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Effect of Medical and Surgical Vagotomy on Gastric Response to Graded Doses of Pentagastrin and Histamine
Vol. 54, No.3 Printed in U.S.A.
GASTROENTEROLOGY
Copyright
© 1968 by The Williams
& Wilkins Co.
EFFECT OF MEDICAL AND SURGICAL VAGOTOMY ON GASTRIC RESPONSE TO GRADED DOSES OF PENTAGASTRIN AND HISTAMINE STANISLAW J. KONTUREK, M.D., ANDRZEJ WYSOCKI, M.D., AND JAN OLEKSY, M.D.
I Department of Medicine and II Department of Surgery, Medical School, Krakow, Poland
The role of vagal innervation in gastric secretion in man has been studied by a number of authors. Most workers agree that medical as well as surgical vagotomy reduces both basal and stimulated gastric acid secretion. 1 - 10 Attempts have been made to determine patterns of gastric secretion, especially the part played by vagal impulses, which would help in indicating the most effective surgical procedure for individual duodenal ulcer patients. 3 , 10-13 The study now reported was designed to study the reduction by medical and surgical vagotomy of gastric secretion induced by increasing doses of histamine and pentagastrin.
Methods Twenty-six patients (22 to 55 years old, weighing 63 to 76 kg) hospitalized with duodenal ulcer disease were selected for study. The diagnosis was established by X-ray demonstration of an ulcer crater or deformation of the bulb. The diagnosis was confirmed at operation in 15 patients. The patients were divided into three groups: I, 22 patients pretreated with hexamethonium and atropine (medical vagotomy); II, 15 patients with surgical vagotomy and pyloroplasty, including 11 patients (III) who had had medical vagotomy. Gastric secretory tests were performed in the early morning after overnight fasting and Received July 17, 1967. Accepted November 20, 1967. Address requests for reprints to: S. J. Konturek, M.D., I Department of Medicine, Medical School, Krakow, Poland. The authors are deeply grateful to Dr. Morton 1. Grossman for his critical advice in the preparation of the manuscript and to Dr. J. D. Fitzgerald for a supply of pentagastrin (lCI 50123).
withholding any antisecretory medication for at least 48 hr prior to the test. A rubber 16 F Levine tube was introduced by the nose under radiological control so that its tip was in the most dependent part of the stomach. During tests the subjects sat in a quiet room, kept at a temperature of 18 to 20 C. Saliva was expectorated when necessary. The gastric content was aspirated by continuous suction with an electric motor set to a pressure of 30 to 50 mm Hg and collected into samples every 5 min. The suction was interrupted every 2 min and air was injected down the tube to ensure constant patency. To improve the collection of the juice the tube was occasionally moved slightly and the subjects were instructed to breathe deeply. After the removal of the fasting content a basal I-hr collection was made. The volume of the juice was measured and HCI concentration was determined by the titration of samples with 0.2 N N aOH using phenol red as an indicator. Basal acid output was calculated from the two last IS-min outputs of I-hr basal collection multiplied by 2. Peak hour output at a given dose level of gastric stimulant was calculated from the four highest consecutive 5min outputs multiplied by 3. Two gastric stimulants were used: histamine diphosphate, the dose of which was expressed as a weight of this salt, and pentapeptide (ICI 50123), named pentagastrin, received as a gift from Dr. J. D. Fitzgerald of Imperial Chemical Industries, Ltd. (England). Gastric stimulants were infused intravenously in 0.15 M NaCI at a rate of 60 ml per hr using the Unipan (Poland) peristaltic pump. Pentapeptide infusion, started with a dose of 0.5 p.g per kg per hr and was raised 4-fold every 60 min, and its dose ranged from 0.5 to 8 p.g per kg per hr. Histamine, used initially in a dose of 20 p.g per kg per hr, w~s doubled every 60 min, and its dose ranged from 20 to 80 p.g per kg per hr. In all tests with histamine, promethazine was administered intramuscularly in a dose of 25 mg Y2 hr before 392
MEDICAL AND SURGICAL VAGOTOMY
March 1968
beginning the stimulant infusion. The secretory tests were usually performed twice a week. The order in which the histamine and gastrin-like penta peptide were used was randomized. In 22 patients gastric secretion was also measured following medical vagotomy as described by Gillespie and Kay; with some modification; i.e., hexamethonium was used intramuscularly in a dose of 50 mg and atropine sulfate subcutaneously in a dose of 1.0 mg 1 hr before starting histamine or pentagastrin infusion. Medical vagotomy was performed about 1 week before surgical vagotomy. The completeness of the vagotomy was assessed by means of the insulin test" with a slight modification.'5 Soluble insulin in a dose of 20 units was injected intravenously and gastric secretion was collected for 2 hr. Vagotomy was regarded as incomplete if the concentration of acid increased 20 mEq per liter or more or if the volume or acid output rose above that of the basal samples in any two consecutive I5-min samples after insulin injection. Postvagotomy histamine and pentagastrin infusions were carried out 2 weeks after surgery. The statistical significance of the results was evaluated by Student's t-test and correlation coefficient.' • Results Before medical vagotomy. Basal gastric acid secretion varied from 2.17 to 19.66
393
mEq per hr and averaged 7.09 mEq per hr ± 0.84 (SE) (fig. 1). Using the criterion for maximal response that doubling the dose did not increase the response, 20 duodenal ulcer patients required 2.0 pog per kg per hr and 2 patients 0.5 pog per kg per hr for maximal response to pentagastrin. The mean maximal acid output for 22 patients was obtained with a dose of 2.0 pog per kg per hr. Maximal response to histamine was reached with a dose of 40 ",g per kg per hr in 18 patients, with 20 pog per kg per hr in 2, and 80 pog per kg per hr in the remaining 2 patients. The mean dose response curve for 22 patients achieved its maximum at a dose of 40 pog of histamine per kg per hr. The mean maximal acid output for pentagastrin was 50.62 mEq per hr ± 4.38 (SE) and for histamine 45.02 mEq per hr ± 4.11 (SE). The difference was not statistically significant. After medical vagotomy. The acid output following medical and surgical vagotomy has been expressed as a percentage decrease from the initial value obtained without vagolytic drugs. Pretreatment with hexamethonium and atropine consistently resulted in reduction of both basal and stimulated gastric acid secretion. The mean percentage reduction for basal secretion in 22 patients after med-
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FIG. 1. The dose response curves to intravenous infusions of graded doses of pentagastrin and histamine from duodenal ulcer patients before and after medical vagotomy. Mean of one test on each out of 22 patients. Vertical bars represent standard errors of the mean.
