Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update

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ORIGINAL ARTICLE

Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update Wen You Zhang a,b, Xue Pei Jiang a,b, Lei Miao a,b, Fei Chi Chen a,b, Zhi Ming Huang a,∗, Xie Lin Huang c a

Departments of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Shangcai Street, Nanbaixiang Town, Ouhai District, 325000 Wenzhou, China b School of First Clinical Medical, Wenzhou Medical University, Chashan Advanced Education Park, 325000 Wenzhou, China c School Renji Clinical Medical, Wenzhou Medical University, Advanced Education Park, Wenzhou, China

Summary Background and objective: Endoscopic retrograde cholangiopancreatography (ERCP) is essential for visualising the biliary tree and pancreatic ducts, and carbon dioxide (CO2 ) insufflation during ERCP is considered an alternative technique to air insufflation for relieving post-procedural abdominal discomfort (abdominal pain and distension). The aim of the present study was to evaluate the effect of CO2 insufflation on the remission of abdominal discomfort and the potential side effects by conducting a meta-analysis. Methods: The method recommended by the Cochrane Collaboration was employed to conduct a meta-analysis of randomised controlled trials (RCTs) of CO2 insufflation versus air insufflation during ERCP. The PubMed, EMBASE, Cochrane Library, ISI Web of Science and China Biology Medicine disc (CBMdisc) databases were comprehensively searched. Results: Nine high-quality RCTs were reviewed. The updated meta-analysis showed that the CO2 groups achieved a lower abdominal pain score [1-hour (SMD: −1.44, 95% CI: −2.76, −0.15), 3hour (SMD: −1.17, 95% CI: −2.18, −0.16) and 6-hour (SMD: −1.39, 95% CI: −2.68, −0.10)], a lower abdominal distension score [1-hour (SMD: −1.05, 95% CI: −1.73, −0.38), 3-hour (SMD: −0.63, 95% CI: −1.10, −0.16) and 6-hour (SMD: −0.54, 95% CI: −0.99, −0.08)] and a lower overall rate of complications (OR: 0.59; 95% CI: 0.37, 0.93). There was no significant difference

∗

Corresponding author. E-mail addresses: [email protected], [email protected] (Z.M. Huang).

http://dx.doi.org/10.1016/j.clinre.2016.10.001 2210-7401/© 2016 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

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between the groups regarding abdominal discomfort immediately after recovery or 24-hour post-procedure. There was no evidence to indicate higher pressure of CO2 (pCO2 ) values in the CO2 groups during the procedure when the patients were under sedation anaesthesia. Conclusions: Compared to air insufflation, CO2 insufflation is currently the preferred method for ERCP and decreases post-procedural abdominal pain and distension without significant side effects. © 2016 Elsevier Masson SAS. All rights reserved.

Introduction Endoscopic retrograde cholangiopancreatography (ERCP) is a popular endoscopic investigation for visualising the biliary tree and pancreatic ducts. However, there is a nonnegligible number of patients who suffer from abdominal pain and distension after the procedure. ERCP may be prolonged and thus requires more insufflation of gas, which can lead to more retained air, which might trigger symptoms [1]. In addition, abdominal pain and distension may also be attributed to complications such as post-ERCP pancreatitis (PEP) or perforation. To the best of our knowledge, carbon dioxide (CO2 ) was first reported in the 1980s by Roger et al. [2] as substitute insufflation gas for colonoscopy, and has proven efficacy in reducing post-procedural discomfort compared with traditional air insufflation [3—6]. In 2007, a doubleblind randomised controlled trial (RCT) by Bretthauer et al. [7] suggested that CO2 insufflation significantly reduced the incidence of abdominal pain after ERCP without an increase in side effects. A similar conclusion was drawn from other RCTs [8—10]. In addition, it was reported that CO2 insufflation achieved satisfactory results in elderly patients [11] and by non-expert endoscopists [12] in recent years. In another double-blind RCT by Kuwatani et al. [13], despite a significant reduction in bowel gas volume by CO2 insufflation (P < 0.01), there was no significant difference between the CO2 and air groups with regard to post-procedural discomfort (abdominal pain, abdominal distension, nausea). Several systematic reviews and meta-analyses [14—16] have also obtained discordant findings regarding this issue. Therefore, we conducted an updated meta-analysis to determine the efficacy and safety of CO2 insufflation in patients undergoing ERCP.

