ORIGINAL ARTICLE ANZJSurg.com
Randomized controlled trial of probiotics after colonoscopy Basil D’Souza,* Timothy Slack,* Shing W. Wong,*† Francis Lam,* Mark Muhlmann,* Jakob Koestenbauer,† Jonathan Dark‡ and Graham Newstead* *Department of Surgery, Prince of Wales Private Hospital, Sydney, New South Wales, Australia †Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia ‡Faculty of Business and Economics, The University of Melbourne, Melbourne, Victoria, Australia
Key words bowel preparation, colonoscopy, probiotic. Correspondence Mr Basil D’Souza, Department of Surgery, Prince of Wales Private Hospital, Suite 17, Level 7, Barker Street, Randwick, NSW 2031, Australia. Email: [email protected] B. D’Souza MBBS, BSc, FRACS; T. Slack MBBS, FRACS; S. W. Wong FRACS, MS; F. Lam MBBS, PhD, FRACS; M. Muhlmann MBBS, FRACS; J. Koestenbauer; J. Dark PhD Econ; G. Newstead FRACS, FRCS. This paper was presented at: (i) Annual Scientific Meeting of the Royal Australasian College of Surgeons in Singapore 2014, in the Killingback Prize Section; and (ii) Tripartite Conference in Birmingham UK 2014, in the British Journal of Surgery (BJS) Prize Section and is a winner of the BJS Prize for the conference. Accepted for publication 22 May 2015. doi: 10.1111/ans.13225
Abstract Background: Up to 20% of patients have ongoing abdominal symptoms at day 2 and beyond following colonoscopy. It was hypothesized that some of these symptoms are related to alterations in gut microbiota secondary to bowel preparation and would improve with probiotics compared with placebo. Methods: Patients were given either a probiotic or placebo capsule in the days following colonoscopy. Colonoscopy was performed with air insufflation. The probiotic capsule contained the strains Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07. Patients recorded their symptoms at 1 h, 1, 2, 4, 7 and 14 days post colonoscopy and returned results once their symptoms had resolved. The primary outcomes used were the length of days to resolution of bloating, abdominal pain and altered bowel function post colonoscopy. Results: A total of 320 patients were randomized. After loss to follow-up and withdrawal, 133 patients were analysed in the probiotic group and 126 in the placebo group. Patients having probiotic had a lower number of pain days following colonoscopy, 1.99 versus 2.78 days (P < 0.033). There was no significant difference in bloating or return to normal bowel habit days (P = 0.139 and 0.265 respectively). Subgroup analysis revealed that patients with pre-existing abdominal pain benefited from probiotics in number of pain days, 2.16 versus 4.08 (P = 0.0498). Conclusion: Our study has shown a significant reduction in the duration of pain days post colonoscopy in patients taking probiotic compared with placebo. No significant effect was seen in terms of return to normal bowel function or bloating post colonoscopy.
Introduction Colonoscopy is one of the most common medical procedures performed. An estimated 14 million colonoscopies are performed in the United States per year.1 Despite this fact, there is little data in the literature regarding abdominal symptoms in the days following colonoscopy. Ko et al.2 showed that up to 20% of patients lose 2 or more days of normal activity from minor symptoms after colonoscopy. Gut microbiota has been shown to be significantly altered with mechanical bowel preparation.3 Alterations in bowel microbiota have been implicated in contributing to symptoms in patients with a variety of pathologies4 and may play a role in the symptoms seen post colonoscopy. Probiotics offer a potential therapeutic option to altered gut microbiota. More recently, there has been an increasing evidence for the therapeutic benefits of a range of probiotics in a variety of © 2015 Royal Australasian College of Surgeons
clinical scenarios including irritable bowel syndrome (IBS),5 antibiotic-associated diarrhoea,6 infectious diarrhoea7 and even pouchitis.8,9 This study investigated the three major end points of length of time of bloating, abdominal pain and altered bowel function in all patients taking probiotic or placebo post colonoscopy following mechanical bowel preparation. Secondary outcome measures were to look at the effect of probiotics on the severity of pain post procedure and subgroup analysis to see if any features were associated with improved outcomes with probiotics.
Methods This study was approved by Belberry Human Research Ethics Committee and by the Medical Advisory Board of the Prince of Wales Private Hospital. Informed consent was obtained from all ANZ J Surg •• (2015) ••–••
2
patients prior to colonoscopy. Consecutive patients presenting for colonoscopy or gastroscopy and colonoscopy were enrolled in the study. All patients had undergone full bowel preparation with three sachets of sodium picosulfate the day prior. Eligible patients underwent colonoscopy and those that were not excluded were then randomized via envelope method to receive probiotic or placebo. Both investigators and participants were blinded to the contents of the bottles which were identical in appearance. Exclusion criteria for study participation prior to colonoscopy were age less than 18, participants already taking probiotics, non-English speaking patients, an immune-compromised patient or patients with an American Society of Anesthesiologists (ASA) score of 3 and above. Patients were excluded after colonoscopy if they had any additional procedure carried out at the time of colonoscopy such as banding of haemorrhoids or sphincterotomy for anal fissure, the finding of any significant pathology at the colonoscopy, for example cancer, obstruction or colitis, any complication from the actual colonoscopy such as perforation, aspiration, heart issues or bleeding. All the procedures were performed using air insufflation. Five experienced endoscopists accredited for gastroscopy and colonoscopy by the Conjoint Committee for Recognition of Training in Gastrointestinal Endoscopy performed the procedures.
