A Multicenter Randomized Controlled Trial Comparing Two Bowel Cleansing Regimens for Colonoscopy After Failed Bowel Preparation.

BACKGROUND & AIMS: Failed bowel preparation for colonoscopy occurs commonly, but the optimal regimen for the subsequent attempt is unknown. High-volume preparations often are used but are not well studied. The objective of this study was to compare the efficacy, tolerability, and safety of 2 regimens for use after failed bowel preparation. METHODS: A multicenter, endoscopist-blinded randomized controlled trial was conducted in patients who previously failed bowel preparation despite adequate compliance. Patients were randomized to 1 of 2 split polyethylene glycol (PEG) regimens, preceded by 15 mg bisacodyl: PEG 2 L the evening before and 2 L the day of colonoscopy (PEG 2+2L+bisacodyl), or 4 L and 2 L (PEG 4+2L+bisacodyl). All patients followed a low-fiber diet on both the third and second day before the procedure, followed by a clear fluid diet the day before and the morning of the colonoscopy. The primary outcome was adequate bowel preparation, defined as a Boston Bowel Preparation Scale total score of 6 or higher, with all segment scores of 2 or higher. Secondary outcomes included adenoma detection rate, advanced adenoma detection rate, sessile serrated lesion detection, cecal intubation rate, tolerability, and adverse events. RESULTS: A total of 196 subjects were randomized at 4 academic centers in Canada (mean age, 60.7 y; SD, 11.4 y; 44.9% were women). There were no significant differences between the PEG 2+2L+bisacodyl and the PEG 4+2L+bisacodyl groups in achieving adequate bowel preparation (91.2% vs 87.6%; P = .44). There were no significant differences with regard to mean adenoma detection rate (37.4% vs 31.5%; P = .41), advanced adenoma detection rate (18.7% vs 11.2%; P = .16), sessile serrated lesion detection (8.8% vs 5.6%; P = .41), and cecal intubation rate (96.7% vs 92.1%; P = .19). The 2 regimens were similarly well tolerated, but PEG 2+2L+bisacodyl was associated with a higher willingness to repeat the bowel preparation (91.2% vs 66.2%; P < .001). CONCLUSIONS: Split-dose 4 L-PEG with 15 mg bisacodyl, along with dietary restrictions, has similar efficacy as a higher-volume preparation, and should be considered for patients who previously failed bowel preparation (ClinicalTrials.gov number, NCT02976805).

The Bowel CLEANsing National Initiative: High-Volume Split-Dose Vs Low-Volume Split-Dose Polyethylene Glycol Preparations: A Randomized Controlled Trial.

BACKGROUND & AIMS: The aim of this study was to compare high-volume polyethylene glycol (PEG) with low-volume PEG with bisacodyl split-dosing regimens. METHODS: Adult outpatients in 10 Canadian tertiary hospitals were randomized, stratified by morning or afternoon colonoscopy, to high-volume split-dose PEG (2 L + 2 L) (High-SD) or low volume (1 L + 1 L) + bisacodyl (15 mg) PEG (Low-SD), with a second randomization to liquid or low-residue diets. The primary end point, using noninferiority hypothesis testing, was adequate bowel cleansing (Boston Bowel Preparation Scale total score of ≥6, with each of 3 colonic segments subscores ≥2). Secondary objectives were willingness to repeat the preparation, withdrawal time, cecal intubation, and polyp detection rates. RESULTS: Over 29 months, 2314 subjects were randomized to High-SD (N = 1157) or Low-SD (N = 1157) (mean age, 56.2 ± 13.4 y; 52.1% women). Colonoscopy indications were 38.2% diagnostic, 36.8% screening, and 25.0% surveillance, with no between-group imbalances in patient characteristics. Low-SD satisfied noninferiority criteria vs High-SD for adequate bowel cleanliness with only marginally inferior results (90.1% vs 88.1%; P = .02; difference, 2.0%; 95% CI [0.0%; 4.5%]). High-SD was associated with lower willingness to repeat (66.9% vs 91.9%; P < .01), was less well tolerated (7.3 ± 2.3 vs 8.1 ± 1.9; P < .01), causing more symptoms. No differences in procedural outcomes were noted except for more frequent cecal intubation rates after High-SD (97.4% vs 95.6%; P = .02). Among the High-SD group, adequate bowel preparation was greater after a clear liquid diet (93.6% vs 87.9%; P < .01), a finding not seen in the Low-SD group. CONCLUSIONS: Low-SD is noninferior to High-SD in providing adequate bowel preparation. Low-SD results in fewer symptoms, with greater willingness to repeat and tolerability. The overall impact of diet was modest.The study was approved by the research ethic boards from all sites and was registered at ClinicalTrials.gov (NCT02547571).

Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction.

RATIONALE: Hypoxic pulmonary vasoconstriction (HPV) optimizes systemic oxygen delivery by matching ventilation to perfusion. HPV is intrinsic to pulmonary artery smooth muscle cells (PASMCs). Hypoxia dilates systemic arteries, including renal arteries. Hypoxia is sensed by changes in mitochondrial-derived reactive oxygen species, notably hydrogen peroxide (H2O2) ([H2O2]mito). Decreases in [H2O2]mito elevate pulmonary vascular tone by increasing intracellular calcium ([Ca2+]i) through reduction-oxidation regulation of ion channels. Although HPV is mimicked by the Complex I inhibitor, rotenone, the molecular identity of the O2 sensor is unknown. OBJECTIVE: To determine the role of Ndufs2 (NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 2), Complex I's rotenone binding site, in pulmonary vascular oxygen-sensing. METHODS AND RESULTS: Mitochondria-conditioned media from pulmonary and renal mitochondria isolated from normoxic and chronically hypoxic rats were infused into an isolated lung bioassay. Mitochondria-conditioned media from normoxic lungs contained more H2O2 than mitochondria-conditioned media from chronic hypoxic lungs or kidneys and uniquely attenuated HPV via a catalase-dependent mechanism. In PASMC, acute hypoxia decreased H2O2 within 112±7 seconds, followed, within 205±34 seconds, by increased intracellular calcium concentration, [Ca2+]i. Hypoxia had no effects on [Ca2+]i in renal artery SMC. Hypoxia decreases both cytosolic and mitochondrial H2O2 in PASMC while increasing cytosolic H2O2 in renal artery SMC. Ndufs2 expression was greater in PASMC versus renal artery SMC. Lung Ndufs2 cysteine residues became reduced during acute hypoxia and both hypoxia and reducing agents caused functional inhibition of Complex I. In PASMC, siNdufs2 (cells/tissue treated with Ndufs2 siRNA) decreased normoxic H2O2, prevented hypoxic increases in [Ca2+]i, and mimicked aspects of chronic hypoxia, including decreasing Complex I activity, elevating the nicotinamide adenine dinucleotide (NADH/NAD+) ratio and decreasing expression of the O2-sensitive ion channel, Kv1.5. Knocking down another Fe-S center within Complex I (Ndufs1, NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 1) or other mitochondrial subunits proposed as putative oxygen sensors (Complex III's Rieske Fe-S center and COX4i2 [cytochrome c oxidase subunit 4 isoform 2] in Complex IV) had no effect on hypoxic increases in [Ca2+]i. In vivo, siNdufs2 significantly decreased hypoxia- and rotenone-induced constriction while enhancing phenylephrine-induced constriction. CONCLUSIONS: Ndufs2 is essential for oxygen-sensing and HPV.

Sodium phosphate is superior to polyethylene glycol in constipated patients undergoing colonoscopy: a systematic review and meta-analysis.

