High-amplitude Propagating Contractions Research Articles

Sacral nerve stimulation effect on colonic motility in pediatric patients.

Sacral nerve stimulation (SNS) is a minimally invasive surgical procedure used to treat refractory constipation in children. While its efficacy in improving symptoms has been studied, its effect on colonic motor function remains unclear. This case series explores SNS's impact on colonic motor function in pediatric patients with idiopathic constipation, using high-resolution colonic manometry (HRCM). Four pediatric patients with chronic idiopathic constipation underwent SNS placement for intractable symptoms and were subsequently evaluated via HRCM. Clinical characteristics, comorbidities, treatment regimens, and outcomes were reviewed. HRCM was conducted during the SNS-off and SNS-on phases. The motility index (MI) was measured during the SNS-off (fasting and postprandial) and SNS-on phases. Four pediatric patients aged 8 to 21 years met the inclusion criteria. In three patients, SNS-induced high-amplitude propagating contractions (HAPCs) were noted, and in one patient, low-amplitude propagating contractions (LAPCs) were noted. In one patient, propagating contractions were induced only when SNS was turned on. MI changes with SNS-on were variable among different patients with an increase in MI in two patients after turning SNS on and a decrease in the other two compared with baseline. Adverse effects following SNS placement remained minimal across all cases. This case series is the first to report SNS effects on colonic motility evaluated by HRCM in pediatrics. We demonstrate that propagating colonic contractions are promptly induced when SNS is turned on. Although the initial effects of SNS on colonic motility were observable, additional investigation is necessary to comprehend the fundamental mechanisms and long-term effectiveness of SNS in pediatric patients.

Clinical utility of colonic low-amplitude propagating contractions in children with functional constipation.

Colonic high-amplitude propagating contractions (HAPC) are generally accepted as a marker of neuromuscular integrity. Little is known about low-amplitude propagating contractions (LAPCs); we evaluated their clinical utility in children. Retrospective review of children with functional constipation undergoing low-resolution colon manometry (CM) recording HAPCs and LAPCs (physiologic or bisacodyl-induced) in three groups: constipation, antegrade colonic enemas (ACE), and ileostomy. Outcome (therapy response) was compared to LAPCs in all patients and within groups. We evaluated LAPCs as potentially representing failed HAPCs. A total of 445 patients were included (median age 9.0 years, 54% female), 73 had LAPCs. We found no association between LAPCs and outcome (all patients, p=0.121), corroborated by logistic regression and excluding HAPCs. We found an association between physiologic LAPCs and outcome that disappears when excluding HAPCs or controlling with logistic regression. We found no association between outcome and bisacodyl-induced LAPCs or LAPC propagation. We found an association between LAPCs and outcome only in the constipation group that cancels with logistic regression and excluding HAPCs (p=0.026, 0.062, and 0.243, respectively). We found a higher proportion of patients with LAPCs amongst those with absent or abnormally propagated (absent or partially propagated) HAPCs compared to those with fully propagated HAPCs (p=0.001 and 0.004, respectively) suggesting LAPCs may represent failed HAPCs. LAPCs do not seem to have added clinical significance in pediatric functional constipation; CM interpretation could rely primarily on the presence of HAPCs. LAPCs may represent failed HAPCs. Larger studies are needed to further validate these findings.

A model for gastrointestinal tract motility in a 4D imaging phantom of human anatomy.

