Intramuscular Neostigmine and Glycopyrrolate Safely Accelerated Bowel Evacuation in Patients with Spinal Cord Injury and Defecatory Disorders

Difficulty with evacuation after spinal cord injury (SCI) may be due to a lack of parasympathetic stimulation of the colon. Prior studies in persons with spinal cord injury have suggested that intravenous administration of neostigmine stimulates colonic motility while glycopyrrolate attenuates some of the cholinergic side effects of neostigmine. We thus performed a double-blind, cross-over study to evaluate the effect of neostigmine/glycopyrrolate injections in patients with SCI and defecatory difficulties. Seven subjects received active treatment (neostigmine 2 mg and glycopyrrolate 0.4 mg intramuscularly) during three consecutive bowel evacuation sessions and were crossed-over to placebo injections for three consecutive sessions. Compared with placebo, neostigmine/glycopyrrolate reduced the total bowel evacuation time from 98.1 ± 7.2 to 74.8 min ± 5.8 (p < 0.05). The lowest heart rate or blood pressure was not significantly different between the treatment and placebo groups. In conclusion, neostigmine/glycopyrrolate may improve bowel evacuation in patients with SCI-related defecatory disorders.     

Gastrointestinal involvement in spinal cord injury: a clinical perspective

Bowel problems occur in 27% to 62% of patients with spinal cord injuries (SCI), most commonly constipation, distention, abdominal pain, rectal bleeding, hemorrhoids, bowel accidents, and autonomic hyperreflexia. The acute abdomen, with a mortality of 9.5%, does not present with rigidity or absent bowel sounds but rather with dull/poorly-localized pain, vomiting, or restlessness, with tenderness, fever, and leukocytosis in up to 50% of patients. Fecal impaction may present with anorexia and nausea. Methods used for bowel care include laxatives, anal massage, manual evacuation, and enemas. Randomized, double-blind studies demonstrated the effectiveness of neostigmine, which increases cholinergic tone, combined with glycopyrrolate, an anticholinergic agent with minimal activity in the colon that reduces extracolonic side-effects. Improved bowel function occurs with anterior sacral root stimulators which may be combined with an S2 to S4 posterior sacral rhizotomy which interrupts the reflex arc by cutting the posterior roots carrying the spasticity-causing sensory nerves. For severe constipation, a colostomy reduces time for bowel care, providing a clean environment so decubitus ulcers may heal. Gallstones occur in 17% to 31% of patients, and acalculous cholecystitis in 3.7% of patients with acute SCI. A high index of suspicion is needed to properly diagnose bowel problems in SCI.     

Neostigmine

BACKGROUND: Ogilvie's syndrome, or acute colonic pseudo-obstruction, is a common and relatively dangerous condition. If left untreated, it may cause ischemic necrosis and colonic perforation, with a mortality rate as high as 50 percent. Neostigmine enhances excitatory parasympathetic activity by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission and enhancing cholinergic action. We hypothesized that neostigmine would restore peristalsis in patients with acute colonic pseudo-obstruction. METHODS: Twenty-eight patients at Fletcher Allen Health Care and The Cleveland Clinic Foundation were treated for acute colonic pseudo-obstruction with neostigmine 2.5 mg IV over 3 minutes while being monitored with telemetry. Mechanical obstruction had been excluded. RESULTS: Complete clinical resolution of large bowel distention occurred in 26 of the 28 patients. Time to pass flatus varied from 30 seconds to 10 minutes after administration of neostigmine. No adverse effects or complications were noted. Of the two patients who did not resolve, one had a sigmoid cancer that required resection and one patient died from multiorgan failure. CONCLUSION: This study supports the theory that acute colonic pseudo-obstruction is the result of excessive parasympathetic suppression rather than sympathetic overactivity. We have shown that neostigmine is a safe and effective treatment for acute colonic pseudo-obstruction.Presented at The American Society of Colon and Rectal Surgeons Annual Meeting, San Antonio, Texas, May 2 to 7, 1998.     