Study design At the conclusion of their colonoscopy, participants were given an envelope containing the trial protocol and questionnaire and an unlabelled bottle of 14 capsules containing either placebo or probiotic. They were instructed to take one capsule on the night of the colonoscopy and then one every subsequent night until they considered their bowel function, bloating and abdominal discomfort to have returned to normal or for a total of 14 days. Participants were then asked to return the questionnaire by mail in a reply-paid envelope. All participants were called after 3 weeks to aid in data collection and assess compliance. Participants were considered lost to follow-up if they were not contactable 4 weeks after their procedure. The questionnaire assessed post-procedural pain using a 10-point visual analogue score. Demographics, periprocedural information and pre-existing symptoms were collected in a prospective database.
D’Souza et al.
Statistics were performed by an independent statistician who was blinded to the randomization. Tests for the differences in end points and controls between probiotic and placebo used a t-test with unequal variance for the continuous variables. Fisher’s exact test was used to test for significant differences in the percentages between groups. Multivariate regression analysis was performed using Eviews version 6.0 (IHS Global Inc., Irvine, CA, USA). It is important to note that patients with increased bloating, pain or abnormal bowel function after 14 days were recorded as >14 days. For the probiotic group, there was one patient with pain and abnormal bowel function greater than 14 days. For the placebo group, there were five patients (two with bloating, one with pain and two with abnormal bowel function). Descriptive statistics treated these observations as being equal to 14 days. Multiple regression analysis used a Tobit procedure to account for the censoring of the end points.
Results A total of 353 consecutive participants were assessed for eligibility. Thirty of these underwent colonoscopy but were excluded from the trial (10 significant pathology, eight with ASA 3 and above, 10 additional procedures performed, two peri-procedural complications – aspiration and arrhythmia). Three patients refused to participate. Randomization was then performed on the remaining 320 participants. The probiotic group had 159 participants and 161 were in the placebo group. Caecal intubation was achieved for all the patients included in the study. There were 20 lost to follow-up and six withdrawals from the probiotic group and 24 lost to follow-up and 11 withdrawals from the placebo group. Therefore, a total of 259 participants were analysed (133 in the probiotic group and 126 in the placebo group). Sixty-three patients underwent both gastroscopy and colonoscopy (32 probiotic group and 31 placebo group; Fig. 1).
The probiotic The probiotic capsule contained Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 in doses of 1.25 × 1010 each, yielding a total content of all strains of 2.5 × 1010 colony forming units (CFUs) per capsule (Inner Health, Health World Limited, Queensland, Australia). The placebo capsules contained the excipient microcrystalline cellulose which was also present in the probiotic capsule.
Statistical analysis This trial was designed to have a 90% power to detect a 15% increase in the number of participants having complete resolution of bowel symptoms and bowel function at day 3 at a 5% level of significance. A recruitment target of 260 participants (130 in each arm) was determined by statistical calculation. A recruitment of 310 participants was targeted to allow for a 20% loss to follow-up and drop out. Patients were analysed on an intention-to-treat basis.
Fig. 1. Consort diagram of patient recruitment through to analysis.