Gastrointestinal (GI) tract motility is one of the main sources for intra/inter-fraction variability and uncertainty in radiation therapy for abdominal targets. Models for GI motility can improve the assessment of delivered dose and contribute to the development, testing, and validation of deformable image registration (DIR) and dose-accumulation algorithms. To implement GI tract motion in the 4D extended cardiac-torso (XCAT) digital phantom of human anatomy. Motility modes that exhibit large amplitude changes in the diameter of the GI tract and may persist over timescales comparable to online adaptive planning and radiotherapy delivery were identified based on literature research. Search criteria included amplitude changes larger than planning risk volume expansions and durations of the order of tens of minutes. The following modes were identified: peristalsis, rhythmic segmentation, high amplitude propagating contractions (HAPCs), and tonic contractions. Peristalsis and rhythmic segmentations were modeled by traveling and standing sinusoidal waves. HAPCs and tonic contractions were modeled by traveling and stationary Gaussian waves. Wave dispersion in the temporal and spatial domain was implemented by linear, exponential, and inverse power law functions. Modeling functions were applied to the control points of the nonuniform rational B-spline surfaces defined in the reference XCAT library. GI motility was combined with the cardiac and respiratory motions available in the standard 4D-XCAT phantom. Default model parameters were estimated based on the analysis of cine MRI acquisitions in 10 patients treated in a 1.5T MR-linac. We demonstrate the ability to generate realistic 4D multimodal images that simulate GI motility combined with respiratory and cardiac motion. All modes of motility, except tonic contractions, were observed in the analysis of our cine MRI acquisitions. Peristalsis was the most common. Default parameters estimated from cine MRI were used as initial values for simulation experiments. It is shown that in patients undergoing stereotactic body radiotherapy for abdominal targets, the effects of GI motility can be comparable or larger than the effects of respiratory motion. The digital phantom provides realistic models to aid in medical imaging and radiation therapy research. The addition of GI motility will further contribute to the development, testing, and validation of DIR and dose accumulation algorithms for MR-guided radiotherapy.

A Model for Gastrointestinal Tract Motility in a 4D Imaging Phantom of Human Anatomy

<h3>Purpose/Objective(s)</h3> Gastrointestinal (GI) tract motility is one of the main sources for intra/inter-fraction variability and uncertainty in validating deformable image registration (DIR) algorithms. We present an implementation of four modes of GI motility in the 4D extended cardiac-torso (XCAT) digital phantom. <h3>Materials/Methods</h3> We consider motility modes that exhibit large amplitude changes in the diameter of the GI tract and may persist over timescales comparable to online adaptive planning and radiotherapy delivery. The following modes are modeled: peristalsis, rhythmic segmentation, high amplitude propagating contractions (HAPC), and tonic contractions. The models are intended for the organ of origin (i.e., peristalsis in esophagus and small intestine; HAPCs in colon) but can be applied to any user-specified GI tract organ. Peristalsis and rhythmic segmentations are modeled by traveling and standing sinusoidal waves. HAPCs and tonic contractions are modeled by traveling and stationary Gaussian waves. Spatial and temporal dispersion are implemented by exponential functions. The model is applied at the control points of the nonuniform rational B-spline (NURBS) surfaces defined in the reference XCAT phantom. The reference NURBS surfaces are dynamically updated at each timepoint based on the user-defined parameters shown in Table 1. GI motility is combined with the respiratory and cardiac motion available in XCAT. Cine MRI acquisitions from 50 fractions of 10 patients treated in a 1.5 T MR-Linac were analyzed to estimate default parameters for each model. <h3>Results</h3> We demonstrate the ability to generate realistic 4D MRI images that simulate four modes of GI motility combined with respiratory and cardiac motion. All modes of motility, except tonic contractions, were observed in the analysis of our cine MRI acquisitions. Peristalsis was the most common. Default parameters estimated from cine MRI data or from literature (if not observed in our measurements) are used as initial values for simulation experiments. <h3>Conclusion</h3> The digital phantom provides realistic models to aid in multimodality imaging research. The addition of GI motility will further contribute to the development, testing, and validation of DIR algorithms for MR-guided radiotherapy.

Effect of Caffeine on Colonic Manometry in Children.

