1064 Gut 1994; 35: 1064-1069 Effect of octreotide on gastrointestinal pressure profiles in health and in functional and organic gastrointestinal disorders Gut: first published as 10.1136/gut.35.8.1064 on 1 August 1994. Downloaded from
K Haruma, J A Wiste, M Camilleri
Abstract study of the clinical efficacy of a long acting The somatostatin analogue, octreotide, somatostatin analogue, octreotide, in patients restores normal pressure profiles in dis- with progressive systemic sclerosis. Octreotide orders of upper gut motility. This study stimulated MMC-like activity (which will be aimed to evaluate the acute effects of referred to as an 'activity front' throughout this octreotide in five healthy subjects and in manuscript) in the small bowel, improved 50 consecutive patients with functional some symptoms, and reduced breath hydrogen (n=22) or organic (n=28) dysmotility. excretion after an oral glucose load, suggesting Antroduodenojejunal manometry was an effect on small bowel bacterial overgrowth.8 performed during three hours' fasting, It is not clear which subsets of patients with for two hours after a standard meal, and progressive systemic sclerosis respond to this 30 minutes after subcutaneous injection of medication, but these new and interesting 50 ,ug octreotide. Antral motility, before observations suggested that octreotide might and after octreotide, and characteristics restore normal motility in patients with upper of spontaneous migrating motor com- gastrointestinal motility disorders. plexes and octreotide induced activity To further address this hypothesis and to fronts were compared. Octreotide inhib- identify which subgroups of patients might ited antral motility and induced a small respond to octreotide treatment, we evaluated intestinal activity front followed by motor a consecutive series of 50 patients with quiescence in all healthy subjects and suspected upper gastrointestinal dysmotility patients. The duration and propagation referred to a single clinical motility laboratory. velocity of activity fronts were greater Our primary aims were to evaluate the effects than those of spontaneous migrating of octreotide on postprandial antral motility motor complexes. Thirty per cent of and to characterise the duration, amplitude, http://gut.bmj.com/ activity fronts began simultaneously at frequency of contractions, and propagation of different levels ofsmall bowel, and in 20%/ the activity front in these patients and in five a second, normally propagated activity healthy volunteers. Our secondary aim was to front developed within 30 minutes of determine from this pilot study whether any octreotide injection. Octreotide induces specific disease subgroups showed responses rapidly propagated, long activity fronts, that could provide the rationale for further even in patients with neuropathology, testing in future studies. on October 1, 2021 by guest. Protected copyright. and this may initially facilitate the intestinal propulsion of chyme. Propulsion may not occur, however, if Methods octreotide induces simultaneous activity fronts or ifthe activity front is followed by PATIENTS AND HEALTHY CONTROLS prolonged quiescence. Inhibition ofantral We studied 50 consecutive patients who were motility suggests that octreotide may not referred for a standard upper gastrointestinal be effective in gastroparesis. motility study and consented to participate. (Gut 1994; 35: 1064-1069) Patients were 15 to 67 years of age (mean: 37-7 years) and there were 37 women and 13 men. All women of childbearing potential had a neg- Upper gastrointestinal manometry is an ative plasma (,B-HCG) pregnancy test within established method for the identification of 24 hours of the motility study. Five healthy stomach and upper small bowel motility volunteers (age range: 30-44 years; mean age: Gastroenterology Research Unit, Mayo disorders.' Studies of pressure profiles in 34-6 years) were recruited by public advertise- Clinic and Mayo these regions correlate well with two broad ment. The research protocol was approved by Foundation, categories of motility disorders - neuropathies the Mayo Institutional Review