BACKGROUND: Constipation is an important and highly prevalent predictor of inadequate bowel preparation during colonoscopy. In North America, between 2 and 28% of the general population suffer from constipation. Despite the high prevalence of constipation, to our knowledge, no meta-analysis on the optimal bowel preparation for constipated patients has been performed. We aimed to systematically review the literature to determine the ideal bowel preparation regiment for patients with chronic constipation. METHODS: A comprehensive search of electronic databases (MEDLINE, EMBASE, SCOPUS, and Web of Science) was performed. We included studies that assessed the quality of bowel preparation in constipated patients receiving different agents prior to colonoscopy. The primary outcome was colon cleanliness. Secondary outcomes included tolerability of the bowel preparation and serious adverse events. RESULTS: Preliminary database search yielded 1581 articles after duplicates were removed. After screening of the titles and abstracts using the exclusion criteria, 358 full-text articles were retained. Full-text articles were reviewed and eight studies meeting the inclusion criteria were included for qualitative synthesis. Three randomized controlled trials identified a total of 1636 constipated patients, of whom 225 were eligible for meta-analysis. Of those, 107 (47.6%) received NaP and 118 (52.4%) received PEG. Patients receiving NaP before colonoscopy had a higher chance of a successful bowel preparation than patients receiving PEG (OR 1.87, CI 1.06 to 3.32, P = 0.003). In the studies comparing PEG to NaP, two found that NaP resulted in greater tolerability of the bowel preparation and one study found that PEG resulted in superior tolerability. CONCLUSIONS: In chronically constipated patients undergoing colonoscopy, the use of NaP may result in superior colonic cleanliness when compared to PEG, however, quality of evidence was low. Further high-quality studies are required to delineate the optimal bowel preparation in patients with constipation.

The Bowel CLEANsing National Initiative: A Low-Volume Same-Day Polyethylene Glycol (PEG) Preparation vs Low-Volume Split-Dose PEG With Bisacodyl or High-Volume Split-Dose PEG Preparations-A Randomized Controlled Trial.

INTRODUCTION: Bowel cleanliness has been shown to be superior with split-dose vs nonsplit preparations; we aimed to directly assess the poorly characterized comparative efficacies of split-dose vs same-day polyethylene glycol (PEG) regimens. METHODS: In this study, one of a series of randomized trials performed across 10 Canadian endoscopy units, patients undergoing colonoscopies between 10:30 and 16:30 were allocated to PEG low-volume same-day (15 mg bisacodyl the day before, 2 L the morning of the procedure), low-volume split-dose (15 mg bisacodyl the day before, 1 L + 1 L), or high-volume split-dose (2 L + 2 L). Coprimary endpoints were adequate bowel cleansing based on the Boston Bowel Preparation Scale using in turn different threshold cutoffs. RESULTS: Overall, 1,750 subjects were randomized equally across the 3 groups, with no differences in adequate bowel cleanliness rates (low-volume same-day, 90.5%; high-volume split-dose, 92.2%; P = 0.34; and low-volume split-dose, 87.9%; P = 0.17) for the Boston Bowel Preparation Scale ≥6 and 2 for each segment. Willingness to repeat the preparation was not significantly different between low-volume same-day (91.0%) and low-volume split-dose (92.5%; P = 0.40) but was greater than the high-volume split-dose (68.9%; P < 0.01). No significant differences were noted for withdrawal time, cecal intubation, or polyp detection rates. DISCUSSION: In this large randomized trial of PEG regimens, low-volume same-day resulted in similar bowel cleanliness compared with high-volume or low-volume split-dosing. Willingness to repeat and tolerability were superior with low-volume same-day compared with high-volume split-dose and similar to low-volume split-dose.

Successful hemostasis of active lower GI bleeding using a hemostatic powder as monotherapy, combination therapy, or rescue therapy.