Coffee and caffeinated products have been widely consumed for many centuries. Previous adult studies have suggested that both coffee and decaffeinated beverages induce colonic motility. However, no study has been conducted in pediatrics, and the role of caffeine alone in pediatric colonic motility needs to be explored. A prospective study of pediatric patients undergoing standard colonic motility testing that were able to consume caffeinated coffee, decaffeinated coffee, and caffeine tablet during colonic manometry. Patients who had a gastrocolonic reflex and high amplitude propagated contractions (HAPCs) in response to intraluminal administration of bisacodyl in the colon were included in the final analyses. Thirty-eight patients were recruited, 22 of which were excluded, 11 due to abnormal studies (no HAPC seen in response to intraluminal response to bisacodyl), and 11 due to inability to consume all study agents or complete the study. Sixteen patients met criteria for final analyses. Intracolonic bisacodyl produced a larger area under the curve (AUC) compared to all other agents. Caffeinated coffee resulted in a higher AUC, motility index (MI), and time to HAPC compared with decaffeinated coffee ( P < 0.05). There was no significant difference between caffeinated coffee and caffeine tablet, or caffeine tablet and decaffeinated coffee. Caffeine is indeed a colonic stimulant; however, other components of caffeinated and non-caffeinated beverages likely induce colonic response and require further evaluation for possible use as a colonic stimulant.

Diverting Ileostomy in Children With Functional Constipation: A Study Evaluating the Utility of Colon Manometry.

Pediatric functional constipation (FC) may require invasive evaluations [like colon manometry (CM)] and surgical interventions [including diverting ostomy (DO)]. We evaluated the utility of CM in guiding surgery after DO. Children with medically refractory FC undergoing an ostomy were included. Institutional Review Board approval was obtained for this retrospective study. Demographics and CM variables [high amplitude propagating contractions (HAPCs)] were recorded. Outcome measures: response to ostomy closure defined as successful if no need for further surgery after ostomy closure, and improvement on baseline CM after ostomy. A CM-guided ostomy closure algorithm was developed based on previous studies. We evaluated the association between response to ostomy closure and demographics, ostomy indication and CM improvement, and evaluated the role of CM predicting response using algorithm. A total of 60 children underwent ostomy for FC (median age: 7.1 years, range 0.15-23.6 years, 50% female). Ostomy was closed in 30 patients and deemed successful in 23 of 30. CM was performed in 42 of 60 patients before ostomy and in 29 of 30 before ostomy closure. We found no association between ostomy outcome and age, gender, weight, imaging studies, follow-up time, time with ostomy, HAPCs, and CM improvement. We found an association between failed response and ostomy indication of antegrade colonic enemas (ACE) failure ( P = 0.026) and successful response when ostomy closure was guided by algorithm ( P = 0.03). DO is a useful intervention in selected children with medically refractory FC, improving colon motility in most. CM can successfully guide the timing and type of ostomy closure. Larger studies are needed to further validate our findings.

Simultaneous assessment of colon motility in children with functional constipation by cine-MRI and colonic manometry: a feasibility study

BackgroundColonic manometry is the current reference standard for assessing colonic neuromuscular function in children with intractable functional constipation (FC). Recently, cine magnetic resonance imaging (cine-MRI) has been proposed as a non-invasive alternative. We compared colonic motility patterns on cine-MRI with those obtained by manometry in children, by stimulating high-amplitude propagating contractions (HAPCs) with bisacodyl under manometric control while simultaneously acquiring cine-MRI.MethodsAfter Institutional Review Board approval, adolescents with FC scheduled to undergo colonic manometry were included. A water-perfused 8-lumen catheter was used for colonic manometry recordings. After an intraluminal bisacodyl infusion, cine-MRI sequences of the descending colon were acquired for about 30 min simultaneously with colonic manometry. Manometry recordings were analysed for HAPCs. MRI images were processed with spatiotemporal motility MRI techniques. The anonymised motility results of both techniques were visually compared for the identification of HAPCs in the descending colon.ResultsData regarding six patients (three males) were analysed (median age 14 years, range 12–17). After bisacodyl infusion, three patients showed a total of eleven HAPCs with colonic manometry. Corresponding cine-MRI recorded high colonic activity during two of these HAPCs, minimal activity during seven HAPCs, while two HAPCs were not recorded. In two of three patients with absent HAPCs on manometry, colonic activity was recorded with cine-MRI.ConclusionsSimultaneous acquisition of colonic cine-MRI and manometry in children with FC is feasible. Their motility results did not completely overlap in the identification of HAPCs. Research is needed to unravel the role of cine-MRI in this setting.