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Vol. 54, No.3
KONTUREK ET AL.
ical vagotomy was about 80. Three of the 22 patients had basal achlorhydria. The mean basal acid secretion averaged 1.47 mEq per hr ± 0.75 (SE) , ranging from o to 4 mEq per hr. Medical vagotomy shifted the dose response curve to the right. The responses to doses which before medical vagotomy produced the maximal responses were reduced by 37% for pentagastrin and 39% for histamine. With further increment in the dose of stimulant, acid outputs were increased, reaching on the average about 76% of the initial value for pentagastrin and 78% for histamine. The percentage of the reduction decreased as doses increased. In all patients except 1 when stimulated with histamine, and in all patients except 3 when stimulated with pentagastrin, the dose response curve continued to climb when the dose of histamine or pentagastrin provoking the maximal response without vagolytic drugs was increased. In 1 patient the dose response curve reached a plateau at the dose of 80 p,g of histamine per kg per hr and in
2 others at 8 p,g of pentagastrin per kg per hr. A significant correlation was demonstrated between the maximal prevagotomy level of HCI secretion and the percentage of HCI reduction after medical vagotomy for histamine (r = 0.573, P < 0.01) and for pentagastrin (r = 0.512, P < 0.05) (fig. 2). Much stronger correlation was found between maximal responses before vagotomy and the highest postvagotomy responses to histamine (r = 0.764, P < 0.01) and to pentagastrin (r = 0.812, P < 0.01) (fig. 3).
After surgical vagotomy and pyloroplasty. Surgical vagotomy was performed
on 15 patients with duodenal ulcers, of whom 11 had had medical vagotomy before operation. All surgically treated patients had negative insulin tests, indicating that vagal section was complete. Mean basal acid output was 2.37 mEq per hr ± 0.91 (SE) and varied from 0 to 6.60 mEq per hr. The mean percentage of the reduction of basal acid secretion was 69. Achlorhydria developed in 2 patients.
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FIG. 2. Relationship between maximal Rei output induced by pentagastrin or histamine and the percentage of reduction of maximal response to these stimulants after medical vagotomy in 22 duodenal ulcer patients. In this and in the subsequent figures maximal response following medical or surgical vagotomy means the highest postvagotomy response obtained by progressive increase in the dose before the appearance of side effects.
395
MEDICAL AND SURGICAL VAGOTOMY
March 1968
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FIG. 3. Effect of medical vagotomy on the maximal acid response to pentagastrin and histamine. Each point indicates the maximal acid output before and after medical vagotomy on each out of 22 duodenal ulcer patients.
In all patients the dose response curve to histamine and pentagastrin was shifted to the right. The doses of histamine and pentagastrin that provoked maximal responses before surgical vagotomy produced on the average 70% of the prevagotomy level for histamine and 47% for pentagastrin. Doubling the dose of histamine and raising the dose of pentagastrin 4-fold produced in all patients further increase of Hel output, reaching 85% of the maximal histamine-induced prevagotomy level and 66% of the maximal prevagotomy pentagastrin-induced level. No attempts to use higher doses of stimulants were made, because nausea and hypotension developed in some patients (fig. 4). A strong significant correlation between the maximal prevagotomy responses and the highest postvagotomy responses was demonstrated for histamine (r = 0.751, P < 0.01) and for pentagastrin stimulation (r = 0.786, P < 0.01) (fig. 5). Also, a slight correlation was shown between maximal prevagotomy level of Hel secretion and the percentage of high-
est Hel reduction in tests with histamine (r = 0.533, P < 0.05) or pentagastrin (r = 0.527, P < 0.05) after surgical vagotomy (fig. 6). No correlation was found between basal prevagotomy acid output and reduction of maximal response to either stimulant. In a group of 11 duodenal ulcer patients medical vagotomy was followed after about 3 weeks by surgical vagotomy. Medical vagotomy reduced the response to all doses of histamine and pentapeptide to a similar degree. Surgical vagotomy reduced the acid response to pentagastrin more markedly than to histamine, but the difference did not reach statistical significance. In all 11 patients doses that were maximal for the intact state produced only submaximal responses to both stimulants after medical and surgical vagotomy. We were unable to demonstrate a significant correlation between the percentage of the decrease of the highest acid outputs after medical and surgical vagotomy for either histamine or pentagastrin stimulation. However, some tendency of larger decreasp. of Hel output
396
Vol. 54, No.3
KONTUREK ET AL. 60 -:;50
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FIG. 4. The dose response curves to intravenous infusions of graded doses of pentagastrin and histamine from duodenal ulcer patients before and after surgical vagotomy. Mean of one test on each out of 15 patients.
