Sensory and autonomic neuropathy in patients with idiopathic slow-transit constipation.

BACKGROUND: Slow-transit constipation (STC) is a severe disorder of unknown aetiology, which may result from an autonomic or sensory neuropathy. This study aimed to investigate patients with STC for the presence of neural dysfunction, and relate the findings to other factors, including any familial associations. METHODS: Thirty-three patients with STC were studied using standard neurophysiological tests and a range of quantitative sensory and autonomic tests. The findings were compared with those of 20 matched control subjects and nine diabetic patients with gastrointestinal symptoms. RESULTS: Twenty of the 33 patients with STC gave a family history of constipation, including an affected identical twin and Hirschsprung's disease (n = 3). None had abnormalities on neurological examination or nerve conduction studies. Fifteen of the 33 patients had abnormalities on quantitative tests, including all six who required a colectomy. Eleven patients with STC had reduced axon-reflex sweating in the presence of normal sweat gland responses (P < 0.001, all patients with STC versus controls). Twelve patients with STC had small sensory fibre dysfunction, with significantly increased thermal thresholds (cool, P < 0.05; warm, P < 0.01); these included six of nine patients with STC and rectal hyposensation. There were similar findings on quantitative testing in diabetic patients. CONCLUSION: Quantitative tests in patients with STC provide evidence of a small fibre neuropathy. The high incidence of a positive family history, particularly a possible association with Hirschsprung's disease, suggests a genetic basis, which deserves further investigation.

Adrenoceptors and colocolonic inhibitory reflex.

The colocolonic inhibitory reflex is characterized by inhibition of proximal colonic motility induced by distal colonic distension. The aim of this study was to investigate the underlying neural mechanisms of this reflex, in vivo, using an isolated loop of canine colon. In five beagle dogs, motility was recorded from an exteriorized colonic loop via a serosal strain gauge connected to a digital data logger and chart recorder. Inflation of a balloon in the distal colon resulted in inhibition of motility in the isolated loop. Inhibition of motor activity persisted following injection of propranolol (100 microg/kg intravenously), a beta-adrenoceptor antagonist, but was abolished following administration of the alpha2-adrenoceptor antagonist yohimbine (200 microg/kg intravenously). This study confirms that the colocolonic inhibitory reflex is mediated via the extrinsic nerves to the colon. As the reflex was abolished by alpha2-, but not beta-adrenoceptor blockade, this indicates that the reflex pathway involves alpha2-adrenoceptors.

Pelvic bioelectrical impedance measurements to detect rectal filling.

Anorectal sensory deficits are an important cause of defecatory disorders and are also a reason for evacuatory difficulties in patients undergoing total anorectal reconstruction. A method to detect rectal filling would be beneficial in such patients. We have investigated the feasibility of detecting rectal filling in vitro and in vivo by measuring changes in pelvic impedance. In vitro, a model of the pelvis was constructed using a cylindrical plastic tank filled with an electrolyte solution (conductivity 3 mS cm(-1)). Conductive Visking tubing representing the rectum was suspended in the tank and incrementally filled with artificial faeces. An impedance meter detected changes in voltage on rectal filling when an alternating current of 2 mA was passed at eight frequencies (4.8 to 612 kHz). In vivo, changes in pelvic bioelectrical impedance upon retrograde and antegrade rectal filling with artificial faeces were evaluated in three pigs, four electrodes being implanted in the pelvis. Impedance measurements accurately detected 'rectal' volume changes in vitro (n = 10, p < 0.0001; Kruskal Wallis), but not in vivo (n = 68, p = 0.48; Kruskal Wallis). This was probably due to extreme sensitivity of the detecting device to movement, a problem that needs to be resolved before this technique could be used in man.

Electrically stimulated smooth muscle neosphincter.