High-resolution manometry reveals different effect of polyethylene glycol, bisacodyl, and prucalopride on colonic motility in healthy subjects: An acute, open label, randomized, crossover, reader-blinded study with potential clinical implications.

Polyethylene glycol (PEG), bisacodyl, and prucalopride have been reported to be more effective than placebo in treating patients with constipation but about 50% of the patients still do not respond to these medications. Only bisacodyl and prucalopride are expected to directly stimulate the colonic motility in humans in vivo. As no previous study has done this, the aim of the study was to investigate the effect of PEG, bisacodyl, and prucalopride as compared to placebo on colonic motility assessed by means of the high-resolution manometry (HRM) in healthy subjects. Ten healthy subjects have been enrolled in an acute, open label, randomized, reader-blinded, crossover study and requested to undergo a colonoscopy-assisted HRM measuring their colonic motility before and after oral administration of 13.8g (two doses) PEG, 10mg bisacodyl, 2mg prucalopride, and placebo. In the human prepared colon, oral administration of PEG significantly increases the number of low-amplitude long distance propagating contractions (p=0.007 vs placebo) while bisacodyl significantly increases the number of high-amplitude propagating contractions (HAPCs) (all p<0.01 vs PEG, prucalopride, and placebo). Prucalopride has no major effect on the number of propagating contractions but increases HAPCs amplitude (p=0.01). In humans, PEG, prucalopride, and bisacodyl have distinct effects on colonic motility. This information has clinical implication, as it indicates that the combination of prucalopride and bisacodyl, normally not considered in clinical practice, could be effective in treating patients with constipation refractory to single medications.

1907-2020: more than one century of colonic mass movements in humans.

Motility of the large bowel may be grossly subdivided in two types of contractile activity: low-amplitude single or cyclic propagated waves and high-amplitude propagated activity. The latter is mainly apt to shift relatively large amounts of colonic contents, and it is related to defecation. The main component of this propagated activity is represented by the radiologically identified mass movements that have a manometric equivalent known as high-amplitude propagated contractions (HAPC). The present article reviews origins and characterization of HAPC in the time course of colonic motility investigations, and correlates it with technological advancements in recent years, putting into perspective the future possible options to better detect and investigate these important physiological events.

Evaluation of Fecal Incontinence in Pediatric Functional Constipation: Clinical Utility of Anorectal and Colon Manometry.

The aim of the study is to evaluate the utility of motility studies in pediatric functional constipation with/without fecal incontinence. Patients with functional constipation and failure to conventional therapy undergoing colonic manometry (CM) and/or anorectal manometry (ARM) manometry were classified as functional constipation without fecal incontinence (FC) or with fecal incontinence (FCI). Clinical data, motility parameters, and treatment outcomes were compared. A total of 280 were included, and all patients underwent CM (229 FC and 51 FCI) and 219 ARM. We found no difference in CM interpretation and presence of normal high amplitude propagating contractions (HAPCs) between groups; however, patients with FCI had higher frequency and presence of HAPCs and normal gastrocolonic meal response (GC). No CM parameter predicted outcomes. In FC, more patients with an abnormal CM responded to therapy compared to those with a normal study (79% vs 65% respectively, P = 0.04). FCI patients had lower median anal resting pressure compared to FC (49 vs 66 mmHg, respectively, P = 0.03); no other ARM parameter differentiated FC from FCI. We found no association between therapy response and ARM interpretation (P = 0.847) or any ARM parameter. A multivariate analysis found only male gender was associated with FCI (P < 0.001). FCI patients have higher frequency of normal CM parameters compared to FC, but overall interpretation was no different. CM helped predict response to therapy in FC but not in FCI. ARM demonstrated no added benefit in the evaluation of functional constipation with/without soiling. Patients with both normal ARM and CM had a lower response to therapy than those with abnormal studies.