© 2015 Royal Australasian College of Surgeons
Probiotics after colonoscopy
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Table 1 Descriptive statistics Variable
Statistic
Controls Age
Mean Standard Mean Standard Mean Standard Mean Standard Mean Standard Mean Standard Mean Standard (%) (%) (%) (%) (%) (%) (%)
Body mass index Midazolam (mg) Fentanyl (mcg) Propofol (mg) Procedure time (min) Time since last dose of bowel preparation (h) Female Previous surgery Buscopan given Procedure (gastroscopy and colonoscopy) Biopsy/polyp taken Prior bloating Prior abdominal pain
Probiotic (n = 133)
Placebo (n = 126)
P value
61.621 13.746 26.854 4.771 2.187 0.824 50.644 22.356 156.136 91.365 19.242 8.191 10.020 1.357 44.7 30.3 6.1 24.2 55.3 16.7 19.7
60.127 12.811 26.916 4.544 2.317 0.838 46.270 22.873 155.040 75.492 19.575 7.663 9.883 1.299 54.0 21.4 4.8 24.6 52.4 19.8 19.8
0.367
deviation deviation deviation deviation deviation deviation deviation
0.915 0.210 0.122 0.916 0.736 0.410 0.135 0.119 0.786 0.946 0.638 0.523 1.000
Table 2 Primary endpoint data (in days post procedure) Variable
Statistic
Probiotic (n = 133)
Placebo (n = 126)
P value
Bloating
Mean Standard deviation Mean Standard deviation Mean Standard deviation
2.000 1.996 1.993 2.398 3.054 2.198
2.517 3.054 2.779 3.361 3.422 3.156
0.111
Pain Return of normal bowel habit
The two groups were evenly matched with regard to demographics and clinical characteristics (Table 1). There were no significant differences in operative procedures, procedural time, biopsies/ polypectomy performed, previous major surgery, time from bowel preparation and intraoperative medication. There was no significant differences between the proportion of cases performed in either the probiotic or placebo group by each endoscopist (P = 0.741). One hundred and fifty-seven patients (81 placebo and 76 probiotic group) reported some abdominal discomfort and 119 patients (59 placebo and 61 probiotic group) reported bloating above precolonoscopy levels in the first 1 h following colonoscopy. Patients having the probiotic had a lower average number of pain days from 2.78 to 1.99 days post colonoscopy (P = 0.032; Table 2). This was confirmed on multivariate regression analysis (P = 0.044) and on Kaplan–Meier survival curve analysis (P = 0.027; Fig. 2). There was no significant benefit of probiotics on length of time of bloating symptoms at 2 versus 2.52 days (P = 0.11). There was also no significant difference in the time to return of normal bowel function between the two groups at 3.05 versus 3.42 days (P = 0.288). Patients having probiotic capsules did not report a significant difference in the severity of pain using the visual analogue scores at 1 h, 1, 2, 4, 7 and 14 days post colonoscopy compared with placebo. © 2015 Royal Australasian College of Surgeons
0.032 0.280
Fig. 2. Kaplan–Meier survival curve for differences in pain resolution between probiotic and placebo (P = 0.028).
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Various subgroup analysis were then performed, the results of which are mentioned here. The tables (Tables S1–S5) can be found in the supporting section. It was found that patients with pre-existing abdominal pain benefit from probiotics. Table S3 reveals that the average number of pain days is lower for the probiotic than the placebo group (2.160 versus 4.084 days, P = 0.072). Multivariate regression analysis indicates that this was significant at the 5% level (P = 0.0498).
Discussion This is the first study to investigate the effectiveness of probiotics in relieving post-colonoscopy symptoms. It is a pilot study intended on reflecting real-world practice in that all-comers (without significant pathology, complication or additional procedure) to a colonoscopy day procedure unit were eligible for inclusion. Our study showed a significant reduction in the length of time taken for resolution of abdominal pain following colonoscopy in patients taking the probiotic tablet compared with placebo. There was no significant reduction in time to resolution of bloating or return of normal bowel function. There is a relative paucity of data looking at minor complications post colonoscopy. This is usually because of the perceived lack of clinical relevance of these symptoms given that they are usually mild and self-limiting. Despite this belief, previous studies have indicated the rate of minor complications to range from 15 to 30% of patients undergoing colonoscopy.10,11 Bini et al. showed that there is a significant association between negative outcomes and decreased satisfaction in patients undergoing colonoscopy. Furthermore, patients who reported negative outcomes were significantly less likely to agree to have an endoscopic procedure in the future if it was deemed necessary. This in turn may result in non-compliance, poor follow-up and wasted resources.10 Having mechanical bowel preparation has been shown to alter gut microbiota.3 In this regard, similarities are drawn to IBS. In fact, early culture-based studies of faecal matter in patients with IBS also showed decreased lactobacilli and bifidobacterium.12 Multiple randomized controlled trials have shown a clinical benefit of probiotic intake in patients with IBS.7 The proposed mechanism of action of probiotics include inhibition of pathogen binding,13 altered immune function,14 improved colonic transit and motility15 and alterations in visceral hypersensitivity.16 A study by Rousseaux et al. also demonstrated that L. acidophilus increased the expression of l-opiod and cannabinoid receptors in normal animals.16 The majority of studies used L. acidophilus or bifidobacterium although with varying strains. It is difficult, however, to make generic comments about these probiotics because of the heterogeneity of the studies, the quantity and variation in strains used and measured outcomes. We had selected the probiotic capsule used in our trial because it is readily available in Australia, not overly expensive and the genus and species used have been extensively investigated in the past. The clinical benefits of probiotics are known to be strain-dependent. The fact that we have used a combination probiotic, however, makes it impossible to know whether the results are due to one of the strains used or a symbiotic effect.
D’Souza et al.
