Journal of Pediatric Gastroenterology & Nutrition:
Effect of Octreotide on Gastrointestinal Motility in Children with Functional Gastrointestinal Symptoms
Di Lorenzo, Carlo; Lucanto, Cristina; Flores, Alejandro F.†; Idries, Shaheen*; Hyman, Paul E.*
Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, *Children's Hospital of Orange County, California; and †Newton Wellesley Hospital, Newton, Massachusetts, U.S.A.
Received March 9, 1998; revised April 27, 1998; accepted May 1, 1998.
Address correspondence and reprint requests to Carlo Di Lorenzo, Children's Hospital of Pittsburgh, University of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, U.S.A.
Background: The somatostatin analogue octreotide has been proposed as a possible therapeutic agent in patients with abnormal gastrointestinal motility. This study was conducted to study the effects of 0.5 µg/kg and 1.0 µg/kg subcutaneous octreotide on antroduodenal motility in children with chronic gastrointestinal disorders.
Methods: Twenty-three children were studied, eight with intestinal pseudo-obstruction, six with nonulcer dyspepsia, six with gastroesophageal reflux disease, and three with intractable constipation. After recording fasting motility for more than 4 hours, the children were randomized to receive 0.5 µg/kg or 1 µg/kg of subcutaneous octreotide. Motility was recorded for another hour after feeding in 12 children.
Results: Phase III of the motor migrating complex was present in 13 of 23 children before and in 21 after octreotide (p < 0.02). All phase III episodes after administration of octreotide except one originated in the small intestine. Phase IIIs after octreotide were longer and were propagated faster than the spontaneous phase IIIs. There were no antral contractions during fasting after octreotide. There was a significant decrease in phase II intestinal motor activity in the hour after administration of octreotide (p < 0.001). There was no difference in effect between the two doses. After feeding, antral contractions were present in all children, and intestinal phase IIIs were not abolished.
Conclusions: In children with chronic bowel disorders, subcutaneous octreotide induced phase IIIs that differed from spontaneous phase IIIs and were not inhibited by meals. Octreotide decreased antral motility during fasting and inhibited intestinal phase II. Feeding abolished the inhibitory effect of octreotide on antral motility.
The normal gastrointestinal motility pattern during fasting is organized into a cycle of three motor phases known together as the interdigestive migrating motor complex (MMC). Phase III of the MMC is the most recognizable pattern and consists of an aborally migrating cluster of contractions 2 minutes long or more at the highest possible frequency for that part of the gastrointestinal tract (1). A meal inhibits the MMC and induces a fed pattern qualitatively similar to phase II but with contractions of greater amplitude and frequency. Abnormalities in fasting and postprandial intestinal motility are found in a variety of childhood functional gastrointestinal disorders including in adolescents with chronic functional gastrointestinal symptoms such as vomiting, abdominal distention, and abdominal pain (2) and in children with nonulcer dyspepsia (3). Although in adults the absence of phase IIIs during a 4-hour manometric study is often associated with dyspeptic symptoms (3) or bacterial overgrowth (4), children without phase III are rarely able to eat in most cases require special nutritional support, often parenteral nutrition (5). In adults, the MMC cycle is longer than in children (6). Consequently, the investigator may miss phase IIIs during a short motility study (3).
Somatostatin is a cyclic tetradecapeptide, also called growth hormone release-inhibiting hormone or somatotropin release-inhibiting factor because it was first reported to suppress growth hormone release from rat pituitary cells (7). Somatostatin acts similarly to a hormone, as a paracrine agent and as a neurotransmitter. It is widely distributed throughout the human gastrointestinal system (8) and acts on gastric muscle cells through the guanine nucleotide regulatory protein G to inhibit adenylate cyclase (9). Several studies have described the pharmacologic effects on gastrointestinal motility of octreotide, an analogue of somatostatin with a longer half-life and higher potency. In healthy subjects and adult patients with functional gastrointestinal disorders, the subcutaneous injection of 50 µg octreotide caused inhibition of gastric antral motility and the prompt induction of phase III-like patterns originating in the duodenum (10). In patients with scleroderma, octreotide evoked intestinal phase IIIs and reduced abnormal breath hydrogen excretion (11).