Characterization of the colonic response to bisacodyl in children with treatment-refractory constipation.

Colonic manometry with intraluminal bisacodyl infusion can be used to assess colonic neuromuscular function in children with treatment-refractory constipation. If bisacodyl does not induce high-amplitude propagating contractions (HAPCs), this can be an indication for surgical intervention. A detailed characterization of the colonic response to intraluminal bisacodyl in children with constipation may help to inform clinical interpretation of colonic manometry studies. Studies were performed in five pediatric hospitals. Analysis included identification of HAPCs, reporting HAPCs characteristics, and an area under the curve (AUC) analysis. Comparisons were performed between hospitals, catheter type, placement techniques, and site of bisacodyl infusion. One hundred and sixty-five children were included (median age 10, range 1-17years; n=96 girls). One thousand eight hundred and ninety-three HAPCs were identified in 154 children (12.3±8.8 HAPCs per child, 0.32±0.21 HAPCs per min; amplitude 113.6±31.5mm Hg; velocity 8.6±3.8mm/s, propagation length 368±175mm). The mean time to first HAPC following bisacodyl was 553±669s. Prior to the first HAPC, there was no change in AUC when comparing pre- vs post-bisacodyl (Z=-0.53, P=.60). The majority of HAPCs terminated in a synchronous pressurization in the rectosigmoid. Defecation was associated with HAPCs (χ2 (1)=7.04, P<.01). Site of bisacodyl administration, catheter type, and hospital location did not alter the response. Intraluminal bisacodyl induced HAPCs in 93% of children with treatment-refractory constipation. The bisacodyl response is characterized by ≥1 HAPC within 12minutes of infusion. The majority of HAPCs terminate in a synchronous pressurization in the rectosigmoid. Optimal clinical management based upon colonic manometry findings is yet to be determined.

Utility of Colon Manometry in Guiding Therapy and Predicting Need for Surgery in Children With Defecation Disorders.

Colon manometry (CM) has emerged as a tool to evaluate children with defecation problems. Our aim was to evaluate the utility of CM in guiding therapy and predicting surgery in pediatric constipation. Retrospective review of children undergoing CM for 4 indications: constipation, fecal incontinence, postsurgical evaluation and chronic intestinal pseudo-obstruction. Variables included age, sex, follow-up, and CM parameters: gastrocolonic response (GC) and quality/quantity of high-amplitude propagating contractions (HAPCs). medical, surgical or no intervention. response to change of therapy guided by CM, response to first intervention guided by CM (CMI) and CM predicting surgery (CMS). Response to therapy was classified according to study indication. Five hundred fifty-five studies (448 patients, 54.4% female; median age 8.9 years) were included, 24% of studies were normal. Change of therapy guided by CM was associated with a high response rate (P = 0.003). Overall response to stimulant laxatives was 48% and was not associated with CM findings. Surgical interventions had a higher response rate than medical or other interventions (P < 0.001). We found no association between the CM interpretation and CMI, but an abnormal CM was predictive of surgery (P < 0.01). GC and presence/number of HAPCs were not associated with CMI or CMS. We also found no association between HAPC quality and CMI but partially propagated HAPCs were predictive of surgery (P < 0.001). Logistic regression analysis showed no factors associated with CMI; however, longer follow up and partially propagated HAPCs were predictive of surgery. CM is useful in pediatric defecation disorders, although not predictive of successful medical intervention, an abnormal CM is predictive of surgery. CM should be performed only after medical interventions have failed and surgery is contemplated.

