Balloon Distension Research Articles

Fasting pyloric diameter and distensibility by functional endoluminal imaging probe in unsedated healthy volunteers.

Recent studies with functional endoluminal imaging probe (EndoFLIP® ) measure physiologic characteristics of the pylorus. EndoFLIP® has the potential to select optimal candidates for gastric peroral endoscopic myotomy (G-POEM). Normative values of the pylorus using EndoFLIP® have not been established. Twenty-four healthy volunteers (20-56years old; 15 females) underwent unsedated, transoral EndoFLIP® measurements of the pylorus after 8h of fasting. Measurements of diameter (DM), balloon pressure, and distensibility index (DI) of the pylorus were obtained twice over 5min at 40, 50, and 60ml balloon distensions. Pyloric DM at 40, 50, and 60ml balloon distensions were 13.0±2.5, 14.3±1.8, and 17.2±2.0mm, respectively. DM with 60ml distension was notably higher than with 40 and 50ml distensions. Pyloric DI at 40, 50, and 60ml distensions were 10.9±4.8, 11.3±5.8, and 11.1±4.3mm2 /mm Hg, respectively (p=0.86). Linear regression and Bland-Altman plots showed similar distribution of the DM and DI during the second minute compared with the full 5-min measurements at 50ml distension, as well as between two sequential measurements using 50ml distension. With 50ml balloon distension, intraindividual coefficients of variation (COVintra ) for DM and DI were 13.8% and 29.6%, respectively, and interindividual COV (COVinter ) were 12.6% and 51.3%, respectively. Similar reproducibility was obtained with 40ml balloon distension. Unsedated EndoFLIP® can be used to characterize human fasting pyloric diameter and distensibility, with best performance observed with 40ml and 50ml distensions and data collection during the second minute. Normative values reported serve as reference values for future studies.

Peripheral apelin mediates visceral hypersensitivity and impaired gut barrier in a rat irritable bowel syndrome model

Growing evidence indicates that visceral hypersensitivity and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). In animal models, these changes are known to be mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4 (TLR4)-proinflammatory cytokine signaling. Apelin, an endogenous ligand of APJ, was reported to modulate CRF-induced enhanced colonic motility. In this context, we hypothesized that apelin also modulates visceral sensation and gut barrier, and tested this hypothesis. We measured visceral pain threshold in response to colonic balloon distention by abdominal muscle contractions assessed by electromyogram in rats. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal (ip) administration of [Ala13]-apelin-13, an APJ antagonist, blocked lipopolysaccharide (LPS)- or CRF-induced visceral hypersensitivity and colonic hyperpermeability (IBS model) in a dose-response manner. These inhibitory effects were blocked by compound C, an AMPK inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor or naloxone in the LPS model. On the other hand, ip [Pyr1]-apelin-13, an APJ agonist, caused visceral hypersensitivity and colonic hyperpermeability, and these effects were reversed by astressin, a CRF receptor antagonist, TAK-242, a TLR4 antagonist or anakinra, an interleukin-1 receptor antagonist. APJ system modulated CRF-TLR4-proinflammatory cytokine signaling to cause visceral hypersensitivity and colonic hyperpermeability. APJ antagonist blocked these GI changes in IBS models, which were mediated via AMPK, NO and opioid signaling. Apelin may contribute to the IBS pathophysiology, and the inhibition of apelinergic signaling may be a promising therapeutic option for IBS.

Peripheral GABAA receptor signaling contributes to visceral hypersensitivity in a mouse model of colitis.

Pain is a common and debilitating symptom of inflammatory bowel disease (IBD). Based on evidence that peripheral GABAA receptor (GAR) inhibition plays an important role in establishing colonic afferent excitability and nociceptive threshold, we hypothesized that the increase in pain associated with IBD is due to, at least in part, a decrease in peripheral GAR-mediated inhibition. Acute colitis was induced with 5 days of dextran sodium sulfate (DSS, 3%) in the drinking water. Visceral sensitivity was assessed with the visceromotor response (VMR) evoked with balloon distention of the colon in control and DSS-treated mice before and after intracolonic administration of GAR agonist muscimol, the high-affinity GAR preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP), the GAR positive allosteric modulator diazepam, or the GAR antagonists gabazine and bicuculline. Low concentrations of muscimol or THIP increased the VMR in DSS-treated mice but not in control mice. However, high concentrations of muscimol decreased the VMR in both control and DSS-treated mice. Diazepam decreased the VMR in both DSS-treated and control mice. By contrast, at a concentration of gabazine that blocks only low-affinity GAR, there was no effect on the VMR in either DSS-treated or control mice, but at concentrations of the antagonist that block low-affinity and high-affinity GAR, the VMR was increased in control mice and decreased in DSS-treated mice. Furthermore, bicuculline increased the VMR in control mice but decreased it in DSS-treated mice. These data suggest that activating of low-affinity GAR or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain in IBD.

