Carbon dioxide insufflation improves intubation depth in double-balloon enteroscopy: a randomized, controlled, double-blind trial

• Introduction
• Methods
• Study design and participants
• Endoscopic procedure
• Intervention
• Evaluation of intubation depth
• Evaluation of pain and discomfort
• Statistical power calculation
• Statistics
• Ethics
• Results
• Intubation depth
• Pain and discomfort
• Discussion
• Acknowledgments
• References

Background and study aims: Double-balloon enteroscopy (DBE) has been proven effective for deep intubation of the small bowel. However, intubation depth is limited by distention of the small bowel due to air insufflation during the procedure. The present trial investigated whether carbon dioxide (CO₂) instead of standard air insufflation would improve intubation depth during DBE, as well as reduce postprocedure pain.

Patients and methods: One hundred and twelve consecutive patients scheduled for DBE at two centers were randomly assigned to either CO₂ or air insufflation during DBE. Patients and endoscopists were blinded with regard to the type of gas used. Intubation depth was registered using a validated form. Patients scored pain and discomfort during and after the examination on a 100-mm visual analog scale.

Results: One hundred patients were eligible for data analysis (48 in the CO₂ group and 52 in the air group). The mean small-bowel intubation depth was extended by 30 % in the CO₂ group compared to the air group (230 vs. 177 cm, P = 0.008). The superiority was most pronounced for oral DBE, with a 71-cm improvement in intubation depth when using CO₂ (295 cm in the CO₂ group vs. 224 cm in the air group, P < 0.001). Patient pain and discomfort were significantly reduced in the CO₂ group at 1 and 3 hours after the examination.

Conclusions: CO₂ insufflation significantly extended intubation depth in DBE. CO₂ insufflation also reduces patient discomfort. CO₂ insufflation may lead to a higher diagnostic and therapeutic yield of DBE, with reduced patient discomfort.

Introduction

Until recently, the small bowel has been a blind spot for gastrointestinal endoscopy, as it has been only partially accessible with conventional endoscopes. Double-balloon enteroscopy (DBE) is a novel endoscopic procedure for visualizing large parts of the small bowel. The method was first described by Yamamoto et al. in 2001 [1]. Since then, DBE has spread rapidly throughout the world. Both endoscopic diagnosis - including biopsy - and treatment can be performed using DBE. Published series have demonstrated that DBE can safely visualize large parts of the small bowel [2] [3] [4].

In any endoscopic procedure, it is mandatory to insufflate gas into the bowel to ensure good visualization. Currently, air is used for this purpose in the vast majority of centers throughout the world. During gastrointestinal endoscopy using air, however, significant amounts of air are usually retained in the gastrointestinal tract [5]. Compared to other methods of gastrointestinal endoscopy, DBE is a lengthy procedure (mean examination time 75 minutes [4]), so the volumes of insufflated air are large, leading to significant distention of the small bowel during and after the examination. Indeed, one of the main technical challenges of DBE is the formation of distended bowel loops and acute angulations with increasing amounts of gas intraluminally. Likewise, the ability of the bowel to be folded onto the endoscope is reduced. Carbon dioxide (CO₂), however, unlike air, is rapidly absorbed from the bowel. The use of CO₂ might therefore reduce this problem. To our knowledge, no research has so far been performed investigating the use of CO₂ in DBE to improve small-bowel intubation depth.

Abdominal pain and discomfort during and after the examination due to the retention of air has been shown to be common during and after endoscopic procedures [5] [6] [7] [8] [9]. The use of CO₂ has been shown to significantly reduce discomfort after colonoscopy, flexible sigmoidoscopy, and endoscopic retrograde cholangiopancreatography (ERCP) in randomized trials [6] [7] [8] [9] [10]. In these studies, CO₂ insufflation almost completely eliminated postprocedure pain due to abdominal distention.

The aim of the present study was to examine whether CO₂ insufflation during DBE facilitates intubation of the small bowel and allows a more complete examination than using standard air insufflation. Furthermore, we investigated whether CO₂ insufflation leads to a reduction of abdominal pain in patients undergoing DBE.

Methods

Study design and participants

The study was designed as a two-center randomized controlled trial. The participating centers were the University Hospital of Münster, Germany, and Rikshospitalet Medical Centre, Oslo, Norway.

Individuals eligible for inclusion were patients referred for DBE for the purpose of examining the small bowel and to whom none of the following exclusion criteria applied: age under 16 years, inability to understand information for participation, pregnancy, and refusal to participate. All eligible individuals were informed about the nature of the study, and those who agreed to participate provided written informed consent before entering the trial. Each eligible participant was randomized by block randomization (blocks of six patients at each center) to one of the two treatment groups (CO₂ or air insufflation).