Decreased colonic motility in persons with chronic spinal cord injury

OBJECTIVES: In persons with spinal cord injury (SCI), several studies have shown that large bowel transit is decreased at the level of the left colon and rectum, and that postprandial colonic response to food is absent. To define these parameters further, the effects of food on colonic motility in persons with SCI were studied and compared to those of spinally intact (SI) individuals. METHODS: The study was conducted in eight subjects with SCI (four paraplegic and four quadriplegic) and six age-matched SI subjects. After routine bowel preparation, colonoscopy was performed with the proximal end of a solid state pressure transducer catheter (four sensors each separated by 10 cm) tethered to the splenic flexure using endoclips (Olympus). The subjects were then allowed to carry out their usual daily activities. Two phases were compared: 1 h before breakfast, designated as the "resting phase," and 1 h during breakfast, designated as the "food-ingestion phase." RESULTS: Baseline colonic activity of the SCI group was significantly less than in SI subjects. During meals, the motility index, mean amplitude of the waves, percent activity, and number of waves was significantly less in the SCI group. In both the SI and SCI groups, a postprandial colonic response was observed. However, in the SCI group, the response was seen only in the descending colon and not in the rectosigmoid region. CONCLUSIONS: SCI decreases colonic motility, and this alteration may relate to difficulty with evacuation. The postprandial colonic response in SCI is present but is suboptimal and confined to the descending colon.     

The Effect of Cisapride on Segmental Colonic Transit Time in Patients with Spinal Cord Injury

Objectives : The pathophysiological consequences of spinal cord injury (SCI) on function of the colon are complex and poorly understood. Regardless of the mechanism, many patients with SCI have deficient bowel control, which is frustrating and difficult to treat. We designed a study to assess whether a new prokinetic medication, cisapride, might be useful in this setting. Methods : Total and segmental colonic transit time were measured using the radiopaque marker technique in nine subjects with spinal cord injury and seven control subjects after the double-blind administration of cisapride (10 mg q.i.d .) or placebo. Results : In five quadriplegic subjects with prolonged colonic transit time, administration of cisapride was found to reduce left-sided colonic transit time from 24.2 to 13.8 h. In three of these five subjects, cisapride administration resulted in subjective improvement. No effect of cisapride on right-sided, rectosigmoid, or total colonic transit time was observed. Conclusion : The data suggest that cisapride might be a useful adjunctive measure in treating a subset of SCI patients with colonic inertia, but a larger study is needed before this can be routinely recommended.     

Does uncomplicated diverticular disease produce symptoms?

A questionnaire dealing with bowel symptoms was administered to 97 outpatients referred for air-contrast barium enema. Subsequenlly, the barium enema was interpreted by a radiologist who did not know the results of the questionnaire. Forty-nine had normal x-rays, and 27 had uncomplicated diverticular disease. Weight loss, rectal bleeding, abdominal pain, and pain at night were as common in those with a normal examination as in those with diverticula. Symptoms of colon dysfunction included abdominal pain relieved by defecation, altered stool frequency and consistency with pain onset, abdominal distension, feeling of incomplete evacuation after defecation, and mucus in the stool. These were equally prevalent in both groups. Therefore, no symptoms could be ascribed to the presence of diverticulaSupported by the Ottawa Foundation of Medical Research.     

Rectosigmoid motility response to sham feeding in irritable bowel syndrome. Evidence of a cephalic phase

Rectosigmoid pressure recordings by means of open-ended perfused catheters were performed on 21 patients with the irritable bowel syndrome (IBS). Motility indexes were calculated in resting conditions, after sham feeding, after a meal, and after 0.5 mg neostigmine intravenously. Each step of stimulation caused a significantly increased motility index compared with the previous step (p less than 0.01). The increase in rectosigmoid pressure activity after sham feeding indicates the existence of a cephalic phase in the postprandial motor response of the colon in IBS.     