A Pilot Study of Clinical Evaluation and Formation Mechanism of Irritable Bowel Syndrome-like Symptoms in Inflammatory Bowel Disease Patients in Remission.

Background/AimsSome inflammatory bowel disease (IBD) patients in remission suffer from irritable bowel syndrome (IBS)-like symptoms (IBD-IBS). The pathogenesis has not yet been elucidated. The study aim is to evaluate relationships among quality of life (QOL), psychological status, and visceral sensitivity, and explore the formation mechanism of IBD-IBS.MethodsForty-seven patients with Crohn’s disease in remission, 24 ulcerative colitis in remission, 26 IBS, and 20 healthy controls were included in the study. The abdominal pain, QOL, anxiety, and depression were evaluated through questionnaires. Visceral sensitivity was measured by rectal balloon distension. The serum levels of 5-hydroxytryptamine (5-HT) and nerve growth factor (NGF) were measured by enzyme-linked immunosorbent assay. The expressions of tryptase, 5-HT, NGF, and related receptors in colonic tissues were detected by immunohistochemistry and western blot.ResultsPrevalence of IBS-like symptoms in Crohn’s disease and ulcerative colitis patients in clinical remission was 29.8% and 50.0%, respectively. The QOL was lower, the anxiety/depression scores were higher in IBD-IBS patients than those without IBS-like symptoms. Additionally, patients with IBD-IBS existed visceral hypersensitivity. Besides, abdominal pain was associated with poor QOL, visceral hypersensitivity, anxiety, and depression in IBD-IBS patients. The number of mast cells (MCs) and expressions of 5-HT, NGF, and related receptors were higher in IBD-IBS patients than those with no such symptoms. The serum levels of 5-HT and NGF positively correlated with abdominal pain and visceral hypersensitivity.ConclusionIBD-IBS patients may have low QOL and psychological abnormalities, as wells as visceral hypersensitivity which may be related to increased 5-HT and NGF levels released from activated mast cells.

Can Propofol Be Used to Assess the Presence of the Rectoanal Inhibitory Reflex During Anorectal Manometry Studies?

To study changes in intra-anal pressure (IAP) and characteristics of the rectoanal inhibitory reflex (RAIR) during anorectal manometry (ARM) in patients undergoing anesthesia induction with propofol. Prospective study in which ARM was performed at baseline while patients were awake and repeated after propofol-induced anesthesia. We studied IAP and the presence and characteristics of the RAIR before and after propofol. A total of 27 patients were included (63% male; 9.2 years). Three patients had obstructive symptoms after Hirschsprung disease repair (HSCR), and 24 had intractable constipation. At baseline, the RAIR was present on 21 of 27 patients and absent on 6 of 27. Of the six patients with an absent RAIR, it remained absent in four of six (three known HSCR, and one new diagnosis of IAS achalasia), and two of six had a normal RAIR during propofol. Therefore, RAIR was present in all patients with constipation. The mean resting IAP was significantly lower after propofol. The percentage of IAS relaxation after lower balloon volume inflations was significantly higher during propofol (P < 0.05). No difference was observed over the latency time or the total relaxation time after propofol. Propofol can be used to assess the presence of the RAIR during ARM in children who are uncooperative and undergoing other procedures under anesthesia. On the other hand, propofol significantly reduces the resting IAP and increases the percentage of internal anal sphincter relaxation after balloon distention. These findings may impact the interpretation to decide if an intervention is needed, or if there is a possible spinal neuropathy.

Blocking peripheral drive from colorectal afferents by subkilohertz dorsal root ganglion stimulation.