There are no reports on the effect of octreotide on antroduodenal motility in children. The purpose of our study was to evaluate the effects of two doses of octreotide on fasting and fed antroduodenal motility in children with chronic gastrointestinal problems associated with motility disorders.
PATIENTS AND METHODS
We studied 23 children (age, 1-18 years; mean, 7.4 years; 12 male) referred for antroduodenal motility studies to clarify the physiology responsible for their symptoms. Diagnoses were chronic intestinal pseudo-obstruction (CIP) in eight, nonulcer dyspepsia in six, refractory gastroesophageal reflux disease in six, and intractable constipation in three. Fourteen children required special means of alimentation (3 received most of their calories by parenteral nutrition and 11 by tube feeding). Mechanical obstruction was excluded in every patient with CIP by contrast radiology within 6 months before the study. We excluded subjects who had primary diseases with secondary gastrointestinal manifestations such as scleroderma, amyloidosis, muscular dystrophy, hypothyroidism, or other diseases or physical conditions that could interfere with the conduct or interpretation of the study. All medications with an effect on gastrointestinal motility were stopped at least 3 days before the study.
Contractions of the gastric antrum and duodenum were measured using a polyvinyl catheter with 6 to 8 radially oriented orifices spaced 3 cm apart. Catheters were perfused with distilled, deionized water by a low-compliance, capillary-infusion system at rates of 0.1 ml/min. After an overnight fast and adequate sedation, the catheter was inserted endoscopically or under fluoroscopic control through the nose or the gastrostomy. Fluoroscopy was used to confirm the correct positioning of the tube, with at least one recording site in the antrum and four in the duodenum. The manometric studies were performed on the day after catheter placement. After recording fasting motility for more than 4 hours, the patients received 0.5 µg/kg or 1 µg/kg octreotide subcutaneously in random order (12 received 0.5 µg/kg and 11 received 1 µg/Kg). After 30 minutes, 12 children were fed a complex solid meal typical for their age. Of the three patients receiving parenteral nutrition, only one was fed and was given the maximum amount of calories he could tolerate without symptoms. Motility was recorded for another hour. We continued recording fasting for additional 30 minutes in the remaining 11 children.
We relied on visual inspection of each study to identify phase IIIs. Phase III was defined as a cluster of repetitive contractions occurring at a maximum rate for the part of the alimentary tract (2-3/min in the antrum and 10-12/min in the small intestine), lasting more than 2 minutes, propagating faster than 3 cm/min more than 6 cm along the duodenum or small intestine (12). Each phase III was considered to have been induced by octreotide when it occurred within the first 30 minutes after drug administration. When the calculated propagation velocity was greater than 25 cm/min, the phase III was regarded as nonmigrating or stationary. When the velocity was less than 0, the migration was regarded as retrograde (12). Duodenal and antral motility indexes (MIs) were calculated for 30 minutes during phase II before and after subcutaneous administration of octreotide by summing the amplitude of all contractions higher than 10 mmHg. The octreotide-induced phase IIIs were excluded from the MI analysis. The MIs at the duodenal recording sites were average to obtained only one value for each patient.
To discriminate neuropathic and myopathic motor abnormalities, we used criteria previously described (12,13). In the absence of a dilated bowel, uncoordinated contractions of normal amplitude were interpreted as neuropathic, and coordinated contractions of reduced amplitude were interpreted as myopathic.
Data were analyzed with the Wilcoxon rank sum test, the chi-square test, and Fisher's exact test, as appropriate. Results in the text are expressed as mean ± standard deviation. Significance was achieved when p < 0.05.