Materials and methods The present meta-analysis was carried out according to Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) statements [17].

search terms used were as follows: ‘endoscopic retrograde cholangiopancreatography’, ‘ERCP’, ‘carbon dioxide’, and ‘CO2 ’. No language restrictions were applied. Observational studies, guidelines, conference abstracts, comments, and review articles were excluded. Two observers (Miao and Chen) worked independently throughout the search process.

Eligibility criteria The eligibility criteria based on the PICO (population, intervention, comparison, and outcomes) principle were as follows: • • • •

patients: adult patients undergoing ERCP; intervention: insufflation of CO2 ; comparison of intervention, insufflation of air; outcome: ERCP procedure data, procedure-related discomfort including abdominal pain and distension, bowel gas volume, and procedure safety; • study design: RCTs.

For studies subjected to duplicate publications, only the latest one was included.

Data extraction The eligible trials were respectively reviewed by two observers (Zhang and Jiang) to extract the relevant general items within the trials, and any controversies were resolved by consensus after discussion. The following items were extracted: first author, year of publication, country, sample size, age and sex, indication for ERCP, CO2 delivery system, sedation, total procedure time, analogue scale scores [18,19] for post-procedural discomfort (abdominal pain and distension) recorded at different time points (0, 1, 3, 6, and 24 hours) after ERCP, radiographic evaluation of residual bowel gas volume and complications. If the required data were not published, the corresponding authors were contacted by mail to obtain the necessary information.

Methodologic quality evaluation Literature search A comprehensive search strategy on the PubMed, EMBASE, Cochrane Library, ISI Web of Science and China Biology Medicine disc (CBMdisc) databases was conducted to identify relevant articles published until June 2016. The

A quality assessment based on the ‘‘risk of bias’’ assessment tool from the Cochrane Handbook for Systematic Reviews of Interventions [20] was performed independently by two of the present authors (Zhang and Jiang), and the following characteristics were assessed:

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

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• selection bias as a result of inadequate generation of a randomized sequence; • performance bias from knowledge of the allocated interventions by participants and personnel; • detection bias from knowledge of the allocated interventions by outcome assessors; • attrition bias from the amount, nature, or handling of incomplete outcome data (including complications/safety and abdominal discomfort); • reporting bias from selective outcome reporting or other potential bias. Outcomes were labelled as ‘low risk’, ‘unclear risk’, and ‘high risk’. Disagreement was resolved through discussion.

Statistical methods Outcomes were represented as odds ratio (OR) with 95% confidence intervals (CIs) for dichotomous data and standardized mean difference (SMD) with 95% CIs for continuous data. We used the quantity I2 to assess heterogeneity between the trials, with low, moderate and high assigned to I2 values of 25, 50 and 75%, respectively [21]. For the homogeneity results, a fixed effects model was adopted, while a random effects model was employed for heterogeneous results. To identify the sources of heterogeneity, subgroup analysis was carried out according to several criteria based on clinical judgement. Moreover, to evaluate the possible impact of selective outcome reporting, we conducted a sensitivity analysis by removing individual studies and calculating the pooled effect of the remainder. Furthermore, we performed a funnel plot analysis to detect publication bias. Review Manager (Version 5.3.4; The Cochrane Collaboration) was used to perform statistical calculations for this meta-analysis.

Results Data flow A total of 216 articles were identified from the database search, and when duplicates were excluded, a total of 80 articles were included. After screening the titles and abstracts, 17 articles remained and detailed reading demonstrated that six of these articles were published as conference abstracts [22—27] and therefore excluded. In addition, we excluded two studies [28,29] following assessment of their methodological quality. The remaining nine RCTs [7—13,30,31] were of high quality and met all the inclusion criteria, and thus were included in the meta-analysis (Fig. 1).

Study characteristics The general information and characteristics of the selected studies are summarised in Table 1. All 9 RCTs were published as full texts, and were conducted in different countries including two in Europe [7,10], two in the USA [8,9], and five in Asia [11—13,30,31]. In total, 1014 patients from 2007 to 2015 were included in these studies, which varied from

Figure 1

Study flow diagram.