Clinical evidence indicates dorsal root ganglion (DRG) stimulation effectively reduces pain without the need to evoke paresthesia. This paresthesia-free anesthesia by DRG stimulation can be promising to treat pain from the viscera, where paresthesia usually cannot be produced. Here, we explored the mechanisms and parameters for DRG stimulation using an ex vivo preparation with mouse distal colon and rectum (colorectum), pelvic nerve, L6 DRG, and dorsal root in continuity. We conducted single-fiber recordings from split dorsal root filaments and assessed the effect of DRG stimulation on afferent neural transmission. We determined the optimal stimulus pulse width by measuring the chronaxies of DRG stimulation to be below 216 µs, indicating spike initiation likely at attached axons rather than somata. Subkilohertz DRG stimulation significantly attenuates colorectal afferent transmission (10, 50, 100, 500, and 1000 Hz), of which 50 and 100 Hz show superior blocking effects. Synchronized spinal nerve and DRG stimulation reveals a progressive increase in conduction delay by DRG stimulation, suggesting activity-dependent slowing in blocked fibers. Afferents blocked by DRG stimulation show a greater increase in conduction delay than the unblocked counterparts. Midrange frequencies (50-500 Hz) are more efficient at blocking transmission than lower or higher frequencies. In addition, DRG stimulation at 50 and 100 Hz significantly attenuates in vivo visceromotor responses to noxious colorectal balloon distension. This reversible conduction block in C-type and Aδ-type afferents by subkilohertz DRG stimulation likely underlies the paresthesia-free anesthesia by DRG stimulation, thereby offering a promising new approach for managing chronic visceral pain.

Phlorizin attenuates visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome

Visceral hypersensitivity and impaired gut barrier are crucial contributors to the pathophysiology of irritable bowel syndrome (IBS), and those are mediated via corticotropin-releasing factor (CRF)−Toll like receptor 4–pro-inflammatory cytokine signaling. Phlorizin is an inhibitor of sodium-linked glucose transporters (SGLTs), and known to have anti-cytokine properties. Thus, we hypothesized that phlorizin may improve these gastrointestinal changes in IBS, and tested this hypothesis in rat IBS models, i.e., lipopolysaccharide (LPS) or CRF-induced visceral hypersensitivity and colonic hyperpermeability. The visceral pain threshold in response to colonic balloon distention was estimated by abdominal muscle contractions by electromyogram, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue. Subcutaneous (s.c.) injection of phlorizin inhibited visceral hypersensitivity and colonic hyperpermeability induced by LPS in a dose-dependent manner. Phlorizin also blocked CRF-induced these gastrointestinal changes. Phlorizin is known to inhibit both SGLT1 and SGLT2, but intragastric administration of phlorizin may only inhibit SGLT1 because gut mainly expresses SGLT1. We found that intragastric phlorizin did not display any effects, but ipragliflozin, an orally active and selective SGLT2 inhibitor improved the gastrointestinal changes in the LPS model. Compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor and naloxone, an opioid receptor antagonist reversed the effects of phlorizin. In conclusions, phlorizin improved visceral hypersensitivity and colonic hyperpermeability in IBS models. These effects may result from inhibition of SGLT2, and were mediated via AMPK, NO and opioid pathways. Phlorizin may be effective for the treatment of IBS.

A35 ASSOCIATIONS BETWEEN AUTONOMIC DYSFUNCTION, COLONIC DYSMOTILITY AND ABSENT DEFECATION REFLEXES IN PATIENTS WITH CHRONIC REFRACTORY CONSTIPATION

Abstract Background A defecation reflex involves sensory information from the colon sent to the central nervous system which results in propulsive motor patterns in the colon through programmed neural activity from the autonomic nervous system. Neurological causes of constipation are recognized but specific neurological pathways that contribute to pathophysiology of the disease is underexplored. Diagnosis and treatment usually do not involve the autonomic nervous system. Aims Our objective was to assess autonomic dysfunction and abnormal defecation reflexes as a possible cause of chronic constipation. Methods Defecation reflexes were assessed by high-resolution colonic manometry through balloon distention, meal intake, and rectal bisacodyl. Specific heart rate variability (HRV) parameters were used to assess general orthostatic autonomic reactivity, and autonomic functioning during high resolution colonic manometry, in 14 patients with chronic refractory constipation considered for surgery. Results All patients had a unique combination of motility, reflex ability and HRV profiles. Patients overall did not generate HAPWs or had lower HAPW amplitude and lower propulsive activity compared to healthy individuals. Half of the 14 patients were tested to have high sympathetic tone based on Baevsky’s stress index prior to HRCM, and 11 of the patients had sympathetic hyper-reactivity and/or low parasympathetic reactivity to at least one type of colonic stimulation during HRCM. Abnormal autonomic tone or autonomic reactivity to colonic stimulation was present in all four patients with absence of the vagosacral defecation reflex. Five of the seven patients with absence of the sacral defecation reflex showed high sympathetic tone or high sympathetic reactivity to stimulation. Only two patients had abnormality in coloanal coordination and this was associated with low parasympathetic reactivity to stimulation in both patients. Conclusions The assumption that colonic resection was needed to remove an inert colon was wrong in most patients, but most patients had some form of reflex abnormality. Sympathetic dominance far outweighed parasympathetic dysfunction. Incorporation of assessments of defecation reflexes and autonomic nervous system activity into diagnosis of chronic refractory constipation provides a comprehensive pathophysiological understanding of specific defective neurological pathways contributing to dysmotility. This forms the basis for our individualized treatment efforts through sacral neuromodulation. Funding Agencies CIHR

Clinical Impact of Rectal Hyposensitivity: A Cross-Sectional Study of 2,876 Patients With Refractory Functional Constipation.