Endoscopic procedure

DBE was performed using the DBE endoscope system (Fujinon Corp., Saitama, Japan), as described in the literature [1] [2] [3] [4]. The DBE endoscope consists of a 200-cm-long video endoscope with an outer diameter of 8.5 mm, and a flexible overtube with a length of 145 cm and an outer diameter of 12 mm. Latex balloons are attached to both the endoscope and the overtube. These balloons are inflated and deflated during insertion, as described elsewhere in detail [1] [2]. All procedures were performed by eight experienced endoscopists (six in Münster, two in Oslo). “Experienced” was defined as having performed at least 50 DBE examinations before participating in the study. Sedation was performed according to current standards at the centers, which involved the use of propofol and pethidine at the Münster center, and midazolam and pethidine at the Oslo center. Fluoroscopy was not used routinely during the study.

Intervention

CO₂ or air (according to individual treatment allocation) was insufflated during the procedures. CO₂ was insufflated using the CO₂Efficient endoscopic insufflator (EZEM Inc., Lake Success, NY, USA). Air was insufflated using the ordinary air inlet system of the endoscope rack. Both patients and endoscopists were blinded with regard to the type of gas being used for any particular patient. To prevent unblinding to the type of gas used by the endoscopists, the air inlet button was hidden from the view of the endoscopist by a nontransparent plastic shield, and the CO₂ regulator was placed behind the endoscopy rack, out of the view of the endoscopists - both measures which have been successfully used in previous studies [7] [8] [10]. The endoscopy assistant was responsible for the allocation of the patient to the treatment group on scene.

Evaluation of intubation depth

The endoscopists estimated the depth of intubation during each examination using a recently described and validated technique [3] [11], where the intubation depth during each maneuver of intubation and withdrawal of the endoscope was estimated and registered on an evaluation form. After completion of the DBE procedure, the individual intubation depths during each maneuver were added up to the total intubation depth. This technique has been used routinely at both centers prior to the present trial by all participating endoscopists. Intubation depth for oral DBEs is defined as intubation distal to the pylorus. For anal DBEs, intubation depth is defined as proximal to the ileocecal valve.

Evaluation of pain and discomfort

A questionnaire containing visual analog scales (VAS; 100-mm) was used to evaluate patient pain during and after the procedure. On this questionnaire, patients were asked to quantify abdominal pain experienced during the examination and at 1, 3, 6, and 24 hours after the procedure, as validated in recent studies [7] [8]. The questionnaire was completed by every participant on the day after the procedure.

Statistical power calculation

Results of a pilot study including the first 40 patients (20 in the CO₂ and 20 in the air group) showed a mean intubation depth in the standard group of 176 cm (standard deviation 92.6 cm). A 25 % improvement in intubation depth when using CO₂ compared to air insufflation was predefined as clinically significant. With 50 patients in each treatment group, the power to detect this difference at a significance level of 5 % was 84 %.

Statistics

End points were analyzed in all patients who successfully completed the study and were thus eligible for data analysis. Comparison of the treatment groups was performed using Student’s t-test and χ² test for continuous and categorical variables, respectively. Differences in mean VAS scores were analyzed by ANOVA for repeated measurements. Statistical significance was defined as P < 0.05. Only two-sided tests were used. All statistical analyses were performed using SPSS 13.0 (SPSS Inc., Chicago, Illinois, USA).

Ethics

The regional ethics committees of the participating centers approved the study protocol. The study is registered in the clinical trial database at www.clinicaltrials.gov (no: NCT00464022).

Results

Altogether 112 consecutive patients were randomized to the two study groups: 58 to air insufflation and 54 to CO₂ insufflation. Twelve patients were excluded from analysis, for the following reasons: empty CO₂ tank (two patients), insufficient bowel cleansing (two patients), lack of language skills to fill in questionnaire (two patients), narrow strictures in proximal jejunum (two patients), toxic megacolon (one patient), accidental drop off the endoscopy bench before exam (one patient), and inability to fill in the questionnaire due to heavy pain because of malignant disease (two patients). Thus, 100 patients were eligible for data analysis: 48 in the CO₂ group and 52 in the air group. Of these, 97 were examined at the Münster center, and three at the center in Oslo.