Both groups in our study were very evenly matched with factors such as body mass index, sex, length of time of procedure and number of polypectomies/biopsies, etc., which have been shown in previous studies to be significant indicators of post-colonoscopy pain.17 We also asked patients about pre-existing abdominal pain and bloating with the view that this may affect their post colonoscopy symptoms. Both groups were evenly matched for patients with either or both of these symptoms. Subgroup analysis of these groups of patients revealed that patients with pre-existing abdominal pain were more likely to benefit from taking the probiotic than those with bloating or bloating and pain combined. However, the numbers in these groups were small and the results need to be interpreted in this context. A total of 63 patients also underwent gastroscopy in conjunction with colonoscopy. Previous studies have reported an increase in post-procedural pain in this group of patients, possibly related to increased procedure time and increased gas insufflation.10,11 However, in our study, a similar proportion patients in this subgroup reported pain and bloating compared with the colonoscopy alone group (P = 0.374 and 0.673) at 1 h. This subgroup of patients also did not show a significant benefit from probiotics in terms of resolution of pain, bloating or return normal bowel function. This may be due to the smaller number of patients analysed here. Carbon dioxide (CO2) insufflation for colonoscopy has been shown in a recent meta-analysis to result in reduced abdominal pain post colonoscopy compared with air insufflation at 1, 6 and 24 h. The maximal effect was at 1 h where the CO2 group was associated with a relative risk of post-procedural pain of 0.26.18 The mechanism of reduced pain is thought to be a combination of rapid absorption from the intestines (160 times more rapidly than nitrogen and 13 times more rapidly than oxygen the two main components of air) and improved visceral blood flow through vasodilatation.19 In our study, we did not have access to CO2 insufflation and hence used air insufflation. This is in keeping with the majority of endoscopy centres in Australia at present although this is gradually changing over time. With CO2, the maximal benefit for pain/bloating compared with air is seen early post procedure but there is still a subgroup of patients (5–32%) that have ongoing symptoms of pain at 24 h post colonoscopy.20 It remains to be seen whether these patients would benefit from the addition of probiotics peri-procedurally.
Conclusion In conclusion, our study has shown that a single capsule of probiotic containing 2.5 × 1010 CFUs of L. acidophilus NCFM and B. lactis Bi-07 taken daily starting on the night after colonoscopy resulted in an earlier resolution of abdominal pain from 2.78 to 1.99 days. We conclude that this reduction in time of post colonoscopy pain is significant in that most patients go back to work the day after their colonoscopy, this is despite the pain being only mild, based on visual analogue scores. The compliance with treatment was high in those who were not lost to follow-up with 98% in each group taking the probiotic according to instructions (three non-compliant in each group), suggesting that this is a simple intervention that would be readily taken up by patients. © 2015 Royal Australasian College of Surgeons
Probiotics after colonoscopy
Newer studies using CO2 insufflation should also aim to measure actual changes in pre- and post probiotic faecal microbiota and correlate that with patient’s symptoms in order to provide some objective measurements to symptom relief. More molecular research is required into the mechanism of action of probiotics leading to more refined hypothesis-driven and patient-focused clinical trials in the future.
Acknowledgement The lead author would like to thank Dr Peter De Cruz, Gastroenterologist, Austin Hospital Melbourne, for his insight and guidance.
References 1. Seeff LC, Richards TB, Shapiro JA et al. How many endoscopies are performed for colorectal cancer screening? Results from CDCs survey of endoscopic capacity. Gastroenterology 2004; 127: 1670–7. 2. Ko C, Riffle S, Shapiro J et al. Incidence of minor complications and time lost from normal activities after screening or surveillance colonoscopy. Gastrointest. Endosc. 2007; 65: 648–56. 3. Watanabe M, Murakami M, Nakao K, Asahara T, Nomoto K, Tsunoda A. Randomized clinical trial of the influence of mechanical bowel preparation on faecal microflora in patients undergoing colonic cancer resection. BJS 2010; 97: 1791–7. 4. Simren M, Barbara G, Flint H et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 2013; 62: 159–76. 5. Dai C, Zheng CH, Jiang M, Ma X, Jiang L. Probiotics and irritable bowel syndrome. World J. Gastroenterol. 2013; 19: 5973–80. 6. Szajewska H, Mrukowicz JZ. Probiotics in the prevention of antibioticassociated diarrhea in children: a meta-analysis of randomized controlled trials. J. Pediatr. 2006; 149: 367–72. 7. Allen SJ, Okoko B, Martinez E, Gregorio G, Dans LF. Probiotics for treating infectious diarrhoea. Cochrane Database Syst. Rev. 2004; (2): CD003048. 8. Gionchetti P, Rizzello F, Helwig U et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blinded, placebo-controlled trial. Gastroenterology 2003; 124: 1202–9. 9. Gionchetti P, Rizzello F, Venturi A et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000; 119: 305–9. 10. Bini E, Firoozi B, Choung R, Ali E, Osman M, Weinshel E. Systematic evaluation of complications related to endoscopy in a training setting: a prospective 30-day outcomes study. Gastrointest. Endosc. 2003; 57: 8–16.