Normal bowel function requires intact sensory pathways. Diminished rectal sensation (rectal hyposensitivity [RH]) is associated with constipation, although its clinical importance remains unclear. Consecutive patients (aged 18-80) attending a tertiary center (2004-2016) for investigation of refractory functional constipation (Rome IV core criteria defined, applied post hoc) were included. Patients completed a clinical symptom questionnaire and underwent anorectal physiologic investigations, including rectal sensory testing (balloon distension) to determine 3 well-established sensory thresholds. Multivariate regression analyses were performed to evaluate associations between RH, symptomology, and allied physiologic investigations. Of 2,876 patients meeting inclusion criteria, 722 (25%) had RH based on ≥1 elevated sensory thresholds (0: n = 2,154 [74.9%]; 1: n = 327 [11.4%]; 2: n = 209 [7.3%]; and 3: n = 186 [6.5%]). A linear relationship existed between increasing number of elevated sensory thresholds and constipation severity (Cleveland Clinic constipation score: mean difference per threshold [95% confidence interval] 0.69 [0.48-0.90]; P < 0.001). Several symptoms were significantly (P < 0.05) associated with RH including: infrequent defecation (odds ratio 1.29 [1.17-1.42]), painful evacuation (1.15 [1.05-1.27]), prolonged toileting (1.14 [1.05-1.24]), and digitation or enema use (1.18 [1.08-1.30]). On defecography, a "functional" evacuation disorder was also associated with RH (1.37 [1.25-1.50], P < 0.001), as was megarectum (2.52 [2.08-3.05], P < 0.001). RH occurs in 25% of patients with refractory functional constipation. Increased number of elevated sensory thresholds is associated with more severe constipation phenotype. These data, in the largest study to date, provide for the first time evidence to show that RH is a major pathophysiologic mechanism in constipation, with recognized clinical impact (http://links.lww.com/AJG/B765).(Equation is included in full-text article.).

Association between pain sensitivity and gray matter properties in the sensorimotor network in women with irritable bowel syndrome.

BackgroundEnhanced perception of visceral stimuli is an important feature of Irritable Bowel Syndrome (IBS), but it is not known whether visceral sensitivity is associated with regional structural brain properties in IBS.MethodsStructural brain magnetic resonance imaging data from 216 women with IBS and 138 healthy women were parcellated with FreeSurfer to define regional gray matter morphometry (volume, cortical thickness, surface area and mean curvature) in the sensorimotor network. General linear models were used to detect group differences between IBS and health. In a second set of 48 female IBS patients, pain threshold, pain intensity ratings during rectal balloon distension, and reported levels of abdominal pain and bloating were correlated with brain regions that showed differences between IBS and health in the first data set.Key ResultsSeveral statistically significant differences between IBS patients and healthy controls were found, mainly higher gray matter volume and cortical thickness in primary somatosensory cortex, secondary somatosensory cortex, and subcortical regions, and lesser gray matter volume, surface area and cortical thickness in posterior insula and superior frontal gyrus. Pain intensity ratings during rectal distension were associated with left primary somatosensory cortical thickness, and pain threshold was associated with right nucleus accumbens volume.Conclusions and InferencesRegional gray matter differences in sensorimotor network are associated with visceral sensitivity and may represent neuroplastic changes in female IBS patients.

Visceral hypersensitivity is together with psychological distress and female gender associated with severity of IBS-like symptoms in quiescent ulcerative colitis.

A subset of ulcerative colitis (UC) patients in remission demonstrate IBS-like symptoms. Visceral hypersensitivity is a key pathophysiological mechanism in IBS, but its relevance to IBS-like symptoms in inactive UC remains unclear. UC patients in remission (UCR) were screened for IBS-like symptoms. Rectal sensitivity was assessed with rectal balloon distensions, with determination of sensory thresholds and unpleasantness/pain intensity ratings. Patients completed questionnaires evaluating gastrointestinal (GI) and psychological symptoms. Age- and gender-matched IBS subjects and healthy controls (HC) also underwent a rectal sensitivity test. We included 36 UCR patients (18 with IBS-like symptoms (UCR+IBS) and 18 without (UCR-IBS)), 36 IBS subjects, and 14 HC. UCR and IBS patients were more sensitive to rectal balloon distensions than HC, but no differences between UCR and IBS patients were observed. UCR+IBS patients had lower sensory thresholds and higher unpleasantness ratings than UCR-IBS. In UCR patients, the overall GI symptom severity, pain, and bloating, but not diarrhea, constipation or satiety, were associated with rectal sensitivity. In multivariate analyses, rectal sensitivity, psychological distress, and female gender were identified as factors independently associated with GI symptom severity. 61% of UCR patients demonstrated rectal hypersensitivity, and these patients more commonly reported at least mild bloating and pain, and overall GI symptoms, compared to those with normal rectal sensitivity. Visceral hypersensitivity was associated with IBS-like symptoms, in particular pain and bloating, in inactive UC. Together with psychological factors and female gender, visceral hypersensitivity seems to be involved in GI symptom generation in quiescent UC.