Eight different endoscopists performed the examinations (six in Münster, two in Oslo), contributing equally to both groups. There were no differences in baseline characteristics between patients in the two treatment groups ([Table 1]). However, we observed a significantly lower mean propofol dose in the CO₂ group than in the air group (290 mg vs. 380 mg, P = 0.02) in oral DBE procedures ([Table 1]).

Intubation depth

The mean small-bowel intubation depth was significantly larger in the CO₂ group than in the air group (230 cm vs. 177 cm, difference 53 cm, P = 0.008). Thus, the intubation depth was increased by 30 % in the CO₂ group compared to the air group. This improvement was related to oral procedures only, with a 71-cm improvement of mean intubation depth (295 cm in the CO₂ group vs. 224 cm in the air group, P < 0.001). In the 41 anal DBE procedures, the mean intubation depth was 122 cm in the CO₂ group and 118 in the air group (P = 0.84).

Pain and discomfort

Patient pain and discomfort were significantly reduced in the CO₂ group at 1 and 3 hours after the examination ([Table 2]).

Discussion

The present trial is the first to investigate the effect of CO₂ insufflation on small-bowel intubation depth in DBE. As shown, CO₂ significantly improves small-bowel intubation depth. The effect was, however, only demonstrated for oral procedures, with a 32 % improvement of intubation depth using CO₂ compared to standard air insufflation.

Air is still the standard gas used for insufflation during gastrointestinal endoscopy, despite the fast-growing body of evidence showing that CO₂ is superior to air for several reasons:

• The use of CO₂ excludes the risk of explosion during polypectomy, which is reported using air [12] [13].

• The use of CO₂ significantly reduces abdominal pain and discomfort after colonoscopy, flexible sigmoidoscopy, and ERCP [5] [6] [7] [8] [9] [10] [14].

This study adds to the evidence that CO₂ insufflation also improves intubation depth during DBE.

The purpose of DBE is deep intubation of the small bowel, by either the oral or the anal route, for diagnosis and treatment of disease in the small bowel. The diagnostic and therapeutic yield of DBE is highly dependent on the depth of intubation. Deep intubation during DBE is limited among other things by the tortuous anatomy of the small bowel. Air insufflation during the procedure unfortunately enhances the loops and reduces their ability to collapse onto the endoscope. Thus, the main hypothesis of the present trial was that insufflation using CO₂, because this gas is more rapidly absorbed from the gastrointestinal tract, would facilitate deeper small-bowel intubation. Indeed, according to our results, CO₂ does lead to a significant improvement of small-bowel intubation. It remains to be shown whether the improved intubation depth results in a better clinical outcome in terms of diagnostic yield or treatment, but this is to be expected.

The present trial also shows that CO₂ reduces abdominal pain after DBE during the first hours after the examination, which is very much in line with recent evidence from other endoscopic procedures [6] [7] [9] [10]. However, we observed that the amount of postprocedural pain was modest in most of the patients in both groups, in contrast to recent trials in colonoscopy and ERCP [6] [7] [9] [10]. The reason for this is unclear, but may be due to routines at the Münster center, which recruited most of the patients. The pain-reducing effect of CO₂ however, is supported in this study, too, by the reduced use of propofol in the CO₂ group. Mean propofol dosage was reduced by 29 mg, which in our opinion is a clinically significant difference. However, the present trial was not powered to show a statistically significant effect on this end point. Larger trials would need to be performed to elaborate further on this finding.

Side effects of the use of CO₂ in gastrointestinal endoscopy - mainly CO₂ retention - have been thoroughly studied in recent trials, without any evidence of such adverse effects [7] [10]. Using the new CO₂Efficient^© CO₂ regulator, we avoided any significant pollution of the endoscopy room, as this device is automatically downregulated when CO₂ is not being used for insufflation into the bowel. Thus, this device is a major improvement compared to the devices marketed by other companies.

The strengths of the present trial are the robust methodology, using a randomized controlled design with blinding of both endoscopist and patient. The groups were similar in their registered baseline characteristics. We did not register variables like body mass index or previous abdominal surgery, which might have an influence on intubation depth. However, the randomized, double-blind design of the study and the significant number of patients included should rule out any skewing of data with regard to both endoscopist and patient characteristics. A limitation of the study, if any, might be that the vast majority of patients were examined at one center. The skewness in inclusion of patients, with the Münster center accounting for 97 out of 100 eligible patients, was firstly due to the higher workload of DBE procedures in Münster compared to Oslo, and secondly because the Oslo center specializes in DBE-ERCP procedures, so many of the DBE procedures in Oslo are DBE-ERCP procedures [15]. As intubation depth is not a major issue during DBE-ERCP, these procedures were not eligible for the present trial. Thirdly, the CO₂ insufflator was delayed for some weeks due to shipping to Norway, and for this reason the Münster center started enrollment of patients in the trial earlier than the Oslo center.

