Oral mannitol for bowel preparation: a dose-finding phase II study.

BACKGROUND: Successful bowel preparation (BP) for colonoscopy depends on the instructions, diet, the laxative product, and patient adherence, which all affect colonoscopy quality. Nevertheless, there are no laxatives which combine effectiveness, safety, easy self-administration, good patient acceptance, and low cost. However, mannitol, a sugar alcohol, could be an attractive candidate for use in clinical practice if it is shown to demonstrate adequate efficacy and safety. AIMS: The present phase II dose-finding study compared three doses of mannitol (50, 100, and 150 g) to identify the best dose to be used in a subsequent phase III study. METHODS: The Boston Bowel Preparation Scale, caecal intubation rate, adherence, acceptability, and safety profile, including measurement of potentially dangerous colonic gas concentrations (CH4, H2, O2), were considered in all patients. A weighted algorithm was used to identify the best mannitol dose for use in the subsequent study. RESULTS: The per-protocol population included 60 patients in the 50 g group, 54 in the 100 g group, and 49 in the 150 g group. The 100 g dose was the best as it afforded optimal colon cleansing efficacy (94.4% of patients had adequate BP), adherence, acceptability, and safety, including negligible gas concentrations. CONCLUSIONS: The present study demonstrated that the colon cleansing efficacy and safety of mannitol were dose dependent. Conversely, gas concentrations were not dose dependent and negligible in all patients. Combined evaluation of efficacy, tolerability, and safety, using a weighted algorithm, determined that mannitol 100 g was the best dose for the phase III study.

Pharmacokinetics of oral mannitol for bowel preparation for colonoscopy.

This study aimed to define the pharmacokinetics (PKs) of oral mannitol used as an osmotic laxative for bowel preparation for colonoscopy. The PKs of oral mannitol was evaluated in a substudy as part of a phase II dose-finding, international, multicenter, randomized, parallel-group, endoscopist-blinded study. Patients were randomly assigned to take 50, 100, or 150 g mannitol. Venous blood samples were drawn at baseline (T0), 1 h (T1), 2 h (T2), 4 h (T4), and 8 h (T8) after completion of mannitol self-administration. The mean mannitol plasma concentrations (mg/ml) were dose-dependent with a consistent difference among doses. The mean maximum concentration (Cmax) ± SD was 0.63 ± 0.15, 1.02 ± 0.28, and 1.36 ± 0.39 mg/ml, in the three dosage groups, respectively. The mean area under the curve from zero to infinity (AUC0-∞) was 2.667 ± 0.668, 4.992 ± 1.706, and 7.403 ± 3.472 mg/ml*h in the 50, 100, and 150 g mannitol dose groups, respectively. Bioavailability was similar in the three dose groups and was just over 20% (0.243 ± 0.073, 0.209 ± 0.081, and 0.228 ± 0.093 in the 50, 100, and 150 g mannitol dose groups, respectively). The present study showed that the bioavailability of oral mannitol is just over 20% and is similar for the three tested doses (50, 100, and 150 g). The linear increase in Cmax, AUC0-t8, and AUC0-∞ must be considered when choosing the oral mannitol dose for bowel preparation to avoid its systemic osmotic effects.

Periendoscopic management of direct oral anticoagulants: a prospective cohort study.

