBA 2681-2012) and was registered in the clinical trial database at http://www. clinicaltrials.gov (NCT01579071).
Blinding and endoscopic procedure This was a single-center, double-blind, prospective, RCT. Participants were allocated randomly to either the CO2 insufflation (CO2) or air insufflation (air) group, by using a randomization schedule generated by using http:// www.randomization.com by an investigator not involved in the work. All endoscopists, patients, and recovery room nurses were blinded to the gas used. A nursing assistant operated the CO2 device (“on” and “off”) as dictated by the randomization. The gas equipment was hidden from the endoscopist by draping and was retained in the endoscopy unit even when not in use. ESD was performed with the aid of a GIF-Q260 or GIFQ260J endoscope (Olympus Medical Systems Corp, Tokyo, Japan); a transparent hood (D-201-10704; Olympus Medical Systems Corp) was attached to the tip of either endoscope. A water-jet junction or a hand-made external water channel was used during ESD, which featured the use of flex, an insulation-tipped knife (IT2; Olympus Medical Systems Corp, Tokyo, Japan), and dual knives. Sodium hyaluronate (Endo-MucoUp 20, BMI Korea Corp, Uiwang, Korea) was locally injected into the submucosa. The electrocautery unit (VIO 300 D; ERBE, Tübingen, Germany) was operated in the endo-cut mode (effect 2; cut duration 2; cut interval 2) running the 40 W swift-coagulation option. All ESD procedures were performed by 5 endoscopists, each of whom had at least 5 years of experience in therapeutic GI endoscopy. All procedures were performed on an inpatient basis. 2 GASTROINTESTINAL ENDOSCOPY Volume
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CO2 insufflation and intraprocedural management CO2 was administered with the aid of a commercial CO2-efficient endoscopic insufflator (Colosence Pro-500; Miraemedics Inc, Sung Nam, Korea) connected to a CO2 bottle. Oxygen saturation, blood pressure, and heart rate were monitored constantly. A combination of propofol and midazolam (given as an intravenous bolus) was used for sedation. After an appropriate sedation level had been attained, continuous drip infusion (1-5 mg/kg/h) of propofol, via a syringe pump, was used to preserve sedation. The volume of oxygen inhaled and the rate of intracellular fluid infusion were increased if cardiopulmonary repression developed, and the rate of propofol infusion was reduced under such circumstances. The target sedation level was moderate to deep. Clinical sedation states were defined by using the practice guidelines of the American Society of Anesthesiologists Task Force.18
Postprocedural management All patients fasted on the day of ESD and the following day. Chest and abdominal radiographs were obtained immediately after ESD and perforations sought. Laboratory tests were run before ESD and on day 1 thereafter. After ESD, analgesics (tramadol; Tridol, Yuhan Corporation, Seoul, Korea; or diclofenac; Dicknol, Myungmoon Pharmaceuticals, Seoul, Korea) were prescribed if any patient complained of severe pain. The day after the procedure, follow-up upper GI endoscopy was performed to search for post-ESD lesions. If any procedural adverse event developed, endoscopic treatment was performed.
Study endpoints and outcome measurements The primary endpoint of the study was the severity of abdominal pain, as recorded on a 100-mm visual analog scale (VAS) 1 hour after ESD. The 100-mm VAS ranged from “no pain” on the left to “pain as bad as it could be” on the right. Abdominal pain estimates were taken 1, 3, 6, and 24 hours after ESD. The secondary endpoints were abdominal distention (waist circumference was measured at the start of the procedure and immediately thereafter by using a tape measure), the amounts of sedative drugs (propofol and midazolam) and analgesics prescribed, and adverse events.
Sample size and statistical analysis The required sample size was estimated via prospective power analysis. Sample size calculation was based on between-group VAS score differences 1 hour after the procedure. By using data available at the time of study planning,4,5,8,19,20 we estimated that the air group would have a mean VAS score of 40 mm and the CO2 group a mean score of 20 mm. Thus, each group had to include 45 www.giejournal.org
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection
Figure 1. Patient flow chart.
patients to afford a 90% power of detection of such a difference at a 2-sided significance level of 5%. Assuming that some dropouts would occur, the recruitment goal was at least 50 patients per group All data were collected prospectively and entered into SPSS software (version 12.0; SPSS Inc, Chicago, Ill). The t test was used to compare between-group means of continuous variables, and the chi-square test (or the Fisher exact test) was used to compare between-group categorical variables. Mean standard deviation (SD) were calculated, and a P value < .05 was considered to reflect statistical significance.