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11. Zubarik R, Fleischer DE, Mastropietro C et al. Prospective analysis of complications 30 days after outpatient colonoscopy. Gastrointest. Endosc. 1999; 50: 322–8. 12. Balsari A, Ceccarelli A, Dubiri F, Fesce E, Poli G. The fecal microbial population in the irritable bowel syndrome. Microbiologica 1982; 5: 185–94. 13. Ahrne S, Nobaek S, Jeppsson B, Alderberth I, Wold A, Molin G. The normal Lactobacillus flora of healthy human rectal and oral mucosa. J. Appl. Microbiol. 1998; 85: 88–94. 14. O’Mahony L, McCarthy J, Kelly P et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005; 128: 541–51. 15. Lee H, Kim Y, Kim J et al. A feasibility study of probiotics pretreatment as a bowel preparation for colonoscopy in constipated patients. Dig. Dis. Sci. 2010; 55: 2344–51. 16. Rousseaux C, Thuru X, Gelot A et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 2007; 13: 35–7. 17. Lee Y, Wang H, Chiu H et al. Factors determining post-colonoscopy pain: prospective study of screening colonoscopy in 1000 subjects. J. Gastroenterol. Hepatol. 2006; 21: 1575–80. 18. Wu J, Hu B. The role of carbon dioxide insufflation in colonoscopy: a systematic review and meta-analysis. Endoscopy 2012; 44: 128–36. 19. Maple JT, Banerjee S, Barth BA et al. Methods of luminal distension for colonoscopy. Gastrointest. Endosc. 2013; 77: 519–25. 20. Dellon ES, Hawk JS, Grimm IS, Shaheen NJ. The use of carbon dioxide insufflation during GI endoscopy: a systematic review. Gastrointest. Endosc. 2009; 69: 843–9.
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Comparison of colonoscopy to colonoscopy and gastroscopy. Table S2 Comparison of probiotic and placebo for colonoscopy and gastroscopy subgroup. Table S3 Comparison of probiotic and placebo for pain subgroup. Table S4 Comparison of probiotic and placebo for bloating subgroup. Table S5 Comparison of probiotic and placebo for bloating and pain subgroup. Table S6 Comparison of pain by operation type. Table S7 Comparison of bloating by operation type.
Randomized controlled trial of probiotics after colonoscopy Basil D’Souza,* Timothy Slack,* Shing W. Wong,*† Francis Lam,* Mark Muhlmann,* Jakob Koestenbauer,† Jonathan Dark‡ and Graham Newstead* *Department of Surgery, Prince of Wales Private Hospital, Sydney, New South Wales, Australia †Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia ‡Faculty of Business and Economics, The University of Melbourne, Melbourne, Victoria, Australia
Key words bowel preparation, colonoscopy, probiotic. Correspondence Mr Basil D’Souza, Department of Surgery, Prince of Wales Private Hospital, Suite 17, Level 7, Barker Street, Randwick, NSW 2031, Australia. Email: [email protected] B. D’Souza MBBS, BSc, FRACS; T. Slack MBBS, FRACS; S. W. Wong FRACS, MS; F. Lam MBBS, PhD, FRACS; M. Muhlmann MBBS, FRACS; J. Koestenbauer; J. Dark PhD Econ; G. Newstead FRACS, FRCS. This paper was presented at: (i) Annual Scientific Meeting of the Royal Australasian College of Surgeons in Singapore 2014, in the Killingback Prize Section; and (ii) Tripartite Conference in Birmingham UK 2014, in the British Journal of Surgery (BJS) Prize Section and is a winner of the BJS Prize for the conference. Accepted for publication 22 May 2015. doi: 10.1111/ans.13225
Abstract Background: Up to 20% of patients have ongoing abdominal symptoms at day 2 and beyond following colonoscopy. It was hypothesized that some of these symptoms are related to alterations in gut microbiota secondary to bowel preparation and would improve with probiotics compared with placebo. Methods: Patients were given either a probiotic or placebo capsule in the days following colonoscopy. Colonoscopy was performed with air insufflation. The probiotic capsule contained the strains Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07. Patients recorded their symptoms at 1 h, 1, 2, 4, 7 and 14 days post colonoscopy and returned results once their symptoms had resolved. The primary outcomes used were the length of days to resolution of bloating, abdominal pain and altered bowel function post colonoscopy. Results: A total of 320 patients were randomized. After loss to follow-up and withdrawal, 133 patients were analysed in the probiotic group and 126 in the placebo group. Patients having probiotic had a lower number of pain days following colonoscopy, 1.99 versus 2.78 days (P < 0.033). There was no significant difference in bloating or return to normal bowel habit days (P = 0.139 and 0.265 respectively). Subgroup analysis revealed that patients with pre-existing abdominal pain benefited from probiotics in number of pain days, 2.16 versus 4.08 (P = 0.0498). Conclusion: Our study has shown a significant reduction in the duration of pain days post colonoscopy in patients taking probiotic compared with placebo. No significant effect was seen in terms of return to normal bowel function or bloating post colonoscopy.