BACKGROUND AND AIMS: Acute lower GI bleeding is a frequent cause of hospital admission. The objective of this study was to evaluate the safety and performance of a hemostatic powder (TC-325/Hemospray) in the treatment of nonvariceal lower GI bleeding. METHODS: Patients were enrolled into this prospective, multicenter, single-arm study at 4 tertiary care centers in Canada. Fifty patients with active lower GI bleeding of multiple different causes (52 bleeding sites) underwent topical endoscopic application of hemostatic powder. The primary endpoint was powder-related adverse events within 30 days of the index procedure. Secondary endpoints were initial hemostasis as well as recurrent bleeding and mortality within 30 days of the index procedure. RESULTS: Most patients (96%) had a single bleeding site, and most bleeding (73%) was due to polypectomy. Overall, the powder was applied as monotherapy in 13 bleeding sites (25%), as combination therapy in 22 bleeding sites (42.3%), and as rescue therapy in 17 bleeding sites (32.7%). Hemostasis was achieved in 98% of patients. No patient experienced a powder-related adverse event. Five patients (10%) developed recurrent bleeding within 30 days. One patient (2%) died within 30 days of powder application, but the death was not directly related to hemostatic powder use. CONCLUSIONS: The hemostatic powder is a safe and effective option for patients with lower GI bleeding of varying causes, and in particular, postpolypectomy hemorrhage. The hemostatic powder is effective as monotherapy, part of a combination approach, or as a rescue therapeutic option for the treatment of nonvariceal lower GI bleeding. (Clinical trial registration number: NCT02099435.).

Simethicone decreases bloating and improves bowel preparation effectiveness: a systematic review and meta-analysis.

BACKGROUND: Simethicone is an adjunct frequently used during bowel preparation before colonoscopy and currently there is no consensus on whether it should be recommended in standard bowel preparation. We performed a systematic review and meta-analysis to determine the effect simethicone has on bowel cleanliness, adenoma detection rate (ADR), and tolerability. METHODS: We searched the literature for studies that compared colon cleansing of patients that received standard bowel preparation alone and in combination with simethicone prior to colonoscopy. The primary outcomes were colon cleanliness, ADR, and tolerability. RESULTS: Sixteen randomized controlled trials with 5630 patients were included in meta-analysis. Overall, polyethylene glycol (PEG) with simethicone improves colon cleansing compared with PEG alone (odds ratio [OR] 1.48, CI 1.11 to 1.97, P = 0.008). This improvement was seen for single dosing (OR 1.83, CI 1.20 to 2.79, P = 0.005) but not for split dosing (OR 1.32, CI 0.72 to 2.43, P = 0.38). Overall, simethicone had no effect on ADR (OR 1.22, CI 0.81 to 1.83, P = 0.33), but in patients receiving single dosing, simethicone significantly increased ADR (OR 1.96, CI 1.22 to 3.16, P = 0.005). The rates of nausea (OR 0.96, CI 0.75 to 1.24, P = 0.75), vomiting (OR 1.00, CI 0.69 to 1.44, P = 0.99), and abdominal pain (OR 0.69, CI 0.40 to 1.18, P = 0.17) were not significantly different between PEG and PEG + simethicone cohorts. For abdominal bloating, the PEG cohort had greater odds of experiencing bloating than the PEG + simethicone cohort (OR 2.33, CI 1.70 to 3.20, P < 0.00001). CONCLUSIONS: Simethicone improves colon cleanliness and ADR; however, this improvement is not seen in patients receiving split-dose PEG. Furthermore, simethicone decreases abdominal bloating but has no effect on nausea, vomiting, and abdominal pain. Simethicone may be a useful bowel preparation adjunct in patients unable to receive split-dose PEG.

Gastric antral vascular ectasia: a prospective study of treatment with endoscopic band ligation.

Gastric antral vascular ectasia (GAVE) is characterized by red, angiomatous lesions in the antrum organized either in stripes or in a diffuse pattern that can be associated with upper gastrointestinal bleeding. Endoscopic band ligation (EBL) has been reported as an effective alternative therapy for patients with GAVE. Consecutive patients with a diagnosis of GAVE were prospectively followed while undergoing EBL every 2 months. Hemoglobin, ferritin, and iron levels were frequently recorded, and clinical follow-up was performed. A total of 21 patients with GAVE were enrolled, and 17 of these patients (81 %) had associated co-morbidities, most frequently cirrhosis and chronic renal failure. A clinical response was achieved in 19 patients (91 %). A significant improvement in the mean hemoglobin level was noted after EBL (P < 0.001), and a significant decrease in blood transfusion requirements per month (P = 0.001). No major complications were observed during the study period. The mean follow-up was 10 months. EBL is an effective and safe treatment for GAVE. Randomized, controlled trials comparing EBL with other endoscopic therapies are warranted.

