ORIGINAL ARTICLE: Clinical Endoscopy

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; how-
ever, the use of CO2 insufflation in ESD remains controversial. This randomized, double-blind, controlled, pro-
spective 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;82:1018-24.)

Endoscopic submucosal dissection (ESD) is a new treat-
ment for early stage cancer of the digestive tract.1 Insuffla-
tion 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, random-
ized 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.
insufflate the lumen with room air. However, a high vol-
ume of insufflated gas can distend the gut, causing post-
procedural pain and discomfort.2 Unlike air, CO2 is
rapidly absorbed by the intestinal mucosa and subse-
quently expired via the lung, possibly decreasing the dura-
tion of bowel distension.3
In several studies, CO2 insufflation reduced procedure-
related 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

1018 GASTROINTESTINAL ENDOSCOPY Volume 82, No. 6 : 2015 www.giejournal.org

Kim et al 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 per-
formed.17 Thus, we conducted a prospective, double-
blind, RCT to assess the efficacy of CO2 insufflation in pa-
tients undergoing gastric ESD.
PATIENTS AND METHODS
Patients
All patients provided written informed consent before
gastric ESD. Between May 2012 and August 2014, all consec-
utive patients undergoing gastric ESD at the Gil Medical Cen-
ter 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 us-
ing 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 assis-
tant 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 GIF-
Q260J endoscope (Olympus Medical Systems Corp, Tokyo,
Japan); a transparent hood (D-201-10704; Olympus Medi-
cal Systems Corp) was attached to the tip of either endo-
scope. 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 Med-
ical Systems Corp, Tokyo, Japan), and dual knives. Sodium
hyaluronate (Endo-MucoUp 20, BMI Korea Corp, Uiwang,
Korea) was locally injected into the submucosa. The elec-
trocautery 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 op-
tion. All ESD procedures were performed by 5 endoscop-
ists, each of whom had at least 5 years of experience in
therapeutic GI endoscopy. All procedures were performed
on an inpatient basis.
www.giejournal.org
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 appro-
priate 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 cir-
cumstances. The target sedation level was moderate to
deep. Clinical sedation states were defined by using the
practice guidelines of the American Society of Anesthesiol-
ogists 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 Pharma-
ceuticals, 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 devel-
oped, 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 pro-
cedure. By using data available at the time of study plan-
ning,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
Volume 82, No. 6 : 2015 GASTROINTESTINAL ENDOSCOPY 1019
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 dif-
ference 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 contin-
uous variables, and the chi-square test (or the Fisher exact
test) was used to compare between-group categorical vari-
ables. 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 pa-
tients underwent gastric ESD at the Department of Gastro-
enterology, 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 signifi-
cant between-group difference was evident in terms of
age, sex, abdominal surgery history, procedure time, loca-
tion of lesion, size of resected lesion, or pathology result.
1020 GASTROINTESTINAL ENDOSCOPY Volume 82, No. 6 : 2015
Kim et al
After-procedure pain assessment
Patients in the CO2 group had lower pain scores at all
times. Figure 2 shows the significant between-group differ-
ences 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 in-
crease in abdominal distension was somewhat greater in
the air than the CO2 group; however, this did not attain sta-
tistical 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
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Kim et al Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection

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
History of smoking, no. (%) 12 (24.0) 15 (28.8) .579
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
Pulmonary disease history*, no. (%) 2 (4.0) 2 (3.8) .968
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
Histology .774
Adenoma 25 27
Adenocarcinoma 24 21
Signet ring cell carcinoma 1 2
Otherx 0 2
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 postpro-
cedural 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 pro-
cedures. Many previous studies, meta-analyses, and a
review have shown that patients undergoing CO2 insuffla-
tion have less postprocedural pain than do those
undergoing air insufflation; the procedures evaluated
include sigmoidoscopy, colonoscopy, double-balloon en-
teroscopy, 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 insuffla-
tion 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

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Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection Kim et al

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, al-
lowing 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
in the present study. Thus, unlike in the cited work, the
effects of sedative drugs on pain were minimal in our pre-
sent 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 pa-
tient’s age. Compared to elder patients, it is considered
that younger patients have higher pain sensitivity and ex-
press 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

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Kim et al Efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection

TABLE 2. Analysis of secondary outcomes to endoscopic treatment as adverse events. The safety
of CO2 as a substitute for air, during insufflation, has
P been confirmed in many endoscopic proce-
Variable CO2 group Air group value
dures.2,4,5,20,22,37 No pulmonary adverse event or CO2
Abdominal circumference, retention has been reported after CO2 insufflation in pa-
mean
SD, cm tients without pulmonary problems, and even in unse-
Before ESD 85.4
12.0 85.6
7.6 .912 lected populations.
After ESD 86.2
12.0 87.1
7.7 .402 Air insufflation is associated with certain uncommon but
Increase in waist circumference 0.9
1.6 1.5
2.7 .164 grave adverse events of endoscopic procedures, including
Dose of sedative drugs,
perforation, tension pneumothorax, air embolism, and
mean
SD, mg abdominal compartment syndrome.38-40 CO2 insufflation
Propofol 363.0
377.1
.720
would be expected to limit such adverse events, because
186.3 209.0 CO2 is more rapidly absorbed from the gut into the blood-
Midazolam 2.6
1.5 3.2
1.3 .064
stream than is air, thus limiting any increase in intra-
abdominal pressure.
Analgesics used, no. of 11 (22.0) 22 (42.3) .028
patients, no. (%) Our study had the following limitations. First, it was con-
ducted at a single center. Second, intravenous sedation was
Adverse events, no. (%)
not standardized. However, the use of CO2 during gastric
Postprocedure hemorrhage 9 (18.0) 15 (28.8) .197
ESD affords significant advantages compared with air insuffla-
Perforation 0 0 N/A tion. Postprocedural pain and the need for analgesics were
Emphysema 0 0 N/A reduced in the CO2 insufflation group. Thus, CO2 rather
Pneumonia 0 0 N/A than air insufflation is recommended during gastric ESD.
Death 0 0 N/A
ESD, Endoscopic submucosal dissection; SD, standard deviation; N/A, not applicable.
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In previous studies, a lower dose of sedative drugs was
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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
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