Introduction Colonoscopy is one of the most common medical procedures performed. An estimated 14 million colonoscopies are performed in the United States per year.1 Despite this fact, there is little data in the literature regarding abdominal symptoms in the days following colonoscopy. Ko et al.2 showed that up to 20% of patients lose 2 or more days of normal activity from minor symptoms after colonoscopy. Gut microbiota has been shown to be significantly altered with mechanical bowel preparation.3 Alterations in bowel microbiota have been implicated in contributing to symptoms in patients with a variety of pathologies4 and may play a role in the symptoms seen post colonoscopy. Probiotics offer a potential therapeutic option to altered gut microbiota. More recently, there has been an increasing evidence for the therapeutic benefits of a range of probiotics in a variety of © 2015 Royal Australasian College of Surgeons
clinical scenarios including irritable bowel syndrome (IBS),5 antibiotic-associated diarrhoea,6 infectious diarrhoea7 and even pouchitis.8,9 This study investigated the three major end points of length of time of bloating, abdominal pain and altered bowel function in all patients taking probiotic or placebo post colonoscopy following mechanical bowel preparation. Secondary outcome measures were to look at the effect of probiotics on the severity of pain post procedure and subgroup analysis to see if any features were associated with improved outcomes with probiotics.
Methods This study was approved by Belberry Human Research Ethics Committee and by the Medical Advisory Board of the Prince of Wales Private Hospital. Informed consent was obtained from all ANZ J Surg •• (2015) ••–••
2
patients prior to colonoscopy. Consecutive patients presenting for colonoscopy or gastroscopy and colonoscopy were enrolled in the study. All patients had undergone full bowel preparation with three sachets of sodium picosulfate the day prior. Eligible patients underwent colonoscopy and those that were not excluded were then randomized via envelope method to receive probiotic or placebo. Both investigators and participants were blinded to the contents of the bottles which were identical in appearance. Exclusion criteria for study participation prior to colonoscopy were age less than 18, participants already taking probiotics, non-English speaking patients, an immune-compromised patient or patients with an American Society of Anesthesiologists (ASA) score of 3 and above. Patients were excluded after colonoscopy if they had any additional procedure carried out at the time of colonoscopy such as banding of haemorrhoids or sphincterotomy for anal fissure, the finding of any significant pathology at the colonoscopy, for example cancer, obstruction or colitis, any complication from the actual colonoscopy such as perforation, aspiration, heart issues or bleeding. All the procedures were performed using air insufflation. Five experienced endoscopists accredited for gastroscopy and colonoscopy by the Conjoint Committee for Recognition of Training in Gastrointestinal Endoscopy performed the procedures.
Study design At the conclusion of their colonoscopy, participants were given an envelope containing the trial protocol and questionnaire and an unlabelled bottle of 14 capsules containing either placebo or probiotic. They were instructed to take one capsule on the night of the colonoscopy and then one every subsequent night until they considered their bowel function, bloating and abdominal discomfort to have returned to normal or for a total of 14 days. Participants were then asked to return the questionnaire by mail in a reply-paid envelope. All participants were called after 3 weeks to aid in data collection and assess compliance. Participants were considered lost to follow-up if they were not contactable 4 weeks after their procedure. The questionnaire assessed post-procedural pain using a 10-point visual analogue score. Demographics, periprocedural information and pre-existing symptoms were collected in a prospective database.
D’Souza et al.
Statistics were performed by an independent statistician who was blinded to the randomization. Tests for the differences in end points and controls between probiotic and placebo used a t-test with unequal variance for the continuous variables. Fisher’s exact test was used to test for significant differences in the percentages between groups. Multivariate regression analysis was performed using Eviews version 6.0 (IHS Global Inc., Irvine, CA, USA). It is important to note that patients with increased bloating, pain or abnormal bowel function after 14 days were recorded as >14 days. For the probiotic group, there was one patient with pain and abnormal bowel function greater than 14 days. For the placebo group, there were five patients (two with bloating, one with pain and two with abnormal bowel function). Descriptive statistics treated these observations as being equal to 14 days. Multiple regression analysis used a Tobit procedure to account for the censoring of the end points.
Results A total of 353 consecutive participants were assessed for eligibility. Thirty of these underwent colonoscopy but were excluded from the trial (10 significant pathology, eight with ASA 3 and above, 10 additional procedures performed, two peri-procedural complications – aspiration and arrhythmia). Three patients refused to participate. Randomization was then performed on the remaining 320 participants. The probiotic group had 159 participants and 161 were in the placebo group. Caecal intubation was achieved for all the patients included in the study. There were 20 lost to follow-up and six withdrawals from the probiotic group and 24 lost to follow-up and 11 withdrawals from the placebo group. Therefore, a total of 259 participants were analysed (133 in the probiotic group and 126 in the placebo group). Sixty-three patients underwent both gastroscopy and colonoscopy (32 probiotic group and 31 placebo group; Fig. 1).
The probiotic The probiotic capsule contained Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 in doses of 1.25 × 1010 each, yielding a total content of all strains of 2.5 × 1010 colony forming units (CFUs) per capsule (Inner Health, Health World Limited, Queensland, Australia). The placebo capsules contained the excipient microcrystalline cellulose which was also present in the probiotic capsule.