BACKGROUND: Most patients undergoing total anorectal reconstruction suffer some degree of incontinence despite the incorporation of an electrically stimulated gracilis neosphincter. As smooth muscle has the ability to maintain prolonged contraction without fatigue, the aim of this study was to assess the feasibility of developing an electrically stimulated smooth muscle neosphincter. METHODS: Electrical stimulation of the rabbit colon was performed via intramural wire electrodes using a constant voltage DC stimulator. Contractile activity was recorded by serosal strain gauges and an intraluminal pressure probe. RESULTS: Basal colonic pressure was 4-13 (median 11) cmH2O. Peak pressures generated by stimulated contractions (10 V, 1 ms, 10 Hz) ranged from 14 to 37 (median 26, n = 36) cmH2O and were significantly higher than those with spontaneous contractions (P = 0.005). During continuous stimulation contractions lasted for 45-96 (median 74) s. Intermittent stimulation using trains of electrical pulses of 1-2-min duration at 1-2-min intervals produced repeated contractions. Alternative contractions were produced when intermittent electrical stimulation was performed at two sites alternately with two pairs of electrodes more than 2.5 cm apart, producing a sustained high-pressure zone. CONCLUSION: An electrically stimulated smooth muscle neosphincter is feasible. It has potential applications in the management of faecal incontinence.

Selective autonomic and sensory deficits in slow transit constipation.

Chronic idiopathic constipation is likely to be a heterogeneous condition. Our previous studies on the stimulated sweating response suggested that autonomic dysfunction may be a cause in a subset of patients. Our aims were to test selectively the neural and sweat gland components of the sweat response and to test unmyelinated sensory fibres so as to determine whether a small fibre neuropathy is present. Twelve female patients with proven slow transit constipation and nineteen age-matched healthy volunteers took part in the study. The sensory tests included thermal thresholds and axon reflex vasodilatation in response to intradermal capsaicin, measured with a laser Doppler. Direct and axon reflex sweating was induced with intradermal methacholine and nicotine, respectively, and measured with an evaporimeter. Non-parametric tests were used for statistical comparison with a group of seven control subjects. Results are expressed as medians and range. All four patients who reported constipation from childhood had a selective deficit of unmyelinated afferent fibre function in the feet, with markedly elevated thresholds to warm sensation (controls 5.2; 4.3-10.6, patients 13.8; 11.8-16.1 delta T (degree C), P < 0.02) and heat pain (controls 10.6; 8.2-14.7, patients 18.1; 13.9-22.6 delta T (degree C), P < 0.05) and a reduced response to capsaicin (controls 47.0; 24-117, patients 13.5; 12-30 delta Flux (V), P < 0.005). In contrast, patients with adult onset constipation (n = 7) had a selective neural sweating deficit (controls 49.8; 32.0-61.8; patients 27.7; 7.3-44.3 g/m2 h, P < 0.05), indicating dysfunction of post-ganglionic sympathetic cholinergic fibres. Patients from both groups were shown to have normally functioning sweat glands in direct response to methacholine. Our findings suggest that patients with severe chronic idiopathic constipation may have selective small fibre neuropathies, of which constipation is a manifestation.

Oral erythromycin improves gastrointestinal motility and transit after subtotal but not total gastrectomy for cancer.

BACKGROUND: Erythromycin has been shown to be a powerful prokinetic of the gastrointestinal tract. Little is known about its value to improve motility and transit in gastrectomized patients. METHODS: Thirteen disease-free patients subjected to subtotal gastrectomy and 11 subjected to total gastrectomy for gastric cancer entered the study. Gastrointestinal transit of a standard 99mTc-labelled meal and fasting motility were studied before and after oral erythromycin. RESULTS: In patients who had subtotal gastrectomy mean(s.d.) gastric half-emptying time was 42(14) min before and 26(11) min after erythromycin (P = 0.011). Before erythromycin prolonged rhythmical contractions (3 per min) were recorded in eight patients, sporadic non-organized contractions in two and prolonged bursts of waves in one. After erythromycin, clustered waves resembling a migrating motor complex (MMC) appeared in eight patients, while rhythmic motor activity was unchanged in three. In patients who had total gastrectomy jejunal half-emptying time was 39(18) min before and 45(12) min after erythromycin. In eight patients, frequent MMCs were recorded, peristaltic in four, synchronous in one, antiperistaltic in two, with clusters of non-propagated waves in one. After erythromycin, longer peristaltic MMCs were recorded in three, antiperistaltic MMCs persisted in two, synchronous in one and clusters of non-propagated waves in two. CONCLUSION: Oral erythromycin improves gastrointestinal transit and motility after subtotal gastrectomy. The findings after total gastrectomy are controversial.

