Role of the Small Intestine Postvagotomy Diarrhea

Transcription

1 GASTROENTEROLOGY 1983;85: Role of the Small Intestine Postvagotomy Diarrhea. In SPIROS D. LADAS, PETER E. T. ISAACS, YOUNUS QUERESHI, and GORDON SLADEN Gastroenterology Unit, Guy's Hospital and Medial Shool, London, United Kingdom The response of the small intestine of 6 normal subjets, 6 vagotomy ontrol subjets, and 5 patients with postvagotomy diarrhea to a hyperosmolar liquid meal was investigated using small intestinal intubation. In the patients with postvagotomy diarrhea, the peak jejunal osmolality ourred earlier and was followed by a shorter small bowel transit time than in the vagotomy and normal ontrols. In the terminal ileum, both fasting and postprandial flow rates were higher in the group with postvagotomy diarrhea, ompared with the other groups. This was assoiated with a high postprandial osmoti load to the olon, due in part to nutrient malabsorption. The postprandial flow of bile aids into the olon was not onsistently related to diarrhea. Postvagotomy diarrhea is probably aused by rapid entry of fluid, eletrolytes, and malabsorbed nutrients into the olon after meals. The rapid movement of an osmoti load through the upper jejunum, onsequent upon the drainage operation, may be the ritial trigger fator. About 25% of all patients who undergo trunal vagotomy and drainage for duodenal uler experiene diarrhea postoperatively, but in 2%-5% the diarrhea is severe and inapaitating (1,2). The pathophysiology of the postvagotomy diarrhea (V + Reeived Otober 18, Aepted May 17, Address requests for reprints to: Dr. G. Sladen, Gastroenterology Unit, Guy's Hospital, St. Thomas Street, London SEl 9RT, United Kingdom. Dr. Ladas' urrent address is Seond Propaedeuti Medial Unit, Evangelismos Hospital, Athens, Greee. Part of this study was supported by a Wellome Trust Foundation Fellowship whih was held by Dr. Ladas. Preliminary ommuniation of this work appeared as an abstrat in Gut 1981, 22:A889-89, and was presented at the Autumn Meeting of the British Soiety of Gastroenterology, Exeter, The authors thank Miss Kate Teasdale for assistane in preparing the manusript by the Amerian Gastroenterologial Assoiation /83/$3. D) syndrome has not yet been defined, although a onsiderable number of different mehanisms have been proposed inluding gastri inontinene (3,4), bile aid malabsorption (5), and ileal seretion (6). In view of this multipliity of etiologi theories, it is not surprising that there is no universally effetive treatment for this syndrome (7-9). The present study was undertaken to investigate the role of the small intestine in the postvagotomy diarrhea syndrome. Small intestinal intubation tehniques were employed and normal subjets, patients with vagotomy and pyloroplasty without diarrhea, and patients with postvagotomy diarrhea were hallenged with a hyperosmolar liquid meal. Materials and Methods Subjets Seventeen patients were studied, inluding 5 patients with postvagotomy diarrhea, 6 patients with vagotomy but no diarrhea (V - D), and 6 subjets without any apparent gastrointestinal disease (N). The vagotomy subjets had all had trunal vagotomy for hroni duodenal uler with a drainage proedure. This was in most ases a pyloroplasty, but 1 subjet with V + D had had a gastrojejunostomy. The V + D group inluded 4 men and 1 woman (56 ± 4 yr old), the V - D group inluded 3 men and 3 women (48 ± 11 yr old), and the normal group inluded 5 men and 1 woman (46 ± 11 yr old). All patients were studied at least 1 yr after operation. The patients with V + D were regularly passing at least three liquid stools per day and had a feal wet weight >35 g/day. None of the subjets studied was on any mediation, apart from 2 patients with V + D who disontinued their treatment with holestyramine 1 days before the study. The patients with V + D had normal jejunal biopsy speimens, baterial population in the jejunal aspirate, serum immunoglobulins G, A, M, small and large bowel barium studies, and Lundh tests of panreati funtion. One of the vagotomy ontrols and 2 patients with V + D had also undergone holeystetomy. The latter patients' diarrhea started after the seond operation (whih was holeystetomy in one and vagotomy in the other). Written informed

