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Gastric secretion as a surgical problem
Gastric
Secretion PANEL J.
as a Surgical
Problem
DISCUSSION
ENGLEBERT DUNPHY, M.D.,Chairman
two Shay rats with ligation,
480 uIcers developed averaging twenty-two per rat. When vagotomy is added, the figures are negative for both. One does not need to caIi in the statistician, X2 formulas, and so on, to see that these two sums are significantly different. On the basis of this, therefore, we can assume that vagotomy without a drainage procedure (because most certainly the Shay rats do not have a drainage procedure) wouId seem to be a perfect operation. In some of Dr. Dragstedt’s earIy studies (I have forgotten whether or not Dr. Woodward was in on these), he made a pioneer observation, namely, that in a total stomach pouch with its vagal fibers intact, marked secretion occurs from that pouch as measured from the cannuia into the footbaI1 bIadder, averaging some 80 mEq. per day over a three week period. If the vagal fibers to that total stomach pouch are cut, a tremendous decrease in acid secretion is noted. Again, we wouId believe that vagotomy is an essentially perfect operation. In work which was done approximateIy ten years ago in our Iaboratories and, at about the same time, confirmed by Dr. Dragstedt and reconfirmed by many others since, a homeostatic mechanism regarding the vagus was noted for the Iirst time; nameiy, when we have a different preparation, such as a Heidenhain pouch, which of course is, by definition, vagotomized to begin with, and when the vagal fibers of the main part of the stomach are intact, the following results pertain: During the first phase, the acid secretion was about 30 mEq. per day over a thirty day period; however, if we vagotomize the main part of the stomach, with the Heidenhain pouch stiI1 remaining exactly the same, we find the resuIt which to us, at that time, was not
J. ENGLEBERT DUNPHY (Portland, Ore.) :This is such a smal1, informal group that I do not think we will have to write out questions. I hope we will have spontaneous questions from the floor. If someone has a burning desire to present a point, we will take a moment or two at the end to cIarify it. I hope we wilI aII enter into a brief review of the problems by questions and answers. The first presentation covering the topic of Gastric Secretion as a Surgical Problem, on VagaI and Adrenal Factors, probabIy with more emphasis on vagal than adrena factors, will be discussed by Dr. Henry Harkins of Seattle. HENRY N. HARKINS (Seattle, Wash.): First, regarding the adrenal factors, which I will just mention in passing, we have done relatively little work on this per se. A paper to calI to your attention is that by Cooper, Bassett and associates, which certainIy indicates that the resistance factor as well as the gastric secretion factor is to be considered. There is aIso the problem as to whether or not the doses of the adrena hormones that have to be given to experimental animals to produce uIcers are physioIogic. Second, regarding the vaga1 factors, we al1 know about the importance of the vagi; however, I would like to comment first very briefIy on homeostatic factors relating to the vagus nerves. If the Shay rat preparation is used, which incorporates starvation for twenty-four hours, pyioric ligation and then after twenty-four hours examination of the anima1, uIcers aIways deveIop. At the same time, if in the Shay vagotomy is performed, uIcers preparation never deveIop. In some of our earIy experiments in twenty‘37
American
Journal 01 Surgery,
Volume rag. January
1~63
Panel expected, nameIy, a marked stimuIatory effect on the secretion of the Heidenhain pouch which must, therefore, have acted by way of the blood stream. This is a demonstration of a homeostatic mechanism. This stimulatory effect, I think, is much weaker than the direct effect of the vagi; however, it does show why in vagotomy, even with drainage procedure, a smaI1 but appreciable incidence of stoma1 uIcers occurs, and, therefore, why it is a good but not a perfect operation. Thirdly, I would like to speak about some of the balancing factors between the vagus and the antrum. W’e have used two or three preparations which have been devised by our residents. One is the IEIA pouch, which is an isolated, extrinsically innervated, antral pouch. The vaga1 fibers to it are intact, but a mucosa1 bridge separates it from the main part of the stomach. The food in the main part of the stomach, \vhich has its vaga1 fibers intact, goes down easily through the gastrojejunal anastomosis. The pouch can be filled, distended or antroneurolysed. Whatever is done to it may affect the Heidenhain pouch by hormona1 routes. An additiona preparation which we have used is antroneuroIysis, separating the “inner tube” from the “outer tube” often through a longitudinal incision; then the incision is sutured. This may be comparable in a way to the Ramstedt operation, in that the Iumen is not entered. In regard to the reIationship between the vagi and the antrum, the statement has been made that when the insuIin test is given or other vagal action occurs, the antrum is affected by the resultant peristaIsis. This could be true. Before insuIin is administered, IittIe peristaltic activity is present; after insuIin is given, there is marked peristaItic activity. Before insuIin is given, a very little secretion is observed from an IEIA pouch; after insulin is given, there is a marked secretion. However, the peristalsis is not directly related, because if the same type of IEIA pouch is used but is antroneurolovscd and then the ins&n given, the peristalsis goes through very niceIy afterwards; in fact, if anything, it is stronger than it was without antroneurolysis; however, no secretory response whatsoever is noted. Again, this shows the relationship between the vagi and the antrum.
Discussion AI1 this gets back to Uvnaos’ report in 1942, which indicated that the antrum and the vagi were functionaIIy connected. Work done since then in our Iaboratory indicates there is a lot of truth to his postuIates of twenty years ago. In the body, several natural parietal cell stimulants include gastrin, histamine and the vagus itseIf, which may act through acetyIcholine. These may potentiate each other. Furthermore, if the vagus is cut, all stimuli may be dulled. Histamine and antral distention wiI1 potentiate each other. When histamine is added to antraI distention, histamine in this dose gives a far greater action than it gave by itseIf. In regard to histamine and gastrin, when histamine is given aIone, there is a smal1 effect; however when added to a baseIine of repeated smaI1 doses of gastrin, the histamine produces a marked effect. The same is true of the reverse, that is, when gastrin is added to histamine. The time intervals and so on have been varied in other dogs, so the effects could not be the resuIt of too short a delay. Dr. DUNPHY: Does anyone want to raise a question about any point just now, just brieffy, to cIarify an issue? If not, we wilI ask Dr. Woodward to proceed with a discussion of “Intestinal InfI uences.” EDWARD R. WOODWARD (GainesviIIe, FIa.): As a nation we are addicted, in both our poIitics and our medica science, to pet phrases, cIich& and sIogans, one might say. Dr. Harkins used one that has been a favorite in recent I think it is here to stay years, “homeostasis.” for a while. I certainly Iind it a very useful one in my own thinking. I Iike to think of homeostasis as a counterbaIance for a physiologic force which, if unchecked, would be harmful to the organism. If we think of hemostasis in this sense, it is hard to Iind a more appropriate use for it than in regard to gastric secretion. The ravages of unchecked gastric secretion are we11 known to a11 of us, and were first pointed out to us IOO years ago in the classic experiments of Claude Bernard. Under physioIogic conditions the secretion of acid gastric juice is, to at least some extent, intermittent. In most animals it is completely so; secretion of acid gastric juice occurs only in feeding, whereas in human beings there is a continuous component.