The Effect of Covid-19 Pandemic on Current and Future Endoscopic Personal Protective Equipment Practices: A National Survey of 77 Endoscopists.

Introduction: The COVID-19 pandemic has raised awareness about the importance of personal protective equipment (PPE). We aimed to study and compare PPE practices among Canadian endoscopists before and after the COVID-19 pandemic. Methods: A 74-item questionnaire was emailed from June 2020 to September 2020 to practicing endoscopists in Canada. Survey questions collected basic demographics and differences between PPE practices pre- and post-COVID-19. PPE practices were categorized into four endoscopic procedure types including upper or lower endoscopy and diagnostic or interventional. Outcomes for specific procedures were reported as rates, with ranges shown when evaluating all procedure types together. Results: A total of 77 respondents completed the survey with the majority of respondents aged 40 to 49 (44%) and identifying as Gastroenterologists (70%). Gender was evenly split (49% females versus 51% males). In the pre-pandemic era, the majority of endoscopists wore gowns (91 to 94%) and all endoscopists wore gloves (100%). However, the majority of endoscopists did not wear surgical masks (21 to 31%), face shields (13 to 34%), eye protection (13 to 21%), hair protection (11 to 13%), or N95 respirators (2 to 3%). In the post-pandemic era, more surgeons plan on wearing face shields (33 to 47%, P = 0.001 to 0.045), goggles (38.5 to 58.7%, P < 0.001), hair protection (33 to 36%, P = 0.011 to 0.024), and a trend suggests more surgeons will wear surgical masks (51 to 61%, P = 0.163 to 0.333). More endoscopists also plan on wearing N95 respirators during lower endoscopy (6 to 7%, P < 0.005). Conclusion: The COVID-19 pandemic has changed the attitudes of many endoscopists regarding future PPE use in routine endoscopy. Ongoing studies are needed to inform new post-pandemic PPE consensus guidelines.

The Impact of Transitioning From Guaiac-Fecal Occult Blood Testing to Fecal Immunochemical Testing in a Canadian Colon Cancer Screening Program.

OBJECTIVES: To determine the impact of transitioning from guaiac-based fecal occult blood testing (gFOBT) to fecal immunochemical testing (FIT) on the detection rate of adenomas, advanced adenomas (AA) and colorectal cancer (CRC). BACKGROUND: Recently, the health region in Edmonton, Alberta switched from gFOBT to FIT for CRC screening. STUDY: A retrospective analysis of all patients, aged 50 to 74 years, referred for colonoscopy from January 1, 2013 to December 31, 2014 due to a positive gFOBT (at least one of three samples positively using the guaiac-based Hemoccult II SENSA in 2013) or FIT (≥75 µg/g of stool, using the Polymedco OC FIT-CHEK in 2014). The primary outcomes were the number of colon cancers, AA and adenomas detected in 2013 and 2014. A comparison between the two tests was also made for the composite outcome of detection of either AA or CRC. RESULTS: Six hundred and forty-nine patients underwent colonoscopy due to a positive gFOBT in 2013, and 2167 patients for a positive FIT in 2014. FIT compared with gFOBT detected more CRC (67 compared with 34), AA (770 compared with 147) and adenomas (1575 versus 320). By multivariable regression analysis adjusted for different demographics and endoscopic metrics, positive FIT was independently associated with higher adenoma detection rate (odds ratio [OR] 2.62; 95% confidence interval [CI] 2.13 to 3.21, P < 0.001), AA detection rate (OR 1.83, 95% CI 1.43 to 2.33, P < 0.001), and the composite outcome of AA and CRC (OR 2.04, 95% CI 1.60 to 2.59, P < 0.001). CONCLUSIONS: Adoption of FIT compared with gFOBT led to higher detection of colon cancer, AA and adenomas.

Multicentre endoscopist-blinded randomised clinical trial to compare two bowel preparations after a colonoscopy with inadequate cleansing: a study protocol.