2 November 1983 POSTV AGOTOMY DIARRHEA 189 onsent was obtained from all 17 subjets. The protool was approved by the Guy's Hospital Committee on Ethial Pratie (January 1982). Experimental Method The meal. After an overnight fast, the volunteers drank a liquid meal (4 kal, 3 ml, ph 6.5, 46 mosm/kg, 18 mmol sodium, 14 mmol potassium). It was latose and gluten free and ontained 16 g of protein (whey and asein hydrolysates), 48 g of arbohydrate (mixture of mono-, oligo-, and polysaharides) and 16 g of fat (8% medium hain triglyerides, wtlwt). One hundred-fifty milligrams of phenol red (.5 mg/ml) was added to the meal as a nonabsorbable marker. Small intestinal intubation. A tehnique similar to that of Phillips and Giller (1) was employed. After an overnight fast, the volunteers swallowed a weighted triplelumen polyvinyl radiopaque tube. After the merury bag had passed into the upper jejunum, the subjet returned to a metaboli ward, ate a normal diet, and was instruted to swallow 15 m of the tube every hour, until m of the tube had been swallowed. The progress of the tube was heked fluorosopially. The desired position was ahieved within 24 h in all but 2 vagotomized subjets, who required 48 h. In 11 of the 17 subjets, the merury bag was plaed in the eum, and in the other 6 subjets in the terminal ileum (length of the tube from the mouth: N, 246 ± 14; V - D, 245 ± 13; V + D, 242 ± 12 m). With the tube in plae, the two aspiration ports were loated -3 m beyond the ligament of Treitz and in the terminal ileum. After an overnight fast, a study was arried out with the subjets semisupine (trunk at 45 to the horizontal). A plasmalike solution (sodium 135, potassium 5, hloride 15, biarbonate 35 mmolll, osmolality 28 mosm/kg) ontaining 1 /LCi of e 4 C]polyethylene glyol (PEG) as marker and 2 gil of PEG 4 as arrier was infused at a rate of.3 mllmin, using a peristalti pump (Harvard model 123A, Harvard Apparatus Co., In., South Natik, Mass.)' through the third lumen, whih opened 25 m proximal to the ileal aspiration port. After a I-h equilibration period, two.5-h samples were olleted from the jejunum and ileum using a syringe pump (perfusor MK IV, Braun AG, Melsungen). The subjets then drank the liquid meal and samples were ontinuously olleted for eight.5-h periods. The aspiration tubes were inspeted ontinuously for hange of the olor of their ontents (jejunum: orange; ileum: red), signifying the presene of phenol red. Small bowel transit time was estimated as the differene between the times taken for phenol red to appear in the jejunal and ileal tubes, whih had the same measured dead spae of about 6 ml. The subjets were asked to report any symptoms. Estimated gonadal irradiation at fluorosopy was 5-7 mrad, and oloni radiation by infused 14C was 7 mrad per study. Analysis of samples and alulations. Immediate measurement of osmolality by freezing point depression (Osmette A osmometer, Preision Systems, Waltham, Mass.) was arried out on the samples, whih were then stored at -2 C. Conentrations of sample omponents were measured as follows: phenol red, by spetrophotometry (wavelength 56 nm) in the samples adjusted to ph 9.2 (11); sodium and potassium by flame photometry; total bile aids by an enzymati fluorometri method (12); and gluose by a gluose oxidase method (13). Dupliate 1-pJ aliquots of eah sample were added to 1 ml of NE 26 sintillation oktail (Nulear Enterprises, Sighthill, Edinburgh) and ounted on a liquid sintillation ounter (Rak-Beta 1214, LKB-Walla, Finland). A olor quenh orretion urve was made using a series of ileal aspirates to whih were added a fixed amount of [ 14 C]PEG and inreasing amounts of phenol red within the range observed in the samples. The ileal flow rate (F;) was alulated as follows: Fi = Fin X [PEG in ] X [PEGoutl-l, where Fin is the infusion rate (.3 mllmin), PEG in is the disintegrations per minute of 14C in the infusate, and PEG out is the disintegrations per minute of 14C in the ileal aspirate. This formula assumes that there is omplete mixing of the infusate with the ileal ontents and that the small volume of the infusate (18 mllh) is ompletely absorbed from the terminal ileum. The assumptions underlying