Electrically stimulated colonic reservoir for total anorectal reconstruction.

Total anorectal reconstruction after abdominoperineal excision of the rectum has failed to achieve perfect continence. Electrically stimulated reservoir evacuation in combination with an electrically stimulated gracilis neoanal sphincter might improve results. A J pouch was constructed in an isolated colonic loop of seven dogs. Bipolar square wave pulses were delivered via two intramural stainless steel electrode pairs at 10 Hz. Stimulation parameters were varied to achieve adequate contraction. Serosal strain gauges recorded spontaneous and stimulated pouch motility. Evacuation was quantified by a volume displacement technique and observed fluoroscopically. Recordings were performed for a median of 3 (range 1-11) months. At 10 Hz and 0.5 ms pulse width, stimulation was required for 2 min and at voltages of 15 V (n = 4), 18 V (n = 1) and 20 V (n = 2) to obtain a contraction of amplitude comparable to that of a spontaneous contraction. Suprathreshold stimulation invariably resulted in colonic pouch contraction. The mean(95 per cent confidence interval (c.i.)) stimulus-response latency was 25.5(1.9) s. The mean(95 per cent c.i.) intraluminal pressure generated during stimulation was 114.1(17.0) cmH2O and 64.6(12.0) cmH2O during spontaneous activity (P < 0.001). In conclusion, electrical stimulation via intramural electrodes produced contraction generating sufficient intraluminal pressure to effect evacuation of a canine colonic pouch. This has potential for incorporation with an electrically stimulated neoanal sphincter in total anorectal reconstruction to improve evacuation and continence.

Prolonged ambulatory canine colonic motility.

Canine gastrointestinal motility is studied at present in animals confined to a small cage or sling. The aims of this study were to record colonic activity over a 24-h period in eight dogs by an ambulatory method. Motility signals from implanted strain gauges were processed and stored via a portable battery-operated amplifier and digital recorder housed in a jacket. Ambulant interdigestive activity was the same as observed in laboratory experiments, with migrating colonic motor complexes (CMCs) and infrequent giant contractions (GCs). Feeding caused a multiphasic alteration in motility for 582.1 +/- 18.1 min (mean +/- SE). There were four distinct phases. During the "early" (0-2 h) postprandial period, phase 1 (mean duration: 55.1 +/- 4.0 min), which was distinguished by CMCs of high frequency and elevated amplitude in the proximal colon, and phase 2 (78.2 +/- 6.2 min), which had CMC characteristics similar to those in the interdigestive period, occurred. Phase 3 (218.8 +/- 13.6 min), a further period of increased motility, and phase 4 (339.1 +/- 14.0 min), characterized by low-amplitude long-duration CMCs, occurred during the "late" (2 h onward) postprandial response. With the exception of phase 3, postprandial phases were not always present following food intake, and their expression was markedly influenced by variations in meal time and by defecation immediately following feeding. Spontaneous defecation was characterized by a variety of motor profiles, with a GC accompanying two-thirds of episodes. We conclude that a more complete picture of canine colonic motility has been documented because of the development of the ambulatory system.

Macrolides in roles beyond antibiotic therapy.