Board. Rochester, MN 55905, USA and myopathies.2 Pharmacological studies K Haruma showing changes in these profiles in health and J A Wiste restoration of normal pressure profiles are UPPER GASTROINTESTINAL MANOMETRY M Camilleri usually a prerequisite for developing new This was performed using a multilumen (n=8 Correspondence to: treatments for these motility disorders. Thus, or 12) assembly with five or six ports placed Dr M Camilleri, Gastroenterology Research several studies have shown that exogenous fluoroscopically across the antroduodenal Unit, Mayo Clinic, 200 First somatostatin induces a migrating motor junction and three or six ports in the duode- Street SW, Rochester, MN 55905, USA. complex (MMC)-like activity front in num and jejunum. The method has been Accepted for publication experimental animals and in healthy human described fully elsewhere.9 Patients stopped 16 November 1993 volunteers.3-7 These observations led to a short taking any medication that might influence $ oni:vr Pt mo ty0 1065
the three-hour fasting period, we characterised the first complex. The velocity of propagation was considered fast when the MMC or activity
front propagated through the duodenum and Gut: first published as 10.1136/gut.35.8.1064 on 1 August 1994. Downloaded from dd jejunum at a rate faster than 11 cm per minute, which is at the 95th centile for propagation velocities in healthy subjects.10 :N . YM-F' L ' The same parameters were documented for
wi ;. ti,i .,
Spontaneous MMC Octreotide induced activity front Thirty eight of 50 patients had one or more spontaneous MMCs during the three hour mi ; Octreotide Duodenum [50mm Hg fasting period. The onset of spontaneous
1 MMCs was recorded in the antrum in nine, Gut: first published as 10.1136/gut.35.8.1064 on 1 August 1994. Downloaded from pylorus in two, duodenum in 22, and jejunum in five. 2 On the other hand, 50 ,ug subcutaneous octreotide induced activity fronts within six 3 minutes (mean: 2-8 min; range: 1 5-5-8 min) Jejunum in all patients. The activity front originated in 1 the antrum or pylorus in one patient each, in the duodenum in 45, and in the jejunum in 2 1_i three (two Roux gastrectomy, one irritable bowel syndrome). In addition, 10 of 50 Normal velocity of propagation Rapid velocity, patients had two activity fronts during the 30 prolonged duration minutes after octreotide. Apart from these activity fronts, the manometric tracings Figure 2: Spontaneous migrating motor complexes (MMC) and octreotide induced activity front in a healthy 44 year old male volunteer. Note the rapid velocity ofpropagation and showed motor quiescence or a noticeable prolonged duration ofthe octreotide induced activityfront in the right panel. Sensors are all paucity of contractions. 10 cm apart. In these 50 patients, 34 activity fronts showed propagation (rapid in 32 (>11 Of the five activity fronts, four showed cm/min); normal in two (<11 cm/min)); there propagation (rapid in three (>1 cm/min); were 14 simultaneous and one retrograde normal in one (<11 cm/min)) and one was activity front. The characteristics of propa- simultaneous. As shown in Table I and Figure gation could not be evaluated in one patient 2, the duration and propagation velocity of the because its onset was at the most distal first activity fronts were significantly increased sensor in the jejunum. In two patients with compared with spontaneous MMCs; in Roux-en-Y gastrojejunostomy, spontaneous contrast, the frequency of contractions and MMCs were disrupted or poorly formed; mean amplitude were similar. The motility of octreotide resulted in well propagated activity the distal antrum was significantly decreased fronts with normal amplitude and frequency of after octreotide compared with 30 minutes contractions in the Roux limb (Fig 3). The before the injection, but this effect was chiefly proportion of propagated octreotide induced on the frequency rather than amplitude of con- activity fronts was similar in the patients