60 to 208 patients per study, the majority of whom were 54 to 66 years of age (except one study that focused on elderly patients with an average age of 82 years [11]). Of the nine RCTs included, five trials [8,10,12,13,30] excluded patients with chronic obstructive pulmonary disease (COPD). In the remaining four trials [7,9,11,31], patients with COPD were excluded only when known CO2 retention was present or the patients required oxygen. By checking the detailed characteristics of the enrolled patients in each study, we confirmed that three [9,11,31] of these trials included patients with respiratory diseases. Continuous monitoring of oxygen saturation, heart rate, and blood pressure was performed in all these trials. Although not directly described in two RCTs [8,9], the measurement of vital signs was suggested in the outcomes. In these studies, the main complications reported included PEP, perforation, bleeding, hypercapnia, hypoxemia, arrhythmia and hypotension.

Quality assessment After preliminary screening, quality assessment of 11 studies was carried out, and two studies [28,29] were excluded because of a relatively high risk of bias. These results are listed in Table 2, and more detailed information is shown in Table S1.

Post-procedural abdominal pain We considered the SMD to be the preferred summary statistic because of the diversity of the involved analogue scales with which post-procedural abdominal discomfort were

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

Study

Country

Centre NO

Sample size

Mean age (SD)

CO2

Air

CO2

Air

Proportion of male (%)

Norway

2

58

58

57 (16)

54 (18)

32.76

USA

1

50

50

57 (NR)

51.7 (NR)

49

USA

1

36

38

60 (15)

59 (16.6)

51.35

Japan

2

40

40

66 (9.8)

68 (10.9)

61.25

Luigiano et al., 2011 [10] Muraki et al., 2013 [11] Nakamura et al., 2014 [11] He et al., 2014 [30] Lee et al., 2015 [31]

Italy

1

37

39

66 (14.6)

67 (16.4)

43.42

Japan

1

106

102

65.0 (NR)

63.5 (NR)

69.71

Japan

1

30

30

82 (5)

82 (6)

51.76

China

1

65

75

NR

NR

60

Korea

1

80

80

65.9 (8.7)

66 (8.9)

65.71

Analogue scale

Experience of endoscopists

Regimes

Level

Midazolam and/or pethidine Propofol

Moderate

100-mm VAS

NR

Deep

NR

Midazolam and fentanyl Midazolam and fentanyl/diazepam and pethidine Propofol and remifentanil

Moderate

10-point VAS 100-mm VAS 10-point VAS

General anaesthesia

100-mm VAS

NR

Deep

—

Moderate

WBS

Nonexpert/expert NR

General anaesthesia Moderate/deep

10-point VAS 10-point VAS

Midazolam and pentazocine Midazolam and/or pentazocine Propofol Midazolam and fentanyl/propofol and fentanyl

Deep

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Sedation and anaesthesia

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NR NR

NR Expert

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Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

Table 1

Exclusion criteria

CO2 delivery system

Duodenoscope

Olympus Europa, Hamburg, Germany NR

COPD

Pre-procedural pain

Bretthauer et al., 2007 [7]

Uncleara,b

Included

NR

ECR; Olympus Medical

Maple et al., 2009 [8]

Excluded

Excluded

Choledocholithiasis; biliary stricture; biliary dilation; bile leak

Dellon et al., 2010 [9]

Includeda

Excluded

Kuwatani et al., 2011 [13]

Excluded

Excluded

Luigiano C 2011 [10]

Excluded

Excluded

Muraki et al., 2013 [12]

Excluded

Excluded

Nakamura et al., 2014 [11]

Includeda

Included

Choledocholithiasis; biliary stricture; bile leak; pancreatitis; jaundice; abnormal LFTs; mass; post-liver transplant evaluation; question PSC; stent change BD or GB stone; benign BD stricture; choledocholithiasis; pancreatitis; cholangiocarcinoma; pancreatic cancer; GB cancer; ampullary tumour; others Benign BD stricture; choledocholithiasis; bile leak; pancreatic cancer; cholangiocarcinoma; ampullary cancer; others BD stone; benign BD stricture; cholangiocarcinoma; pancreatic cancer; GB cancer; IPMN; pancreatic divisum; autoimmune pancreatitis; other BD stone; cholangiocarcinoma; pancreatic cancer; benign BD stricture; autoimmune pancreatitis, others