these alulations have been disussed in detail by Levitt and Bond (14). Statistial analysis. Results in the text, tables, and figures, unless otherwise stated, are presented as mean ± 1 SD. Analysis of variane for single-fator experiments was used as appropriate (15) to test for signifiant differenes among the groups studied. Results The hanges of osmolality with time in the upper jejunum are shown in Figure 1. Although the highest osmolalities observed postprandially were similar in the three groups (F2.14 =.63), the peak of the osmolality urve appeared very early in patients with V + D (3 min), later in the vagotomy ontrols (6 min), and even later in the normal subjets (9 min). The umulative perent area under the jejunal osmolality urves showed that the time interval between and 3 min inluded 31.9 ± 8.2% of the total area under the urve in the patients with V + D, whih is signifiantly different from 16.3 ± 5.4% and 9.4 ± 7.4% estimated for the vagotomy ontrols and the normal subjets, respetively (F2.14 <.1). The small bowel transit times of phenol red were signifiantly different in the three groups (F 2.14 <.2) being 25 ± 13 min in the patients with V + D, 48 ± 23 min in the vagotomy ontrols, and 65 ± 11 min in the normals. The ileal flow rates are illustrated in Figure 2. All the observed inreases of ileal flow oinided with the appearane of phenol red in the ileal aspiration tube. From the ileal flow rate, the amount of fluid and solute entering the olon postprandially was estimated for the interval between the arrival of phenol red in the terminal ileum and the return of the ileal flow rate to the baseline. This interval was

3 19 LADAS ET AL. GASTROENTEROLOGY Vol. 85, No Meal Q) 42 V-D 39 -.S. 36 J2 a E 33 3 :l 'ijj"..., V+D N meal (FZ,14 <.5). Subtration of ([Na] + [K]) x 2 from the measured osmolality gives an estimate of noneletrolyte, mainly nutrient, onentration. Estimated values for the oloni load of malabsorbed nutrient are shown in Table 1. The differenes among the three groups were highly signifiant (F2,14 <,1). Nutrient malabsorption was onfirmed diretly by the observation that gluose was present in all the postprandial V - D and V + D ileal samples and in some normal subjets. The gluose onentrations measured in eah subjet ranged from.18 to.69 mmolil in the normals, 4.7 to 68.8 mmolil in the vagotomy ontrols, and 1.3 to 53.6 mmolil in the patients with V + D. It was estimated that the malabsorbed gluose aounted for up to.2% (normals), 8% (vagotomy ontrols), and 15% (patients with V + D) of the 48 g of the arbohydrate ingested. The total bile aid load entering the olon postprandially is shown in Figure 3. The load is higher in most vagotomized patients than in normal ontrols, but there is onsiderable overlap between patients with and without diarrhea. It is of interest that the largest loads are observed in the 3 patients who had a holeystetomy. This resulted from high ileal bile aid onentrations (both fasting and postprandial) rather than rapid ileal flow rates Time (hours) Figure 1. Mean ± 1 SD of fasting and postprandial jejunal osmolality in normal persons (N: open triangles), patients with vagotomy and pyloroplasty without diarrhea (V - D: open irles), and patients with postvagotomy diarrhea (V + D: losed irles). The osmolality of the meal ingested was 46 mosm/kg Meal + 2 h for the patients with V + D, and the postprandial oloni inflow of the vagotomy ontrols and the normals was therefore estimated over the 2 h after the first appearane of phenol red. In the Table, both the fasting (p <.2) and the postprandial (p <.1) ileal flow rates were signifiantly higher in the patients with V + D than in the two ontrol groups. The osmoti load entering the olon postprandially was greater in V + D than in N or V - D subjets (FZ,14 <.1, Table 1). This resulted from the high ileal flow and inreased osmolality. Whereas in N and V - D subjets the osmolality of ileal fluid was little affeted by the passage of the meal (35 ± 5 mosm/kg in both groups), in the patients with V + D this osmolality rose to 324 ± 2 mosm/kg after the o CIl r o Time (hours) Figure 2. Mean ± 1 SD of fasting and postprandial ileal flow rate in the same groups as in Figure 1.