In conclusion, the present trial shows that CO₂ insufflation significantly extends intubation depth during DBE. CO₂ insufflation may thus lead to a higher diagnostic and therapeutic yield of DBE, with reduced patient discomfort. CO₂ should be used as standard insufflation gas in DBE.

Acknowledgments

Dr. Bretthauer and Dr. Domagk contributed equally to the study. This study is registered at www.clinicaltrials.gov (no. NCT00464022). EZEM Inc. provided the CO₂ insufflators used in this study free of charge. The study received no other funding or sponsoring.

Competing interests: None

References

• 1 Yamamoto H, Sekine Y, Saito Y. et al . Total enteroscopy with a non-surgical steerable double-balloon method.  Gastrointest Endosc. 2001;  53 216-220
  Search in Google Scholar
• 2 May A, Nachbar L, Wardak A. et al . Double-balloon enteroscopy: preliminary experience in patients with obscure gastrointestinal bleeding or chronic abdominal pain.  Endoscopy. 2003;  35 985-991
  Thieme ConnectPubMedSearch in Google Scholar
• 3 May A, Nachbar L, Ell C. Double-balloon enteroscopy (push-and-pull enteroscopy) of the small bowel: feasibility and diagnostic and therapeutic yield in patients with suspected small bowel disease.  Gastrointest Endoc. 2005;  62 62-70
  CrossrefPubMedSearch in Google Scholar
• 4 Ell C, May A, Nachbar L. et al . Push-and-pull enteroscopy in the small bowel using the double-balloon technique: results of a prospective European multicenter study.  Endoscopy. 2005;  37 613-616
  Thieme ConnectPubMedSearch in Google Scholar
• 5 Hussein A MJ. Carbon dioxide insufflation for more comfortable colonoscopy.  Gastrointest Endosc. 1984;  30 68-70
  CrossrefPubMedSearch in Google Scholar
• 6 Stevensen G W. et al . Pain following colonoscopy: elimination with carbon dioxide.  Gastrointest Endosc. 1992;  38 564-567
  CrossrefPubMedSearch in Google Scholar
• 7 Bretthauer M, Thiis-Evensen E, Hoff G. et al . A randomized controlled trial to assess the safety and efficacy of carbon dioxide insufflation in colonoscopy.  Gut. 2002;  50 604-607
  CrossrefPubMedSearch in Google Scholar
• 8 Bretthauer M, Hoff G, Thiis-Evensen E. et al . Carbon dioxide insufflation reduces discomfort due to flexible sigmoidoscopy in colorectal cancer screening.  Scand J Gastroenterol. 2002;  37 1103-1108
  CrossrefPubMedSearch in Google Scholar
• 9 Sumanac K, Zealley I, Fox B. et al . Minimizing postcolonoscopy abdominal pain by using CO₂ insufflation: a prospective, randomized, double blind, controlled trial evaluating a new commercially available CO₂ delivery system.  Gastrointest Endosc. 2002;  56 190-194
  CrossrefPubMedSearch in Google Scholar
• 10 Bretthauer M, Seip B, Aasen S. et al . Carbon dioxide insufflation for more comfortable ERCP: a randomized controlled double-blind trial.  Endoscopy. 2007;  39 58-64
  Thieme ConnectPubMedSearch in Google Scholar
• 11 May A, Nachbar L, Schneider M. et al . Push-and-pull enteroscopy using the double-balloon technique: method of assessing depth of insertion and training of the endoscopy technique using the Erlangen endo-trainer.  Endoscopy. 2005;  37 66-70
  Thieme ConnectPubMedSearch in Google Scholar
• 12 Carter H G. Explosion in the colon during electrodesiccation of polyps.  Am J Surg. 1952;  84 514-516
  CrossrefPubMedSearch in Google Scholar
• 13 Josemanders D FGM, Spillenaar Bilgen E J, van Sorge A A. et al. Colonic explosion during endoscopic polypectomy: avoidable complication or bad luck?.  Endoscopy. 2006;  38 943-944
  PubMedSearch in Google Scholar
• 14 Church J, Delaney C. Randomized, controlled trial of carbon dioxide insufflation during colonoscopy.  Dis Colon Rectum.. 2003;  46 322-326
  CrossrefPubMedSearch in Google Scholar
• 15 Aabakken L, Bretthauer M, Line P D. Double balloon enteroscopy for endoscopic retrograde cholangiography in patients with Roux-Y anastomoses.  Endoscopy. 2007;  39 1068-1071
  Thieme ConnectPubMedSearch in Google Scholar