INTRODUCTION: Inadequate bowel preparation is common and negatively impacts colonoscopy quality. The objective of this study is to compare two bowel preparation regimens in cleansing the colon after an index colonoscopy with failed bowel preparation. METHODS AND ANALYSIS: This is a phase III, multicentre, randomised clinical trial comparing two bowel preparation regimens after failure to adequately cleanse at the index colonoscopy. Regimen A consists of 4 L split-dose polyethylene glycol electrolyte solution (PEG-ELS) and Regimen B consists of 6 L split-dose PEG-ELS, both preceded by 15 mg of bisacodyl the day before the procedure along with a low-fibre diet 3 and 2 days before the procedure followed by a clear fluid diet starting the day before the procedure. The primary outcome is adequate bowel preparation, defined as a Boston Bowel Preparation Scale (BBPS) score of ≥6 with each segment score ≥2. Secondary outcomes include mean BBPS score, bowel preparation adequacy using the US Multi-Society Task Force on Colorectal Cancer definition, detection rate by polyp subtype, caecal intubation rate, mean Validated Patient Tolerability Questionnaire for Bowel Preparation score, subject willingness to repeat the preparation and faecal incontinence rate. ETHICS AND DISSEMINATION: The study will be conducted in accordance with Good Clinical Practice guidelines and local institutional standards. Study findings will be disseminated at an international gastroenterology conference and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02976805; Pre-results.

Acute Liver Injury Associated with Khat Use in a 24-Year-Old Male.

Chewing khat leaves (Catha edulis) is common cultural practice in Eastern African countries. Khat has been implicated in cases of acute liver injury, sometimes leading to liver failure and requiring transplantation. We report the case of a 24-year-old gentleman presenting with symptoms of acute liver failure. Bloodwork demonstrated hepatocyte-predominant liver injury. Microbiological and serological hepatitis panels were negative, and his liver biopsy demonstrated acute cholestatic hepatitis. He admitted to regular khat use for several years prior to his presentation. His liver function tests improved with cessation of khat use. This is the first reported case of acute khat-associated hepatitis in Canada. Considering cultural practices such as khat chewing in presentations of acute liver injury are important when caring for diverse patient populations.

In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats.

BACKGROUND: Alveolar hypoxia acutely elicits pulmonary vasoconstriction (HPV). Chronic hypoxia (CH), despite attenuating HPV, causes pulmonary hypertension (CH-PHT). HPV results, in part, from inhibition of O2-sensitive, voltage-gated potassium channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). CH decreases Kv channel current/expression and depolarizes and causes Ca2+ overload in PASMCs. We hypothesize that Kv gene transfer would normalize the pulmonary circulation (restore HPV and reduce CH-PHT), despite ongoing hypoxia. METHODS AND RESULTS: Adult male Sprague-Dawley rats were exposed to normoxia or CH for 3 to 4 weeks and then nebulized orotracheally with saline or adenovirus (Ad5) carrying genes for the reporter, green fluorescent protein reporter+/-human Kv1.5 (cloned from normal PA). HPV was assessed in isolated lungs. Hemodynamics, including Fick and thermodilution cardiac output, were measured in vivo 3 and 14 days after gene therapy by use of micromanometer-tipped catheters. Transgene expression, measured by quantitative RT-PCR, was confined to the lung, persisted for 2 to 3 weeks, and did not alter endogenous Kv1.5 levels. Ad5-Kv1.5 caused no mortality or morbidity, except for sporadic, mild elevation of liver transaminases. Ad5-Kv1.5 restored the O2-sensitive K+ current of PASMCs, normalized HPV, and reduced pulmonary vascular resistance. Pulmonary vascular resistance decreased at day 2 because of increased cardiac output, and remained reduced at day 14, at which time there was concomitant regression of right ventricular hypertrophy and PA medial hypertrophy. CONCLUSIONS: Kv1.5 is an important O2-sensitive channel and potential therapeutic target in PHT. Kv1.5 gene therapy restores HPV and improves PHT. This is, to the best of our knowledge, the first example of K+ channel gene therapy for a vascular disease.