Gastric
Secretion
as a Surgical
ProbIem
along at this high level. U’hen the vagi are cut there is a rather marked fall of about 73 per cent, indicating that the secretion here (,apparently 25 per cent of it) was coming from the intestinal phase. W!hen the antrum is rcintroduced into the duodenum there is a sharp rise. This is not strictly a physiologic experiment; therefore, we can only guess from this that the intestinal phase ssems less important than either the nervous or gastrin phases. In a somewhat different experiment, using a vagaIly innervated small Pavlov pouch, an animal secreted at an extremely high level xvith the antral, nervous and intestinal phases all being present. When the antrum is taken out of continuity with the gastrointestinal tract, a pronounced fall in secretion occurs, and then there is another faII after the vagi to the stomach pouch are sectioned, indicating again that of the three phases the intestinal phase is probabIy the least significant. The best guess from many different experiments would be that it probably accounts for from 5 to 25 per cent of gastric secretion in human beings under normal conditions. On the inhibitory side we have a much more complex picture, and I will take you from the clear to the obscure. I think \ve can generalize in the first place by stating that the inhibitory roIe of the intestine on gastric secretion and on gastric function, in generaI, is undoubtedly far more important than its excitatory role. It is probably the singIe most important factor in the contro1 and inhibitory regulation of gastric secretion. The intestine acts on the stomach in at least four different ways. This is probably an o\-ersimphhcation. First of all, acid in the intestine inhibits gastric motility and delays gastric acid in the intestine emptying. Secondly, inhibits gastric secretion. Third, fat am I reIated substances in the intestine inhibit gastric motility. Fourth, fat and similar substances in the intestine inhibit gastric secretion. The first of these is very clear and very nearly compIeteIy worked out; this is the inhibitory effect of acid on gastric motility and gastric emptying. The Iine drawing which was shown depicts an experimental method for studying this in human beings. The pressure in the balloons is used as a recording of motility, using transducer-recorder poIygraphs. We can introduce acid into the duodenum at this point, while we measure the
The intestine is of extreme importance in the homeostasis of gastric secretion in both directions. It both stimulates and inhibits gastric secretion. We will omit a discussion of the important solid organ appendages of the intestine, the liver and pancreas; in both cases there is sufficient evidence to say that, in all probability, they normally play an important role in gastric digestion. We will also omit a discussion of the coIon, since there has, as yet, been no evidence that under normal conditions it pIays a role; in fact, the dista1 smal1 intestine probabIy does not play an important part in gastric acid secretion. We are concerned, therefore, primarily with the duodenum and the proximal jejunum. We will start with the clear cut and concIude with the less obvious importance of the intestine in the control of gastric secretion. On the excitatory side it is quite clear: we understand the intestinal phase of gastric secretion. This is the third and last of three phases of gastric secretion. It is humoral in origin and probably hormona1, and the best guess at the present time is that the intestina1 hormone is probably distinct from the antraI hormone. The intestinal phase was discovered by Lim and Ivy thirty-five years ago in Chicago, and this is the preparation used by them. In a totahy isolated stomach pouch in the dog, the vagi were cut in preparing the pouch. In this case the secretion of acid gastric juice from the stomach is quite small in amount when compared with what happens when the antrum is reintroduced into the intestine. However, this contrast is not as great as you might think, because in the absence of acid, of course, the antrum does not exert its inhibitory effect. The humoral nature of this was established by transplanting the stomach subcutaneously and deriving a completely new bIood supply, thus indicating that a nervous mechanism was not involved and that for all intents and purposes it was a hormona1 mechanism. In an attempt to establish the relative importance of the intestinal phase of gastric secretion, we have to try to correlate data from many different experiments, and I wilI discuss only a few. In this particular preparation, with the totally isoIated stomach pouch and the vagi intact, daily secretion on a standard diet goes ‘39
Pane1
Discussion
motility and gastric secretion in both the duodenum and stomach simultaneously. We control this by putting a smalI amount of normal saline soIution into the duodenum; the gastric contractions recorded here go on unchanged. Then, a small amount of hydrochIoric acid is introduced into the duodenum, and the gastric contractions are totaIIy abolished for this period which amounts to about eighteen minutes. In this particuIar patient, a human subject, the duodenal contractions were aIso inhibited, but this is not constant. To work out the mechanism of this, work was performed in dogs, in which animal exactIy the same phenomenon is observed. After control studies, this particular dog, which had a duodenal fistuIa for introduction of the acid, had celiac gangIionectomy. FoIIowing celiac ganglionectomy the introduction of acid into the duodenum had absoIuteIy no effect on gastric contractions. Therefore, this is a compIeteIy nervous mechanism. It has a11 the physioIogic characteristics of a nervous mechanism, extremeIy short Iatent period and rather short duration of effect. This is what the neurophysiologists refer to as an “axon reflex.” Both sides of the arc are in the peripheral postganglionic sympathetics. From here on we get into areas of Iess cIearIy defined knowledge. Next we have the effect of acid on gastric secretion. The inhibitory effect of acid in the duodenum on gastric secretion was discovered in PavIov’s Iaboratory. It was worked out extensiveIy in this country by Pincus, Thomas and Rehfuss in PhiIadelphia in the middIe 1930’s. We know only some refinements in addition to what they described at that time. No doubt the acid in the duodenum does inhibit the secretion of gastric juice, and I beIieve we have Iocalized it to a certain extent. In a preparation used in our Iaboratory, a fistuIa is made of the duodenum from just beyond the major pancreatic duct to the Iigament of Treitz. This totaIIy isoIated, doubleended fistula then can be irrigated with acid while gastric secretion is stimulated from the Heidenhain pouch. We used the most physioIogic stimuIus one can imagine, namely, a mea1. After contro1 studies were performed, this dog was fed whiIe the duodenum was perfused with 0.1 norma HCI. You wiI1 note that there is a pronounced rise in voIume and acid concentration which
paraIIeIed exactIy the animaI’s response without duodena1 perfusion with acid. This acts as an introduction to indicate that probabIy the inhibitory effect of acid on gastric secretion is more sharpIy IocaIized than other inhibitory factors in the smaI1 intestine, and that the very important first portion of the duodenum, which was not incIuded in this fistuIa, is probabIy the site for at least most of the inhibitory effect or acid on gastric secretion. A somewhat controversial experiment is the Mann-WiIIiamson preparation, which results promptIy in a margina uIcer at this point. This was originaIIy thought to be the result of lack of neutraIization of the acid-gastric materia1 as it exits from the stomach. Later, it became apparent that faiIure of acid inhibition might pIay a rote, and this was supported by data indicating that gastric secretion in this preparation is very sharply increased over the norma levels. In any event, further work since this time indicates that the explanation of this particular marginal uIcer is probably even much more complicated. However, I think there is no question that this factor of absence of acid inhibition in the duodenum probabIy plays a role in the MannWiIIiamson ulcer. When we discuss fat, we reaIIy get into vague territory. In some areas we know so little about it that it is hardIy worthwhile taIking about. Here again we come to the name of Ivy. During the golden period of gastroenterologic investigations in his Iaboratory at Northwestern, he discovered the hormone produced by fat in the intestine, enterogastrone. Now we know so much about it, we are not even sure it exists; if it does exit, there must be at Ieast two of them. Another preparation has been very useful in the Iaboratory. In the dog a gastric cannula provides ready access to the stomach, whereas a cutaneous fistula prepared by this Roux-Y Ioop makes a very handy way to introduce materia1 into the intestine at the desired IeveI. We now measure gastric motility through the gastric fistuIa. We put some norma saline soIution into the duodenum. We find no effect on gastric motility. At this point we introduce a very smaII amount, about 20 cc., of 0.1 norma acid into the duodenum and we note that an immediate suppression of gastric mo140