Evidence for differential reflex regulation of cholinergic and noncholinergic parasympathetic nerves innervating the airways

The hypothesis that cholinergic and nonadrenergic, noncholinergic parasympathetic nerves innervating the airways are subject to differential reflex regulation was addressed. Pronounced contractile and relaxant parasympathetic reflex responses could be evoked by intravenous histamine, laryngeal mucosal application of capsaicin, inhaled capsaicin, or electrical stimulation of the vagal afferent nerves projecting to the esophagus and abdominal viscera. These data suggest that activation of multiple vagal afferent nerve subtypes can initiate both cholinergic and noncholinergic parasympathetic reflexes in the airways. Conversely, hypoxia or activation of the diving response from the nose evoked only cholinergic contractile reflexes. All contractile and relaxant responses evoked by these stimuli were absent in vagotomized animals or in animals pretreated with the ganglionic blocker trimethaphan, confirming their reflex and parasympathetic nature. The data indicate that cholinergic and noncholinergic parasympathetic nerves regulating airway caliber in guinea pigs are comprised of two distinct parasympathetic pathways that are subject to differential reflex regulation. This previously unrecognized complexity of autonomic regulation of airway caliber has potentially important implications for the mechanisms of airways hyperresponsiveness.     

Cholinesterase activity is similar in C3H/HeJ and A/J mice and does not account for their different bronchoconstrictor responsiveness.

Significant interstrain variation in airway responsiveness to acetylcholine (ACh) exists in inbred mouse strains. We hypothesized that part of the variation may be due to between-strain differences in cholinesterase activity. We asked if administration of neostigmine (an acetylcholinesterase inhibitor) and/or succinylcholine (an agent which competes for and inhibits butyrylcholinesterase) altered ACh responsiveness in hyporesponsive C3H/HeJ and hyperresponsive A/J mouse strains. Airway responses to ACh were measured by the airway pressure time index in the presence and absence of succinylcholine (10 mg/kg) and/or neostigmine (0.7 mg/kg). In addition, acetylcholinesterase and butyrylcholinesterase activity were directly measured. Acetylcholinesterase and butyrylcholinesterase inhibition increased airway responses to acetylcholine in both strains, but did not eliminate or decrease the differences in airway responsiveness to ACh previously seen in the two strains. Cholinesterase activities in the two strains were not significantly different. We conclude that differences in either acetylcholinesterase or butyrylcholinesterase in the A/J or C3H/HeJ mouse strains are unlikely to contribute to the differences in airway responsiveness to exogenously administered cholinergic agonists.     

Idiopathic intestinal pseudoobstruction. Report of a case, with intraluminal studies of mechanical and electrical activity, and response to drugs

Intraulminal recordings of motility were made from a patient with chronic idiopathic intestinal pseudoodstruction. Contractile activity was recorded from esophagus and duodenum with and without cholinergic stimulation. Electrical activity was recorded from duodenum with and without cholinergic stimulation. Contractile and electrical activities were recorded from the sigmoid colon at rest and after morphine. Gastric fundic relaxation was measured during balloon distention. This patient showed abnormalities of esophageal function similar to achalasia, while gastric fundic relation was impared, with a more rapid rise in pressure on distention than is seen in normal persons. Duodenal and colonic electric control and response activities were present on occasion. Duodenal contractions occurred in response to both bethanechol and edrophonium. Therefore, the efferent cholinergic system of the small bowel appears to be functional in this case of idiopathic intestinal pseudoobstruction. The nonardrenergic inhibitory control of esophagus and gastric fundus appears to be functioning abnormally.     