Erythromycin and other macrolides with a closely related structure are widely used antibiotics. Side-effects related to administration of such drugs are mostly gastrointestinal. The direct effect of erythromycin on gastrointestinal motility was studied; it was found to have a stimulatory effect proximally, on stomach and duodenal motility, with an apparent distal inhibition. Gastric emptying was accelerated by erythromycin via an antroduodenal coordination mechanism, an effect that has proved to be beneficial in surgical and medical conditions in which gastroparesis is a problem. Erythromycin is now used experimentally and clinically; it has been found to accelerate gastric as well as gallbladder emptying and to have an effect on the oesophagus. Analogues of erythromycin have been developed that have potent gastrointestinal activity but little or no antibacterial potential. Macrolides modulate the antibacterial action of neutrophils, with some action on the oxidative burst. Finally, two new macrolide immunosuppressants have been developed that compare favourably with traditional drugs.

Effects of cholinoceptor and 5-hydroxytryptamine3 receptor antagonism on erythromycin-induced canine intestinal motility disruption and emesis.

1. Erythromycin administration is associated with gastrointestinal problems, disturbed gastrointestinal motility and emesis. This study in the dog investigates the underlying mechanisms. 2. Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs. All drugs were administered intravenously. 3. Erythromycin (7 mg kg-1) increased contractions of the proximal small intestine, and caused emesis in all fasted dogs and in 5 dogs after food. Atropine (50 mg kg-1 min-1) and hexamethonium (10 mg kg-1 h-1) partially inhibited the GI motility effects but did not significantly reduce emesis. 4. Metoclopramide at a high dose (2 mg kg-1 h-1) reduced the incidence of emesis in the presence of increased intestinal motility, but a low dose (150 micrograms kg-1 h-1) was ineffective. 5. A 5-hydroxytryptamine3 (5-HT3) receptor antagonist, MDL 72222 (1 mg kg-1), reduced emesis when given alone and combined with metoclopramide (low dose). The 5-HT4 receptor agonist BRL24924 (Renzapride, 1 mg kg-1) had no effect on emesis either alone in combination with metoclopramide. 6. In conclusion, erythromycin-induced GI motility disturbances and emesis are not causally related. Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated, emesis occurs at least in part via a 5-hydroxytryptaminergic mechanism, but does not involve the dopamine system.

Detection of subclinical autonomic neuropathy in constipated patients using a sweat test.

Chronic idiopathic constipation may be the result of an autonomic neuropathy. This hypothesis was tested in 23 constipated patients and 17 age matched controls, using the acetylcholine sweat spot test devised to test autonomic integrity in diabetes. Acetylcholine (0.01%) was injected in the dorsum of the foot painted with a mixture of starch and iodine. Active sweat glands appeared on the surface of the skin as small black dots which were photographed and counted, using a grid with 60 subareas. Two measurements were made: the number of dots per unit subarea (sweat spot test score) and the % number of abnormal subareas (with less than six spots). These two parameters were correlated. The median sweat spot test score was 9.53 in patients and 13.92 in controls (p = 0.0001), the receiver operating characteristic curve showing that a score of 12 delimited normal and abnormal subjects. Increasing age was correlated with a low score in patients, probably because of prolonged symptoms. Seventy per cent of patients and one control had a borderline or abnormal number of subareas. These results suggest that idiopathic constipation is associated with a degree of autonomic denervation. The sweat spot test is an easy, inexpensive method to test this hypothesis and deserves a place in the clinical assessment of slow transit constipated patients.

Versatile digital data logger: storage of gastrointestinal motility data.

An inexpensive four-channel data logger for recording gastrointestinal potentials is described. A 512 K bytes memory and a sampling speed of 1.25 Hz per channel is adequate for these potentials and permits recordings for up to 27 hours. The small size and light weight allow the device to be carried in a pocket so that recordings can be made while the subject is freely ambulatory. A separate replay unit allows the data stored in the data logger to be presented to a chart recorder or to an interface card in a PC AT. This interface, a Microsoft C vers 5.0 program and the computer display the data as single frames or scrolled, expanded or condensed on either the time or amplitude axis. From the computer the data can be written to a printer and displayed as a chart or to an ASCII format file which can be used for analysis with statistical packages. Examples of recordings from both man and dog are illustrated and the analogue recorded data are compared with data digitally recorded. It is suggested that the data logger has many applications where long-term slow potential changes must be recorded under specially difficult conditions.