Gastric
Secretion
tility occurs; after a rather short time, this gradually returns untiI contractions are the same as ever. A sharp contrast is noted when the same volume of 20 cc. of olive oil is introduced into the duodenum. Now the gastric contractions continue unchanged for a latent period, which lasts from five to twenty minutes; then, instead of the sudden drop characteristic of the nervous mechanism, a gradual fall off occurs indicating a humoral or hormonal mechanism. Once this inhibition of gastric motility is introduced by fat, it lasts not for minutes but for hours. So, we have the established fact that fat in the small intestine has a very powerful inhibitory effect on gastric motility and delays gastric emptying very definitely, a fact which of course was discovered originally by Beaumont. The recent work of Menguy has been most interesting in this regard; his work with the role of fat in the inhibition of gastric secretion has indicated clearly that, in addition to fat, at least some of the normal contents of the small intestine, which would include bile, pancreatic juice and succus entericus, must be present if inhibition of gastric secretion by fat is to occur. Perhaps we cannot sharply separate the effect of fat on motility and secretion. At least the following particular experiment leans somewhat in that direction. The experiment was with a Thirty-Vella fistula of the duodenum in a dog which also has a gastric cannula. Here we introduce 0.1 normal HCI into the Thirty-Vella loop and get inhibition of gastric motility. Here again we repeated this with acid-gastric juice, and inhibition occurred. Then, when we use olive oiI, even though in the present case it has been mixed with pancreatic juice and bile, no inhibition of gastric motility occurs. So, in this way the inhibitory effect of fat on gastric motility seems to behave very much the same as the same inhibitory mechanism on gastric secretion. I would like to end on a slight note of levity, and this has to do with the effect of alcohol on the intestine. Alcohol is absorbed through the intestine so rapidIy that it might just as well be given intravenously. When an amount of alcohol equivalent to about one can of beer is introduced into a dog with a Heidenhain pouch and a Thirty-Vella loop of the duodenum, a very startling stimulation of gastric
as a Surgical
Problem
secretion occurs, and the volume and free acid concentration increase almost as much as if the dog had been given histamine. As we follow the blood levels, we find that within thirty minutes the blood has reached exactly the same level, as if the dog had received the same dose of alcohol direct1.y into the vein. Therefore, this effect of alcohol is the general parenteral effect of alcohol in stimuIating parietal cell activity, and is not stimulation of the intestinal phase of gastric secretion. It probably explains the rather unusual sensitivity to alcohol that is seen in many gastrectomized patients because of the rapid absorption from the intestine, whereas the stomach itself absorbs very little alcohol. CHAIRMAN DUNPHY: The next presentation
will be on “Ulceration in the Patient with Cirrhosis,” by Dr. C. Stuart Welch of Albany, New York. C. STUART WELCH (Albany, N. Y.): There seems to be pretty fair agreement among physicians who have been interested in cirrhosis of the liver and in performing portacaval shunt ulceration does surgery, that gastroduodenal occur m these patients in a higher incidence than in a comparable group of the same age and status. Furthermore, I think almost all surgeons who have been performing shunt surgery have noticed duodenal or gastric ulcers appearing in postshunt patients with higher than incidental frequency, and in
patients in whom no ulcer seemed to exist previously. This has led to clinica and experimental investigation on the possible mechanisms or mechanism of ulcerogenesis in cirrhosis of the liver. First of all, what is the incidence of gastroduodenal ulceration in patients with cirrhosis? A great many studies have been made. The incidence has been reported as low as 3 per cent by some, and by others as high as 25 per cent. Fifty-five patients were autopsied consecutiveIy for two years, and we found ten ulcers or 18 per cent. I think this figure agrees with that of a great many other peopIe who have studied this. It is probabIy slightly or significantly higher than might be found in patients of comparable ages, which might be about IO or 12 per cent. Of great interest to me in this study was another
subject
that
is concerning
surgeons
Panel performing shunt work, namely, the incidence of gallstones in cirrhosis. The incidence of gaIlstones and cholecystitis in these patients is rather high. We have 31 per cent cholecystic disease in this group of fiftyfive patients. In a group of male patients from our Veterans Hospital the incidence of gallstones at the time of shunt was 25 per cent in a male population. We have had two patients with postoperative acute cholecystitis, one of whom died. We rather recommend choIecystectomy at the time of shunt in patients who have gahstones. In patients who are studied beforehand with a gastrointestina1 series, as they al1 are who are coming up for shunt, we have found an incidence of ulceration to be only I 2 per cent. While the clinical impression is that shunts are &erogenic in patients, there is insuffrcient data at the present time to clearIy estabIish their relationship; however, in our own experience we have been impressed with the occurrence of uIceration in 4 of I12 patients who definitely did not have an ulcer before, as far as we know, and two of whom had severe hemorrhages requiring operation. The experimental work on ulcerogenesis has been done in dogs. Although it is difficult to make a great many conclusions, it is of interest because it is quite unlike the human situation, and only portions of the situation can be studied. We do not have good preparations for this study of liver disease in dogs. Cirrhosis simulating the human type cannot be produced in dogs, and even portal hypertension is diffrcult to make and sustain. As a matter of fact, the correIation is not good between the experimenta work in dogs and the findings in human subjects. It has been found, however, that the influence of a portacava1 shunt is to cause a hypersecretion of gastric juice. This hypersecretion responds to protein ingestion and is not abohshed by antrectomy or vagectomy, and is probably reiated to the intestinal phase of gastric secretion. A shunting of some substance around the liver would seem to be implicated as an etiologic mechanism. What this substance is, is not clear; whether it is histamine or whether there is another unknown substance is not yet determined. Gastrin and even hepatocellular damage of the liver have also been implicated in some studies. Of course there are unknown factors in the
Discussion cause of ulcer, whether or not the patient has cirrhosis of the Iiver. The relationship of hyperacidity in ulcerogenesis in the cirrhotic patient, however, is not the same as we find in normal human subjects, because patients with cirrhosis do not have hypersecretion of acid and they have rather low acidities or normal acidities. Even those patients who have de’inite ulcers do not very often have hyperacidity, although the acidity is higher than it is in patients with cirrhosis without ulceration. Is the local factor of great importance? We might consider that it is because, as you know, in operating on patients with cirrhosis of the liver, very delinite structura1 changes occur throughout the abdominal viscera, that is, edema and very good evidence of obstruction of the lymphatic system, How much this might relate to the cause of ulcer on the basis of Iowered tissue resistance, I do not know. A very important study has been done by Ostroff at the Brigham Hospital on gastric secretion in patients with cirrhosis and patients who have been shunted. He has not only tried to determine the influence of shunt on acidity in his patients with cirrhosis; however, he also has attempted to eliminate other factors which might be causative, such as hormona1 factors. I think he has definiteIy shown that patients who do have a portacaval shunt do begin to secrete more gastric juice after operation, and, therefore, in the postshunt patient we must come to the conclusion that diversion of some substance from the liver, which comes from the intestine, is of etiologic importance. The clinica significance of gastroduodena1 ulceration in the patient with cirrhosis has to do with two important questions, I think. The first we can dismiss in a few minutes. If a portacaval shunt is ulcerogenic, or if it does increase hyperacidity, should we perform any prophylactic antiulcer procedure at the time of portacaval shunt, particularly in patients who have an obvious duodenal ulcer? Conceivably, vagectomy and pyloroplasty could be performed without too much trouble, although we hesitate to add any operation that is not absoIuteIy necessary in patients having shunts. An added procedure is particularly unwise in those patients in poor condition or in whom there is considerable blood loss or the operation may have been prolonged.