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FIG. 5. Effect of surgical vagotomy on the maximal acid response to pentagastrin and histamine. Each point indicates the maximal response before and after vagotomy in 15 duodenal ulcer patients.
following surgical vagotomy was noted in some patients with larger depression of Hel output caused by medical vagotomy (fig. 7). Discussion
The increased practice of vagotomy and drainage procedure as surgical treatment
of duodenal ulceration has focused attention on the effect of this operation on gastric secretion. It is generally agreed that there is a mean reduction of more than 50% in the acid secretion induced by the augmented histamine test in the early postvagotomy phase l - 4 , 6 as well as after a long period of time. 5
397
MEDICAL AND SURGICAL VAGOTOMY
March 1968
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FIG. 6. Correlation between maximal HCI output induced by pentagastrin and histamine and the percentage reduction of maximal responses to these stimulants after surgical vagotomy in 15 duodenal ulcer patients. >
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FIG. 7. Correlation between the percentage decrease of acid secretion induced by pentagastrin or histamine after medical and surgical vagotomy in 11 duodenal ulcer patients.
Barabas et aU showed that vagotomy and pyloroplasty also resulted in the lowering of all portions of the dose response curve for gastrin. According to this report,
the mean secretory response to histamine was about twice as much reduced as the response to gastrin. This would mean that vagotomy in man more markedly impairs
398
KONTUREK ET AL.
the responsiveness of the parietal cells to histamine than to gastrin. The present study confirms our previous findingS that pentagastrin infused intravenously in increasing doses produces a slightly higher maximal rate of acid secretion from the vagally innervated stomach and a smaller response after surgical vagotomy than does histamine. The administration of stimulants in graded intravenous doses resulted in the highest acid secretion at 2.0 p.g per kg per hr of pentagastrin and 40 p.g per kg per hr of histamine. Further increase of the dose of stimulants resulted in diminished peak HCI outputs, probably as a result of the phenomenon of tachyphylaxis. One could object to the validity of this procedure which involves infusion of the agents in progressively increasing doses and which tends to decrease the supramaximal acid response. Our previous study 9 in which maximal acid responses were obtained in man either by graded intravenous doses or separate intravenous single dose infusions showed that tachyphylaxis occurred in both secretory procedures. In the first instance the fall in acid response was observed at supramaximal dose of the stimulants, and in the latter one at the end of 90 min of continuous infusion of one dose of pentagastrin or histamine. To diminish the possible effects of tachyphylaxis on our results only the peak values of the dose response curves were used to determine the observed maximal acid response before and after medical or surgical vagotomy. The main advantage of the particular secretory procedure and the dose scales used in our present study is that they constitute an easy and convenient method to obtain dose response curves to pentagastrin and histamine. Pretreatment with hexamethonium and atropine significantly reduced the acid response to all tested doses of histamine and pentagastrin. Since fixed doses of anticholinergic agents were administered the degree of reduction of HCI response should depend to a certain degree on the range of individual weights of our patients. Although the atropine dose in our present report was
Vol. 54, No.3
increased about 3 times compared with that proposed originally for medical vagotomy by Gillespie and Kay, it is not certain whether vagal blockage was complete and it seems that further study is needed to determine the maximal inhibitory doses of both agents administered in medical vagotomy. It is also not certain whether maximal response to both stimulants is reduced after medical vagotomy, because the dose response curve was shifted to the right and serious side effects prevented the administration of a sufficiently large dose of pentagastrin or histamine to satisfy the criterion of maximal response. The doses of both stimulants required for maximal and supramaximal response before medical vagotomy resulted only in submaximal response after this procedure. A similar shift to the right of the dose response curve for histamine after medical vagotomy was reported by Raju and Narielvala,1° who constructed the curve from the single one-dose subcutaneous injections of histamine and were also unable to reach the plateau, although 80 and 100 p.g per kg per hr of histamine were used. Since the percentage of reduction of acid secretion in our study decreased with increasing doses of pentagastrin or histamine, it seems that the cholinergic innervation plays a greater role in the stimulation by smaller than by larger doses of histamine and pentagastrin. Surgical vagotomy and pyloroplasty also lowered the dose response curve to all levels of histamine and pentagastrin, shifting them to the right. For the same reason as after medical vagotomy we could not reach the maximal responses to either stimulant after surgical vagotomy. Our results remain in some disagreement with the report of Payne and Kay,4 who studied the dose of histamine required for maximal response after surgical vagotomy. They used after vagotomy 2 or 3 times higher doses of histamine than before the operation and did not find any tendency of acid secretion to approach the prevagotomy level. This discrepancy could be explained by the different modes of histamine administration. Payne and Kay used his-
March 1968
MEDICAL AND SURGICAL VAGOTOMY