Effects of atropine sulfate and neostigmine on gastric electrical activity in human subjects--electrogastrographic study

BACKGROUND/AIMS: There are few reports about the cholinergic regulation of gastric electrical activities using percutaneous electrogastrograms (EGG). To determine the effect of intravenous administration of a vagal blocker (atropine sulfate) or a vagal stimulator (neostigmine) on gastric electrical activities EGG was utilized in this study. METHODOLOGY: EGG was recorded before and after administration of a vagal blocker (atropine sulfate, 0.02mg/kg) and/or vagal stimulator (neostigmine, 0.008mg/kg) in six normal volunteers. RESULTS: After administration of atropine sulfate, the original waves on EGG almost disappearedand decreased amplitudes were detected by visual inspection in all subjects. Moreover, increase amplitude on EGG was clearly demonstrated after administration of neostigmine in all subjects. It was also shown that the effects of these medicines persisted more than 60 minutes after injection. CONCLUSIONS: These findings suggest that the EGG reflected gastric motility, and that neurological regulation of EGG was mediated through the vagal and/or cholinergic efferent pathway.     

Early resolution of Ogilvie's syndrome with intravenous neostigmine

PURPOSE: Our aim was to assess the value of a parasympathomimetic drug (neostigmine) in the early resolution of acute colonic pseudo-obstruction (Ogilvie's syndrome). METHODS: A prospective study was undertaken in 18 consecutive patients (mean age, 76 (range, 31–87) years) with acute colonic pseudo-obstruction. After a varying period of conservative treatment in all cases, 16 patients with persistent, massive abdominal distention were given intravenous neostigmine. RESULTS: A rapid and satisfactory clinical and radiologic decompression of the large bowel was obtained in 12 patients (75 percent) after a single dose of the drug; another patient had complete resolution after a second dose, and the other 3 patients had only partial resolution, in one of them after a second dose of the drug. No patient required surgical decompression of the bowel. CONCLUSION: These results give support to the theory of excessive parasympathetic suppression in most cases of Ogilvie's syndrome. The treatment with intravenous neostigmine has proved very effective, preventing in many cases prolonged periods of uncomfortable and potentially hazardous conventional conservative management and avoiding surgical treatment in a consecutive series of patients.Presented in part at the XIX Congress of the European Federation of the International College of Surgeons (ICS)-National Congress of the Spanish Section of the ICS, Tenerife, Spain, October 12 to 14, 1995.     

Rectodynamics — quantifying rectal evacuation

A new technique is described which allows the graphic quantitation of voluntary rectal evacuation. The subject is asked to evacuate 100 ml of barium sulphate paste as rapidly and completely as possible. Using a weight transducer it is possible to determine the maximum emptying rate, time to achieve maximum emptying and proportion of barium evacuated. Normal subjects evacuate quickly and completely. Patients with severe constipation demonstrate a variable evacuation disturbance.     

The Effects of Ipratropium Bromide on Histamine-Induced Bronchoconstriction in Subjects with Cervical Spinal Cord Injury

Previously, we reported that a majority of subjects with chronic cervical spinal cord injury (SCI) demonstrated airway hyperreactivity in response to inhaled methacholine. To further investigate mechanisms of airway hyperreactivity, 15 male subjects with cervical SCI were challenged with aerosolized histamine, and on a separate day responders were rechallenged 30 min after the inhalation of 72 μg of ipratropium bromide. Twelve of 15 subjects demonstrated airway hyper-responsiveness to histamine (geometric mean PC₂₀ of 1.27 mg/ml), which was not blocked by pretreatment with ipratropium bromide (geometric mean PC₂₀ 1.50 mg/ml). Baseline forced vital capacity and forced expiratory volume in 1 sec were not significantly different between responders and nonresponders (2.8 ± 0.6 vs. 3.0 ± 0.4 L and 2.3 ± 0.6 vs. 2.4 ± 0.2 L, respectively). Findings that subjects with cervical SCI are hyperresponsive to methacholine and histamine, chemical agents with direct action through distinct receptor systems, suggest that bronchial hyperreactivity in these subjects represents a nonspecific process similar to that observed in patients with asthma.     