OBJECTIVE: To assess the frequency of adverse events associated with periendoscopic management of direct oral anticoagulants (DOACs) in patients undergoing elective GI endoscopy and the efficacy and safety of the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) recommendations (NCT02734316). DESIGN: Consecutive patients on DOACs scheduled for elective GI endoscopy were prospectively included. The timing of DOAC interruption and resumption before and after the procedures were recorded, along with clinical and procedural data. Procedures were stratified into low-risk and high-risk for GI-related bleeding, and patients into low-risk and high-risk for thromboembolic events. Patients were followed-up for 30 days for major and clinically relevant non-major bleeding events (CRNMB), arterial and venous thromboembolism and death. RESULTS: Of 529 patients, 38% and 62% underwent high-risk and low-risk procedures, respectively. There were 45 (8.5%; 95% CI 6.3% to 11.2%) major or CRNMB events and 2 (0.4%; 95% CI 0% to 1.4%) thromboembolic events (transient ischaemic attacks). Overall, the incidence of bleeding events was 1.8% (95% CI 0.7% to 4%) and 19.3% (95% CI 14.1% to 25.4%) in low-risk and high-risk procedures, respectively. For high-risk procedures, the incidence of intraprocedural bleeding was similar in patients who interrupted anticoagulation according to BSG/ESGE guidelines or earlier (10.3%vs10.8%, p=0.99), with a trend for a lower risk as compared with those who stopped anticoagulation later (10.3%vs25%, p=0.07). The incidence of delayed bleeding appeared similar in patients who resumed anticoagulation according to BSG/ESGE guidelines or later (6.6%vs7.7%, p=0.76), but it tended to increase when DOAC was resumed earlier (14.4%vs6.6%, p=0.27). The risk of delayed major bleeding was significantly higher in patients receiving heparin bridging than in non-bridged ones (26.6%vs5.9%, p=0.017). CONCLUSION: High-risk procedures in patients on DOACs are associated with a substantial risk of bleeding, further increased by heparin bridging. Adoption of the BSG/ESGE guidelines in periendoscopic management of DOACs seems to result in a favourable benefit/risk ratio. TRIAL REGISTRATION NUMBER: NCT02734316; Pre-results.

Endoscopic electrocautery dilation of benign anastomotic colonic strictures: a single-center experience.

BACKGROUND: Benign anastomotic colonic stenosis sometimes occur after surgery and usually require surgical or endoscopic dilation. Endoscopic dilation of anastomotic colonic strictures by using balloon or bougie-type dilators has been demonstrated to be safe and effective in multiple uncontrolled series. However, few data are available on safety and efficacy of endoscopic electrocautery dilation. The aim of our study was to retrospectively investigate safety and efficacy of endoscopic electrocautery dilation of postsurgical benign anastomotic colonic strictures. METHODS: Sixty patients (37 women; median age 63.6 years, range 22.6-81.7) with benign anastomotic colonic or rectal strictures treated with endoscopic electrocautery dilation between June 2001 and February 2013 were included in the study. Anastomotic stricture was defined as a narrowed anastomosis through which a standard colonoscope could not be passed. Only annular anastomotic strictures were considered suitable for electrocautery dilation which consisted of radial incisions performed with a precut sphincterotome. Treatment was considered successful if the colonic anastomosis could be passed by a standard colonoscope immediately after dilation. Recurrence was defined as anastomotic stricture reappearance during follow-up. RESULTS: The time interval between colorectal surgery and the first endoscopic evaluation or symptoms development was 7.3 months (1.3-60.7). Electrocautery dilation was successful in all the patients. There were no procedure-related complications. Median follow-up was 35.5 months (2.0-144.0). Anastomotic stricture recurrence was observed in three patients who were successfully treated with electrocautery dilation and Savary dilation. CONCLUSIONS: Endoscopic electrocautery dilation is a safe and effective treatment for annular benign anastomotic postsurgical colonic strictures.

pH Impedance vs. traditional pH monitoring in clinical practice: an outcome study.

BACKGROUND: The addition of impedance to 24-h pH monitoring has allowed detection of weakly acidic reflux, but the extent to which pH-impedance (pH-MII) monitoring improves outcomes is unknown. METHODS: This was a prospective observational study. Patients referred for pH or pH-MII monitoring completed a standardized questionnaire on improvement in the dominant symptom, their satisfaction, and treatment at 3 and 12 months after the test during a telephone interview. RESULTS: A total of 184 patients (mean age, 52 years, range, 19-82 years; 35 % with typical symptoms; and 89 % tested off therapy) completed pH (n = 92) or pH-MII monitoring (n = 92) over a period of 15 months. The two arms were similar in terms of demographic, clinical, and endoscopic variables. Ten patients in the pH-MII arm showed evidence of weakly acidic reflux disease. There was no difference in the percentage of patients in the pH and pH-MII monitoring arms who experienced improvement in their dominant symptom after 3 (58 vs. 63 %; p = 0.621) or 12 months (66 vs. 70 %; p = 0.234), and the same was true for patient satisfaction. There were also no between-group difference in the use of proton pump inhibitors (PPIs) after 3 (63 vs. 68.5 %; p = 0.437) or 12 months (47 vs. 60.5 %; p = 0.051). PPIs were prescribed more frequently after a positive test (p < 0.001) although they were used by 45.6 % of the negative patients. Only one patient underwent fundoplication. CONCLUSIONS: Two-thirds of patients undergoing pH-MII monitoring experience a positive outcome, similarly to what occurs after traditional pH monitoring. Physicians often pay little attention to the test results, especially if they are negative.