tamine subcutaneously in one-dose injections, whereas in our study graded doses of histamine were infused intravenously. With the ranges of histamine and pentagastrin used in our present study and the resultant dose response curves, it was impossible to determine whether the level of maximal response is changed after medical and surgical vagotomy, because nausea with both histamine and pentagastrin and hypotension with histamine stimulation were observed in some patients. A climbing shape of the dose response curve to both stimulants after surgical vagotomy implies that, if sufficiently large doses of these stimulants were administered, the maximal prevagotomy level of acid secretion could be restored. It would suggest that following vagotomy the acid response of the stomach decreases probably as a result of the depression of background release of antral hormone or of direct activation of parietal cells. Similar conclusions have been drawn by Broome et al. I7 in their report on the effect of antrectomy and vagotomy in duodenal ulcer patients and by Emas and GrossmanIS, 19 in their studies on the effect of truncal vagotomy on acid and pepsin responses to gastrin and histamine in cats and dogs. Although we have demonstrated a slight tendency for patients with high prevagotomy maximal acid secretion to show a greater decrease after surgical vagotomy, the predominant effect of this procedure is that the high secretors before vagotomy are high secretors after the operation. It is also true for medical vagotomy. A slight correlation between the maximal acid output and the decrease in maximal response to histamine and pentagastrin after both types of vagotomy suggests that the parietal cells of patients with high acid secretion might possess a higher degree of cholinergic tone than those of patients with a normal or low level of maximal acid output. The poor correlation of the results of medical and subsequent surgical vagotomy performed on the same 11 duodenal ulcer patients does not provide a satisfactory
399
basis for the selection of duodenal ulcer patients for the most effective surgical procedure by determining the role played by vagal impulses in gastric acid secretion. The decrease of the response was more pronounced with pentagastrin than with histamine after surgical vagotomy. We cannot find a satisfactory explanation of the difference between the effect of pharmacological and surgical vagotomy on acid secretion induced by histamine and pentagastrin. Summary
In three groups of duodenal ulcer patients-I, 22 patients pretreated with hexamethonium and atropine (medical vagotomy); II, 15 patients with surgical vagotomy; and III, 11 patients with both medical and surgical vagotomy-the acid responses to graded doses of histamine and pentagastrin infused intravenously were studied. Medical as well as surgical vagotomy lowered the dose response curve at all levels, shifting it to the right. Medical vagotomy resulted in the reduction of HCI secretion to similar degree for histamine and pentagastrin, whereas surgical vagotomy reduced more markedly the response to pentagastrin than to histamine. A strong correlation was shown between the maximal responses to pentagastrin and histamine before and after medical and surgical vagotomy. A significant correlation was demonstrated also between the prevagotomy maximal acid output to both stimulants and the percentage of reduction of HCI secretion to these stimulants induced by medical and surgical vagotomy. REFERENCES 1. Gillespie, 1. E., D. H. Clark, A. W. Kay, and H. 1. Tankel. 1960. The effect of antrectomy, vagotomy with gastrojejunostomy and antrectomy with vagotomy on spontaneous and maximal acid output in man. Gastroenterology 38: 361--367. 2. Gelb, A. M., I. D. Boronofski, and H. D. Janowitz. 1961. The effect of vagotomy and pyloroplasty on the maximal acid response to histamine. Gut 2: 240-245.
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3. Gillespie, I. E., and A. W. Kay. 1961. Effect
of medical and surgical vagotomy on the augmented histamine test in man. Brit. Med. J. 1: 1557-1562. 4. Payne, R. A., and A. W. Kay. 1962. The effect of vagotomy on the maximal acid secretory response to histamine in man. Clin. Sci. 22: 373--382. 5. Bell, P. R. F. 1964. The long term effect of vagotomy on the maximal acid response to histamine in man. Gastroenterology 46:
12. 13.
14.
387-391.
6. Bitsch, V., P. M. Christiansen, V. Faber, and P. Rodbro. 1966. Gastric secretory patterns before and after vagotomy. Lancet 1: 1288--
15.
1291.
7. Barabas, A. P., R. A. Payne, I. D. A. Johnston, and G. P. Burns. 1966. The effect of vagotomy on gastrin stimulated gastricacid secretion in man. Lancet 1: 118-119. 8. Konturek, S. J. 1967. Gastrin-like pentapeptide (ICI 50123): a potent gastric stimulant in man. Amer. J. Dig. Dis .12: 285-291. 9. Konturek, S. J., and J. Oleksy. 1967. Potentiation between pentapeptide (ICI 50123) and histamine in the stimulation of gastric secretion in man. Gastroenterology 53: 912-917. 10. Raju, S., and F. M. Narielvala. 1966. Acid
secretory response to graded doses of histamine after "medical" vagotomy. Gut 7: 474477. 11. Checketts, R. G., I. E. Gillespie, and A. W.
16.
17.
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Kay. 1966. Propanthelene as an agent for medical vagotomy. Gut 7: 200--202. Orr, I. M. 1962. Selective surgery for peptic ulcer. A review. Gut 3: 97-105. Gundry, R. K., R. M. Donaldson, C. A. Pinderhughes, and E. Barrabee. 1967. Patterns of gastric secretion in patients with duodenal ulcer; correlations with clinical and personality features. Gastroenterology 52: 176-184. Hollander, F. 1951. In Methods in medical research, Vol. 4, p. 166. Year Book Publishers, Inc., Chicago. Bank, S., I. N. Marks, and I. H. Louw. 1966. The effect of propathelene on gastric-acid secretion after vagotomy. Lancet 2: 831-833. Fisher, R. A. 1950. Statistical methods for research workers, Ed. 10. Oliver and Boyd, London. Broome, A., H. Bergstrom, and L. Olbe. 1967. Maximal acid response to histamine in duodenal ulcer patients .subjected to resection of the antrum and duodenal bulb followed by vagotomy. Gastroenterology 52: 952-
958. 18. Emas, S., and M. I. Grossman. 1967. Effect
of truncal vagotomy on acid and pepsin responses to histamine and gastrin in dogs. Amer. J. Physiol. 212: 1007-1012. 19. Emas, S., and M. I. Grossman. 1967. Effect of truncal vagotomy on acid and pepsin responses to histamine and gastrin in conscious cats. Amer. J. Physiol. In press.
GASTROENTEROLOGY
Copyright
© 1968 by The Williams
& Wilkins Co.