Epidural anaesthesia and postoperative colorectal motility — a possible hazard to a colorectal anastomosis

The effects of epidural anaesthesia (EDA, mepivacaine) and EDA in combination with atropine and neostigmine on postoperative intestinal motility were studied in 17 patients undergoing operation for cancer of the rectum or sigmoid colon. Motility was recorded by a volumetric technique. Epidural anaesthesia (EDA) increased motor activity in the small bowel as well as in the left colon and rectum. Phasic motility dominated in the small intestine whereas tonic and segmental contractions were recorded from the large bowel. EDA induced a powerful tonic contraction with a concomitant shortening of the rectum. This effect was inhibited by atropine. The influence of atropine/ neostigmine on left colonic motor activity was studied in six patients before and during EDA in a cross-over fashion. When administered alone, atropine/neostigmine did not cause any motility increase. Atropine/neostigmine administered during EDA, however, elicited a significant increase of motility. The increase of intestinal motor activity induced by EDA may expose a newly constructed colorectal anastomosis to undue strain in the immediate postoperative period. When EDA is used in combination with general anaesthesia, particular attention should be directed towards the use of neostigmine for reversing the effect of nondepolarizing muscle relaxants. Atropine appears under such circumstances not to protect from the excitatory effects of this drug on colorectal motility.     

Giant migrating contractions during defecation in the dog colon

The colonic motor correlates of defecation were studied in 5 conscious dogs. A set of six strain-gauge transducers were implanted on the colon of each dog. An implanted cannula gave access to the terminal ileum. During a total control recording period of 230 h we observed 12 large-amplitude contractions that occurred spontaneously in the proximal colon and migrated caudad. We called them giant migrating contractions. The mean amplitude of these contractions was 2.8 times larger than the mean peak amplitude of phasic contractions during colonic motor complexes. The following stimuli were applied to induce defecation: 2 mg/kg guanethidine (i.v.), 30 micrograms/kg neostigmine (i.v.), 1-4 ml/kg castor oil (p.o.), 200 ml of 25% glucose (into ileum), and rectal distention by a balloon (120 ml). In 85% of experiments with guanethidine, neostigmine, glucose, and castor oil, giant migrating contractions occurred before defecation. The giant migrating contractions migrated over the entire colon or a part of its length. The migration velocity varied from 0.2 to 3.2 cm/s (mean +/- SE, 0.82 +/- 0.1 cm/s). In 11% of the experiments, giant contractions occurred almost simultaneously at different recording sites at the time of defecation. In 4% of the experiments giant contractions occurred only at a single site. Balloon expulsion was only rarely accompanied by giant contractions in the colon, and then occurred only at a distal site and did not migrate. We conclude that the colon has spontaneous but infrequent large-amplitude caudad-migrating contractions. These contractions may be the motor equivalent of mass movements. Defecation is usually preceded by colonic giant migrating contractions. The giant migrating contractions may provide a major force for defecation and be partially responsible for the evacuation of the colon during defecation. However, evacuation of contents such as a balloon seems to be possible without giant migrating contractions.     

Involvement of the hippocampus in central nervous system-mediated glucoregulation in rats

To find out whether the hippocampus is involved in central nervous system-mediated glucoregulation, we injected saline, neostigmine, dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, and prostaglandin F2 alpha into the dorsal hippocampus in anesthetized fed rats. After injection of dopamine, norepinephrine, bombesin, beta-endorphin, somatostatin, or prostaglandin F2 alpha, the level of hepatic venous plasma glucose did not differ from that in saline-treated control rats. However, neostigmine, an inhibitor of acetylcholine esterase, caused a dose-dependent increase in the hepatic venous plasma glucose concentration. This neostigmine-induced hyperglycemia was dose-dependently suppressed by coadministration of atropine, but not by hexamethonium. Injection of neostigmine (5 X 10(-8) mol) resulted in an increase not only in glucose but also in glucagon, epinephrine, and norepinephrine in hepatic venous plasma. In bilateral adrenalectomized rats, neostigmine-induced hyperglycemia was suppressed, but the hepatic venous plasma glucose concentration still increased significantly. These results indicate that the hippocampus is involved in central nervous system-mediated glucoregulation through cholinergic muscarinic activation, partly via epinephrine secretion.     