4 November 1983 POSTV AGOTOMY DIARRHEA 191 Table 1. Flow of Fluid and Osmoles from Ileum to Colon Group of patients N (n = 6) V - D (n = 6) V + D (n = 5) Ileal fluid flow (ml/h) Fasting Postprandial 49 ± 6 53 ± ± ± ± ± 52 Postprandial osmolar flow (mosm/h) Total Due to nutrient 15 ± ± ± ± ± ± 8.3 Mean ± 1 SD of the fasting and postprandial ileal flow of fluid and postprandial flow of osmoles (total and noneletrolyte) in normal subjets (N), patients with vagotomy and pyloroplasty without diarrhea (V - D), and patients with postvagotomy diarrhea (V + D) after a liquid meal. Clinial Information The diarrhea of the 2 V + D patients who had also undergone holeystetomy improved after treatment with holestryramine (Questran, 4 g q.i.d.), whereas the same treatment was of no benefit to 2 other patients. Three of the V + D patients had diarrhea during the perfusion, and the other 2 patients had diarrhea between 3 and 6 h later. In all ases, the stools were red beause of the presene of phenol red. None of the vagotomy ontrols or normal subjets experiened diarrhea during or after the study. Disussion The present study desribes the ourse of small intestinal events after the ingestion of a hyperosmolar liquid meal in patients with postvagotomy diarrhea. Studies to date have learly shown rapid gastri emptying of liquid meals after vagotomy and pyloroplasty (16,17). However, it is ontroversial whether patients with V + D have a faster gastri emptying rate than vagotomy ontrols (3,4,18). Although we did not diretly assess gastri emptying in our patients, the observation that, in the group with V + D, the jejunal osmolality urve was shifted to the left and was of a shorter duration than that in the ontrol subjets an be attributed to a more rapid entry into and passage from the upper jejunum of the postprandial osmoti load. Contrary results have been published by Temple et al. (18), who found signifiantly different initial jejunal osmolalities in patients with V + D ompared with normal subjets, but no differene in the time-ourse of osmolality of jejunal ontents of V + D and V - D subjets after a milk and surose meal. However, latase defiieny was not speifially exluded, and, beause latose is a slowly absorbed disaharide (19), this may have masked differenes between their groups of patients. The small bowel transit time of phenol red was signifiantly different in the three groups studied beause of the shorter transit in the patients with V + D. Similar results have been reported by MKelvey (4) who measured whole gut transit after hypertoni liquid meals, and by Bond and Levitt (2) who used breath hydrogen determinations after ingestion of latulose by patients with partial gastretomy and vagotomy. Our observation that patients with V + D had a signifiantly higher fasting ileal flow rate than the two ontrast groups is of interest beause intestinal perfusion studies have suggested that patients with V + D have an ileal defet with a seretory, and more permeable, epithelium (6). However, it is also possible that there is an inreased flow of fluid from above in the fasting state in these subjets. This ould only be larified by diret measurement of jejunal flow rate. The most striking differene between the patients with V + D and the vagotomy ontrols was the very high postprandial ileal flow rate in the former group. When a plasmalike solution is infused into the olon of healthy subjets at similar rates over an hour, diarrhea is produed (21). All of our V + D subjets E -.S '5 a. u u u.d ' e a. B J o [J [J [J V+D o &. 22> V-D N Figure 3. Postprandial bile aid oloni input in normal subjets (open irle), patients with vagotomy and pyloroplasty without diarrhea (open triangle), and patients with postvagotomy diarrhea (open square). The losed triangles and squares represent patients who had undergone holeystetomy in addition to vagotomy.

5 192 LADAS ET AL. GASTROENTEROLOGY Vol. 85. No.5 had diarrhea after the meal, oiniding with the passage of phenol red through the small intestine. Perfusion studies have suggested that jejunal absorptive apaity is unimpaired in patients with V + D (22), but very rapid transit through the jejunum ould impair nutrient absorption. In our patients with V + D, the total postprandial osmoti load entering the olon was three times greater than that in the vagotomy ontrol subjets, and 35% of this load is presumed to be nutrient in origin. Carbohydrate malabsorption was demonstrated diretly in both groups of vagotomized subjets by the variably high ileal gluose onentrations, but the magnitude of malabsorption in V + D patients was twie that of the V - D patients. Bile aid malabsorption has been suggested as the ause of the V + D syndrome (5,23,24). However, studies to date have never demonstrated any signifiant differene in total feal bile aid exretion in patients with V + D ompared with vagotomy ontrols (5,24,25). In the present study, there was inreased ileal flow of bile aids in most of the vagotomy subjets, but marked overlap of the results in those with and without diarrhea. The bile aid flows