Usefulness of low- and high-volume multiple rapid swallowing during high-resolution manometry.

BACKGROUND: It has been suggested that multiple rapid swallowing should be added to oesophageal manometry. AIM: To prospectively evaluate whether 10 and 200 mL multiple rapid swallowing provide different information concerning motor function. METHODS: 30 consecutive patients with oesophageal symptoms, 13 achalasia patients after successful pneumatic dilation and 19 healthy subjects performed eight 5 mL single swallows, two 10 mL and one 200 mL multiple rapid swallowing. RESULTS: Almost all of the healthy subjects and two-thirds of the patients with oesophageal symptoms showed motor inhibition during both 10 and 200 mL multiple rapid swallowing. The oesophago-gastric pressure gradient was significantly higher during 200 mL multiple rapid swallowing within each group (p < 0.01), and significantly higher in the achalasia patients than in the other two groups (p < 0.0001). Presence of a contraction and increased contraction strength in comparison with single swallows were both more frequent after 10 mL than after 200 mL multiple rapid swallowing in the healthy subjects and the patients (p<0.05). CONCLUSION: Motor inhibition could be similarly evaluated by means of 10 and 200 mL multiple rapid swallowing; 10 mL evaluated the after-contraction, whereas 200 mL multiple rapid swallowing was more valuable in identifying increased resistance to outflow.

Impedance pH Monitoring: Intra-observer and Inter-observer Agreement and Usefulness of a Rapid Analysis of Symptom Reflux Association.

BACKGROUND/AIMS: Symptom reflux association analysis is especially helpful for evaluation and management of proton pump inhibitor (PPI) re-fractory patients. An accurate calculation requires manual editing of 24-hour multichannel intraluminal impedance-pH (MII-pH) tracings after automatic analysis. Intra- and inter-observer agreement as well as reliability of rapid editing confined to the time around symptomatic episodes are unknown. Aim of this study was to explore these topics in a prospective multicenter study. METHODS: Forty consecutive patients who were off PPI therapy underwent MII-pH recordings. After automatic analysis, their tracings were anonymized and randomized. Three experienced observers, each one trained in a different European center, independently per-formed manual editing of 24-hour tracings on 2 separate occasions. Values of symptom index and symptom association proba-bility for acid and non acid reflux were transformed into binary response (i.e., positive or negative). RESULTS: Intra-observer agreement on symptom reflux association was 92.5% to 100.0% for acid and 85.0% to 97.5% for non-acid reflux. Inter-observer agreement was 100.0% for acid and 82.5% to 95.0% for non-acid reflux. Values for symptom index and symptom association probability were similar. Concordance between 24-hour and rapid (2 minutes-window before each symp-tomatic episode) editings for symptom reflux association occured in 39 to 40 patients (acid) and in 37 to 40 (non-acid), de-pending on the observer. CONCLUSIONS: Intra- and inter-observer agreement in classifying patients with or without symptom reflux association at manual editing of 24-hour tracings was high, especially for acid reflux. Classifying patients according to a rapid editing showed excellent con-cordance with the 24-hour one and can be adopted in clinical practice.

Effect of Cold Water on Esophageal Motility in Patients With Achalasia and Non-obstructive Dysphagia: A High-resolution Manometry Study.

BACKGROUND/AIMS: Swallowing of cold liquids decreases amplitude and velocity of peristalsis in healthy subjects, using standard manometry. Patients with achalasia and non obstructive dysphagia may have degeneration of sensory neural pathways, affecting motor response to cooling. To elucidate this point, we used high-resolution manometry. METHODS: Fifteen healthy subjects, 15 non-obstructive dysphagia and 15 achalasia patients, after pneumatic dilation, were studied. The 3 groups underwent eight 5 mL single swallows, two 20 mL multiple rapid swallows and 50 mL intraesophageal water infusion (1 mL/sec), using both water at room temperature and cold water, in a randomized order. RESULTS: In healthy subjects, cold water reduced distal contractile integral in comparison with water at room temperature during single swallows, multiple rapid swallows and intraesophageal infusion (ratio cold/room temperature being 0.67 [95% CI, 0.48-0.85], 0.56 [95% CI, 0.19-0.92] and 0.24 [95% CI, 0.12-0.37], respectively). A similar effect was seen in non-obstructive dysphagia patients (0.68 [95% CI, 0.51-0.84], 0.69 [95% CI, 0.40-0.97] and 0.48 [95% CI, 0.20-0.76], respectively), whereas no changes occurred in achalasia patients (1.06 [95% CI, 0.83-1.29], 1.05 [95% CI, 0.77-1.33] and 1.41 [95% CI, 0.84-2.00], respectively). CONCLUSIONS: Our data suggest impairment of esophageal reflexes induced by cold water in patients with achalasia, but not in those with non obstructive dysphagia.

