Citations

AbstractBackgroundIn order to understand the pathophysiology of rectal sensorimotor dysfunctions in women with fecal incontinence (FI) and rectal urgency, we evaluated the effects of a muscarinic antagonist and an adrenergic α2 agonist on these parameters.MethodsFirstly, rectal distensibility and sensation were evaluated with a barostat and sinusoidal oscillation at baseline and after randomization to intravenous saline or atropine in 16 healthy controls and 44 FI patients. Thereafter, FI patients were randomized to placebo or clonidine for 4 wk; rectal compliance and sensation were revaluated thereafter. The effect of atropine and clonidine on rectal functions and the relationship between them were evaluated.ResultsAt baseline, compared to controls, rectal capacity was lower (P = .03) while the mean pressure (P = .02) and elastance (P = .01) during sinusoidal oscillation were greater, signifying reduced distensibility, in FI. Compared to placebo, atropine increased (P ≤ .02) the heart rate in controls and FI and reduced (P = .03) the variability in rectal pressures during sinusoidal oscillation in controls. Clonidine increased rectal compliance (P = .04) and reduced rectal capacity (P = .03) in FI. The effects of atropine and clonidine on compliance (r = .44, P = .003), capacity (r = .34, P = .02), pressures during sinusoidal oscillation (r = .3, P = .057), pressure (r = .6, P < .0001), and volume sensory thresholds (r = .48, P = .003) were correlated.ConclusionsThe effects of atropine and clonidine on rectal distensibility and sensation were significantly correlated. A preserved response to atropine suggests that reduced rectal distensibility is partly reversible, mediated by cholinergic mechanisms, and may predict the response to clonidine, providing a pharmacological challenge.

AbstractBackgroundThe reproducibility of gastric emptying (GE) measured with scintigraphy in patients is poorly understood. Our aims were to assess the intra and inter‐individual reproducibility of these parameters in patients with upper gastrointestinal symptoms.MethodsSixty patients (21 diabetics, 39 non‐diabetics) with upper gastrointestinal symptoms underwent scintigraphic‐assessment of GE of a solid meal (296 kcal, 30% fat) over 4 hours on two occasions at an average interval of 15 days. The concordance correlation coefficient (CCC), intra and inter‐individual coefficients of variation (COV) of GE endpoints were analyzed.ResultsThe GE t1/2 was 134 ± 8 minutes (mean ± SEM) for the first and 128 ± 6 minutes for the second study. The mean (95% CI) CCC between the two studies was 0.79 (0.67, 0.87) for GE at 1 hour, 0.83 (0.75, 0.9) for GE at 2 hours, 0.54 (0.34, 0.7) for GE at 4 hours, and 0.79 (0.68, 0.86) for GE t1/2. However, in 18 of 60 patients (30%), the characterization of GE as normal, delayed, or rapid differed between the first and second studies. For gastric empting t1/2, the inter‐individual coefficients of variation was 40%; the intra‐individual COV was 20%, comparable in diabetics and non‐diabetics, and greater in patients with rapid (28%) than delayed (18%) or normal GE (12%).Conclusions & InferencesAmong patients with upper gastrointestinal symptoms, GE measured with scintigraphy is relatively reproducible. In 30% of cases, the interpretation was different between the two assessments. Hence, a diagnosis of gastroparesis based on a single study may occasionally be inaccurate.

AbstractWhile the pharmacological armamentarium for chronic constipation has expanded over the past few years, a substantial proportion of constipated patients do not respond to these medications. This review summarizes the pharmacological and behavioral options for managing constipation and details the management of refractory constipation. Refractory constipation is defined as an inadequate improvement in constipation symptoms evaluated with an objective scale despite adequate therapy (ie, pharmacological and/or behavioral) that is based on the underlying pathophysiology of constipation. Minimally invasive (ie, rectal irrigation and percutaneous endoscopic colostomy) and surgical therapies are used to manage refractory constipation. This review appraises these options, and in particular, percutaneous endoscopic colostomy, which as detailed by an article in this issue, is a less invasive option for managing refractory constipation than surgery. While these options benefit some patients, the evidence of the risk: benefit profile for these therapies is limited.

AbstractBackgroundEndoanal MRI and MR defecography are used to identify anal sphincter injury and disordered defecation. However, few studies have evaluated findings in asymptomatic healthy people. The effects of BMI and parity on rectoanal motion and evacuation are unknown.MethodsIn 113 asymptomatic females (age 50 ± 17 years, Mean ± SD) without risk factors for anorectal trauma, anal sphincter appearance, anorectal motion, and pelvic organ prolapse were evaluated with MRI. The relationship between age, BMI, and parity and structural findings were evaluated with parametric and non‐parametric tests.ResultsThe anal sphincters and puborectalis appeared normal in over 90% of women. During dynamic MRI, the anorectal angle was 100 ± 1º (Mean ± SEM) at rest, 70 ± 2° at squeeze, and 120 ± 2° during defecation. The change in anorectal angle during squeeze (r = −.25, P < .005), but not during evacuation (r = .13, P = .25) was associated with age. In the multivariable models, BMI (P < .01) and parity (P < .01) were, respectively, independently associated with the intersubject variation in the anorectal angle at rest and the angle change during squeeze. Ten percent or fewer women had had descent of the bladder base or uterus 4 cm or more below the pubococcygeal line or a rectocele measuring 4 cm or larger. Only 5% had a patulous anal canal.ConclusionsIn addition to age, BMI and parity also affect anorectal motion in asymptomatic women. These findings provide age‐adjusted normal values for rectoanal anatomy and pelvic floor motion.