tractions (Table II). with evidence of extrinsic neuropathy (six http://gut.bmj.com/ of eight), functional disease (16 of 22 in functional dyspepsia or irritable bowel CLINICAL DIAGNOSIS OF PATIENT GROUP syndrome), mechanical obstruction (three of In the 50 consecutive patients, the clinical four), or idiopathic gastroparesis (eight of 11). diagnosis was irritable bowel syndrome in 17, functional dyspepsia in five, idiopathic
gastroparesis in 12, extrinsic neuropathy in COMPARISON OF QUANTITATED MANOMETRIC on October 1, 2021 by guest. Protected copyright. eight (three diabetic autonomic neuropathy, PRESSURE ACTIVITIES IN PATIENTS four post gastric surgery, and one paraneo- During the three-hour fasting period, 12 of 50 plastic syndrome secondary to a small cell lung patients had no spontaneous MMCs, and carcinoma), chronic idiopathic intestinal in five, MMCs started in the jejunum. pseudo-obstruction in three, mechanical Motility of the small intestine could not be obstruction in three, duodenal malrotation in evaluated in one patient because of technical one, and progressive systemic sclerosis in one. problems. Thus, 37 spontaneous MMCs were available for the purpose of unpaired statistical comparisons with octreotide induced activity MANOMETRIC STUDIES IN PATIENTS fronts. Manometric pressure profiles recorded in We were able to analyse the duration, these patients were classified as follows: number of contractions, mean amplitude, and normal in 18 patients; postprandial antral site of origin of activity fronts in all patients. hypomotility in 17; features consistent with a The velocity of propagation was measured in neuropathy in 10; mechanical obstruction in 34 of the 50 patients. Measurements were not four; and features suggestive of a myopathy in possible in the remaining 16 - in one patient, one. the activity front started at the most distal jejunal sensor, in one the activity front was TABLE II Effects ofoctreotide on antral motility in five retrograde, and in 14 activity fronts were healthy volunteers (mean (SEM)) simultaneous. Antral motility could not be evaluated in two patients with previous total or Before After octreotide octreotide subtotal gastrectomy, and in two further patients for technical reasons. In the remaining Frequency of contractions (no/30 min) 44-6 (5-7) 11-2 (3-7)* 46 patients, antral contractions were inhibited Mean amplitude of contractions completely in eight (Fig 4) and the mean (mm Hg) 44-6 (5-9) 35-6 (3 2) Motility index (mm Hg 30 min) 11-2 (0-4) 7-8 (0-8)t amplitude of contractions after octreotide injection was evaluated in 38 patients. *p<0-01; tp<0 05. The duration and propagation velocity of Octreotide 's effects on upper gut motility 1 067
Octreotide induced spontaneous MMCs and the first activity Spontaneous MMC activity front fronts (Table III and Fig 5).
Gastric pouch 3 min 50 mm Hg .Octreotide The frequency of contractions and the
motility index of the distal antrum were Gut: first published as 10.1136/gut.35.8.1064 on 1 August 1994. Downloaded from 1 significantly decreased after octreotide compared with the 30 minutes before 2 injection; however, the mean amplitude of contractions was similar (Table IV). Four 3 patients (two with idiopathic gastroparesis, one with mechanical obstruction, and one with progressive systemic sclerosis) had an increase Roux limb- proximal in antral motility index after octreotide. ,,.A& middle ADVERSE EFFECTS Octreotide did not cause any adverse effects in distal aLA-J-1-1-16, the five healthy volunteers. Six of 50 patients Figure 3: Manometric tracingfrom a 52 year old women with Roux-en-Y gastrectomy. developed the following symptoms: vomiting The fasting tracing (left) shows abnormalities in the propagation ofthe spontaneous in three, abdominal cramps in one, and migrating motor complex (MMC). A well propagated activityfront occurs after octreotide epigastric pain in one. Two of the patients (right). (one with vomiting and one with abdominal cramps) complained of similar symptoms in 3 minr during spontaneous MMCs the fasting 3mi [50 mm Hg%Octreotide period. Antroduodenal IIb Discussion Our study shows that 50 pug octreotide causes 2 j appreciable changes in the pressure profiles of the upper gastrointestinal tract in health and 3 11 disease. The most consistent findings, which are likely to be