S0501 Is Endoflip Useful and Reproducible for Assessment of Anorectal Sensation in Healthy Subjects?

INTRODUCTION: Abnormal anorectal sensation is commonly associated with anorectal disorders. Endoflip® is a novel technology that can measure anal canal sensation and distensibility. Aim: To determine anorectal sensory properties in healthy subjects using Endoflip and examine its reproducibility and validity. METHODS: Healthy subjects completed two studies of anal Endoflip, two weeks apart. An EndoFLIP probe (3-mm diameter, 8-cm long, highly compliant bag with 16 impedance sensors) was placed in the anus with center of balloon located in mid anal canal. Stool sensations (1 = no, 2 = First, 3 = Constant, 4 = Desire, 5 = Urgency to defecate) and discomfort/pain sensation (Likert 0-4) were assessed at each distending volume 10, 20, 30, 40, and 50 ml. Ramp and intermittent balloon distensions were performed in random sequence and during rest and squeeze. Test re-test reliability were assessed using intra-class correlation coefficient (ICC). RESULTS: Twelve healthy subjects (M/F = 5/7, 28.2 ± 9.5 years) participated. Mean scores for stool-like sensation increased stepwise, with both ramp and intermittent distensions, during rest and squeeze (Tables 1 and 2). Mean scores for discomfort/pain increased slightly and were below 0.8 (Table 1). For ramp distention, stool sensation during test showed high reproducibility for 10, 30, and 50 ml (ICC >0.686, P < 0.03, Table 1), and during squeeze for all balloon distension volumes (Table 1). For intermittent distention, the stool sensation at rest and with 10 ml and 20 mL were significantly reproducible, as well as for all distensions during squeeze manuever, and these were also highly reproducible (ICC > 0.681, P < 0.035, Table 2). Discomfort/pain during rest and squeeze for most balloon volumes high reproducibility (ICC > 0.764, P < 0.013, Tables 1 and 2). CONCLUSION: Endoflip is a reliable, noninvasive and useful tool for assessing anorectal stool sensation and discomfort. Data from ramp and intermittent methods were similar. It is potentially useful for assessment of anorectal sensation in anorectal disorders.Table 1Table 2

S0458 Does Fecal Incontinence Symptom Severity Evaluated by Symptom Summation and Individual Fecal Incontinence Components Predict Rectal Hypersensitivity in a Large Fecal Incontinence Cohort?

INTRODUCTION: Rectal sensation contributes significantly to the process of continence. Rectal hypersensitivity (RH) has been associated with a greater perception to defecate, increase lifestyle restrictions, and decrease quality of life domains in patients with fecal incontinence (FI). RH to rectal sensation measurements during an anorectal manometry (ARM) are often reported by patients with FI. Our hypothesis is that higher self-reported FI symptom severity will be associated with RH. METHODS: Retrospective cross-sectional study was conducted on 955 FI patients ≥18 years of age who were referred for ARM at a single tertiary medical center from 6/11 to 3/20. All patients completed the Fecal Incontinence Severity Index (FISI) questionnaire (0–61 scale: higher scores representing greater symptom severity). FISI components, gas (0–12), mucous (0–12), liquid (0–19), and stool (0–18) were scored using the patient validated metrics instead of physician values. RH was defined as balloon distention volume documented in the FI literature: First Sensation (FS) as ≤38 ml and Urge-to-Defecate (UD) as ≤80 ml. Independent t-tests were performed to assess the mean difference of FISI summation (FISI-Sum) and FISI components (FISI-C) between FI patients categorized as RH vs. normal rectal sensation (NRS) and sex (male vs. female). A P-value of ≤0.05 was considered statistically significant. RESULTS: Demographics (N = 955) were as follows: mean age 60.4 ± 14.1 years (19–91), mean BMI 29.3 ± 6.6, 73.6% female, and 90.7% Caucasian. No demographics differences between genders. The mean FISI-Sum and FISI-C scores for entire sample were 35.8 ± 12.5: Gas (10.2 ± 2.7), Mucous (7.9 ± 3.4), Liquid (13.5 ± 4.3), and Stool (12.8 ± 3.6). RH measured by FS and UD criteria for the sample were 29.1% and 49.1%. No significant differences in FISI-Sum and FISI-C related to RH using FS besides Liquid incontinence reported greater severity by NRS (P = 0.001) (Table 1). No significant differences in FISI-Sum and FISI-C between the RH and NRS groups in males. Females in the NSR group self-reported greater Liquid incontinence (P = 0.003) vs. the RH group measured by FS and no differences between RH and NRS groups using UD. CONCLUSION: Rectal hypersensitivity did not predict FI severity and may reduce the amount of liquid FI in patients. Therefore, the use of anorectal rectal function testing including rectal sensation metrics and rectal sensory re-training are necessary for evaluating and improving defecatory sensations.Table 1