EFFECT OF MEDICAL AND SURGICAL VAGOTOMY ON GASTRIC RESPONSE TO GRADED DOSES OF PENTAGASTRIN AND HISTAMINE STANISLAW J. KONTUREK, M.D., ANDRZEJ WYSOCKI, M.D., AND JAN OLEKSY, M.D.
I Department of Medicine and II Department of Surgery, Medical School, Krakow, Poland
The role of vagal innervation in gastric secretion in man has been studied by a number of authors. Most workers agree that medical as well as surgical vagotomy reduces both basal and stimulated gastric acid secretion. 1 - 10 Attempts have been made to determine patterns of gastric secretion, especially the part played by vagal impulses, which would help in indicating the most effective surgical procedure for individual duodenal ulcer patients. 3 , 10-13 The study now reported was designed to study the reduction by medical and surgical vagotomy of gastric secretion induced by increasing doses of histamine and pentagastrin.
Methods Twenty-six patients (22 to 55 years old, weighing 63 to 76 kg) hospitalized with duodenal ulcer disease were selected for study. The diagnosis was established by X-ray demonstration of an ulcer crater or deformation of the bulb. The diagnosis was confirmed at operation in 15 patients. The patients were divided into three groups: I, 22 patients pretreated with hexamethonium and atropine (medical vagotomy); II, 15 patients with surgical vagotomy and pyloroplasty, including 11 patients (III) who had had medical vagotomy. Gastric secretory tests were performed in the early morning after overnight fasting and Received July 17, 1967. Accepted November 20, 1967. Address requests for reprints to: S. J. Konturek, M.D., I Department of Medicine, Medical School, Krakow, Poland. The authors are deeply grateful to Dr. Morton 1. Grossman for his critical advice in the preparation of the manuscript and to Dr. J. D. Fitzgerald for a supply of pentagastrin (lCI 50123).
withholding any antisecretory medication for at least 48 hr prior to the test. A rubber 16 F Levine tube was introduced by the nose under radiological control so that its tip was in the most dependent part of the stomach. During tests the subjects sat in a quiet room, kept at a temperature of 18 to 20 C. Saliva was expectorated when necessary. The gastric content was aspirated by continuous suction with an electric motor set to a pressure of 30 to 50 mm Hg and collected into samples every 5 min. The suction was interrupted every 2 min and air was injected down the tube to ensure constant patency. To improve the collection of the juice the tube was occasionally moved slightly and the subjects were instructed to breathe deeply. After the removal of the fasting content a basal I-hr collection was made. The volume of the juice was measured and HCI concentration was determined by the titration of samples with 0.2 N N aOH using phenol red as an indicator. Basal acid output was calculated from the two last IS-min outputs of I-hr basal collection multiplied by 2. Peak hour output at a given dose level of gastric stimulant was calculated from the four highest consecutive 5min outputs multiplied by 3. Two gastric stimulants were used: histamine diphosphate, the dose of which was expressed as a weight of this salt, and pentapeptide (ICI 50123), named pentagastrin, received as a gift from Dr. J. D. Fitzgerald of Imperial Chemical Industries, Ltd. (England). Gastric stimulants were infused intravenously in 0.15 M NaCI at a rate of 60 ml per hr using the Unipan (Poland) peristaltic pump. Pentapeptide infusion, started with a dose of 0.5 p.g per kg per hr and was raised 4-fold every 60 min, and its dose ranged from 0.5 to 8 p.g per kg per hr. Histamine, used initially in a dose of 20 p.g per kg per hr, w~s doubled every 60 min, and its dose ranged from 20 to 80 p.g per kg per hr. In all tests with histamine, promethazine was administered intramuscularly in a dose of 25 mg Y2 hr before 392
MEDICAL AND SURGICAL VAGOTOMY
March 1968
beginning the stimulant infusion. The secretory tests were usually performed twice a week. The order in which the histamine and gastrin-like penta peptide were used was randomized. In 22 patients gastric secretion was also measured following medical vagotomy as described by Gillespie and Kay; with some modification; i.e., hexamethonium was used intramuscularly in a dose of 50 mg and atropine sulfate subcutaneously in a dose of 1.0 mg 1 hr before starting histamine or pentagastrin infusion. Medical vagotomy was performed about 1 week before surgical vagotomy. The completeness of the vagotomy was assessed by means of the insulin test" with a slight modification.'5 Soluble insulin in a dose of 20 units was injected intravenously and gastric secretion was collected for 2 hr. Vagotomy was regarded as incomplete if the concentration of acid increased 20 mEq per liter or more or if the volume or acid output rose above that of the basal samples in any two consecutive I5-min samples after insulin injection. Postvagotomy histamine and pentagastrin infusions were carried out 2 weeks after surgery. The statistical significance of the results was evaluated by Student's t-test and correlation coefficient.' • Results Before medical vagotomy. Basal gastric acid secretion varied from 2.17 to 19.66
393
mEq per hr and averaged 7.09 mEq per hr ± 0.84 (SE) (fig. 1). Using the criterion for maximal response that doubling the dose did not increase the response, 20 duodenal ulcer patients required 2.0 pog per kg per hr and 2 patients 0.5 pog per kg per hr for maximal response to pentagastrin. The mean maximal acid output for 22 patients was obtained with a dose of 2.0 pog per kg per hr. Maximal response to histamine was reached with a dose of 40 ",g per kg per hr in 18 patients, with 20 pog per kg per hr in 2, and 80 pog per kg per hr in the remaining 2 patients. The mean dose response curve for 22 patients achieved its maximum at a dose of 40 pog of histamine per kg per hr. The mean maximal acid output for pentagastrin was 50.62 mEq per hr ± 4.38 (SE) and for histamine 45.02 mEq per hr ± 4.11 (SE). The difference was not statistically significant. After medical vagotomy. The acid output following medical and surgical vagotomy has been expressed as a percentage decrease from the initial value obtained without vagolytic drugs. Pretreatment with hexamethonium and atropine consistently resulted in reduction of both basal and stimulated gastric acid secretion. The mean percentage reduction for basal secretion in 22 patients after med-
60
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.s
~ 40
a.. f--
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30
I
~ 20
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w
a..