The cholinesterase inhibitor neostigmine indirectly stimulates muscarinic M1/M2/M3 receptors, thereby reducing colonic distension in acute colonic pseudo-obstruction. We investigated the dose-response profile for the colonic sensorimotor effects of neostigmine and bethanechol, a direct muscarinic M2/M3 agonist in humans. A barostat-manometric assembly recorded phasic pressures, tone, and pressure-volume relationships (compliance) in the descending colon and rectum of 30 healthy subjects who received intravenous neostigmine (0.25, 0.75, or 1.5 mg; n = 15) or subcutaneous bethanechol (2.5, 5, or 10 mg; n = 15). Sensation to luminal distension was also assessed. Thereafter, the effects of neostigmine and bethanechol on colonic transit (geometric center) were compared with those of saline by scintigraphy in 21 subjects. Both drugs increased colonic phasic pressure activity, reduced rectal compliance, and enhanced urgency during rectal distension. Neostigmine also reduced colonic and rectal balloon volumes, reflecting increased tone by an average of 12% and 25% for the highest dose, respectively. Only neostigmine reduced colonic compliance, accelerated colonic transit [mean geometric center at 90 min 2.5 vs. 1.0 (placebo)], and increased pain perception during colonic distension. We conclude that neostigmine has more prominent colonic motor and sensory effects than bethanechol. Moreover, neostigmine induces coordinated colonic propulsion, perhaps by stimulating muscarinic M1 receptors in the myenteric plexus.

Our objectives were to characterize colonic viscoelastic properties of the human descending colon by assessing pressure-volume (P-V) relationships during barostatic balloon distension. In 16 healthy subjects, a balloon was inflated to 44 mmHg and then deflated to 0 mmHg in 4-mmHg steps at 10, 30, and 60 ml/min, allowing volume fluctuations to stabilize at each pressure increment. Thereafter, these “quasi-static” P-V curves were compared with “dynamic” distensions to 300 ml, at 1 and 10 ml/s, before and after intravenous atropine in another five subjects. During quasi-static curves, balloon volume stabilized at each pressure increment. Quasi-static P-V curves were reproducible within individuals and approximated to a power exponential function and revealed hysteresis, indicative of viscoelasticity. Body mass index influenced quasi-static P-V curves during inflation but not during deflation. The colon was less compliant during dynamic distensions at 10 ml/s than during quasi-static distensions. Atropine increased quasi-static compliance and attenuated differences between quasi-static and rapid distensions. We conclude that colonic viscoelastic properties can be assessed by quasi-static P-V curves. Rapid colonic distension activated neural reflexes, thereby reducing colonic compliance compared with quasi-static distensions.

The effects of pharmacological modulation of adrenergic receptors on colonic motor and sensory function are unclear. We studied 40 healthy volunteers in a single-blind design; 12 received saline, and the remaining 28 received either clonidine, yohimbine, phenylephrine, or ritodrine. A barostat-manometric assembly in the left colon recorded drug effects on fasting and postprandial motor function, compliance, and sensation in response to standardized phasic balloon distensions delivered in random order. Clonidine reduced and yohimbine increased fasting, but not postprandial tone, by 63.2 ± 22.3% and 24.8 ± 8.8% (SE), respectively. Clonidine tended to reduce fasting phasic activity in the descending and sigmoid colon. A power exponential model provided the best fit to the compliance curve. Clonidine significantly increased colonic compliance. Clonidine reduced and yohimbine increased colonic perception of pain but not gas sensation during distension. Phenylephrine and ritodrine did not influence colonic motor or sensory function in the present studies. Thus α2-receptors modulate fasting colonic tone and compliance and alter perception of pain but not gas during mechanical stimulation of the colon.

Our aims were to assess the role of adrenergic modulation in the hyperventilation-induced increase in colonic tone. Of 40 healthy volunteers, 12 received placebo (saline) and the remaining 28 received either clonidine, yohimbine, phenylephrine, or ritodrine. Time-frequency mapping of heart rate based on Wigner distribution assessed variations in parasympathetic and sympathetic activity during hyperventilation. Tone in the descending colon was recorded by a barostat balloon before, during, and after 5 min of hyperventilation. Heart rate spectral analysis suggested diminished sympathetic and vagal activity during hyperventilation and increased sympathetic and vagal activity after hyperventilation. Adrenergic agents influenced ( P = 0.01) the tonic response after, but not during, hyperventilation. Yohimbine reduced the increment in colonic tone after hyperventilation compared with saline ( P < 0.05) and clonidine ( P = 0.002); phenylephrine and ritodrine had no effects. Different mechanisms modulate the increase in colonic tone during and after hyperventilation. Yohimbine attenuates the increase in colonic tone after hyperventilation probably by enhancing inhibitory sympathetic input to the colon.

The Institute of Medicine and US Food and Drug Administration (FDA) recognize that activating clinical trials in the United States is lengthy and inefficient. Downstream consequences include increased expense, suboptimal accrual, move of clinical trials overseas, and delayed availability of treatments for patients. An in‐tandem processing initiative is here highlighted that transformed the activation of clinical trials (TACT), reduced the activation time by 70%, and offers a paradigm for enhanced translational readiness.