Statistical analysis This trial was designed to have a 90% power to detect a 15% increase in the number of participants having complete resolution of bowel symptoms and bowel function at day 3 at a 5% level of significance. A recruitment target of 260 participants (130 in each arm) was determined by statistical calculation. A recruitment of 310 participants was targeted to allow for a 20% loss to follow-up and drop out. Patients were analysed on an intention-to-treat basis.
Fig. 1. Consort diagram of patient recruitment through to analysis.
© 2015 Royal Australasian College of Surgeons
Probiotics after colonoscopy
3
Table 1 Descriptive statistics Variable
Statistic
Controls Age
Mean Standard Mean Standard Mean Standard Mean Standard Mean Standard Mean Standard Mean Standard (%) (%) (%) (%) (%) (%) (%)
Body mass index Midazolam (mg) Fentanyl (mcg) Propofol (mg) Procedure time (min) Time since last dose of bowel preparation (h) Female Previous surgery Buscopan given Procedure (gastroscopy and colonoscopy) Biopsy/polyp taken Prior bloating Prior abdominal pain
Probiotic (n = 133)
Placebo (n = 126)
P value
61.621 13.746 26.854 4.771 2.187 0.824 50.644 22.356 156.136 91.365 19.242 8.191 10.020 1.357 44.7 30.3 6.1 24.2 55.3 16.7 19.7
60.127 12.811 26.916 4.544 2.317 0.838 46.270 22.873 155.040 75.492 19.575 7.663 9.883 1.299 54.0 21.4 4.8 24.6 52.4 19.8 19.8
0.367
deviation deviation deviation deviation deviation deviation deviation
0.915 0.210 0.122 0.916 0.736 0.410 0.135 0.119 0.786 0.946 0.638 0.523 1.000
Table 2 Primary endpoint data (in days post procedure) Variable
Statistic
Probiotic (n = 133)
Placebo (n = 126)
P value
Bloating
Mean Standard deviation Mean Standard deviation Mean Standard deviation
2.000 1.996 1.993 2.398 3.054 2.198
2.517 3.054 2.779 3.361 3.422 3.156
0.111
Pain Return of normal bowel habit
The two groups were evenly matched with regard to demographics and clinical characteristics (Table 1). There were no significant differences in operative procedures, procedural time, biopsies/ polypectomy performed, previous major surgery, time from bowel preparation and intraoperative medication. There was no significant differences between the proportion of cases performed in either the probiotic or placebo group by each endoscopist (P = 0.741). One hundred and fifty-seven patients (81 placebo and 76 probiotic group) reported some abdominal discomfort and 119 patients (59 placebo and 61 probiotic group) reported bloating above precolonoscopy levels in the first 1 h following colonoscopy. Patients having the probiotic had a lower average number of pain days from 2.78 to 1.99 days post colonoscopy (P = 0.032; Table 2). This was confirmed on multivariate regression analysis (P = 0.044) and on Kaplan–Meier survival curve analysis (P = 0.027; Fig. 2). There was no significant benefit of probiotics on length of time of bloating symptoms at 2 versus 2.52 days (P = 0.11). There was also no significant difference in the time to return of normal bowel function between the two groups at 3.05 versus 3.42 days (P = 0.288). Patients having probiotic capsules did not report a significant difference in the severity of pain using the visual analogue scores at 1 h, 1, 2, 4, 7 and 14 days post colonoscopy compared with placebo. © 2015 Royal Australasian College of Surgeons
0.032 0.280
Fig. 2. Kaplan–Meier survival curve for differences in pain resolution between probiotic and placebo (P = 0.028).
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Various subgroup analysis were then performed, the results of which are mentioned here. The tables (Tables S1–S5) can be found in the supporting section. It was found that patients with pre-existing abdominal pain benefit from probiotics. Table S3 reveals that the average number of pain days is lower for the probiotic than the placebo group (2.160 versus 4.084 days, P = 0.072). Multivariate regression analysis indicates that this was significant at the 5% level (P = 0.0498).