The evaluation of GI-pill gastrointestinal electronic capsule for colonic transit test in patients with slow transit constipation.

The evaluation of GI-pill gastrointestinal electronic capsule for colonic transit test in patients with slow transit constipation (STC) was studied. STC patients (n = 162) were randomly divided into experimental group (n = 84, orally taken GI-pill gastrointestinal electronic capsule and X-ray granule capsule) and control group (n = 78, orally taken X-ray granule capsule). Comparison of the time in colonic transit test between the two groups was conducted. The data of GI-pill gastrointestinal electronic capsule in vivo time, time of capsule passing through the colon, the number of high amplitude propagating contractions (HAPCs), and physiological response ratio were analyzed. There were no significant differences in the whole colonic transit test time, right colonic transit time, left colonic transit time, and rectosigmoid colonic transit time between experimental group and control group (p > 0.05). All patients had no abdominal pain, nausea, vomiting, black stool, difficulty in electronic capsule excretion, or any other discomfort during the test. GI-pill gastrointestinal electronic capsule can continuously evaluate the dynamic characteristics of digestive tract in STC patients and is consistent with X-ray granule capsule, which is meaningful to clinical application.

Preservation of the colo-anal reflex in colonic transection and post-operative Hirschsprung's disease: Potential extrinsic neural pathway.

The colo-anal reflex is a distinct reflex whereby the internal anal sphincter (IAS) relaxes in association with colonic high amplitude propagating contractions (HAPCs) in contrast to the recto-anal inhibitory reflex (RAIR), which is characterized by IAS relaxation upon rectal distension. The RAIR is mediated by the myenteric plexus and therefore absent in Hirschsprung disease. We retrospectively assessed the presence and the characteristics of the colo-anal reflex in children in whom large bowel continuity had been surgically disrupted to assess the role of the extrinsic nervous system in the reflex. High-resolution (HR) colonic manometry and HR-anorectal manometry were used to evaluate both colonic and anal motor activity in ten children with treatment-unresponsive slow transit constipation (STC), who had previously undergone left-sided colostomy formation with consequent disruption of the bowel continuity, and in two children with Hirschsprung's disease (HSCR), who had previously undergone distal colon resection followed by Duhamel pull-through. Eight children with STC, normal colonic motor activity, and preserved large bowel continuity served as a control group. The presence and characteristics of colo-anal reflex were analyzed. In the study group, all patients showed the presence of both normal HAPCs and the presence of the colo-anal reflex. In two cases of HSCR, RAIR was absent; however, both patients demonstrated a colo-anal reflex. In children with disrupted continuity of the colon and/or abnormal anal reflex, the colo-anal reflex is still preserved suggesting that it is mediated by a different pathway from the RAIR, possibly an extrinsic neural pathway.

Segmental colonic dilation is associated with premature termination of high-amplitude propagating contractions in children with intractable functional constipation.

Colonic dilation is common in children with intractable functional constipation (FC). Our aim was to describe the association between segmental colonic dilation and colonic dysmotility in children with FC. We performed a retrospective study on 30 children with intractable FC (according to the Rome III criteria) who had undergone colonic manometry and contrast enema within a 12-month time period. Colonic diameter was measured at 5cm intervals from the anal verge up to the splenic flexure. Moreover, the distance between the lateral margins of the pedicles of vertebra L2 was measured to provide a ratio (colonic diameter or length/distance between the lateral margins; "standardized colon size" [SCS]). All manometry recordings were visually inspected for the presence of high-amplitude propagating contractions (HAPCs); a parameter for colonic motility integrity. The intracolonic location of the manometry catheter sensors was assessed using an abdominal X-ray. Colonic segments with HAPCs had a significantly smaller median diameter than colonic segments without HAPCs (4.08cm vs 5.48cm, P<.001; SCS 1.14 vs 1.66, P=.001). Children with prematurely terminating HAPCs had significantly larger SCS ratios for colonic diameter than children with fully propagating HAPCs (P=.008). SCS ratios for the length of the rectosigmoid and the descending colon and the SCS ratio for sigmoid colon diameter were significantly larger in children with FC compared to a previously described normative population (P<.0001, P<.0001 and P=.0007 respectively). Segmental colonic dilation was associated with prematurely terminating HAPCs and may be a useful indicator of colonic dysmotility.