physiologically relevant, are the noticeable inhibition of postprandial distal Descending _ 6 P' duodenum antral motility and the prompt induction of an activity front with similar mean amplitude Distal iA_ and frequency of contractions as observed http://gut.bmj.com/ duodenum in spontaneous MMCs. The duration and Figure 4: Octreotide induced inhibition ofpostprandial antral phasic pressure activity and propagation characteristics of the octreotide a simultaneous activityfront in a 45 year old woman with irritable bowel syndrome. induced activity front, however, are signifi- cantly different from those of the spontaneous the first activity fronts were significantly MMCs observed in the same individuals. In increased compared with spontaneous MMCs. most patients with irritable bowel syndrome, The frequency of contractions and mean functional dyspepsia, and chronic idiopathic on October 1, 2021 by guest. Protected copyright. amplitude were similar in the two groups intestinal pseudo-obstruction, octreotide (Table III and Fig 2). inhibited antral motility and induced either Ten patients (20%) developed a second simultaneous or rapidly propagated activity activity front during the 30 minutes after fronts. In one patient, a retrograde, rapidly octreotide (Fig 5). The second activity propagated activity front was induced. The fronts started in the duodenum from 6&7 to degree of antral inhibition and the proportion 14 minutes after the first activity front, and ofpropagated activity fronts were similar in the the propagation velocity and number of diagnostic subgroups in this heterogenous contractions were similar to those observed group of 50 patients. during spontaneous MMCs, and reduced In patients with evidence of an extrinsic relative to the first activity fronts. The mean neuropathy, such as diabetic autonomic amplitude of contractions of the second neuropathy, and those with surgical vagotomy activity fronts was decreased relative to both and Roux-en-Y gastrojejunostomy in which the Roux jejunal loop is disconnected from the duodenal pacemaker, there was a clear TABLE III Characteristics ofspontaneous migrating motor complexes (MMC) and octreotide induced activityfronts in patients (mean (SEM)) difference between the abnormally developed or propagated spontaneous MMCs and the Octreotide induced activityfront normal configuration and aboral propagation Spontaneous MMC (n=37) First (n=50) Second (n-=JO) of the activity front induced by octreotide. The normal direction of propagation and rapid Duration (min) 4-8 (0 4) 9 0 (0-7) 4 71 (0 7) Frequency of contractions (no/min) 11-7 (0 2) 11-7 (0 2) 11-7 (0 2) velocity of the intestinal activity front in these Mean amplitude of contractions (mm Hg) 30-2 (1-5) 28-2 (1-3) 20-0 (2-1)t patients may provide the basis for propulsion Propagation velocity (cm/min) 10-2 (1-0) 24-9 (2 9)t 7-85 (1 1) of chyme which is possibly of therapeutic *p<0O05: compared with spontaneous MMC and second activity front; tp<0 05: compared benefit. We had only one patient with systemic with spontaneous MMC and first activity front. sclerosis and hence were unable to assess *Data on propagation excluded from analysis in 16 patients who had simultaneous (n= 14) or retrograde (= 1) activity fronts, or activity front observed only at the most distal site in the critically octreotide's potential benefit in jejunum (n = 1). myopathic disorders.8 1 068 Haruma, Wiste, Camilleri
3 min octreotide induced activity fronts, however, + Octreotide [50 mm Hg differed markedly from those of MMC previously reported in prolonged studies Descending duodenum t _iSi performed in laboratory or ambulatory Gut: first published as 10.1136/gut.35.8.1064 on 1 August 1994. Downloaded from settings. 12 13 Hence, the overall message would Distal probably have been identical if our fasting duodenum observation had been longer. Proximal 1 A second series of activity fronts was jejunum observed in 10 patients and one healthy subject 2 , | during the 30 minutes after octreotide. Interestingly, all of the characteristics of the second activity front except amplitude were similar to those of the spontaneous MMCs.