M. Bretthauer, MD

Department of Gastroenterology

Rikshospitalet-Radiumhospitalet Medical Centre

Oslo

Norway

Email: michael.bretthauer@rikshospitalet.no

References

• 1 Yamamoto H, Sekine Y, Saito Y. et al . Total enteroscopy with a non-surgical steerable double-balloon method.  Gastrointest Endosc. 2001;  53 216-220
  Search in Google Scholar
• 2 May A, Nachbar L, Wardak A. et al . Double-balloon enteroscopy: preliminary experience in patients with obscure gastrointestinal bleeding or chronic abdominal pain.  Endoscopy. 2003;  35 985-991
  Thieme ConnectPubMedSearch in Google Scholar
• 3 May A, Nachbar L, Ell C. Double-balloon enteroscopy (push-and-pull enteroscopy) of the small bowel: feasibility and diagnostic and therapeutic yield in patients with suspected small bowel disease.  Gastrointest Endoc. 2005;  62 62-70
  CrossrefPubMedSearch in Google Scholar
• 4 Ell C, May A, Nachbar L. et al . Push-and-pull enteroscopy in the small bowel using the double-balloon technique: results of a prospective European multicenter study.  Endoscopy. 2005;  37 613-616
  Thieme ConnectPubMedSearch in Google Scholar
• 5 Hussein A MJ. Carbon dioxide insufflation for more comfortable colonoscopy.  Gastrointest Endosc. 1984;  30 68-70
  CrossrefPubMedSearch in Google Scholar
• 6 Stevensen G W. et al . Pain following colonoscopy: elimination with carbon dioxide.  Gastrointest Endosc. 1992;  38 564-567
  CrossrefPubMedSearch in Google Scholar
• 7 Bretthauer M, Thiis-Evensen E, Hoff G. et al . A randomized controlled trial to assess the safety and efficacy of carbon dioxide insufflation in colonoscopy.  Gut. 2002;  50 604-607
  CrossrefPubMedSearch in Google Scholar
• 8 Bretthauer M, Hoff G, Thiis-Evensen E. et al . Carbon dioxide insufflation reduces discomfort due to flexible sigmoidoscopy in colorectal cancer screening.  Scand J Gastroenterol. 2002;  37 1103-1108
  CrossrefPubMedSearch in Google Scholar
• 9 Sumanac K, Zealley I, Fox B. et al . Minimizing postcolonoscopy abdominal pain by using CO₂ insufflation: a prospective, randomized, double blind, controlled trial evaluating a new commercially available CO₂ delivery system.  Gastrointest Endosc. 2002;  56 190-194
  CrossrefPubMedSearch in Google Scholar
• 10 Bretthauer M, Seip B, Aasen S. et al . Carbon dioxide insufflation for more comfortable ERCP: a randomized controlled double-blind trial.  Endoscopy. 2007;  39 58-64
  Thieme ConnectPubMedSearch in Google Scholar
• 11 May A, Nachbar L, Schneider M. et al . Push-and-pull enteroscopy using the double-balloon technique: method of assessing depth of insertion and training of the endoscopy technique using the Erlangen endo-trainer.  Endoscopy. 2005;  37 66-70
  Thieme ConnectPubMedSearch in Google Scholar
• 12 Carter H G. Explosion in the colon during electrodesiccation of polyps.  Am J Surg. 1952;  84 514-516
  CrossrefPubMedSearch in Google Scholar
• 13 Josemanders D FGM, Spillenaar Bilgen E J, van Sorge A A. et al. Colonic explosion during endoscopic polypectomy: avoidable complication or bad luck?.  Endoscopy. 2006;  38 943-944
  PubMedSearch in Google Scholar
• 14 Church J, Delaney C. Randomized, controlled trial of carbon dioxide insufflation during colonoscopy.  Dis Colon Rectum.. 2003;  46 322-326
  CrossrefPubMedSearch in Google Scholar
• 15 Aabakken L, Bretthauer M, Line P D. Double balloon enteroscopy for endoscopic retrograde cholangiography in patients with Roux-Y anastomoses.  Endoscopy. 2007;  39 1068-1071
  Thieme ConnectPubMedSearch in Google Scholar

M. Bretthauer, MD

Department of Gastroenterology

Rikshospitalet-Radiumhospitalet Medical Centre

Oslo

Norway

Email: michael.bretthauer@rikshospitalet.no