Gastric
Secretion
as a SurgicaI
ProbIem
in with a massive hemorrhage they are not easy to perform. As you know, the IeveI of ammonia will not help you much. It may be high in patients bleeding from ulcer as well as varices. Presently Dr. Harold Welsh, in our hospital, is studying something that I think may be definitely of value in differentiating ulcer hemorrhage from variceal hemorrhage. He is studying the urobilinogen content of gastric aspirates in patients with massive bleeding from the upper gastrointestina1 tract. Urobilinogen should not be present in systemic blood and, therefore, should probabIy not be present in patients with bleeding from duodenal or gastric ulcer; however, if they are bleeding from a varix, urobilinogen should be present. Dr. Welsh has a modest series of twenty-two patients now. In six patients with bIeeding from varices, urobilinogen was present, and in the other sixteen with bleeding from ulcer, it was not present. There seems to be, therefore, a definite relationship between peptic ulcer and cirrhosis of the liver and portacaval shunt. I might say I believe the incidence of gastric ulcer in patients who have come to operation for bleeding is higher than it should be, which might have some reIation to the cause. We should be aware of the possibility of the cirrhotic patient with bleeding from an ulcer and try to get the patient to undergo operation early, because I find the mortality is prohibitiveIy high when gastrectomy for ulcer is performed late, that is, after three or four days of conservative management. CHAIRMAN DUNPHY: Fourth in this series of presentations will be “Zollinger-EIIison Diathesis : Pathophysiology and Current Status,” by Dr. Robert M. Zollinger of Columbus, Ohio. ROBERT M. ZOLLINCER (CoIumbus, Ohio): There is increasing evidence in our opinion that the pancreas can play a significant roIe in the hormonal stimulation of gastric juice. As you know now, nonbeta islet-cell tumors can produce an intractable uIcer diathesis characterized by gigantic hypersecretion which leads to a fulminating ulcer diathesis, enteritis, or both. The most characteristic location of the uIcer has been just distal to the ligament of Treitz. Approximately 132 case reports of a fulminating ulcer diathesis associated with certain islet-ceI1 tumors of the pancreas strongly support a relationship between the two. This rela-
More important, I think, is the question of whether or not a patient who bleeds with cirrhosis is indeed bleeding from his varices or is bleeding from a gastric or duodenal ulcer. This may influence our immediate treatment. it should influence immediate Particularly, treatment for those surgeons who prefer to use temporizing measures in the treatment of hemorrhage from varices, because if a patient is bleeding from a gastric or duodenal ulcer and has cirrhosis of the liver, an immediate operation should be performed; it is much more effective than it would be three, four, five or six days Iater when the patient is depleted and has had multiple blood transfusions. Patients with cirrhosis cannot stand bIood loss and blood replacement too well. We have found the mortahty to be very high in patients with a bIeeding ulcer and with cirrhosis, In fact, every one of these patients undergoing gastrectomy as an emergency has died. Using a program of earIy emergency surgery in suitable patients with cirrhosis who bleed, we should be able to get some of them by; however, again 1 do not know just what procedure we should use. I would rather guess the simplest one possible would be the best, perhaps such as transfixing the bleeding base of the ulcer and performing vagectomy. Of course, small resection might be indicated, In one patient who had a very large ulcer in the second portion of the duodenum, I performed gastrectomy, leaving the ulcer in sight and transhxing it as best I could; however, he died subsequently of a hemorrhage from it. Therefore, I am not sure that transfixion of the bleeding point is adequate. It is hard to make the diagnosis of the cause of bIeeding in some patients with cirrhosis. We are using the Sengstaken balloon much less than before, preferring gastric hypothermia in the treatment of bleeding from varices, as we do in the treatment of uIcer hemorrhage. Local hypothermia is not much help in differential diagnosis; however, the tamponade by baboon is of some help. That is to say, if the patient continues to bleed after the tamponade, one must be highly suspicious of gastric varices or duodenal ulcer. However, I have been fooled by hemorrhage stop with the use of the tamponade even though the patient was bIeeding from a duodenal ulcer. There are, of course, other methods of investigation; however, when the patient comes ‘43
Pane1
Discussion
tionship has been proved by Gregory of Liver~001, who has been able to make a picric acid extract of these islet-ceI1 tumors as well as their metastasis which is a potent gastric secretagogue. He has shown that these extracts are similar to gastrin in every respect. He has suggested that these tumors yieId an extract about thirty-five times more potent than that extracted from a similar weight of hog antrum. Like Doctor Code and others in this country, my associates Doctors Dan Elliott and Gerald EndahI have confirmed the findings of Gregory. Extracts of five nonbeta cell tumors and two liver metastasis from such tumors have produced a typica gastrin response in the standardized PavIov pouch dog preparation. Since 62 per cent of these tumors are mahgnant, it is important to remember that the metastasis can continue the fulminating ulcer diathesis even though a primary tumor in the pancreas has been successfuIIy resected. Total gastrectomy is indicated even in the presence of metastasis and active uIcer disease, since these tumors tend to grow slowly, and perforation is a constant threat if any acid producing tissue is retained by a subtotal resection. WhiIe 25 per cent of the 132 reported cases have been associated with more than one adenoma, we know of no evidence that adenomas other than those of the pancreas produce a gastric secretagogue. Gregory extracts of adenomas of the parathyroid, thyroid and adrena gland have al1 faiIed to produce a secretagory response from the PavIov pouch of the dog. The same has been true for the beta ceII adenomas (insuhnoma) and carcinoid tumors. The nonbeta islet-cell tumors are the only endocrine tumors known so far, from which the gastric secretagogue can be extracted. The main cIinica1 problem is to control the overproduction of hydrochloride. This is a difhcuIt and chahenging probIem unIess the patient has a sohtary tumor which can be removed. UnfortunateIy, it wouId seem from
the reported cases that there are multiple sites for the production of the gastrosecretagogue hormone. The high incidence of malignancy and the high incidence of metastasis, as well as multilocations in the pancreas, account for the multipIe sites. On the basis of the figures, a failure rate of 55 per cent could be predicted as long as any acid secreting surface remains. The resuhs of conservative procedures so far have been disappointing. It is understandable that any surgeon is loathe to perform a total gastrectomy; however, this is the procedure of choice. Excision of a Iocal tumor has corrected the uIcer diathesis in some cases; nevertheless, there is already a recurrent uIcer rate of 60 per cent. A recurrence rate of 57 per cent has taken place with the more radicaI procedures on the stomach, including vagotomy. Since earIy recurrence with hemorrhage and perforation may occur even after radical gastric resection, the mortality for the more conservative procedure is equa1 to, if not greater than that which follows tota gastrectomy. Further work is required to identify this hormone. Furthermore, no convincing evidence is known, of which cell produces gastric secretagogue. This is especiahy bafhing since extracts of the cIinicaIIy fibrosed pancreas, as we11 as the experimentahy produced atrophied pancreas, appear to contain a similar, although Iess potent gastric secretagogue, than the nonbeta islet-cell tumors. It is becoming increasingly clear that a better understanding of gastric secretion may come through a better understanding of the role of the pancreas. CHAIRMAN DUNPHY: I would Iike to congratulate the four speakers on their really superb presentations of complicated subjects in such a short time. I remember that some years ago Dr. John Homans of Harvard, told me that the way to get to be a professor was to study mechanisms of gastric secretion in duodenal uIcer. I think we have seen four brilIiant exampIes of how to use this route today.