S0358 Role of Endoscopic Functional Luminal Imaging Probe (EndoFLIP) for the Management of Post Myotomy Clinical Failure

INTRODUCTION: Peroral Endoscopic Myotomy (POEM) and Laparoscopic Heller myotomy (LHM) have evolved as effective management tools in relieving lower esophageal sphincter (LES) pressure in patients with esophageal motility disorders. However, a small percentage of patients fail to improve or relapse after time. The challenge remains in identifying the patients who might benefit from repeat myotomy as opposed to conservative managements. In the following study, we describe the role of endolumenal functional lumen imaging probe (EndoFLIP), in addition to high-resolution manometry (HRM), for managing such patients. METHODS: This was a multicenter, international retrospective study conducted between January 2015 and October 2019. Patients with a diagnosis of achalasia, esophagogastric junction outflow obstruction (EGJOO), diffuse esophageal spasm (DES), or jackhammer esophagus (JE) who underwent a prior failed myotomy were included. Clinical success of post repeat myotomy in the form of POEM was considered the primary outcome. RESULTS: A total of 72 patients [Female = 28 (39%), mean age 55 ± 17.3] with clinical failure and Eckardt score (ES) > 3 who underwent post LHM (33) or POEM (39) were included. On HRM evaluation, 27 were deemed candidates for repeat myotomy based on abnormal integrated relaxation pressure (IRP) measurements >15mmHg. On EndoFLIP evaluation,13/27 had an abnormal distensibility index (DI) < 2.8 mm2/mmHg at 40 ml balloon volume distension (Figure 1). A total of 30 patients underwent conservative management - pneumatic balloon dilation (n = 9) and repeat myotomy (n = 33) (Table 1). Post repeat myotomy mean ES improved from 5.8 ± 2.7 to 1.1 ± 1.4, (P < 0.001), and median DS improved from 2 (IQR: 1-3) to 1 (0-2), (P = 0.03), at a median follow-up time of 2 (IQR: 0-4.5) months post-procedure. Clinical success was achieved in 23/33 (70%) of the patients (Table 2). DI at 40 m balloon distension volume (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.02-2.1) was identified to be the best independent predictors of clinical success post repeat myotomy, with DI < 3.3 mm2/mmHg having sensitivity and specificity of 64% and 80%, respectively, for predicting clinical success. Therefore, the theoretical impact of EndoFLIP utilization for the management and diagnosis was in 16/72 (22%). CONCLUSION: The findings of this study demonstrate the important role of using EndoFLIP, in addition to HRM, in evaluating patients with clinical failure post myotomy.Figure 1Table 1Table 2

Imipramine improves visceral sensation and gut barrier in rat models of irritable bowel syndrome

An impaired gut barrier, possibly leading to visceral hypersensitivity has been recently recognized to be one of the pivotal pathophysiology of irritable bowel syndrome (IBS). We previously showed that lipopolysaccharide (LPS), corticotropin-releasing factor (CRF), and repeated water avoidance stress (WAS) induce visceral hypersensitivity and colonic hyperpermeability via pro-inflammatory cytokine signaling (rat IBS models). Although the precise mechanisms of action are unclear, imipramine, a tricyclic antidepressant, improves IBS symptoms, and also has anticytokine properties. In this study, we hypothesized that imipramine improves the gut barrier to ameliorate IBS symptoms. To test this hypothesis, we determined its effects on visceral hypersensitivity and colonic hyperpermeability in rat IBS models. The visceral pain threshold in response to colonic balloon distention was electrophysiologically estimated by abdominal muscle contractions, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue in vivo. Subcutaneous imipramine injection (7, 20, 50 mg/kg) dose-dependently inhibited LPS-induced (1 mg/kg, subcutaneously) visceral hypersensitivity and colonic hyperpermeability. Imipramine also blocked these gastrointestinal (GI) changes induced by CRF (50 μg/kg, intraperitoneally) or repeated WAS (1 h daily for 3 days). Yohimbine (an α2-adrenoceptors antagonist), sulpiride (a dopamine D2 receptor antagonist), and naloxone hydrochloride (an opioid receptor antagonist) reversed these effects of imipramine in the LPS model. Therefore, imipramine may block GI changes in IBS via α2-adrenoceptors, dopamine D2, and opioid signaling. The improvement in the gut barrier resulting in inhibition of visceral pain is considered a valid mechanism of imipramine to ameliorate IBS symptoms.