BEFORE MEDICAL VAGOTOMY AFTER
10
BASAL
0.5 20.0
2.0 40.0
0 •
...----...
.--- ..
0----0
8.0 PENTAGASTRIN I'g/kg/hr.
80.0 HISTAMINE 1'>l/kg/hr.
FIG. 1. The dose response curves to intravenous infusions of graded doses of pentagastrin and histamine from duodenal ulcer patients before and after medical vagotomy. Mean of one test on each out of 22 patients. Vertical bars represent standard errors of the mean.
394
Vol. 54, No.3
KONTUREK ET AL.
ical vagotomy was about 80. Three of the 22 patients had basal achlorhydria. The mean basal acid secretion averaged 1.47 mEq per hr ± 0.75 (SE) , ranging from o to 4 mEq per hr. Medical vagotomy shifted the dose response curve to the right. The responses to doses which before medical vagotomy produced the maximal responses were reduced by 37% for pentagastrin and 39% for histamine. With further increment in the dose of stimulant, acid outputs were increased, reaching on the average about 76% of the initial value for pentagastrin and 78% for histamine. The percentage of the reduction decreased as doses increased. In all patients except 1 when stimulated with histamine, and in all patients except 3 when stimulated with pentagastrin, the dose response curve continued to climb when the dose of histamine or pentagastrin provoking the maximal response without vagolytic drugs was increased. In 1 patient the dose response curve reached a plateau at the dose of 80 p,g of histamine per kg per hr and in
2 others at 8 p,g of pentagastrin per kg per hr. A significant correlation was demonstrated between the maximal prevagotomy level of HCI secretion and the percentage of HCI reduction after medical vagotomy for histamine (r = 0.573, P < 0.01) and for pentagastrin (r = 0.512, P < 0.05) (fig. 2). Much stronger correlation was found between maximal responses before vagotomy and the highest postvagotomy responses to histamine (r = 0.764, P < 0.01) and to pentagastrin (r = 0.812, P < 0.01) (fig. 3).
After surgical vagotomy and pyloroplasty. Surgical vagotomy was performed
on 15 patients with duodenal ulcers, of whom 11 had had medical vagotomy before operation. All surgically treated patients had negative insulin tests, indicating that vagal section was complete. Mean basal acid output was 2.37 mEq per hr ± 0.91 (SE) and varied from 0 to 6.60 mEq per hr. The mean percentage of the reduction of basal acid secretion was 69. Achlorhydria developed in 2 patients.
100
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•
~
~
N
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n
FIG. 2. Relationship between maximal Rei output induced by pentagastrin or histamine and the percentage of reduction of maximal response to these stimulants after medical vagotomy in 22 duodenal ulcer patients. In this and in the subsequent figures maximal response following medical or surgical vagotomy means the highest postvagotomy response obtained by progressive increase in the dose before the appearance of side effects.
395
MEDICAL AND SURGICAL VAGOTOMY
March 1968
... 60
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FIG. 3. Effect of medical vagotomy on the maximal acid response to pentagastrin and histamine. Each point indicates the maximal acid output before and after medical vagotomy on each out of 22 duodenal ulcer patients.
In all patients the dose response curve to histamine and pentagastrin was shifted to the right. The doses of histamine and pentagastrin that provoked maximal responses before surgical vagotomy produced on the average 70% of the prevagotomy level for histamine and 47% for pentagastrin. Doubling the dose of histamine and raising the dose of pentagastrin 4-fold produced in all patients further increase of Hel output, reaching 85% of the maximal histamine-induced prevagotomy level and 66% of the maximal prevagotomy pentagastrin-induced level. No attempts to use higher doses of stimulants were made, because nausea and hypotension developed in some patients (fig. 4). A strong significant correlation between the maximal prevagotomy responses and the highest postvagotomy responses was demonstrated for histamine (r = 0.751, P < 0.01) and for pentagastrin stimulation (r = 0.786, P < 0.01) (fig. 5). Also, a slight correlation was shown between maximal prevagotomy level of Hel secretion and the percentage of high-
est Hel reduction in tests with histamine (r = 0.533, P < 0.05) or pentagastrin (r = 0.527, P < 0.05) after surgical vagotomy (fig. 6). No correlation was found between basal prevagotomy acid output and reduction of maximal response to either stimulant. In a group of 11 duodenal ulcer patients medical vagotomy was followed after about 3 weeks by surgical vagotomy. Medical vagotomy reduced the response to all doses of histamine and pentapeptide to a similar degree. Surgical vagotomy reduced the acid response to pentagastrin more markedly than to histamine, but the difference did not reach statistical significance. In all 11 patients doses that were maximal for the intact state produced only submaximal responses to both stimulants after medical and surgical vagotomy. We were unable to demonstrate a significant correlation between the percentage of the decrease of the highest acid outputs after medical and surgical vagotomy for either histamine or pentagastrin stimulation. However, some tendency of larger decreasp. of Hel output
396
Vol. 54, No.3
KONTUREK ET AL. 60 -:;50
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"-
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FIG. 4. The dose response curves to intravenous infusions of graded doses of pentagastrin and histamine from duodenal ulcer patients before and after surgical vagotomy. Mean of one test on each out of 15 patients.