The manometry findings were suggestive of neuropathy in 18 children and were consistent with myopathy in 2 children in whom pseudo-obstruction had been diagnosed. Three children (two with constipation and one with nonulcer dyspepsia) had normal findings.
In 13 of 23 children (56.5%) a spontaneous phase III occurred during fasting. Of the 10 without phase IIIs, 8 had CIP, 1 had severe dyspepsia, and 1 had gastroesophageal reflux disease which had caused an esophageal stricture. After octreotide injection, 21 of 23 children (91.3%) had at least one phase III (p < 0.02 vs. children with spontaneous phase IIIs). The two children without phase III had CIP and were TPN dependent. In 20 children, there were no antral contractions during fasting after octreotide administration. All octreotide-induced phase IIIs originated in the small bowel, except one that originated in the antrum (p < 0.0001 vs. phase IIIs originating in the small bowel before octreotide; Fig. 1). The first phase III occurred 5.5 ± 1.1 minutes after octreotide injection. Octreotide-induced phase IIIs were longer (5.9 ± 0.5 minutes vs. 3.9 ± 0.4 minutes; p < 0.01) and propagated faster (12 ± 0.9 cm/min vs. 8.1 ± 1 cm/min; p < 0.05) than spontaneous phase IIIs. Nine children had five or more phase IIIs with alternation of phase I and phase III, without phase II, and four had simultaneous or retrograde phase IIIs in the hour after octreotide was administered (Fig. 2). In the two children with myopathy, octreotide induced low-amplitude (<25 mmHg) phase IIIs. Small bowel MI during phase II decreased after octreotide (274 ± 52 mmHg/30 min vs. 859 ± 136 mmHg/30 min before octreotide; p < 0.001). In the patients who were not fed, the motor effects of octreotide lasted for at least 1 hour after injection.
There were no differences in ability to induce a phase III, time before onset of phase III, duration of phase III, and MI between patients receiving the two different doses of octreotide (Table 1). After feeding, antral contractions were present in all children (antral MI: 1418 ± 201 mmHg/30 min), the duodenal MMCs were not abolished, and 73% of the postprandial phase IIIs had an antral component (Fig. 3). The two patients without octreotide-induced phase IIIs during fasting were not fed. Octreotide caused no adverse reaction in any of the subjects investigated.
Somatostatin and its synthetic analogue octreotide have been used in gastroenterology as antisecretory and "antimotility" agents. There is no difference in the actions of somatostatin and octreotide (14) except for the duration of their effects. The circulating half-life of somatostatin is 2 minutes (15). Octreotide, after subcutaneous administration, has a half-life of 1 to 2 hours, with prolonged duration of action (6-12 hours), because of resistance to biodegradation and a high affinity with somatostatin receptors (15).
The inhibitory effects of octreotide on gastrointestinal motility are used for treating dumping syndrome (15,16), controlling bleeding from esophageal varices and peptic ulcers, and reducing the volume of diarrhea of patients with ileostomy, short bowel syndrome, intestinal graft-versus-host disease, radiation colitis, intestinal fistula, and vasoactive intestinal peptide-secreting tumors (17). In healthy subjects, a subcutaneous dose of octreotide accelerates the initial phase of gastric emptying but prolongs intestinal transit time (18,19). Other studies have reported significant inhibitors of solid and liquid gastric emptying after intravenous infusion of somatostatin (20) and gastric food retention after subcutaneous octreotide administration in healthy subjects (21). Verne et al (22) recorded improvement of gastrointestinal symptoms in adults with CIP (idiopathic or secondary to scleroderma) but only in patients with five or more phase IIIs after octreotide injection (22). Other investigators recorded symptomatic improvement in a 51-year-old woman with scleroderma and intestinal pseudo-obstruction treated with octreotide for 10 months (23).