EZEM Inc; Lake Success UCR; Olympus Medical

He et al., 2014 [30]

Excluded

Excluded

NR

Lee et al., 2015 [31]

Includeda

Excluded

BD stone; pancreatic cancer; benign BD stricture; cholangiocarcinoma; periampullary cancer; metastatic malignancy; chronic pancreatitis; others

NR

Olympus Medical Systems

NR

EZEM Inc; Lake Success NR

FUJINON, Inc, Saitama, Japan NR

NR

JF260V or TJF240; Olympus Medical System Corp JF260V; Olympus

UCR; Olympus Medical ENDO CO2 PRO-500; MIRAE Medics

JF260V or TJF240; Olympus Medical, Tokyo, Japan

VAS: visual analogue scale; WBS: Wong-Baker FACES pain rating scale; NR: not reported; COPD: chronic obstructive pulmonary disease; BD: bile duct; GB: gall bladder; LFT: liver function tests; PSC: primary sclerosing cholangitis; IPMN: intraductal mucinous neoplasm; NR: not reported. a Patients with COPD were excluded if known CO retention or the need for oxygen existed. 2 b Although announced in the exclusion criteria, no detailed information was given to ensure whether patients complicated with COPD were included.

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Main indications for ERCP

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Efficacy and safety of carbon dioxide insufflation versus air insufflation

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

Table 1

5

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data (complications/safety)

Incomplete outcome data (abdominal discomfort)

Selective reporting/other

Bretthauer et al., 2007 [7] Maple et al., 2009 [8] Dellon et al., 2010 [9] Kuwatani et al., 2011 [13] Luigiano et al., 2011 [10] Huang et al., 2011 [28] Muraki et al., 2013 [11] Nakamura et al., 2014 [11] He et al., 2014 [30] Lee et al., 2015 [31] Huang et al., 2015 [29]

Low risk Low risk Low risk Low risk Low risk High riskc Low risk Low risk Low risk Low risk Low risk

Low risk Low risk Low risk Unclear riskb Low risk High riskc Unclear riskb Unclear riskb High riskd Unclear riskb High riskc

Low risk Low risk Low risk Low risk Low risk Low risk Low risk Low risk Low risk Low risk High riske

Low risk Low risk Low risk Low risk Low risk Low risk Low risk Low risk Low risk Low risk High riske

Low Low Low Low Low Low Low Low Low Low Low

High riska Low risk Low risk Low risk Low risk Low risk Unclear riskf Low risk Low risk Low risk Low risk

Low Low Low Low Low Low Low Low Low Low Low

c d e f

risk risk risk risk risk risk risk risk risk risk risk

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a

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b

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risk risk risk risk risk risk risk risk risk risk risk

Unbalanced missing data with 19/58 from intervention group and 6/58 from control group because of non-response to the VAS questionnaire. Insufficient information. Mentioned but not described in detail, probably not done. Allocated by an open random allocation schedule. No blinding of participants and outcome assessment. No analogue scale score was evaluated in this study.

W.Y. Zhang et al.

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

Table 2

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Figure 2 Forest plot of comparison: CO2 insufflation vs. air insufflation, outcome: analog scales scores of abdominal pain immediately, 1-hour, 3-hour, 6-hour, and 24-hour after ERCP.

recorded. A random-effect model was used because obvious heterogeneity existed. The pooled SMD of post-procedural abdominal discomfort values at various times (immediately after recovery, 1-hour, 3-hour, 6-hour and 24-hours post-ERCP) are shown in Fig. 2. The results indicated that CO2 insufflation relieved abdominal pain at 1-hour (SMD: −1.44, 95% CI: −2.76, −0.15, P = 0.03, I2 = 97%), 3-hour (SMD: −1.17, 95% CI: −2.18, −0.16, P = 0.02, I2 = 97%) and 6-hour (SMD: −1.39, 95% CI: −2.68, −0.10, P = 0.03, I2 = 96%) post-ERCP, but failed to induce significant pain relief immediately after recovery

(SMD: −1.33, 95% CI: −2.88, 0.21, P = 0.09, I2 = 96%) and 24 hours later (SMD: −0.57, 95% CI: −1.21, 0.07, P = 0.08, I2 = 94%).