A new method for assessing anal distensibility with a barostat and magnetic resonance imaging in healthy and constipated women.

Defecation requires relaxation of the internal and external anal sphincters. High anal resting pressure is associated with painful constipation, defecatory disorders, and increased healthcare utilization in constipated patients; the mechanisms are unclear. Perhaps patients with a high anal resting pressure have a less distensible canal, which impedes defecation. In 50 of 64 participants (33 healthy and 17 constipated women), anal pressures and distensibility were measured, respectively, with manometry and balloon distention combined with magnetic resonance imaging; rectal balloon expulsion time (BET) was also studied. The BET (P=.006) was longer, and the mean (SD) rectoanal pressure gradient (-58[40] vs -34[26] mmHg, P=.03) was more negative in constipated than healthy women; anal resting pressure was not different. During anal distention, the balloon expanded rapidly at an opening pressure of 49 (18) mmHg, which was lower (P<.0001) than resting pressure (90 [25] mmHg). The resting pressure was correlated with the opening pressure (r=0.57, P<.0001) and inversely (r=-0.38, P=.007) with maximum volume but not with anal distensibility (volume-pressure slope). In healthy women, the difference (opening-resting pressure) was correlated with anal relaxation during evacuation (r=0.35, P=.04). Anal distensibility and sensory thresholds were not different between constipated and healthy women. Among healthy and constipated women, a greater anal resting pressure is correlated with greater opening pressure and lower maximum volume during distention, and, hence, provides a surrogate marker of anal distensibility. The difference (opening-resting pressure), which reflects anal relaxation during distention, is correlated with anal relaxation during evacuation. Anal resting pressure and distensibility were comparable in healthy and constipated women.

Rectal Distension Increased the Rectoanal Gradient in Patients with Normal Rectal Sensory Function.

Frequent observation of abnormal manometric patterns consistent with dyssynergia in healthy volunteers has warranted the need for reassessment of the current methods to enhance the diagnostic value of anorectal manometry in functional defecatory disorders. Whether rectal distention at simulated evacuation will affect anorectal pressure profile and increase rectoanal gradient is not known. One hundred and eight consecutive patients with chronic constipation, 93 females, median age 53years (interquartile range: 40-65), were studied. Simulated evacuation was performed firstly with empty balloon and subsequently after balloon distention to 50 and 100ml. Anorectal pressures were compared. We also performed subgroup analysis in relation to outcome of balloon expulsion test (BET). In addition, we studied the effect of rectal distension on the rectoanal pressure gradient with respect to rectal sensory function. Rectal balloon distension at simulated evacuation improved rectoanal gradient and decreased the rate of dyssynergia during high-resolution anorectal manometry. In subgroup analysis, the increase in rectoanal gradient and correction of dyssynergia with rectal distension was limited to the patients who had normal BET and normal rectal sensory function. Rate of anal relaxation, residual anal pressures, and rectoanal gradient were significantly different between patients with and without normal BET at 50ml of rectal distension. Rectoanal gradient recorded only after rectal distension, along with BMI and maximum tolerable volumes, could predict BET results independently in patients with chronic constipation. Rectal distension during simulated evacuation will affect the anorectal pressure profile. Increase in rectoanal gradient and correction of dyssynergia was only significant in patients with normal rectal sensory function and normal BET.

Intraoperative use of a functional lumen imaging probe during peroral endoscopic myotomy in patients with achalasia: A single-institute experience and systematic review.