RESULTS Patients Between May 2012 and August 2014, a total of 117 patients underwent gastric ESD at the Department of Gastroenterology, Gil Medical Center, Gachon University. Allocation of patients to study groups and the reasons for exclusion are shown in Figure 1. Seven patients were excluded, and thus 110 patients were assigned randomly to receive either type of insufflation. Those who did not complete questionnaires (n Z 8) were excluded from final analyses, finally leaving 102 included in the analyses, of whom 50 received CO2 (CO2 group) and 52 air (air group) insufflation. Patient characteristics are shown in Table 1. No significant between-group difference was evident in terms of age, sex, abdominal surgery history, procedure time, location of lesion, size of resected lesion, or pathology result. www.giejournal.org
After-procedure pain assessment Patients in the CO2 group had lower pain scores at all times. Figure 2 shows the significant between-group differences in 100-mm VAS scores at 1, 3, 6, and 24 hours after ESD (CO2 group vs air group; before ESD: 2.0 8.3 vs 1.9 8.4; P Z .963; 1 hour: 35.2 30.3 vs 48.5 29.0; P Z .026; 3 hours: 27.8 25.1 vs 42.5 28.4; P Z .007; 6 hours: 18.4 19.0 vs 34.8 28.2; P Z .001; and 24 hours: 9.2 13.1 vs 21.9 20.1, P < .001). The pain line approached the baseline level (no pain) 24 hours after ESD in the CO2 group. Figure 3 shows the proportions of patients with scores of 0 (no pain) in the 2 treatment groups at each time point. More patients in the CO2 group reported no pain at all times. The between-group difference was significant both 1 hour (20% vs 3.8%; P Z .011) and 24 hours after ESD (54% vs 25%; P Z .003).
Secondary outcomes Secondary outcomes are shown in Table 2. The mean increase in abdominal distension was somewhat greater in the air than the CO2 group; however, this did not attain statistical significance (þ 0.9 cm vs þ 1.5 cm; P Z .164). The amounts of sedatives required did not differ between the 2 groups (CO2 group vs air group; propofol: 363.0 186.3 mg vs 377.1 209.0 mg; P Z .720; midazolam: 2.6 1.5 mg vs 3.2 1.3 mg; P Z .064). The percentages of patients requesting analgesics were 22.0% (11/50) in the CO2 group and 42.3% (22/52) in the air group (P Z .028). Procedure-related adverse events are listed in Table 2. Nine patients in the CO2 group and 15 in the air group Volume
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TABLE 1. Patient characteristics Variable
CO2 group
Air group
P value
Total no. of patients
50
52
Age, mean SD, y
61.8 9.5
62.0 7.5
.925
Sex, male/female
34/16
38/14
.574
BMI, mean, kg/m2
24.2
24.3
.862
12 (24.0)
15 (28.8)
.579
History of smoking, no. (%) History of alcohol, no. (%)
18 (36.0)
28 (53.8)
.070
Hypertension, no. (%)
15 (30.0)
20 (38.5)
.368
Diabetes mellitus, no. (%)
10 (20.0)
10 (19.2)
.922
2 (4.0)
2 (3.8)
.968
Pulmonary disease history*, no. (%) Cardiovascular disease historyy, no. (%)
2 (4.0)
1 (1.9)
.535
Abdominal surgery historyz, no. (%)
6 (12.0)
10 (19.2)
.315
Current analgesic taking, no. (%)
1 (2)
0 (0)
.305
Procedure time, mean SD, min
48.8 26.9
48.6 31.1
.972
Location
.871
Antrum
24
27
Body
17
16
Angle
6
7
Cardia
2
2
Fundus
1
0
Tumor size, mean SD, mm
13.7 7.0
16.7 9.9
.088
Resection size, mean SD, mm
32.2 8.3
35.1 10.3
.126
Adenoma
25
27
Adenocarcinoma
24
21
Signet ring cell carcinoma
1
2
Otherx
0
2
Histology
.774
SD, Standard deviation; BMI, body mass index. *Pulmonary disease history of 4 cases all had old tuberculosis scar. yCardiovascular disease history of 3 cases all had angina pectoris. zAbdominal surgeries include appendectomy, cholecystectomy, hysterectomy, cesarean section, subtotal colectomy. xOthers included GI stromal tumor, heterotopic pancreas.
experienced adverse events (P Z .197); all were postprocedural hemorrhages. No serious cardiopulmonary adverse events occurred. All patients recovered after endoscopic hemostasis.
DISCUSSION This prospective, double-blind, RCT revealed that CO2 insufflation during gastric ESD reduced postprocedural abdominal pain compared with air insufflation. The pain levels were significantly lower at 1, 3, and 6 hours, and even at 1 day after the procedure. The proportions of CO2 group patients with VAS scores of 0 were higher, compared with the air group, up to 24 hours after the procedures. Many previous studies, meta-analyses, and a review have shown that patients undergoing CO2 insufflation have less postprocedural pain than do those 4 GASTROINTESTINAL ENDOSCOPY Volume
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undergoing air insufflation; the procedures evaluated include sigmoidoscopy, colonoscopy, double-balloon enteroscopy, and ERCP.2,4,5,7,9,12,20-27 This is because CO2 is rapidly absorbed from the GI tract into the blood, with subsequent pulmonary excretion.4,5,22 A few RCTs have suggested that CO2 insufflation did not reduce procedure-related pain measured by using VASs.28-30 However, only a few studies have evaluated CO2 insufflation during endoscopic resection. Most studies did not focus on procedure-related pain but rather on safety and feasibility.13,14,31 A PubMed search yielded only one study exploring the efficacy of CO2 insufflation during gastric ESD.17 In that study, Maeda et al17 found that the GI tract contained less gas after CO2 insufflation, but no between-group difference in either postprocedural pain or discomfort was noted. To the best of our knowledge, this result of the present study is the second RCT to compare CO2 and air www.giejournal.org
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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection
Figure 2. Time-dependent changes in 100-mm visual analog scale scores after endoscopic submucosal dissection in the CO2 and air groups. Values are the mean standard deviation. VAS, visual analog scale; ESD, endoscopic submucosal dissection.