4 The mechanism resulting in successive activity fronts in these patients, and their different Figure 5: Octreotide induced repeated activity fronts with different propagation velocities in propagation velocity when compared with a 30 year old woman with chronic idiopathic intestinal pseudo-obstruction. The the first octreotide induced fronts are unclear propagation ofthe second activity front is normal. Note the paucity of contractions at all and deserve further study. From a practical levels between the two activity fronts. standpoint, it is possible that the second fronts, which are propagated aborally at a normal This study provides the first demonstration velocity (7 *9 (1 1) cm/min), may contribute to that octreotide inhibits antral motility, and greater clearance of small bowel contents and induces duodenojejunal activity fronts that are may account for the beneficial clinical effects characterised by prolonged duration and by a reported in upper gut motility disorders such rapid propagation velocity or simultaneous as systemic sclerosis.8 onset at several sites. Previous studies showed The propulsive capacity of octreotide- that somatostatin induces activity fronts induced activity fronts was not investigated with normal3 6 or slow propagation,7 8 and the in this study. However, the simultaneous or duration of the activity front was reported retrograde nature of 15/49 activity fronts to be similar to that of spontaneous MMCs. would suggest that there would be little The reason for the different results in our antegrade movement of small bowel content studies may be attributed in part to the during these motor events. Indeed, most of the different experimental design relative to other published reports to date suggest that studies, which were usually performed during octreotide retards intestinal transit, since it or to use fasting,8 the of natural forms of has been effective in controlling diarrhoea in http://gut.bmj.com/ somatostatin (somatostatin-14 and -28) rather several patient groups, including carcinoid than octreotide. Soudah et al reported that syndrome,14 diabetes mellitus,15 ileostomy a smaller dose of subcutaneous octreotide diarrhoea,16 and short gut syndrome.17 (10 pug) decreased the propagation velocity in Octreotide prolongs the mouth to caecum normal subjects during fasting.8 But in their transit time in healthy subjects and in patients study only two recording sites were located in with diarrhoea-predominant irritable bowel
the small bowel, compared with our studies syndrome,18 and scintigraphically measured on October 1, 2021 by guest. Protected copyright. with four to seven sites in the small intestine, pyloro-caecal transit of radiolabelled solid each separated by 10 cm. In a postprandial residue. 19 Although, 34 of 49 activity fronts are study of healthy volunteers, Neri et al normally or rapidly propagated, the effects of showed that somatostatin- 14 induced octreotide in health, functional disease, and activity fronts with normal duration and organic dysmotilities may not be beneficial propagation velocity.6 The differences from because of the prolongation of transit and the our observations may reflect the nature of the general paucity of intestinal contractility after somatostatin molecule rather than dosages, the induction of an activity front. which are comparable with those used in our Our observations in the distal stomach studies. It is also important to acknowledge present an unequivocal and significant inhibi- that our study design (three hours' fasting) tion of postprandial antral phasic pressure restricted the ability to define the intrinsically activity. These effects were not previously variable properties of the MMC in each noted in studies using somatostatin-146 or - individual. More prolonged monitoring 28.7 Two previous studies suggested that might have provided better control data. somatostatin inhibits gastric motility in The duration and propagation velocity of humans.3 20 Thus, Stadaas et al showed that infusion of somatostatin at 0 05 mg/h and 0 5 mg/h significantly reduced gastric motility TABLE IV Effects ofoctreotide on antral motility in patients in response to distention by monitoring