Discussion This is the first study to investigate the effectiveness of probiotics in relieving post-colonoscopy symptoms. It is a pilot study intended on reflecting real-world practice in that all-comers (without significant pathology, complication or additional procedure) to a colonoscopy day procedure unit were eligible for inclusion. Our study showed a significant reduction in the length of time taken for resolution of abdominal pain following colonoscopy in patients taking the probiotic tablet compared with placebo. There was no significant reduction in time to resolution of bloating or return of normal bowel function. There is a relative paucity of data looking at minor complications post colonoscopy. This is usually because of the perceived lack of clinical relevance of these symptoms given that they are usually mild and self-limiting. Despite this belief, previous studies have indicated the rate of minor complications to range from 15 to 30% of patients undergoing colonoscopy.10,11 Bini et al. showed that there is a significant association between negative outcomes and decreased satisfaction in patients undergoing colonoscopy. Furthermore, patients who reported negative outcomes were significantly less likely to agree to have an endoscopic procedure in the future if it was deemed necessary. This in turn may result in non-compliance, poor follow-up and wasted resources.10 Having mechanical bowel preparation has been shown to alter gut microbiota.3 In this regard, similarities are drawn to IBS. In fact, early culture-based studies of faecal matter in patients with IBS also showed decreased lactobacilli and bifidobacterium.12 Multiple randomized controlled trials have shown a clinical benefit of probiotic intake in patients with IBS.7 The proposed mechanism of action of probiotics include inhibition of pathogen binding,13 altered immune function,14 improved colonic transit and motility15 and alterations in visceral hypersensitivity.16 A study by Rousseaux et al. also demonstrated that L. acidophilus increased the expression of l-opiod and cannabinoid receptors in normal animals.16 The majority of studies used L. acidophilus or bifidobacterium although with varying strains. It is difficult, however, to make generic comments about these probiotics because of the heterogeneity of the studies, the quantity and variation in strains used and measured outcomes. We had selected the probiotic capsule used in our trial because it is readily available in Australia, not overly expensive and the genus and species used have been extensively investigated in the past. The clinical benefits of probiotics are known to be strain-dependent. The fact that we have used a combination probiotic, however, makes it impossible to know whether the results are due to one of the strains used or a symbiotic effect.
D’Souza et al.
Both groups in our study were very evenly matched with factors such as body mass index, sex, length of time of procedure and number of polypectomies/biopsies, etc., which have been shown in previous studies to be significant indicators of post-colonoscopy pain.17 We also asked patients about pre-existing abdominal pain and bloating with the view that this may affect their post colonoscopy symptoms. Both groups were evenly matched for patients with either or both of these symptoms. Subgroup analysis of these groups of patients revealed that patients with pre-existing abdominal pain were more likely to benefit from taking the probiotic than those with bloating or bloating and pain combined. However, the numbers in these groups were small and the results need to be interpreted in this context. A total of 63 patients also underwent gastroscopy in conjunction with colonoscopy. Previous studies have reported an increase in post-procedural pain in this group of patients, possibly related to increased procedure time and increased gas insufflation.10,11 However, in our study, a similar proportion patients in this subgroup reported pain and bloating compared with the colonoscopy alone group (P = 0.374 and 0.673) at 1 h. This subgroup of patients also did not show a significant benefit from probiotics in terms of resolution of pain, bloating or return normal bowel function. This may be due to the smaller number of patients analysed here. Carbon dioxide (CO2) insufflation for colonoscopy has been shown in a recent meta-analysis to result in reduced abdominal pain post colonoscopy compared with air insufflation at 1, 6 and 24 h. The maximal effect was at 1 h where the CO2 group was associated with a relative risk of post-procedural pain of 0.26.18 The mechanism of reduced pain is thought to be a combination of rapid absorption from the intestines (160 times more rapidly than nitrogen and 13 times more rapidly than oxygen the two main components of air) and improved visceral blood flow through vasodilatation.19 In our study, we did not have access to CO2 insufflation and hence used air insufflation. This is in keeping with the majority of endoscopy centres in Australia at present although this is gradually changing over time. With CO2, the maximal benefit for pain/bloating compared with air is seen early post procedure but there is still a subgroup of patients (5–32%) that have ongoing symptoms of pain at 24 h post colonoscopy.20 It remains to be seen whether these patients would benefit from the addition of probiotics peri-procedurally.
Conclusion In conclusion, our study has shown that a single capsule of probiotic containing 2.5 × 1010 CFUs of L. acidophilus NCFM and B. lactis Bi-07 taken daily starting on the night after colonoscopy resulted in an earlier resolution of abdominal pain from 2.78 to 1.99 days. We conclude that this reduction in time of post colonoscopy pain is significant in that most patients go back to work the day after their colonoscopy, this is despite the pain being only mild, based on visual analogue scores. The compliance with treatment was high in those who were not lost to follow-up with 98% in each group taking the probiotic according to instructions (three non-compliant in each group), suggesting that this is a simple intervention that would be readily taken up by patients. © 2015 Royal Australasian College of Surgeons
Probiotics after colonoscopy
Newer studies using CO2 insufflation should also aim to measure actual changes in pre- and post probiotic faecal microbiota and correlate that with patient’s symptoms in order to provide some objective measurements to symptom relief. More molecular research is required into the mechanism of action of probiotics leading to more refined hypothesis-driven and patient-focused clinical trials in the future.
Acknowledgement The lead author would like to thank Dr Peter De Cruz, Gastroenterologist, Austin Hospital Melbourne, for his insight and guidance.
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Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Comparison of colonoscopy to colonoscopy and gastroscopy. Table S2 Comparison of probiotic and placebo for colonoscopy and gastroscopy subgroup. Table S3 Comparison of probiotic and placebo for pain subgroup. Table S4 Comparison of probiotic and placebo for bloating subgroup. Table S5 Comparison of probiotic and placebo for bloating and pain subgroup. Table S6 Comparison of pain by operation type. Table S7 Comparison of bloating by operation type.