Figure 3. Percentages of patients who were pain-free (score of 0 on the visual analog scale) after endoscopic submucosal dissection, showing statistically significant differences between 2 time points. ESD, endoscopic submucosal dissection.
insufflation during gastric ESD. Our data differ from those of a 2013 Japanese study17 for several reasons. First, in the cited work, pain levels were very low in both groups, rendering it difficult to compare them. In our present work, postprocedural pain was evident in both groups, allowing comparisons to be made. Second, the cited work used propofol and pentazocine as sedative drugs, but we used only propofol and midazolam. Midazolam is a weaker analgesic than pentazocine.32,33 Pentazocine is a drug of the benzomorphan class of opioids used to treat moderate to severe pain. It is known to have a strong analgesic effect. In addition, pentazocine is reported to provide analgesia about 4 hours.32 Pentazocine was not used for the patients www.giejournal.org
in the present study. Thus, unlike in the cited work, the effects of sedative drugs on pain were minimal in our present work, rendering the effects of CO2 insufflation more apparent. Finally, the present study’s patient age was almost 10 years younger than that of the prior study’s patient’s age. Compared to elder patients, it is considered that younger patients have higher pain sensitivity and express pain actively to a medical team. For these reasons, it would have affected the measurement of postprocedure pain. We sought to assess objectively the extent of abdominal distension after procedures by measuring the change in waist circumference. Compared with the air group, waist Volume
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TABLE 2. Analysis of secondary outcomes
CO2 group
Air group
P value
Before ESD
85.4 12.0
85.6 7.6
.912
After ESD
86.2 12.0
87.1 7.7
.402
0.9 1.6
1.5 2.7
.164
Propofol
363.0 186.3
377.1 209.0
.720
Midazolam
2.6 1.5
3.2 1.3
.064
11 (22.0)
22 (42.3)
.028
9 (18.0)
15 (28.8)
.197
0
0
N/A
Variable Abdominal circumference, mean SD, cm
Increase in waist circumference Dose of sedative drugs, mean SD, mg
Analgesics used, no. of patients, no. (%) Adverse events, no. (%) Postprocedure hemorrhage Perforation Emphysema
0
0
N/A
Pneumonia
0
0
N/A
Death
0
0
N/A
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to endoscopic treatment as adverse events. The safety of CO2 as a substitute for air, during insufflation, has been confirmed in many endoscopic procedures.2,4,5,20,22,37 No pulmonary adverse event or CO2 retention has been reported after CO2 insufflation in patients without pulmonary problems, and even in unselected populations. Air insufflation is associated with certain uncommon but grave adverse events of endoscopic procedures, including perforation, tension pneumothorax, air embolism, and abdominal compartment syndrome.38-40 CO2 insufflation would be expected to limit such adverse events, because CO2 is more rapidly absorbed from the gut into the bloodstream than is air, thus limiting any increase in intraabdominal pressure. Our study had the following limitations. First, it was conducted at a single center. Second, intravenous sedation was not standardized. However, the use of CO2 during gastric ESD affords significant advantages compared with air insufflation. Postprocedural pain and the need for analgesics were reduced in the CO2 insufflation group. Thus, CO2 rather than air insufflation is recommended during gastric ESD.
ESD, Endoscopic submucosal dissection; SD, standard deviation; N/A, not applicable.
REFERENCES
circumference increased less in the CO2 group, but statistical significance was not attained. In previous studies, bowel gas and flatus levels were measured either radiographically or by recording changes in abdominal circumference.17,22,23,34,35 Residual gas volumes (assessed via colonoscopy) were less in groups undergoing CO2 insufflation,34,35 as was bowel distension as measured by abdominal radiography.22,23 However, we measured only the change in abdominal circumference, which is an indirect indicator of residual gas. This may explain the betweenstudy differences observed. In previous studies, a lower dose of sedative drugs was required when endoscopic procedures were done under CO2 rather than air insufflation.9,16 In our present study, we used two sedative drugs, midazolam and propofol. Although the depth of sedation was not strictly controlled, the amounts of sedative drugs used were similar in both groups. Therefore, measurement of postprocedural pain would have been affected similarly by the sedatives in each group. The numbers of patients requiring postprocedural analgesics were compared. Analgesics were given on patient demand, and the air group requested more analgesics than did the CO2 group, showing that severe pain was rare in the latter group. The frequency of adverse events (all postprocedural hemorrhages) associated with gastric ESD in the present study was 23.5% but did not differ between the groups. We experienced more side effects than did previous studies17,36 because we considered both nonbleeding visible vessels and actively bleeding vessels subjected 6 GASTROINTESTINAL ENDOSCOPY Volume
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