144
Secretion PANEL J.
as a Surgical
Problem
DISCUSSION
ENGLEBERT DUNPHY, M.D.,Chairman
two Shay rats with ligation,
480 uIcers developed averaging twenty-two per rat. When vagotomy is added, the figures are negative for both. One does not need to caIi in the statistician, X2 formulas, and so on, to see that these two sums are significantly different. On the basis of this, therefore, we can assume that vagotomy without a drainage procedure (because most certainly the Shay rats do not have a drainage procedure) wouId seem to be a perfect operation. In some of Dr. Dragstedt’s earIy studies (I have forgotten whether or not Dr. Woodward was in on these), he made a pioneer observation, namely, that in a total stomach pouch with its vagal fibers intact, marked secretion occurs from that pouch as measured from the cannuia into the footbaI1 bIadder, averaging some 80 mEq. per day over a three week period. If the vagal fibers to that total stomach pouch are cut, a tremendous decrease in acid secretion is noted. Again, we wouId believe that vagotomy is an essentially perfect operation. In work which was done approximateIy ten years ago in our Iaboratories and, at about the same time, confirmed by Dr. Dragstedt and reconfirmed by many others since, a homeostatic mechanism regarding the vagus was noted for the Iirst time; nameiy, when we have a different preparation, such as a Heidenhain pouch, which of course is, by definition, vagotomized to begin with, and when the vagal fibers of the main part of the stomach are intact, the following results pertain: During the first phase, the acid secretion was about 30 mEq. per day over a thirty day period; however, if we vagotomize the main part of the stomach, with the Heidenhain pouch stiI1 remaining exactly the same, we find the resuIt which to us, at that time, was not
J. ENGLEBERT DUNPHY (Portland, Ore.) :This is such a smal1, informal group that I do not think we will have to write out questions. I hope we will have spontaneous questions from the floor. If someone has a burning desire to present a point, we will take a moment or two at the end to cIarify it. I hope we wilI aII enter into a brief review of the problems by questions and answers. The first presentation covering the topic of Gastric Secretion as a Surgical Problem, on VagaI and Adrenal Factors, probabIy with more emphasis on vagal than adrena factors, will be discussed by Dr. Henry Harkins of Seattle. HENRY N. HARKINS (Seattle, Wash.): First, regarding the adrenal factors, which I will just mention in passing, we have done relatively little work on this per se. A paper to calI to your attention is that by Cooper, Bassett and associates, which certainIy indicates that the resistance factor as well as the gastric secretion factor is to be considered. There is aIso the problem as to whether or not the doses of the adrena hormones that have to be given to experimental animals to produce uIcers are physioIogic. Second, regarding the vaga1 factors, we al1 know about the importance of the vagi; however, I would like to comment first very briefIy on homeostatic factors relating to the vagus nerves. If the Shay rat preparation is used, which incorporates starvation for twenty-four hours, pyioric ligation and then after twenty-four hours examination of the anima1, uIcers aIways deveIop. At the same time, if in the Shay vagotomy is performed, uIcers preparation never deveIop. In some of our earIy experiments in twenty‘37
American
Journal 01 Surgery,
Volume rag. January
1~63
Panel expected, nameIy, a marked stimuIatory effect on the secretion of the Heidenhain pouch which must, therefore, have acted by way of the blood stream. This is a demonstration of a homeostatic mechanism. This stimulatory effect, I think, is much weaker than the direct effect of the vagi; however, it does show why in vagotomy, even with drainage procedure, a smaI1 but appreciable incidence of stoma1 uIcers occurs, and, therefore, why it is a good but not a perfect operation. Thirdly, I would like to speak about some of the balancing factors between the vagus and the antrum. W’e have used two or three preparations which have been devised by our residents. One is the IEIA pouch, which is an isolated, extrinsically innervated, antral pouch. The vaga1 fibers to it are intact, but a mucosa1 bridge separates it from the main part of the stomach. The food in the main part of the stomach, \vhich has its vaga1 fibers intact, goes down easily through the gastrojejunal anastomosis. The pouch can be filled, distended or antroneurolysed. Whatever is done to it may affect the Heidenhain pouch by hormona1 routes. An additiona preparation which we have used is antroneuroIysis, separating the “inner tube” from the “outer tube” often through a longitudinal incision; then the incision is sutured. This may be comparable in a way to the Ramstedt operation, in that the Iumen is not entered. In regard to the reIationship between the vagi and the antrum, the statement has been made that when the insuIin test is given or other vagal action occurs, the antrum is affected by the resultant peristaIsis. This could be true. Before insuIin is administered, IittIe peristaltic activity is present; after insuIin is given, there is marked peristaItic activity. Before insuIin is given, a very little secretion is observed from an IEIA pouch; after insulin is given, there is a marked secretion. However, the peristalsis is not directly related, because if the same type of IEIA pouch is used but is antroneurolovscd and then the ins&n given, the peristalsis goes through very niceIy afterwards; in fact, if anything, it is stronger than it was without antroneurolysis; however, no secretory response whatsoever is noted. Again, this shows the relationship between the vagi and the antrum.
Discussion AI1 this gets back to Uvnaos’ report in 1942, which indicated that the antrum and the vagi were functionaIIy connected. Work done since then in our Iaboratory indicates there is a lot of truth to his postuIates of twenty years ago. In the body, several natural parietal cell stimulants include gastrin, histamine and the vagus itseIf, which may act through acetyIcholine. These may potentiate each other. Furthermore, if the vagus is cut, all stimuli may be dulled. Histamine and antral distention wiI1 potentiate each other. When histamine is added to antraI distention, histamine in this dose gives a far greater action than it gave by itseIf. In regard to histamine and gastrin, when histamine is given aIone, there is a smal1 effect; however when added to a baseIine of repeated smaI1 doses of gastrin, the histamine produces a marked effect. The same is true of the reverse, that is, when gastrin is added to histamine. The time intervals and so on have been varied in other dogs, so the effects could not be the resuIt of too short a delay. Dr. DUNPHY: Does anyone want to raise a question about any point just now, just brieffy, to cIarify an issue? If not, we wilI ask Dr. Woodward to proceed with a discussion of “Intestinal InfI uences.” EDWARD R. WOODWARD (GainesviIIe, FIa.): As a nation we are addicted, in both our poIitics and our medica science, to pet phrases, cIich& and sIogans, one might say. Dr. Harkins used one that has been a favorite in recent I think it is here to stay years, “homeostasis.” for a while. I certainly Iind it a very useful one in my own thinking. I Iike to think of homeostasis as a counterbaIance for a physiologic force which, if unchecked, would be harmful to the organism. If we think of hemostasis in this sense, it is hard to Iind a more appropriate use for it than in regard to gastric secretion. The ravages of unchecked gastric secretion are we11 known to a11 of us, and were first pointed out to us IOO years ago in the classic experiments of Claude Bernard. Under physioIogic conditions the secretion of acid gastric juice is, to at least some extent, intermittent. In most animals it is completely so; secretion of acid gastric juice occurs only in feeding, whereas in human beings there is a continuous component.