Functional testing: pharyngeal pH monitoring and high-resolution manometry.

The following paper on functional testing of the pharynx includes commentaries on the use of 24-h pH-impedance testing to identify patients with nonacid reflux and the caveats associated with automatic and visual analysis; the potential diagnostic yield of ambulatory high-resolution manomentry (HRM), particularly in identifying non-cardiac chest pain and transient lower esophageal sphincter relaxations; the differential manometric identification of conditions facilitated by using solid swallows, and the advantages of the newly developed ResTech oropharyngeal pH probe in the detection of proximal reflux events.

Increased prandial air swallowing and postprandial gas-liquid reflux among patients refractory to proton pump inhibitor therapy.

BACKGROUND & AIMS: Many patients with gastroesophageal reflux disease (GERD) have persistent reflux despite treatment with proton pump inhibitors (PPIs). Mixed gas-liquid reflux events are more likely to be perceived as symptomatic. We used esophageal impedance monitoring to investigate whether esophageal gas is processed differently among patients with GERD who do and do not respond to PPI therapy. METHODS: We performed a prospective study of 44 patients with typical reflux symptoms with high levels of esophageal acid exposure during a 24-hour period; 18 patients were fully responsive, and 26 did not respond to PPI therapy. Twenty-four-hour pH impedance recordings were analyzed for fasting and prandial air swallows and reflux characteristics, including the presence of gas in the refluxate. RESULTS: PPI-refractory patients had a higher number (83.1 ± 12.7 vs 47.8 ± 7.3, P < .05) and rate (10.5 ± 1.4 vs 5.9 ± 0.8/10 minutes, P < .05) of prandial air swallows than patients who responded to PPI therapy; they also had a higher number (25.5 ± 4.0 vs 16.8 ± 3.3, P < .05) and proportion (70% ± 0.03% vs 54% ± 0.06%, P < .05) of postprandial, mixed gas-liquid reflux. Symptoms of PPI-refractory patients were more often preceded by mixed gas-liquid reflux events than those of PPI responders. Fasting air swallowing and other reflux characteristics did not differ between patients who did and did not respond to PPIs. CONCLUSIONS: Some patients with GERD who do not respond to PPI therapy swallow more air at mealtime than those who respond to PPIs and also have more reflux episodes that contain gas. These factors, combined with mucosal sensitization by previous exposure to acid, could affect perception of symptoms. These patients, who can be identified on standard 24-hour pH impedance monitoring, might be given behavioral therapy to reduce mealtime air swallowing.

Diagnostic yield of 96-h wireless pH monitoring and usefulness in patients' management.

OBJECTIVE: To get insight into usefulness of 96-h wireless monitoring in diagnosis of gastro-esophageal reflux disease (GERD) and in patients' management. MATERIAL AND METHODS: 51 patients who underwent 96-h wireless and 51 matched patients who underwent 24-h traditional pH monitoring were enrolled and retrospectively contacted with a structured telephone interview. RESULTS: In the wireless group, the 96-h recording improved (p < 0.05) the diagnostic yield compared with the first 48-h recording by allowing Symptom Association Probability to be measured in eight more patients and by decreasing indeterminate tests from 11 to 5. After pH monitoring, concordance between results of the test and treatment for GERD was higher in the wireless compared with the traditional group, 78% versus 58% of the patients (p < 0.05). Both improvement/disappearance of the clinically relevant symptom and satisfaction (score of 1-10) at time of the telephone interview were however similar in the two groups, 73% versus 65% and 7.0 versus 6.5. CONCLUSIONS: Wireless pH monitoring prolonged to 96 h increased the likelihood to exclude/confirm GERD as the cause of the clinically relevant symptoms in those patients with an indeterminate result for GERD after the first 48 h. Outcome was however similar to the one of traditional pH monitoring.