Post-procedural bowel distention The CO2 groups suffered from less post-procedural abdominal distention at 1-hour (SMD: −1.05, 95% CI: −1.73, −0.38, P = 0.002, I2 = 80%), 3-hour (SMD: −0.63, 95% CI: −1.10, −0.16, P = 0.008, I2 = 83%), and 6-hour (SMD: −0.54, 95%

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

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Figure 3 Forest plot of comparison: CO2 insufflation vs. air insufflation, outcome: analog scales scores of abdominal distension immediately, 1-hour, 3-hour, 6-hour, and 24-hour after ERCP.

CI: −0.99, −0.08, P = 0.02, I2 = 62%) post-ERCP. There was no significant difference between the groups immediately after recovery (SMD: −0.99, 95% CI: −2.13, −0.15, P = 0.09, I2 = 93%) and 24 hours later (SMD: −0.01, 95% CI: −0.20, 0.17, P = 0.89, I2 = 10%) (Fig. 3). In addition, radiographic evaluation of bowel residual gas volume was conducted in five trials [7,11,13,30,31]. When defining radiographic data into four grades (no distention, light distention, moderate distention, severe distention), Bretthauer et al. [7] found a significant difference in the severity of bowel distention between the two groups (P = 0.06), and this was confirmed in the study by He et al. [30] (P = 0.041). In the three remaining trials, gas volume score (GVS) [32] was used to evaluate residual bowel gas volume. Kuwatani et al. [13] first reported a significantly lower GVS in the CO2 group immediately after ERCP (P < 0.01), and similar outcomes were observed by Nakamura et al. [11] at 2-hour post-ERCP (P < 0.01) and by Lee et al. [31] at both 2-hour (P < 0.01) and 12-hour post-ERCP (P = 0.017).

Safety of CO2 insufflation and complications Four RCTs [7,9—11] performed pressure of CO2 (pCO2 ) measurements, and the results are listed in Table 3. In two of these trials [9,11], no significant difference was observed between the groups. However, in the RCT by Luigiano et al. [10], which was conducted under general anaesthesia, the peak pressure of end-tidal CO2 (PetCO2 ) values during the procedure and the PetCO2 values before endotracheal extubation were significantly higher in the CO2 group than in the air group. However, these high values decreased when the ventilation was increased [10]. Although Bretthauer et al. [7] reported that no clinical or statistically significant differences were observed between the two groups, we attempted to pool the pCO2 data from the article using a ttest. The results showed that the CO2 group had a decreased risk of hypercapnia (P < 0.001). A significant decrease in overall complications was observed in the CO2 arm (OR: 0.59; 95% CI: 0.37, 0.93, P = 0.02) without significant heterogeneity (I2 = 0) (Fig. 4).

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

Nakamura et al., 2014 [11]

Transcutaneous pCO2 Transcutaneous pCO2 PetCO2 PaCO2 Transcutaneous pCO2

n

Pre-procedure (mmHg)

(CO2 /air)

CO2

Air

28/34 36/38 37/39

34.5 ± 1.7 40.3 ± 4.6 29.8 ± 1.8 38.3 ± 1.1 40.0 ± 2.0

37.5 ± 1.7 40.5 ± 6.2 30.0 ± 1.6 38.5 ± 1.4 40.0 ± 1.0

30/30

P value

< 0.01 0.89 0.645 0.691 0.54

Max level (mmHg) CO2

Air

42.8 ± 2.3 48.7 ± 6.4 39.0 ± 8.3 46.3 ± 8.3 43.0 ± 2.0

51.8 ± 3.9 50.1 ± 11.8 34.7 ± 1.3 43.1 ± 2.3 43.0 ± 2.0

P value

< 0.01 0.56 0.01 0.765 0.86

Post-procedure (mmHg) CO2

Air

36.8 ± 1.7 — 32.6 ± 2.6 40.7 ± 2.2 41.0 ± 2.0

46.5 ± 3.2 — 30.7 ± 1.3 40.7 ± 2.3 41.0 ± 2.0

P value

< 0.01 — 0.02 0.89 0.69

pCO2 : pressure of CO2 ; PetCO2 : pressure of end-tidal CO2 ; PaCO2 : pressure of arterial CO2 .

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Measurement

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Available pCO2 data involved in selected trails.