Gastric
Secretion
as a Surgical
ProbIem
along at this high level. U’hen the vagi are cut there is a rather marked fall of about 73 per cent, indicating that the secretion here (,apparently 25 per cent of it) was coming from the intestinal phase. W!hen the antrum is rcintroduced into the duodenum there is a sharp rise. This is not strictly a physiologic experiment; therefore, we can only guess from this that the intestinal phase ssems less important than either the nervous or gastrin phases. In a somewhat different experiment, using a vagaIly innervated small Pavlov pouch, an animal secreted at an extremely high level xvith the antral, nervous and intestinal phases all being present. When the antrum is taken out of continuity with the gastrointestinal tract, a pronounced fall in secretion occurs, and then there is another faII after the vagi to the stomach pouch are sectioned, indicating again that of the three phases the intestinal phase is probabIy the least significant. The best guess from many different experiments would be that it probably accounts for from 5 to 25 per cent of gastric secretion in human beings under normal conditions. On the inhibitory side we have a much more complex picture, and I will take you from the clear to the obscure. I think \ve can generalize in the first place by stating that the inhibitory roIe of the intestine on gastric secretion and on gastric function, in generaI, is undoubtedly far more important than its excitatory role. It is probably the singIe most important factor in the contro1 and inhibitory regulation of gastric secretion. The intestine acts on the stomach in at least four different ways. This is probably an o\-ersimphhcation. First of all, acid in the intestine inhibits gastric motility and delays gastric acid in the intestine emptying. Secondly, inhibits gastric secretion. Third, fat am I reIated substances in the intestine inhibit gastric motility. Fourth, fat and similar substances in the intestine inhibit gastric secretion. The first of these is very clear and very nearly compIeteIy worked out; this is the inhibitory effect of acid on gastric motility and gastric emptying. The Iine drawing which was shown depicts an experimental method for studying this in human beings. The pressure in the balloons is used as a recording of motility, using transducer-recorder poIygraphs. We can introduce acid into the duodenum at this point, while we measure the
The intestine is of extreme importance in the homeostasis of gastric secretion in both directions. It both stimulates and inhibits gastric secretion. We will omit a discussion of the important solid organ appendages of the intestine, the liver and pancreas; in both cases there is sufficient evidence to say that, in all probability, they normally play an important role in gastric digestion. We will also omit a discussion of the coIon, since there has, as yet, been no evidence that under normal conditions it pIays a role; in fact, the dista1 smal1 intestine probabIy does not play an important part in gastric acid secretion. We are concerned, therefore, primarily with the duodenum and the proximal jejunum. We will start with the clear cut and concIude with the less obvious importance of the intestine in the control of gastric secretion. On the excitatory side it is quite clear: we understand the intestinal phase of gastric secretion. This is the third and last of three phases of gastric secretion. It is humoral in origin and probably hormona1, and the best guess at the present time is that the intestina1 hormone is probably distinct from the antraI hormone. The intestinal phase was discovered by Lim and Ivy thirty-five years ago in Chicago, and this is the preparation used by them. In a totahy isolated stomach pouch in the dog, the vagi were cut in preparing the pouch. In this case the secretion of acid gastric juice from the stomach is quite small in amount when compared with what happens when the antrum is reintroduced into the intestine. However, this contrast is not as great as you might think, because in the absence of acid, of course, the antrum does not exert its inhibitory effect. The humoral nature of this was established by transplanting the stomach subcutaneously and deriving a completely new bIood supply, thus indicating that a nervous mechanism was not involved and that for all intents and purposes it was a hormona1 mechanism. In an attempt to establish the relative importance of the intestinal phase of gastric secretion, we have to try to correlate data from many different experiments, and I wilI discuss only a few. In this particular preparation, with the totally isoIated stomach pouch and the vagi intact, daily secretion on a standard diet goes ‘39
Pane1
Discussion
motility and gastric secretion in both the duodenum and stomach simultaneously. We control this by putting a smalI amount of normal saline soIution into the duodenum; the gastric contractions recorded here go on unchanged. Then, a small amount of hydrochIoric acid is introduced into the duodenum, and the gastric contractions are totaIIy abolished for this period which amounts to about eighteen minutes. In this particuIar patient, a human subject, the duodenal contractions were aIso inhibited, but this is not constant. To work out the mechanism of this, work was performed in dogs, in which animal exactIy the same phenomenon is observed. After control studies, this particular dog, which had a duodenal fistuIa for introduction of the acid, had celiac gangIionectomy. FoIIowing celiac ganglionectomy the introduction of acid into the duodenum had absoIuteIy no effect on gastric contractions. Therefore, this is a compIeteIy nervous mechanism. It has a11 the physioIogic characteristics of a nervous mechanism, extremeIy short Iatent period and rather short duration of effect. This is what the neurophysiologists refer to as an “axon reflex.” Both sides of the arc are in the peripheral postganglionic sympathetics. From here on we get into areas of Iess cIearIy defined knowledge. Next we have the effect of acid on gastric secretion. The inhibitory effect of acid in the duodenum on gastric secretion was discovered in PavIov’s Iaboratory. It was worked out extensiveIy in this country by Pincus, Thomas and Rehfuss in PhiIadelphia in the middIe 1930’s. We know only some refinements in addition to what they described at that time. No doubt the acid in the duodenum does inhibit the secretion of gastric juice, and I beIieve we have Iocalized it to a certain extent. In a preparation used in our Iaboratory, a fistuIa is made of the duodenum from just beyond the major pancreatic duct to the Iigament of Treitz. This totaIIy isoIated, doubleended fistula then can be irrigated with acid while gastric secretion is stimulated from the Heidenhain pouch. We used the most physioIogic stimuIus one can imagine, namely, a mea1. After contro1 studies were performed, this dog was fed whiIe the duodenum was perfused with 0.1 norma HCI. You wiI1 note that there is a pronounced rise in voIume and acid concentration which
paraIIeIed exactIy the animaI’s response without duodena1 perfusion with acid. This acts as an introduction to indicate that probabIy the inhibitory effect of acid on gastric secretion is more sharpIy IocaIized than other inhibitory factors in the smaI1 intestine, and that the very important first portion of the duodenum, which was not incIuded in this fistuIa, is probabIy the site for at least most of the inhibitory effect or acid on gastric secretion. A somewhat controversial experiment is the Mann-WiIIiamson preparation, which results promptIy in a margina uIcer at this point. This was originaIIy thought to be the result of lack of neutraIization of the acid-gastric materia1 as it exits from the stomach. Later, it became apparent that faiIure of acid inhibition might pIay a rote, and this was supported by data indicating that gastric secretion in this preparation is very sharply increased over the norma levels. In any event, further work since this time indicates that the explanation of this particular marginal uIcer is probably even much more complicated. However, I think there is no question that this factor of absence of acid inhibition in the duodenum probabIy plays a role in the MannWiIIiamson ulcer. When we discuss fat, we reaIIy get into vague territory. In some areas we know so little about it that it is hardIy worthwhile taIking about. Here again we come to the name of Ivy. During the golden period of gastroenterologic investigations in his Iaboratory at Northwestern, he discovered the hormone produced by fat in the intestine, enterogastrone. Now we know so much about it, we are not even sure it exists; if it does exit, there must be at Ieast two of them. Another preparation has been very useful in the Iaboratory. In the dog a gastric cannula provides ready access to the stomach, whereas a cutaneous fistula prepared by this Roux-Y Ioop makes a very handy way to introduce materia1 into the intestine at the desired IeveI. We now measure gastric motility through the gastric fistuIa. We put some norma saline soIution into the duodenum. We find no effect on gastric motility. At this point we introduce a very smaII amount, about 20 cc., of 0.1 norma acid into the duodenum and we note that an immediate suppression of gastric mo140