The role of delayed gastric emptying and impaired oesophageal body motility.

Delayed gastric emptying in a variable proportion of patients with gastro-oesophageal reflux disease has been observed in most series, however a relationship between delayed gastric emptying and increased gastro-oesophageal reflux has not been convincingly demonstrated. Enhanced postprandial accommodation and delayed emptying of the proximal stomach have been described, but some controversy exists. Impaired primary peristalsis is often present especially in patients with oesophagitis and its prevalence increases with increasing severity of inflammatory mucosal lesions. Patients with gastro-oesophageal reflux disease often have defective triggering of secondary peristalsis independently of presence of oesophagitis. It is presently unclear if impaired oesophageal motility is a primary defect or an irreversible consequence of inflammation. Attempts at pharmacological improvement of impaired oesophageal motility have been so far disappointing. Patients with partially preserved neuromuscular structures need to be identified in order to select them for new prokinetic therapy.

Computer simulator among experts involved in screening colonoscopy.

BACKGROUND: In the era of screening colonoscopy, assessment of operator competence is warranted. AIM: To evaluate feasibility of a computer simulator (CS) use for assessment of competence in colonoscopy by investigating performance of expert endoscopists at CS. SUBJECTS: Twenty expert endoscopists involved in screening colonoscopy. METHODS: Experts returned a questionnaire regarding personal practice (duration of activity, number of colonoscopies in the last year and assistance by a nurse) and performances (percentage of caecal intubation and polyp detection rate). One easy and one difficult colonoscopy were proposed at CS in randomized order. RESULTS: Participation rate was 75%. Caecal intubation rate in clinical practice was more than 90% for all experts. At CS, time to caecal intubation and number of attempts for ileal intubation were significantly lower during easy versus difficult colonoscopy (P<0.01 for both items); interestingly, percentage of mucosa explored was higher (P<0.05) during the difficult simulation. Withdrawal time >/=6 min was achieved by 40 and 33% of experts during the easy and difficult simulation, respectively. Independent of simulation difficulty, time with loop was lower (P<0.05) for experts using hands-free insertion (n = 8) compared with those using nurse assistance in their clinical practice (n = 7). No correlation was found between scores at CS and performance in clinical practice. CONCLUSION: Scores at CS are sensitive to the rate of technical difficulty and nurse assistance during daily practice. Withdrawal time is often shorter than required for high accuracy in polyp detection. CS could be a well-accepted tool for assessment of competence.

Subcardial 24-h wireless pH monitoring in gastroesophageal reflux disease patients with and without hiatal hernia compared with healthy subjects.

OBJECTIVES: After meals, highly acidic gastric juice is present in the subcardial region, the so-called acid pocket. Patients with gastroesophageal reflux disease (GERD) have a higher frequency of acidic reflux. Our aim was to investigate the possible differences in subcardial pH in GERD over 24 h and the role of hiatal hernia (HH), using a wireless capsule. METHODS: A total of 14 healthy volunteers (4 men, 24-60 years), 10 GERD patients without HH (4 men, 25-68 years), and 11 GERD patients with HH >or=3 cm (2 men, 46-74 years) underwent 24-h wireless pH monitoring 2 cm below the squamocolumnar junction. All patients had increased 24-h acid reflux. A standardized lunch was given to all study subjects. RESULTS: No capsule detached during the 24-h recording. Median 24-h pH was similar in healthy subjects, and in patients without and with HH, median: 1.4 (interquartile range: 1.2 -1.9), 1.5 (1.3 -1.7), and 1.4 (1.3 -1.7), respectively. Similar results were seen in the supine period. Median pH after the standardized meal was often highly acidic, 2.7 (1.5 - 3.2), 1.9 (1.6 - 2.3), and 2.5 (1.6 - 3.2), respectively. The first minute with a median pH <2 occurred 14 min (4 - 49), 14 min (6 - 25), and 20 min (4 - 43), respectively, P=NS, after the end of the meal. Similar data were observed on pooling all meals together. CONCLUSIONS: Subcardial pH is confirmed to be highly acidic early after meals, but it is similar over 24 h in healthy subjects and GERD patients independent of the presence of HH.