in the 3 patients who had also undergone holeystetomy (i.e. 2 patients with V + D and 1 vagotomy ontrol) were notably high. Bile aids, whih an interfere with oloni absorption of water and eletrolytes (26), may ontribute to the diarrhea of patients who have undergone the ombined operation (27). More studies on holeystetomized subjets are needed to larify this point. The present study has identified several funtional abnormalities in patients with the V + D syndrome, namely, the rapid imposition of an osmoti load into the upper jejunum, rapid small bowel transit, possibly abnormal intestinal handling of fluid in the fasting state and, in some patients, a high oloni input of bile aids (espeially in those with holeystetomy). Understanding the interplay of these fators ould help in planning rational treatment of these patients. Antidiarrheal agents are often unsuessful (7), whereas bile aid binding agents (8,28,29) and reonstrution of the pylorus (9) an be very effetive. In partiular, holestyramine is very suessful when vagotomy and pyloroplasty are ombined with holeystetomy (28). When it fails, it is probable that very rapid gastri emptying is the major disturbane and reonstrution of the pylorus (9) or losure of a gastroenterostomy may be of great value. Indeed, it seems likely that rapid gastri emptying onsequent upon the drainage proedure is the major fator responsible for most of these disturbanes, rather than the vagotomy itself. To onfirm this it would be neessary to do similar studies in patients with rapid gastri emptying, but with intat vagus nerves. Referenes 1. Johnson D. Humphrey CS, Walker BE. Pulvertaft CN. Goligher Je. Vagotomy without diarrhoea. Br Med J 1972;3: Kennedy T. Whih vagotomy? In: Truelove SC. Lee E. eds. Topis in gastroenterology 5. London: Blakwell. 1977; George JD. Connell AM, Kennedy T. Gastri emptying in patients with post-vagotomy diarrhoea (abstr). Gut 1968; 9: MKelvey STD. Gastri inontinene and post vagotomy diarrhoea. Br J Surg 197;57: Allan JG, Gerskowith VP, Russell RI. The role of bile aids in the pathogenesis of postvagotomy diarrhoea. Br J Surg 1974; 61: Krag E, Malhow-Moller A, Frederiksen HI. et al. Pathophysiologial mehanisms of diarrhoea and dumping after vagotomy and pyloroplasty (abstr). Eur J Clin Invest, 198;1:abstrat p2. 7. Collins CD. Lomotil in the treatment of postvagotomy diarrhoea. Br Med J 1966;2: Ayulo JA. Cholestyramine in postvagotomy diarrhoea. Am J Gastroenterol 1972;57: Frederiksen HJB, Staehr Johansen T, Christiansen PM. Postvagotomy diarrhoea and dumping treated with reonstrution of the pylorus. Sand J Gastroenterol 198;15: Phillips SF, Giller J. The ontribution of the olon to eletrolyte and water onservation in man. J Lab Clin Med 1973; 81: Shedl HP, Clifton JA. Small intestinal absorption of steroids. Gastroenterology 1961;41: Talalav P. Enzymati analysis of steroid hormones. In: Glik D, ed. Methods of biohemial analysis. Vol 8. New York: Intersiene Publishers, 196: Dahlqvist A. Method of assay of intestinal disaharidases. Anal Biohem 1964;7: Levitt MD, Bond J. Use of the onstant perfusion tehnique in the nonsteady state. Gastroenterology 1977;73: Winer BJ. Statistial priniples in experimental design. Tokyo: MGraw-Hill, Kogakusha, Hall WH, Read Re. Effet of vagotomy on gastri emptying. Am J Dig Dis 197;15: MaGregor I, Parent I. Meyer JH. Gastri emptying of liquid meals and panreati and biliary seretion after subtotal gastretomy or trunal vagotomy and pyloroplasty in man. Gastroenterology 1977;72: Temple JG, Birh A, Sheilds R. Postprandial osmoti and fluid hanges in the upper jejunum after trunal vagotomy and drainage in man. Gut 1975;16: Welsh JD, Griffiths WJ. Breath hydrogen test after oral latose in postgastretomy patients. Am J Clin Nutr 198;33: Bond JH, Levitt MD. Use of breath hydrogen (Hz) to quantitate small bowel transit time following partial gastretomy. J Lab Clin Med 1977;9: Debongnie JC, Phillips SF. Capaity of the human olon to absorb fluid. Gastroenterology 1978;74: Bunh GA, Shields R. The effets of vagotomy on the intestinal handling of water and eletrolytes. Gut 1973;14: Sarpello JH, Sladen GE. Post-vagotomy diarrhoea (letterl. Lanet 1977;i: Dunombe VM, Bolin TD, Davis AE. Double-blind trial of holestyramine in post-vagotomy diarrhoea. Gut 1977;18: Blake G, MKelvey STD. Faeal bile aid exretion in patients with diarrhoea following vagotomy and holeystetomy. European Soiety for Surgial Researh 15th Congress Brussels, 198:12(Suppl 1): Wingate DL, Krag E, Mekhjian SH, Phillips SF. Relationships

6 November 1983 POSTVAGOTOMY DIARRHEA 193 between ion and water movement in the human jejunum, ileum and olon during perfusion with bile aids. Clin Si Mol Med 1973;43: Taylor TV, Lambert ME, Qureshi S, Torrane B. Should holeystetomy be ombined with vagotomy and pyloroplasty? Lanet 1978;i: Condon JR, Robinson V, Suleman MI, Fan VS, MKeown MD. The ause and treatment of postvagotomy diarrhoea. Br J Surg 1975;62: Taylor TV, Lambert ME, Torrane HB. Value of bile aid binding agents in post-vagotomy diarrhoea. Lanet 1978; i:635-6.