AimThe functional lumen imaging probe (FLIP) is a recently developed technique to evaluate the esophagogastric junction (EGJ) distensibility. Unlike timed barium esophagogram (TBE) and high-resolution manometry (HRM), FLIP can be used during peroral endoscopic myotomy (POEM). The aim of this study was to evaluate the association of intraoperative FLIP parameters with clinical outcomes as recorded in a single-center database and to investigate a systematic review of literatures.MethodsWe reviewed consecutive patients diagnosed with achalasia and scheduled for POEM between June 2016 and March 2019 in our tertiary referral hospital. All patients underwent intraoperative FLIP assessment during POEM. The final FLIP measurements were compared between the patients with good and poor clinical response. We comprehensively reviewed studies evaluating whether intraoperative FLIP measurements reflected clinical outcomes.ResultsWe evaluated 23 patients with achalasia who underwent intraoperative FLIP before and after POEM. Two exhibited poor clinical responses after 3 months (Eckardt scores = 3). The final distensibility index (DI) did not differ significantly between good and poor responders (5.01 [4.52] vs. 4.91 [3.63–6.20] mm2/mmHg at a balloon distension of 50-mL, median [IQR], P = 0.853). The final DI did not differ significantly between post-POEM reflux esophagitis and non-reflux esophagitis groups (6.20 [5.15] vs. 4.23 [1.79] mm2/mmHg at a balloon distension of 50-mL, median [IQR], P = 0.075).ConclusionsA systematic review of both prospective and retrospective studies including our data indicated that the final intraoperative FLIP measurements did not differ significantly between good and poor responders. Further study with more patients is necessary to explore whether FLIP can predict short- and long-term clinical responses.

Sa2034 FEASIBILITY OF THE PER-ORAL TRANSESOPHAGEAL ENDOSCOPIC CRUROPLASTY (POTEC) OF THE DIAPHRAGMATIC HIATUS: A SURVIVAL STUDY

Transluminal and intramural endoscopic procedures continue to increase in type and variety. In an acute animal model, we developed a Natural Orifice Transluminal Endoscopic Surgery (NOTES) procedure to access the diaphragmatic hiatus and perform cruroplasty. The Per Oral Transesophageal Endoscopic Cruroplasty (POTEC) was found to reliably and repeatedly identify all important structures at the diaphragmatic hiatus and perform a cruroplasty. The goals of this survival study were to ensure animals tolerated the procedure well without post-procedural complications and also to use the endoluminal functional imaging probe to show objective evidence that the endosuturing of the crura was effective. The survival study protocol was performed under IACUC approval and completed with the assistance of a veterinary medicine team. The POTEC procedure was completed in each Yorkshire pig as previously described. Ease of procedure was assessed via a Likert scale from 1-5. The EndoFLIP (Medtronic) device was used to determine esophageal diameter and distensibility prior to the procedure, immediately following the procedure, and immediately before necropsy which was performed 4-6 weeks following the procedure. Seven animals to date underwent the POTEC procedure under the survival protocol. At necropsy, the cruroplasty was intact in all animals. Two of the seven animals were euthanized early. One was euthanized due to fasciculation and knuckling (felt secondary to anesthesia/positioning). Pleuritis was appreciated without evidence of iatrogenic injury. The second animal was euthanized for decreased PO intake. Necropsy showed an abscess at the site of the suture and pleuritis. Three of the other animals showed no post-procedural symptoms. Necropsy showed adequate healing with microabscesses located at the site of the suture which were cultured and grew porcine oral flora. Two more animals are currently awaiting necropsy. The average Likert score for the procedures was 1.57 out of 5. At the time of the analysis, data on the EndoFLIP device was available on one animal. In that animal, with balloon distention to 40cc pre-procedure, diameter was 13.55mm and distensibility was 4.05mm2/mmHg. Prior to necroscopy, diameter was reduced to 10mm and distensibility to 1.7 mm2/mmHg. A NOTES approach to the diaphragmatic hiatus is feasible and reliable as determined in the acute animal protocol. The survival study shows that despite contained microabscesses at the endosuture site, 5 of 7 animals did well post-procedurally and were without symptoms. The Likert score from the endoscopist suggests that the procedure can be accomplished without difficulty once familiar. Preliminary EndoFLIP studies suggest that cruroplasty does clinically tighten the esophagus at the level of the LES.

Randomised clinical trial: linaclotide vs placebo—a study of bi‐directional gut and brain axis

SummaryBackgroundLinaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS‐C) symptoms, but how it improves pain in humans is unknown.AimsTo investigate the effects of linaclotide and placebo on the afferent and efferent gut‐brain‐gut signalling in IBS‐C patients, in a randomised clinical trial.MethodsPatients with IBS‐C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi‐directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal‐anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto‐cortical and cortico‐rectal evoked potentials.ResultsThirty‐nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups. The efferent cortico‐anorectal and spino‐anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS‐QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13).ConclusionsLinaclotide prolongs afferent gut‐brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS‐C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS‐C patients.ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323.