Gastric
Secretion
tility occurs; after a rather short time, this gradually returns untiI contractions are the same as ever. A sharp contrast is noted when the same volume of 20 cc. of olive oil is introduced into the duodenum. Now the gastric contractions continue unchanged for a latent period, which lasts from five to twenty minutes; then, instead of the sudden drop characteristic of the nervous mechanism, a gradual fall off occurs indicating a humoral or hormonal mechanism. Once this inhibition of gastric motility is introduced by fat, it lasts not for minutes but for hours. So, we have the established fact that fat in the small intestine has a very powerful inhibitory effect on gastric motility and delays gastric emptying very definitely, a fact which of course was discovered originally by Beaumont. The recent work of Menguy has been most interesting in this regard; his work with the role of fat in the inhibition of gastric secretion has indicated clearly that, in addition to fat, at least some of the normal contents of the small intestine, which would include bile, pancreatic juice and succus entericus, must be present if inhibition of gastric secretion by fat is to occur. Perhaps we cannot sharply separate the effect of fat on motility and secretion. At least the following particular experiment leans somewhat in that direction. The experiment was with a Thirty-Vella fistula of the duodenum in a dog which also has a gastric cannula. Here we introduce 0.1 normal HCI into the Thirty-Vella loop and get inhibition of gastric motility. Here again we repeated this with acid-gastric juice, and inhibition occurred. Then, when we use olive oiI, even though in the present case it has been mixed with pancreatic juice and bile, no inhibition of gastric motility occurs. So, in this way the inhibitory effect of fat on gastric motility seems to behave very much the same as the same inhibitory mechanism on gastric secretion. I would like to end on a slight note of levity, and this has to do with the effect of alcohol on the intestine. Alcohol is absorbed through the intestine so rapidIy that it might just as well be given intravenously. When an amount of alcohol equivalent to about one can of beer is introduced into a dog with a Heidenhain pouch and a Thirty-Vella loop of the duodenum, a very startling stimulation of gastric
as a Surgical
Problem
secretion occurs, and the volume and free acid concentration increase almost as much as if the dog had been given histamine. As we follow the blood levels, we find that within thirty minutes the blood has reached exactly the same level, as if the dog had received the same dose of alcohol direct1.y into the vein. Therefore, this effect of alcohol is the general parenteral effect of alcohol in stimuIating parietal cell activity, and is not stimulation of the intestinal phase of gastric secretion. It probably explains the rather unusual sensitivity to alcohol that is seen in many gastrectomized patients because of the rapid absorption from the intestine, whereas the stomach itself absorbs very little alcohol. CHAIRMAN DUNPHY: The next presentation
will be on “Ulceration in the Patient with Cirrhosis,” by Dr. C. Stuart Welch of Albany, New York. C. STUART WELCH (Albany, N. Y.): There seems to be pretty fair agreement among physicians who have been interested in cirrhosis of the liver and in performing portacaval shunt ulceration does surgery, that gastroduodenal occur m these patients in a higher incidence than in a comparable group of the same age and status. Furthermore, I think almost all surgeons who have been performing shunt surgery have noticed duodenal or gastric ulcers appearing in postshunt patients with higher than incidental frequency, and in
patients in whom no ulcer seemed to exist previously. This has led to clinica and experimental investigation on the possible mechanisms or mechanism of ulcerogenesis in cirrhosis of the liver. First of all, what is the incidence of gastroduodenal ulceration in patients with cirrhosis? A great many studies have been made. The incidence has been reported as low as 3 per cent by some, and by others as high as 25 per cent. Fifty-five patients were autopsied consecutiveIy for two years, and we found ten ulcers or 18 per cent. I think this figure agrees with that of a great many other peopIe who have studied this. It is probabIy slightly or significantly higher than might be found in patients of comparable ages, which might be about IO or 12 per cent. Of great interest to me in this study was another
subject
that
is concerning
surgeons
Panel performing shunt work, namely, the incidence of gallstones in cirrhosis. The incidence of gaIlstones and cholecystitis in these patients is rather high. We have 31 per cent cholecystic disease in this group of fiftyfive patients. In a group of male patients from our Veterans Hospital the incidence of gallstones at the time of shunt was 25 per cent in a male population. We have had two patients with postoperative acute cholecystitis, one of whom died. We rather recommend choIecystectomy at the time of shunt in patients who have gahstones. In patients who are studied beforehand with a gastrointestina1 series, as they al1 are who are coming up for shunt, we have found an incidence of ulceration to be only I 2 per cent. While the clinical impression is that shunts are &erogenic in patients, there is insuffrcient data at the present time to clearIy estabIish their relationship; however, in our own experience we have been impressed with the occurrence of uIceration in 4 of I12 patients who definitely did not have an ulcer before, as far as we know, and two of whom had severe hemorrhages requiring operation. The experimental work on ulcerogenesis has been done in dogs. Although it is difficult to make a great many conclusions, it is of interest because it is quite unlike the human situation, and only portions of the situation can be studied. We do not have good preparations for this study of liver disease in dogs. Cirrhosis simulating the human type cannot be produced in dogs, and even portal hypertension is diffrcult to make and sustain. As a matter of fact, the correIation is not good between the experimenta work in dogs and the findings in human subjects. It has been found, however, that the influence of a portacava1 shunt is to cause a hypersecretion of gastric juice. This hypersecretion responds to protein ingestion and is not abohshed by antrectomy or vagectomy, and is probably reiated to the intestinal phase of gastric secretion. A shunting of some substance around the liver would seem to be implicated as an etiologic mechanism. What this substance is, is not clear; whether it is histamine or whether there is another unknown substance is not yet determined. Gastrin and even hepatocellular damage of the liver have also been implicated in some studies. Of course there are unknown factors in the
Discussion cause of ulcer, whether or not the patient has cirrhosis of the Iiver. The relationship of hyperacidity in ulcerogenesis in the cirrhotic patient, however, is not the same as we find in normal human subjects, because patients with cirrhosis do not have hypersecretion of acid and they have rather low acidities or normal acidities. Even those patients who have de’inite ulcers do not very often have hyperacidity, although the acidity is higher than it is in patients with cirrhosis without ulceration. Is the local factor of great importance? We might consider that it is because, as you know, in operating on patients with cirrhosis of the liver, very delinite structura1 changes occur throughout the abdominal viscera, that is, edema and very good evidence of obstruction of the lymphatic system, How much this might relate to the cause of ulcer on the basis of Iowered tissue resistance, I do not know. A very important study has been done by Ostroff at the Brigham Hospital on gastric secretion in patients with cirrhosis and patients who have been shunted. He has not only tried to determine the influence of shunt on acidity in his patients with cirrhosis; however, he also has attempted to eliminate other factors which might be causative, such as hormona1 factors. I think he has definiteIy shown that patients who do have a portacaval shunt do begin to secrete more gastric juice after operation, and, therefore, in the postshunt patient we must come to the conclusion that diversion of some substance from the liver, which comes from the intestine, is of etiologic importance. The clinica significance of gastroduodena1 ulceration in the patient with cirrhosis has to do with two important questions, I think. The first we can dismiss in a few minutes. If a portacaval shunt is ulcerogenic, or if it does increase hyperacidity, should we perform any prophylactic antiulcer procedure at the time of portacaval shunt, particularly in patients who have an obvious duodenal ulcer? Conceivably, vagectomy and pyloroplasty could be performed without too much trouble, although we hesitate to add any operation that is not absoIuteIy necessary in patients having shunts. An added procedure is particularly unwise in those patients in poor condition or in whom there is considerable blood loss or the operation may have been prolonged.