Construction of a neoanal sphincter by transposition of the gracilis muscle and prolonged neuromuscular stimulation for the treatment of faecal incontinence.

Six patients incapacitating faecal incontinence, in whom conventional treatment had either failed or was contraindicated, were treated by a new technique. A neonanal sphincter was constructed by transposing the gracilis muscle around the anal canal. Chronic neuromuscular stimulation via an implanted electrical stimulator was then used in an attempt to convert the muscle to a slow twitch fatigue resistant muscle. Physiological measurements suggested that this conversion had begun, enabling the neosphincter to mount a sustained contraction. Five patients had their covering stomas closed, and continence was improved in all of them. However, one patient could not cope psychologically with the stimulator, and another patient was continent for long periods only when the neosphincter was used in conjunction with a silastic plug. This new technique may benefit selected patients with incontinence whose only alternative would be a permanent stoma.

Electrically stimulated sartorius neosphincter: canine model of activation and skeletal muscle transformation.

The sartorius muscle was transposed into the abdominal cavity of six dogs, passed around a Thiry-Vella loop and sutured to itself to form a neosphincter. The muscle was activated by electrical stimulation and on contraction the neosphincter stopped or reduced the flow of saline through the Thiry-Vella loop in all animals until the onset of muscle fatigue. Continuous low frequency stimulation was used to transform the skeletal muscle, and when studied after a mean of 8 weeks of stimulation (range 6-11 weeks) the neosphincter stopped the flow for a significantly longer period of time (P = 0.027). Associated with the improved neosphincter function was a significant decrease in the fusion frequency (P = 0.003) and prolongation of the stimulus-peak tension time as assessed by a strain gauge sutured to the neosphincter muscle (P = 0.002). The changes in the contraction properties of the skeletal muscle suggest that continuous low frequency stimulation transformed the muscle fibres from type 2 to type 1, resulting in improved fatigue resistance and potential for continuous sphincter activity.

Effect of feeding on motor activity of canine stomach.

The motor response of the canine stomach to test meals of varied nutrient content and physical state, administered either orally or intraduodenally, was studied. Oral feeding abolished regular contractions in the proximal stomach. There was a simultaneous fall in the proximal gastric baseline force, which slowly recovered to the preprandial level, at which time regular contractions returned. The magnitude and duration of these events varied with the type of meal, as did the distal gastric response, which was characterized by abolition of the fasting motor pattern and establishment of continuous low-amplitude contractions. Duodenal feeding of a nutrient, but not nonnutrient, meal abolished fasting motor activity in both proximal and distal stomach but did not induce either a fall in proximal gastric baseline force or distal gastric contractions. These results suggest that stimulation of duodenal as well as gastric receptors is required to elicit the normal prandial response of both proximal and distal stomach.

Macrolides and gastrointestinal motility.

Erythromycin was the first macrolide used clinically, and it is still the most widely prescribed in spite of reports of gastrointestinal side-effects. Erythromycin was given iv or orally to fasted and fed dogs with sensors implanted on the gastrointestinal tract for the measurement of motility. There was a large increase in stomach and upper small bowel contractile activity, accompanied by nausea and vomiting, while the distal small bowel appeared inhibited. Similar effects were seen in man. By contrast, two 16-membered macrolides, spiramycin and josamycin, did not produce such side-effects when given either orally or intravenously to dogs.

Comparison of the side effects and gastrointestinal motility observed after administration of erythromycin and josamycin to dogs.

The effects of intravenous erythromycin and josamycin on gastrointestinal motility in dogs have been compared. Erythromycin interrupted the basal motility pattern in the fasted state and induced irregular bursts of spikes in both the fasted and fed states. Emesis occurred in all the dogs in the fasted state experiments and in four out of six dogs in the fed state experiments. Josamycin did not disturb gastrointestinal motility and no dog showed signs of discomfort. The difference in the chemical structure of erythromycin and josamycin is the main reason for their differential effect on the gastrointestinal tract.