Sequential incremental doses of bisacodyl increase the diagnostic accuracy of colonic manometry.

Colonic manometry is the standard diagnostic modality for evaluating colonic motility in children. Intraluminal bisacodyl is routinely used to trigger high-amplitude propagating contractions (HAPCs), a feature of normal colonic motility. Usually, only a single dose (0.2mg/kg) is suggested. We retrospectively explored whether the use of an additional higher (0.4mg/kg) dose of bisacodyl increases the yield of colonic manometry. In 103 children (median age: 8.8years, range 3.2-15.7years) with a diagnosis of slow transit constipation, colonic motility was recorded for 1h before and 1h after each of two incremental doses of bisacodyl (low, L, dose: 0.2mg/kg, max 10mg; high, H, dose: 0.4mg/kg, max 20mg) and the characteristics of HAPCs analyzed. High-amplitude propagating contractions were seen in 85 children. H dose significantly increased the proportion of patients with fully propagated HAPCs (H dose: 57/103 [55%], L dose: 27/103 [26%], p<0.001), paralleling the significant decrease in the proportion with partially propagated HAPCs (H dose: 29/103 [28%], L dose: 47/103 [46%], p<0.01). Mean HAPC number significantly increased throughout the colon at H compared to L dose (7.2±5.05 vs 5.6±5.1, p<0.05). Finally, the proportion of patients with normal pressure wave morphology of HAPCs significantly increased with higher dose (H dose: 55/85 [65%], L dose: 27/85 [32%], p<0.001). An additional higher dose of bisacodyl during colonic manometry improves colonic neuromuscular function suggesting its use might improve interpretation and decision making in children with slow transit constipation.

Prucalopride induces high-amplitude propagating contractions in the colon of patients with chronic constipation: a randomized study.

This study compared prucalopride, a selective, prokinetic, 5-HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high-amplitude propagating contractions (HAPCs) in patients with chronic constipation. This randomized, cross-over, reader-blinded study was conducted at a single site in the USA. The study was open to men and women aged 18-75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1 ]) in the 12 h after treatment administration. Analyses were also conducted at two co-primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2 ); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3 ). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity. Thirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12-h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2 ) and mean AUC, force, and amplitude (HAPC3 ) compared with PEG3350. Adverse events were mild or moderate. Prucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation. ClinicalTrials.gov number NCT01707667.

Short-Term Effects of Relamorelin on Descending Colon Motility in Chronic Constipation: A Randomized, Controlled Trial.

The pentapeptide ghrelin agonist, relamorelin, accelerates colonic transit in patients with chronic constipation (CC). In a murine model, relamorelin decreased excitability of colonic circular smooth muscle cells and colonic intraluminal pressure. To determine short-term effects of relamorelin on colonic motility measured by barostat and multilumen manometry in CC. In a placebo-controlled, single-dose, double-blind, randomized study in patients with CC, we investigated the motor effects of relamorelin, 100 μg, SQ (12 patients) compared to placebo SQ (six patients). A motility-barostat balloon assembly was used to measure colonic compliance; tone and phasic pressure activity were measured before and after a 1000-kcal milkshake meal (administered ~60 min post-medication). Overall "background" phasic pressure activity was assessed by: average amplitude and motility index (MI = ln[sum amplitudes × #contractions + 1]) over defined periods. High-amplitude propagating contractions (HAPCs) were characterized by amplitude >75 mmHg and propagating contractions >50 mmHg; both were propagated over at least 10 cm. Postprandial HAPCs were the primary end point. The study sample had 80% power to detect an increase of 3.3 HAPCs in the hour post-meal. Relamorelin, 100 μg, significantly induced more pre-meal propagated contractions [PCs of either >50 or >75 mmHg] compared to placebo (p < 0.05). Relamorelin also induced more post-meal PCs >50 or >75 mmHg than placebo. Relamorelin did not significantly alter colonic compliance, fasting or postprandial phasic pressure activity (20 min pre-meal fasting MI) or tone, and 60 min postprandial phasic pressure amplitude or MI, or tone. Relamorelin stimulates propagated colonic contractions without alteration of background irregular contractions in CC. ClinicalTrial.Gov registration number: NCT 01781104.