Gastric
Secretion
as a SurgicaI
ProbIem
in with a massive hemorrhage they are not easy to perform. As you know, the IeveI of ammonia will not help you much. It may be high in patients bleeding from ulcer as well as varices. Presently Dr. Harold Welsh, in our hospital, is studying something that I think may be definitely of value in differentiating ulcer hemorrhage from variceal hemorrhage. He is studying the urobilinogen content of gastric aspirates in patients with massive bleeding from the upper gastrointestina1 tract. Urobilinogen should not be present in systemic blood and, therefore, should probabIy not be present in patients with bleeding from duodenal or gastric ulcer; however, if they are bleeding from a varix, urobilinogen should be present. Dr. Welsh has a modest series of twenty-two patients now. In six patients with bIeeding from varices, urobilinogen was present, and in the other sixteen with bleeding from ulcer, it was not present. There seems to be, therefore, a definite relationship between peptic ulcer and cirrhosis of the liver and portacaval shunt. I might say I believe the incidence of gastric ulcer in patients who have come to operation for bleeding is higher than it should be, which might have some reIation to the cause. We should be aware of the possibility of the cirrhotic patient with bleeding from an ulcer and try to get the patient to undergo operation early, because I find the mortality is prohibitiveIy high when gastrectomy for ulcer is performed late, that is, after three or four days of conservative management. CHAIRMAN DUNPHY: Fourth in this series of presentations will be “Zollinger-EIIison Diathesis : Pathophysiology and Current Status,” by Dr. Robert M. Zollinger of Columbus, Ohio. ROBERT M. ZOLLINCER (CoIumbus, Ohio): There is increasing evidence in our opinion that the pancreas can play a significant roIe in the hormonal stimulation of gastric juice. As you know now, nonbeta islet-cell tumors can produce an intractable uIcer diathesis characterized by gigantic hypersecretion which leads to a fulminating ulcer diathesis, enteritis, or both. The most characteristic location of the uIcer has been just distal to the ligament of Treitz. Approximately 132 case reports of a fulminating ulcer diathesis associated with certain islet-ceI1 tumors of the pancreas strongly support a relationship between the two. This rela-
More important, I think, is the question of whether or not a patient who bleeds with cirrhosis is indeed bleeding from his varices or is bleeding from a gastric or duodenal ulcer. This may influence our immediate treatment. it should influence immediate Particularly, treatment for those surgeons who prefer to use temporizing measures in the treatment of hemorrhage from varices, because if a patient is bleeding from a gastric or duodenal ulcer and has cirrhosis of the liver, an immediate operation should be performed; it is much more effective than it would be three, four, five or six days Iater when the patient is depleted and has had multiple blood transfusions. Patients with cirrhosis cannot stand bIood loss and blood replacement too well. We have found the mortahty to be very high in patients with a bIeeding ulcer and with cirrhosis, In fact, every one of these patients undergoing gastrectomy as an emergency has died. Using a program of earIy emergency surgery in suitable patients with cirrhosis who bleed, we should be able to get some of them by; however, again 1 do not know just what procedure we should use. I would rather guess the simplest one possible would be the best, perhaps such as transfixing the bleeding base of the ulcer and performing vagectomy. Of course, small resection might be indicated, In one patient who had a very large ulcer in the second portion of the duodenum, I performed gastrectomy, leaving the ulcer in sight and transhxing it as best I could; however, he died subsequently of a hemorrhage from it. Therefore, I am not sure that transfixion of the bleeding point is adequate. It is hard to make the diagnosis of the cause of bIeeding in some patients with cirrhosis. We are using the Sengstaken balloon much less than before, preferring gastric hypothermia in the treatment of bleeding from varices, as we do in the treatment of uIcer hemorrhage. Local hypothermia is not much help in differential diagnosis; however, the tamponade by baboon is of some help. That is to say, if the patient continues to bleed after the tamponade, one must be highly suspicious of gastric varices or duodenal ulcer. However, I have been fooled by hemorrhage stop with the use of the tamponade even though the patient was bIeeding from a duodenal ulcer. There are, of course, other methods of investigation; however, when the patient comes ‘43
Pane1
Discussion
tionship has been proved by Gregory of Liver~001, who has been able to make a picric acid extract of these islet-ceI1 tumors as well as their metastasis which is a potent gastric secretagogue. He has shown that these extracts are similar to gastrin in every respect. He has suggested that these tumors yieId an extract about thirty-five times more potent than that extracted from a similar weight of hog antrum. Like Doctor Code and others in this country, my associates Doctors Dan Elliott and Gerald EndahI have confirmed the findings of Gregory. Extracts of five nonbeta cell tumors and two liver metastasis from such tumors have produced a typica gastrin response in the standardized PavIov pouch dog preparation. Since 62 per cent of these tumors are mahgnant, it is important to remember that the metastasis can continue the fulminating ulcer diathesis even though a primary tumor in the pancreas has been successfuIIy resected. Total gastrectomy is indicated even in the presence of metastasis and active uIcer disease, since these tumors tend to grow slowly, and perforation is a constant threat if any acid producing tissue is retained by a subtotal resection. WhiIe 25 per cent of the 132 reported cases have been associated with more than one adenoma, we know of no evidence that adenomas other than those of the pancreas produce a gastric secretagogue. Gregory extracts of adenomas of the parathyroid, thyroid and adrena gland have al1 faiIed to produce a secretagory response from the PavIov pouch of the dog. The same has been true for the beta ceII adenomas (insuhnoma) and carcinoid tumors. The nonbeta islet-cell tumors are the only endocrine tumors known so far, from which the gastric secretagogue can be extracted. The main cIinica1 problem is to control the overproduction of hydrochloride. This is a difhcuIt and chahenging probIem unIess the patient has a sohtary tumor which can be removed. UnfortunateIy, it wouId seem from
the reported cases that there are multiple sites for the production of the gastrosecretagogue hormone. The high incidence of malignancy and the high incidence of metastasis, as well as multilocations in the pancreas, account for the multipIe sites. On the basis of the figures, a failure rate of 55 per cent could be predicted as long as any acid secreting surface remains. The resuhs of conservative procedures so far have been disappointing. It is understandable that any surgeon is loathe to perform a total gastrectomy; however, this is the procedure of choice. Excision of a Iocal tumor has corrected the uIcer diathesis in some cases; nevertheless, there is already a recurrent uIcer rate of 60 per cent. A recurrence rate of 57 per cent has taken place with the more radicaI procedures on the stomach, including vagotomy. Since earIy recurrence with hemorrhage and perforation may occur even after radical gastric resection, the mortality for the more conservative procedure is equa1 to, if not greater than that which follows tota gastrectomy. Further work is required to identify this hormone. Furthermore, no convincing evidence is known, of which cell produces gastric secretagogue. This is especiahy bafhing since extracts of the cIinicaIIy fibrosed pancreas, as we11 as the experimentahy produced atrophied pancreas, appear to contain a similar, although Iess potent gastric secretagogue, than the nonbeta islet-cell tumors. It is becoming increasingly clear that a better understanding of gastric secretion may come through a better understanding of the role of the pancreas. CHAIRMAN DUNPHY: I would Iike to congratulate the four speakers on their really superb presentations of complicated subjects in such a short time. I remember that some years ago Dr. John Homans of Harvard, told me that the way to get to be a professor was to study mechanisms of gastric secretion in duodenal uIcer. I think we have seen four brilIiant exampIes of how to use this route today.
144