Before After contractions by means of a single, flaccid, thin No octreotide octreotide walled bag filled with water.20 It is not clear Frequency of contractions (no/30 min) 46t 29-3 (2-66) 14-5 (2.46)* from these studies whether somatostatin Mean amplitude of contractions (mm Hg) 38t 42-7 (2 03) 40-1 (3-13) affected the fundus or antrum and which Motility index (mm Hg 30 min) 46t 9-75 (0 7-06 37) (0-52)* molecular form of somatostatin was used. *p The effects of somatostatin on postprandial secretory complex-like activity in man. Gastroenterology 1980; 78: 1212. antral motor function have not been previously 6 Neri M, Cuccurullo F, Marzio L. Effect of somatostatin on reported. Our data are supported by the gallbladder volume and small intestinal motor activity in humans. Gastroenterology 1990; 98: 316-21. results of gastric emptying studies. Delayed 7 von der Ohe M, Layer P, Wollny C, Ensinck JW, Peeters of solid meals21 22 also sug- TL, Beglinger C, Goebell H. Somatostatin 28 and Gut: first published as 10.1136/gut.35.8.1064 on 1 August 1994. Downloaded from gastric emptying coupling of human interdigestive intestinal motility and gests that somatostatin inhibits antral motility; pancreatic secretion. Gastroenterology 1992; 103: 974-81. results have been reported regard- 8 Soudah HC, Hasler WL, Owyang C. Effect of octreotide on conflicting intestinal motility and bacterial overgrowth in sclero- ing the effects of somatostatin on gastric derma. NEnglJMed 1991; 325: 1461-9. Taken together with 9 Malagelada J-R, Camilleri M, Staghellini V. Manometric emptying of liquids.21-24 diagnosis of gastrointestinal motility disorders. New York: our observations, these data suggest that Thieme Publishers, 1986. to benefit patients 10 Rees WDW, Malagelada J-R, Miller U, Go VLW. Human octreotide is unlikely interdigestive and postprandial gastrointestinal motor and with motility disorders affecting the distal gastrointestinal hormone patterns. Dig Dis Sci 1982; 27: antral hypomotility is usually 321-9. stomach, since 11 Analysis ofvariance (ANOVA). Ch 18. In: Statview. Abacus associated with impaired gastric emptying of Concepts: Berkeley, CA, 1992: 319-32. 12 Kellow JE, Borody TJ, Phillips SF, Tucker RL, Haddad solids.25 AC. Human interdigestive motility: variations in patterns In summary, our study suggests that from esophagus to colon. Gastroenterology 1986; 91: the inco- 386-95. octreotide may potentially correct 13 Wilson P, Anselmino M, Hinder RA, Quigley EMM. ordinated but normal amplitude pressure Ambulatory antroduodenal manometry in man: develop- neuropathies ment and validation. Gastroenterologv 1992; 103: A1402. profiles of patients with extrinsic 14 Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, of the small bowel; nevertheless, studies Hahn RG. Treatment of the malignant carcinoid small bowel syndrome. NEnglJrMed 1986; 315: 663-6. published to date suggest it delays 15 Mourad FH, Gorard D, Thillainayagam AV, Colin-Jones transit. Moreover, it is unlikely to benefit D, Farthing MJG. Effective treatment of diabetic diar- Its rhoea with somatostatin analogue, octreotide. Gut 1992; patients with impaired distal antral motility. 33: 1578-80. potential role in functional gastrointestinal 16 Williams NS, Cooper JC, Axon ATR, King RFGJ, Baker seems M. Use of a long-acting somatostatin analogue in control- disease has recently been studied, and it ling life threatening ileostomy diarrhoea. BMJ 1984; 289: to reduce rectal sensation in health and in 1027-8. 27 17 Nightingale JMD, Walker ER, Burnham WR, Farthing patients with irritable bowel syndrome.26 MJG, Lennard-Jones JE. Octreotide (a somatostatin Our study suggests that patients with extrinsic analogue) improves the quality of life in some patients and with a short intestine. Alimentary Pharmacology and neuropathy (such as, diabetes, vagotomy) Therapeutics 1989; 3: 367-73. Roux-en-Y reconstruction after gastric surgery 18 O'Donnell LJD, Watsow AJM, Cameron D, Farthing MJG. in Effect of octreotide on mouth-to-caecum transit time in are the most likely to show improvement healthy subjects in the irritable bowel syndrome. patterns of motility. 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