Neural regulation of airway smooth muscle tone

Airway smooth muscle is innervated by sympathetic and parasympathetic nerves. When activated, airway nerves can markedly constrict bronchi either in vivo or in vitro, or can completely dilate a precontracted airway. The nervous system therefore plays a primary role in regulating airway caliber and its dysfunction is likely to contribute to the pathogenesis of airways diseases. The predominant contractile innervation of airway smooth muscle is parasympathetic and cholinergic in nature, while the primary relaxant innervation of the airways is comprised of noncholinergic (nitric oxide synthase- and vasoactive intestinal peptide-containing) parasympathetic nerves. These parasympathetic nerves are anatomically and physiologically distinct from one another and differentially regulated by reflexes. Sympathetic-adrenergic nerves play little if any role in directly regulating smooth muscle tone in the human airways. Activation of airway afferent nerves (rapidly adapting receptors, C-fibers) can evoke increases in airway smooth muscle parasympathetic nerve activity, or decreases in parasympathetic nerve activity (through activation of slowly adapting receptors). Extrapulmonary afferents can also modulate nerve mediated regulation of airway smooth muscle tone. In guinea pigs and rats, peripheral activation of tachykinin-containing airway afferent nerves evokes bronchospasm via release of substance P and neurokinin A. This effect of airway afferent nerve activation appears to be unique to guinea pigs and rats. The actions and interactions between the components of airway innervation are discussed.     

Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder

BACKGROUND & AIMS: Prucalopride (PRU) is a selective benzofuran 5-hydroxytryptamine(4)-receptor agonist with gastrointestinal and colonic prokinetic activities. We evaluated the effects of PRU on gastrointestinal and colonic transit in patients with constipation. METHODS: Gastrointestinal and colonic transit were measured over 48 hours in 40 patients who fulfilled modified Rome I criteria for functional constipation. Patients had no evidence of a rectal evacuation disorder. Subjects were randomized to receive a daily dose of 2 or 4 mg PRU or placebo in a double-blind, parallel-group design. Each treatment lasted 7 days. The transit test was performed over the last 48 hours of the study. Effects on gastric emptying, small bowel transit, and colonic transit were analyzed using Kruskal-Wallis and Wilcoxon rank sum tests. RESULTS: Of 61 patients screened, 40 were eligible and randomized. Two patients withdrew because of adverse events. PRU accelerated overall gastric emptying and small bowel transit. PRU tended to accelerate overall colonic transit with significantly faster overall colonic transit and ascending colon emptying with the 4-mg dose. CONCLUSIONS: PRU accelerates transit through the stomach, small bowel, and colon in patients with constipation unassociated with a rectal evacuation disorder.     

Perforation of the colon and rectum during administration of barium enema

Conclusions Perforation of the colon or rectum, with an attendant high mortality rate, is apt to occur during administration of barium enema in patients in whom the bowel has been weakened by disease or trauma. This accident is probably more common than reports in medical literature would indicate. Five cases have been presented in which either intraperitoneal or extraperitoneal rupture of a previously defective bowel occurred during barium enema administration. Rupture was due to excessive distention of the wall of the bowel by inflation of a Bardex retention balloon in two patients. Pressure of an ordinary barium enema on a diseased and weakened colon wall was probably the reason for intraperitoneal perforation in two of the other cases. Added precautions and care by the clinician and the radiologist will aid in preventing this catastrophe in some cases where the bowel is susceptible because of disease or injury. Read at the meeting of the American Proctologic Society, Los Angeles, California, June 29 to July 3, 1958.