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FIG. 5. Effect of surgical vagotomy on the maximal acid response to pentagastrin and histamine. Each point indicates the maximal response before and after vagotomy in 15 duodenal ulcer patients.
following surgical vagotomy was noted in some patients with larger depression of Hel output caused by medical vagotomy (fig. 7). Discussion
The increased practice of vagotomy and drainage procedure as surgical treatment
of duodenal ulceration has focused attention on the effect of this operation on gastric secretion. It is generally agreed that there is a mean reduction of more than 50% in the acid secretion induced by the augmented histamine test in the early postvagotomy phase l - 4 , 6 as well as after a long period of time. 5
397
MEDICAL AND SURGICAL VAGOTOMY
March 1968
. 70
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FIG. 6. Correlation between maximal HCI output induced by pentagastrin and histamine and the percentage reduction of maximal responses to these stimulants after surgical vagotomy in 15 duodenal ulcer patients. >
i
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411
5D
H
1D
PER CliNT OF Hct DK,",," AFTER IIItEDICAL. VA~TOMV
FIG. 7. Correlation between the percentage decrease of acid secretion induced by pentagastrin or histamine after medical and surgical vagotomy in 11 duodenal ulcer patients.
Barabas et aU showed that vagotomy and pyloroplasty also resulted in the lowering of all portions of the dose response curve for gastrin. According to this report,
the mean secretory response to histamine was about twice as much reduced as the response to gastrin. This would mean that vagotomy in man more markedly impairs
398
KONTUREK ET AL.
the responsiveness of the parietal cells to histamine than to gastrin. The present study confirms our previous findingS that pentagastrin infused intravenously in increasing doses produces a slightly higher maximal rate of acid secretion from the vagally innervated stomach and a smaller response after surgical vagotomy than does histamine. The administration of stimulants in graded intravenous doses resulted in the highest acid secretion at 2.0 p.g per kg per hr of pentagastrin and 40 p.g per kg per hr of histamine. Further increase of the dose of stimulants resulted in diminished peak HCI outputs, probably as a result of the phenomenon of tachyphylaxis. One could object to the validity of this procedure which involves infusion of the agents in progressively increasing doses and which tends to decrease the supramaximal acid response. Our previous study 9 in which maximal acid responses were obtained in man either by graded intravenous doses or separate intravenous single dose infusions showed that tachyphylaxis occurred in both secretory procedures. In the first instance the fall in acid response was observed at supramaximal dose of the stimulants, and in the latter one at the end of 90 min of continuous infusion of one dose of pentagastrin or histamine. To diminish the possible effects of tachyphylaxis on our results only the peak values of the dose response curves were used to determine the observed maximal acid response before and after medical or surgical vagotomy. The main advantage of the particular secretory procedure and the dose scales used in our present study is that they constitute an easy and convenient method to obtain dose response curves to pentagastrin and histamine. Pretreatment with hexamethonium and atropine significantly reduced the acid response to all tested doses of histamine and pentagastrin. Since fixed doses of anticholinergic agents were administered the degree of reduction of HCI response should depend to a certain degree on the range of individual weights of our patients. Although the atropine dose in our present report was
Vol. 54, No.3
increased about 3 times compared with that proposed originally for medical vagotomy by Gillespie and Kay, it is not certain whether vagal blockage was complete and it seems that further study is needed to determine the maximal inhibitory doses of both agents administered in medical vagotomy. It is also not certain whether maximal response to both stimulants is reduced after medical vagotomy, because the dose response curve was shifted to the right and serious side effects prevented the administration of a sufficiently large dose of pentagastrin or histamine to satisfy the criterion of maximal response. The doses of both stimulants required for maximal and supramaximal response before medical vagotomy resulted only in submaximal response after this procedure. A similar shift to the right of the dose response curve for histamine after medical vagotomy was reported by Raju and Narielvala,1° who constructed the curve from the single one-dose subcutaneous injections of histamine and were also unable to reach the plateau, although 80 and 100 p.g per kg per hr of histamine were used. Since the percentage of reduction of acid secretion in our study decreased with increasing doses of pentagastrin or histamine, it seems that the cholinergic innervation plays a greater role in the stimulation by smaller than by larger doses of histamine and pentagastrin. Surgical vagotomy and pyloroplasty also lowered the dose response curve to all levels of histamine and pentagastrin, shifting them to the right. For the same reason as after medical vagotomy we could not reach the maximal responses to either stimulant after surgical vagotomy. Our results remain in some disagreement with the report of Payne and Kay,4 who studied the dose of histamine required for maximal response after surgical vagotomy. They used after vagotomy 2 or 3 times higher doses of histamine than before the operation and did not find any tendency of acid secretion to approach the prevagotomy level. This discrepancy could be explained by the different modes of histamine administration. Payne and Kay used his-
March 1968
MEDICAL AND SURGICAL VAGOTOMY