In our study, we showed that a subcutaneous injection of octreotide induced phase IIIs in almost all children, regardless of the type and severity of the underlying bowel disease. Such phase IIIs have amplitude and frequency similar to the spontaneous phase IIIs but start in the duodenum, are longer, and migrate faster than the spontaneous phase IIIs. Some of the phase IIIs recorded after octreotide administration are repetitive and do not migrate. In a minority of children, we also identified retrograde clusters of contractions. This phenomenon has been described in healthy control subjects who had 14 simultaneous and one retrograde cluster out of 34 recorded phase III-like clusters (10).
The effect of octreotide injection differs from the action of intravenous erythromycin. Erythromycin induces fasting phase IIIs recorded always in the stomach and propagating to the duodenum, but only in children who have spontaneous phase IIIs. Octreotide-induced phase IIIs originate in the small bowel and are associated with inhibition of antral motility. The mechanisms by which octreotide may affect antroduodenal motility can be several. There could be a direct local effect on the small bowel. In the dog, only the intraarterial and not the intravenous infusion of somatostatin-induced ectopic phase IIIs which started just below the perfused segment (24). The investigators hypothesized that somatostatin relieved the intestine locally from an inhibitory mechanism. The rise of endogenous plasma somatostatin associated with spontaneous phase III would therefore facilitate its migration from stomach to small bowel. The action of octreotide could also be mediated by suppression of motilin release. Motilin seems to be among the hormones with the greatest sensitivity to the suppressive action of octreotide (25). Antral phase IIIs are induced by motilin or motilin agonists such as erythromycin, and octreotide inhibits antral phase IIIs (26). Soudah et al. (11) showed a reduction in motilin concentration during octreotide treatment in patients with scleroderma and in normal subjects. We have previously recorded antral contractions during administration of octreotide after pretreatment with erythromycin (27).
We have also noted that the inhibition of antral motility is overcome by the meal. Normally the meal has a disruptive effect on MMCs. This effect is related to multiple factors including the energy content of meal, the nature of nutrients, and the frequency of meals and is mediated by neuronal and hormonal factors (28). In our study, after infusion of octreotide, the meal overcame octreotide's inhibition of antral motility but did not disrupt the duodenal fasting pattern. Gastric distention, intraduodenal acid, fat, and bile salts are potent stimuli for release of motilin. Our observations support the hypothesis of octreotide's inhibiting antral motility by effecting motilin release, with the meal relieving the inhibition.
We did not elicit any differences in motility activity between the two doses of octreotide. In dogs, low doses of intravenous somatostatin induced an isolated phase III, whereas the frequency of stationary phase III increased with higher doses (29).
It has been suggested that long-term use of octreotide could have noxious effects on other gastrointestinal organs. Octreotide inhibits gallbladder emptying, thus predisposing to formation of gallstones. The latter effect seems to vanish after 6 days of treatment, probably because of desensitization of the target organ (30). Other investigators have shown that long-term octreotide treatment increases the fasting and the residual postprandial gallbladder volume by reducing the rate and extent of gallbladder emptying (31). An increase in oral intake in patients previously dependent on parenteral nutrition may balance the lithogenic effect of octreotide.
There were no side effects during the study. Haruma et al. (10) described vomiting, abdominal cramps, and epigastric pain in 6 of 50 patients studied, 2 of which had the same symptoms during the spontaneous MMCs. Other have reported nausea, abdominal cramps, diarrhea, malabsorption of fat, and flatulence (17). At present, there is no information on possible octreotide effects on patients' growth because long-term treatments have been described only in adults. Octreotide's inhibition of insulin release might reduce glucose tolerance, although octreotide's ability to delay the absorption of carbohydrates and to inhibit the growth hormone and glucagon secretion seems to balance these effects (17).
In conclusion, low doses of subcutaneous octreotide induced phase IIIs which differed from spontaneous phase IIIs of MMCs and persisted for up to 1 hour after injection. The effects of octreotide were elicited even in children with severe motility disorders. The inhibitory effect of octreotide during fasting on the stomach suggests a rationale for its use, especially in patients fed through jejunostomies or for its use in combination with erythromycin or the ingestion of a meal.
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