Colonic migrating motor complexes, high amplitude propagating contractions, neural reflexes and the importance of neuronal and mucosal serotonin.

The colonic migrating motor complex (CMMC) is a critical neurally mediated rhythmic propulsive contraction observed in the large intestine of many mammals. It seems to be equivalent to the high amplitude propagating contractions (HAPCs) in humans. This review focuses on the probable neural mechanisms involved in producing the CMMC or HAPC, their likely dependence on mucosal and neuronal serotonin and pacemaker insterstitial cells of Cajal networks and how intrinsic neural reflexes affect them. Discussed is the possibility that myenteric 5-hydroxytryptamine (5-HT) neurons are not only involved in tonic inhibition of the colon, but are also involved in generating the CMMC and modulation of the entire enteric nervous system, including coupling motility to secretion and blood flow. Mucosal 5-HT appears to be important for the initiation and effective propagation of CMMCs, although this mechanism is a longstanding controversy since the 1950s, which we will address. We argue that the slow apparent propagation of the CMMC/HAPC down the colon is unlikely to result from a slowly conducting wave front of neural activity, but more likely because of an interaction between ascending excitatory and descending (serotonergic) inhibitory neural pathways interacting both within the myenteric plexus and at the level of the muscle. That is, CMMC/HAPC propagation appears to be similar to esophageal peristalsis. The suppression of inhibitory (neuronal nitric oxide synthase) motor neurons and mucosal 5-HT release by an upregulation of prostaglandins has important implications in a number of gastrointestinal disorders, especially slow transit constipation.

Effect of short‐chain fatty acids and acidification on the phasic and tonic motor activity of the human colon

The effects of bacterial fermentation on human colonic motor activity could be explained by colonic acidification or short-chain fatty acid (SCFA) production. We compared in healthy volunteers the colonic motor effects of intracolonic infusion of neutral or acidic saline solutions and then of neutral or acidic solutions containing an SCFA mixture. 20 healthy volunteers swallowed a probe (with an infusion catheter, 6 perfused catheters and a balloon connected to a barostat) that migrated into the colon. Colonic motor activity was recorded in fasting basal state (1h), during (3h) and after (2h) intracolonic infusion in a random order on two consecutive days of 750mL of NaCl at pH 7.0 (neutral saline) or 4.5 (acidic saline) in 10 volunteers (first experiment) and of an SCFA mixture (acetic acid 66%, propionic acid 24% and butyric acid 10%; 100mM) at pH 7.0 or 4.5 in 10 other volunteers (second experiment). We determined for each hour a global motility index (reflecting phasic activity recorded by all catheters), the mean balloon volume (reflecting tonic activity), and the mean number of high-amplitude-propagated contractions (HAPCs). Intracolonic infusion of neutral or acidic solutions containing saline or an SCFA mixture did not change the global motility index, the barostat balloon volume, or the HAPC number compared with basal values. Under our experimental conditions, these findings suggest that the stimulation of colonic motor activity induced by carbohydrate fermentation is not explained by the acidification of the colonic contents or the resulting production of SCFAs.