Efficacy and safety of carbon dioxide insufflation versus air insufflation

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Table 3

9

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Figure 4

Forest plot of comparison: CO2 insufflation vs. air insufflation, outcome: complication occurrence odds.

Figure 5

Forest plot of comparison: CO2 insufflation vs. air insufflation, outcome: total procedure time.

Total procedure time There was no significant difference between the groups with regard to total procedure time (SMD: 0, 95% CI: −0.17, 0.16, P = 0.97), and no significant heterogeneity was observed (I2 = 0) (Fig. 5).

difference between the groups when the trial [7] with high risk of attrition bias (as a result of unbalanced missing VAS scores data) was removed (SMD: −0.60, 95% CI: −1.34, 0.13, P = 0.11, I2 = 94%), indicating that pain relief caused by CO2 insufflation was an unstable outcome.

Publication bias Subgroup analysis and sensitivity analysis Individual subgroup analyses for post-procedural abdominal pain (1-hour and 3-hour) and complications were conducted according to several criteria, and the results are listed in Table 4. CO2 insufflation did not induce significant pain relief at 1 hour or 3 hours after ERCP when excluding trials [7], irrespective of patients with pre-procedural abdominal pain. In addition, when RCTs [30] included Asian patients or single-centre studies [8—10,30] were introduced into the subgroup analyses, CO2 insufflation did not significantly reduce abdominal pain 1 hour after ERCP. Similar outcomes were also found in the moderate sedation subgroup [7,9] and the general anaesthesia subgroup [10,30]. With regard to ERCP-related complications, the benefit of CO2 insufflation disappeared in the multi-centre subgroup [7,13], and CO2 insufflation resulted in fewer complications in the moderate sedation subgroups [7,9,11,31]. Because only a limited number of trials provided visual analogue scale (VAS) scores data at individual time points, we performed a sensitivity analysis of abdominal pain 3 hours after ERCP (6 trials). The results showed no significant

Because the basic principle that tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta-analysis [20], we only performed a

Figure 6 Funnel plot of comparison: CO2 insufflation vs. air insufflation, outcome: complication.

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Efficacy and safety of carbon dioxide insufflation versus air insufflation Table 4

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Subgroup analysis of post-procedural abdominal pain (1-hour and 3-hour) and complications.

Strategy 1-hour post-procedure Design scope Single-centre Multi-centre Sedation/anaesthesia Moderate sedation Deep sedation General anaesthesia Population Non-Asian Asian Pre-procedure abdominal pain Included Excluded 3-hour post-procedure Pre-procedure abdominal pain Included Excluded Complications Design scope Single-centre Multi-centre Sedation/anaesthesia Moderate sedation Deep sedation General anaesthesia

Subgroup

Reference

SMD (95% CI)

P for heterogeneity

P for overall effect

188 vs. 202 39 vs. 52

[8—10,30] [7]

−0.78 (−1.78,−0.23) −4.22 (−4.96,−3.47)

< 0.001 —

0.129 < 0.001

89 vs. 102 50 vs. 50 102 vs. 114

[7,9] [8] [10,30]

−1.97 (−6.35,2.40) −0.60 (−1.00,−0.20) −1.42 (−3.98,1.14)

< 0.001 — < 0.001

0.377 0.003 0.276

162 vs. 179 65 vs. 70

[7—10] [30]

−1.80 (−3.57,−0.04) −0.13 (−0.46,0.20)

< 0.001 < 0.001

0.045 0.444

39 vs. 52 188 vs. 202

[7] [8—10,30]

−4.22 (−4.96,−3.47) −0.78 (−1.78,−0.23)

— < 0.001

< 0.001 0.129

39 vs. 52 254 vs. 268

[7] [9,10,13,30,31]

−4.10 (−4.83,−3.37) −0.56 (−1.22, 0.09)

— < 0.001

< 0.001 0.094

404 vs. 414 98 vs. 98

[8—11,30,31] [7,13]

0.54 (0.33, 0.89) 1.00 (0.27, 3.65)

0.633 1

0.016 1

164 vs. 166 236 vs. 232 102 vs. 114

[7,9,11,31] [8,11,13,31] [10,30]

0.38 (0.17, 0.86) 0.78 (0.40, 1.54) 0.61 (0.20, 1.89)

0.88 0.395 0.677

0.019 0.481 0.393

SMD: standardized mean difference; P: P-values.

tentative funnel plot analysis for complications (nine studies). No significant publication bias was detected (Fig. 6).