tamine subcutaneously in one-dose injections, whereas in our study graded doses of histamine were infused intravenously. With the ranges of histamine and pentagastrin used in our present study and the resultant dose response curves, it was impossible to determine whether the level of maximal response is changed after medical and surgical vagotomy, because nausea with both histamine and pentagastrin and hypotension with histamine stimulation were observed in some patients. A climbing shape of the dose response curve to both stimulants after surgical vagotomy implies that, if sufficiently large doses of these stimulants were administered, the maximal prevagotomy level of acid secretion could be restored. It would suggest that following vagotomy the acid response of the stomach decreases probably as a result of the depression of background release of antral hormone or of direct activation of parietal cells. Similar conclusions have been drawn by Broome et al. I7 in their report on the effect of antrectomy and vagotomy in duodenal ulcer patients and by Emas and GrossmanIS, 19 in their studies on the effect of truncal vagotomy on acid and pepsin responses to gastrin and histamine in cats and dogs. Although we have demonstrated a slight tendency for patients with high prevagotomy maximal acid secretion to show a greater decrease after surgical vagotomy, the predominant effect of this procedure is that the high secretors before vagotomy are high secretors after the operation. It is also true for medical vagotomy. A slight correlation between the maximal acid output and the decrease in maximal response to histamine and pentagastrin after both types of vagotomy suggests that the parietal cells of patients with high acid secretion might possess a higher degree of cholinergic tone than those of patients with a normal or low level of maximal acid output. The poor correlation of the results of medical and subsequent surgical vagotomy performed on the same 11 duodenal ulcer patients does not provide a satisfactory
399
basis for the selection of duodenal ulcer patients for the most effective surgical procedure by determining the role played by vagal impulses in gastric acid secretion. The decrease of the response was more pronounced with pentagastrin than with histamine after surgical vagotomy. We cannot find a satisfactory explanation of the difference between the effect of pharmacological and surgical vagotomy on acid secretion induced by histamine and pentagastrin. Summary
In three groups of duodenal ulcer patients-I, 22 patients pretreated with hexamethonium and atropine (medical vagotomy); II, 15 patients with surgical vagotomy; and III, 11 patients with both medical and surgical vagotomy-the acid responses to graded doses of histamine and pentagastrin infused intravenously were studied. Medical as well as surgical vagotomy lowered the dose response curve at all levels, shifting it to the right. Medical vagotomy resulted in the reduction of HCI secretion to similar degree for histamine and pentagastrin, whereas surgical vagotomy reduced more markedly the response to pentagastrin than to histamine. A strong correlation was shown between the maximal responses to pentagastrin and histamine before and after medical and surgical vagotomy. A significant correlation was demonstrated also between the prevagotomy maximal acid output to both stimulants and the percentage of reduction of HCI secretion to these stimulants induced by medical and surgical vagotomy. REFERENCES 1. Gillespie, 1. E., D. H. Clark, A. W. Kay, and H. 1. Tankel. 1960. The effect of antrectomy, vagotomy with gastrojejunostomy and antrectomy with vagotomy on spontaneous and maximal acid output in man. Gastroenterology 38: 361--367. 2. Gelb, A. M., I. D. Boronofski, and H. D. Janowitz. 1961. The effect of vagotomy and pyloroplasty on the maximal acid response to histamine. Gut 2: 240-245.
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3. Gillespie, I. E., and A. W. Kay. 1961. Effect
of medical and surgical vagotomy on the augmented histamine test in man. Brit. Med. J. 1: 1557-1562. 4. Payne, R. A., and A. W. Kay. 1962. The effect of vagotomy on the maximal acid secretory response to histamine in man. Clin. Sci. 22: 373--382. 5. Bell, P. R. F. 1964. The long term effect of vagotomy on the maximal acid response to histamine in man. Gastroenterology 46:
12. 13.
14.
387-391.
6. Bitsch, V., P. M. Christiansen, V. Faber, and P. Rodbro. 1966. Gastric secretory patterns before and after vagotomy. Lancet 1: 1288--
15.
1291.
7. Barabas, A. P., R. A. Payne, I. D. A. Johnston, and G. P. Burns. 1966. The effect of vagotomy on gastrin stimulated gastricacid secretion in man. Lancet 1: 118-119. 8. Konturek, S. J. 1967. Gastrin-like pentapeptide (ICI 50123): a potent gastric stimulant in man. Amer. J. Dig. Dis .12: 285-291. 9. Konturek, S. J., and J. Oleksy. 1967. Potentiation between pentapeptide (ICI 50123) and histamine in the stimulation of gastric secretion in man. Gastroenterology 53: 912-917. 10. Raju, S., and F. M. Narielvala. 1966. Acid
secretory response to graded doses of histamine after "medical" vagotomy. Gut 7: 474477. 11. Checketts, R. G., I. E. Gillespie, and A. W.
16.
17.
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Kay. 1966. Propanthelene as an agent for medical vagotomy. Gut 7: 200--202. Orr, I. M. 1962. Selective surgery for peptic ulcer. A review. Gut 3: 97-105. Gundry, R. K., R. M. Donaldson, C. A. Pinderhughes, and E. Barrabee. 1967. Patterns of gastric secretion in patients with duodenal ulcer; correlations with clinical and personality features. Gastroenterology 52: 176-184. Hollander, F. 1951. In Methods in medical research, Vol. 4, p. 166. Year Book Publishers, Inc., Chicago. Bank, S., I. N. Marks, and I. H. Louw. 1966. The effect of propathelene on gastric-acid secretion after vagotomy. Lancet 2: 831-833. Fisher, R. A. 1950. Statistical methods for research workers, Ed. 10. Oliver and Boyd, London. Broome, A., H. Bergstrom, and L. Olbe. 1967. Maximal acid response to histamine in duodenal ulcer patients .subjected to resection of the antrum and duodenal bulb followed by vagotomy. Gastroenterology 52: 952-
958. 18. Emas, S., and M. I. Grossman. 1967. Effect
of truncal vagotomy on acid and pepsin responses to histamine and gastrin in dogs. Amer. J. Physiol. 212: 1007-1012. 19. Emas, S., and M. I. Grossman. 1967. Effect of truncal vagotomy on acid and pepsin responses to histamine and gastrin in conscious cats. Amer. J. Physiol. In press.