Discussion CO2 is rapidly absorbed by gastrointestinal mucosa and easily expelled through the respiratory system [33], indicating a potential advantage in reducing residual gas volume and intraluminal pressure. These effects also reduce interference with mucosal blood flow, which results in pain relief regardless of sedation protocols [34]. In the present metaanalysis, the CO2 groups yielded more satisfactory outcomes than the air groups in terms of post-procedural abdominal pain (1-hour, 3-hour and 6-hour post-ERCP), which was consistent with previous studies [14,15]. It seems that postprocedural pain relief decreased over time [31], but no significant difference was observed between the groups immediately after recovery. We speculate that the negative outcome at this time point may have been caused by a prolonged antalgic effect and a limited sample size. At 24-hours post-ERCP, Shi et al. [15] inferred that bowel peristalsis is usually restored, and that both CO2 and air remaining in the bowel have already been absorbed or expelled [15]. No significant relief of abdominal distension was observed in the latest meta-analysis [15], which combined VAS scores data from three trials [10,13,28]. As the results of more RCTs were reported recently, we pooled five trials

[10,11,13,30,31] and demonstrated a reduction in postprocedural abdominal distension (1-hour, 3-hour and 6-hours post-ERCP) in patients who underwent CO2 insufflation. In addition, reduced bowel distension was confirmed by radiographic evaluations. Evaluation of a new technique requires not only the establishment of its efficacy, but also the assessment of its potential side effects. With respect to safety, by individually reviewing the available quantitative data reported in four RCTs [7,9—11], we found in patients with uncontrolled COPD under sedation anaesthesia that there was no obvious superiority for CO2 insufflation compared with traditional air insufflation in increasing the arterial pCO2 level. However, it should be noted that in patients undergoing general anaesthesia and tracheal intubation, a significant elevation of arterial PetCO2 does occur but is temporary and easily controlled. Another interested outcome is that the data from Bretthauer’s trial demonstrated a lower risk of arterial pCO2 elevation in the CO2 group; however, we suggest that this unreasonable outcome should be considered cautiously, because the baseline pCO2 values between the two groups were significantly different. Moreover, the meta-analysis revealed a lower complication rate in the CO2 group. To determine possible reasons for this finding, we defined complications as procedurerelated complications (PEP, perforation, and bleeding) and cardiopulmonary complications (hypercapnia, hypoxemia, arrhythmia, and hypotension). Given that there is no definite

Please cite this article in press as: Zhang WY, et al. Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2016.10.001

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12 evidence to show that CO2 insufflation increased the risk of hypercapnia and hypoxemia in these studies, we suggest that this may have decreased the incidence of procedure-related complications. Muraki et al. [12] reported that CO2 insufflation reduced oedema in the papilla of Vater by limiting pain as a result of body movement and movement of the intestinal tract, and might reduce pressure in the intra-pancreatic duct by limiting bowel hyperextension [12]. However, we did not perform a subgroup analysis at this point because of the limited sample size. In accordance with previous systematic reviews and meta-analyses [14,15], no significant difference in total procedure time was detected between the two groups in the eight trials. The present meta-analysis has several limitations, which need to be discussed further. First, there is non-negligible heterogeneity within this meta-analysis, which may be caused by the design scope, clinical characteristics of the patients, indication for ERCP, sedation protocols, and experience of the endoscopists, and the subgroup analysis conducted was insufficient to eliminate this heterogeneity. Second, the sensitivity analysis revealed limited reliability of post-procedural pain relief by CO2 insufflation; thus, further assessment is required with more RCTs. Third, a costeffectiveness analysis was not performed because of the lack of data.

Conclusion The present meta-analysis shows that compared with air insufflation, CO2 insufflation is superior in decreasing abdominal pain and distension after ERCP. The application of CO2 insufflation is safe in patients under sedation anaesthesia and may lead to a reduction in procedure-related complications. More RCTs are necessary to further determine the heterogeneity and verify the conclusions.

Funding The authors of this meta-analysis did not receive financial support for technical assistance.

Disclosure of interest The authors declare that they have no competing interest.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.clinre.2016.10.001.

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