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Gastric secretory tests
Gastric
Secretory
Tests*
Pro and Con EDWARDPASSARO,JR., M.D. AND H. EARL GORDON,M.D., Los Angeles,
From the Surgical Service, Wadsworth Hospital, Veterans Administration Center, Los Angeles, California 90073, and the Department of Surgery, UCLA School of Medicine, Los Angeles, California 90024.
HE role of the gastric secretory test in clinical practice is poorly defined A variety of tests are employed and a variety of interpretations are given to the results. The purpose of this paper is to discuss some of the pros and cons of gastric secretory tests in view of the work carried out in our laboratory. It is hoped that a more rational approach to the clinical use of these tests will result. Gastric secretory tests serve to indicate a patient’s level of secretion, to determine completeness of vagotomy, to aid in the diagnosis of gastroduodenal disease, and to investigate pathophysiologic relationships. Various tests have been employed in order to evaluate these factors, the two commonly used types being (1) basal secretion followed by a stimulant and (2) a nocturnal twelve hour collection. Stimulants for the various tests include a test meal, caffeine, insulin, 2-desoxy-D-glucose, histamine, histamine in combination with antihistamines and, more recently, betazole hydrochloride (His&Jog). Histalog has been shown to have advantages over other stimulants; it produces no side effects, the maximal acid response achieved is greater than that produced by histamine, and it is safe and simple to administer [I]. Histalog has become the standard stimulant in our laboratory. The nocturnal secretory test has long enjoyed a reputation as being diagnostic in peptic ulcer disease. Proponents of the test
T
Culi$wniu
claim it gives a more meaningful evaluation of the patient’s basal secretion than shorter tests performed during waking hours [2]. Admittedly, the test is more cumbersome for the patient and difficult to monitor to assure good collection. To obviate some of the problems with adequate collection, we have employed a plastic double lumen gastric sump tube (Bardi@ Andersen tube). A total of 1,134 gastric secretory tests have been conducted in the surgical gastric secretory laboratory at Wadsworth Hospital over the past four years. These studies have all been carried out in male patients. A group of 105 “normal patients” were included for control purposes; this group was composed of patients awaiting inguinal herniorraphy who, on the basis of history and laboratory tests, gave no indication of having peptic ulcers or other serious illnesses. A Histalog secretory test was carried out in 665 patients as follows: in 285 before operation and 105 after operation for peptic ulcer, in 170 patients with miscellaneous diagnoses, and in 105 “normal” patients. A Hollander test was performed in 359 patients as follows: in 144 before operation and 198 after operation for peptic ulcer and in 47 patients with miscellaneous diagnoses. MATERIALAND METHODS The patient arrives in the laboratory in the morning after an overnight fast. The patient is seated and a plastic nasogastric tube is passed to a level approximately 60 cm. from the nares and the residuum is aspirated by hand and collected. Although placement of the nasogastric tube under fluoroscopic control may possesscertain advantages,
* Presented at the Thirty-Eighth Annual Meeting of the Pacific Coast Surgical Association, Monterey, California, February 19-22, 1967. Vol. 114, August
1967
333
Passaro and Gordon
334 .. . .
RESULTS
.
:9 t
0% 080 8 ,@ 02,
0
x
FIG. 1. Peak acid response in patients with two types of ulcers and control patients after administration of Histalog.
Perhaps the greatest source of confusion regarding secretory tests concerns their value in the diagnosis of duodenal ulcer disease. In Figure 1, the peak acid responses in a group of patients with duodenal ulcer are compared to those in a control group. It can be seen that although there is a difference in the mean level of secretion, the secretory values of the patients with duodenal ulcer greatly overlap those of the control group. Only one fifth of the patients with duodenal ulcer have a peak rate of secretion beyond the range of the control group. Popular opinion to the contrary, the secretory response of most patients with duodenal ulcer falls within the normal range. Neither volume of juice, nor acid concentration, nor rate of secretion serves to separate these two groups further [4]. If a comparison is made between the group with duodenal ulcer and the control group in each decade of life, however, a statistically significant difference is seen. (Table I.) Thus, older patients with duodenal ulcer tend to have a level of gastric secretion which is significantly higher than their peers in the control group. The results in patients with gastric ulcer were more variable. Although the average level of secretion in this group was lower than that in the control group or the group of patients with
it is seldom practicable. As a test for correct placement of the tube, 50 ml. of saline solution is instilled through the tube and then immediately aspirated. Recovery of 45 to 50 ml. is taken as an indication of a dependent positioning of the tube.* If a smaller volume is collected, the position of the tube is changed until an adequate amount can be recovered. A pump, applying intermittent low suction, is used to collect gastric juice over the next hour as a basal measurement (B). The pump is disconnected at fifteen minute intervals throughout the test and hand aspiration performed to insure complete recovery and patency of the tube. Histalog, in the dose of 1.5 mg./kg. of body weight, is given intramuscularly at the end of the basal period and collections are made during the next two hours. A 2 ml. sample from each collection is titrated with 0.1 NaOH to pH 7.0 with an automatic titrator. * A Hi&dog secretory test was repeated in seventeen patients from three to fourteen days after the initial study. Excellent reproducibility (r = 0.7 to 0.9) of the results was achieved during all collection periods, verifying this simple technic for tube placement. The most reproducible part of the secretory curve was the “peak acid output,” defined as the highest output in any two consecutive fifteen minute periods [S] .
INSULIN !O u. 1.v 4 -*---._..
R
8
12
I
16
15 4MIN. PE&ODS FIG. 2. Gastric acid response to Hollander test. American Journal
of Surgery
Gastric Secretory Tests
335
TABLE I MEANS AND SIGNIFICASCE
LEVELS
OF DIFFERENCES AND
Patients Thirty-Nine Years Old or Less
BETWEEN
IN THOSE
GASTRIC
WITH
SECRETORY
RESPONSE
IN
NORMAL
PATIENTS
ULCERS
Patients Forty through Patients Fifty through Forty-Nine Years Old Fifty-Nine Years Old
Patients Sixty Years or More
Variable
1. Response 2. Basal 3. 1 4. 2 5. 3 6. 4 7. Total 1 8. 5 9. 6 10. 7 11. 8 12. Total 2 13. Peak 14. Location 15. Age SampleSize
0.14 0.91 1.70 4.72 6.02 7.20 19.91 7.58 5.66 5.67 4.83 23.74 15.66 4.2 32.1 19
0.70 1.49 2.42 6.73 8.14 8.75 26.89 8.75 8.87 7.67 6.89 32.30 19.58 3.9 33.7 37
.05
10 NS* .05 .Ol NS .05 NS .Ol .05 .05 .05 .05 NS NS
0.16 0.92 2.11 5.47 6.63 7.21 21.70 7.29 6.73 6.67 5.23 25.92 15.68 4.3 44.9
0.53 1.39 2.39 7.07 8.53 9.18 27.63 9.55 8.88 8.09 7.17 33.83 20.78 4.1 44.6
22
63
.05
10 NS .05 .05 .05 .05 .05 .05
.10 .Ol .Ol .Ol NS NS
NS
0.25 0.77 1.53 4.90 6.82 7.40 21.01 7.28 6.10 5.85 5.15 24.39 15.62 3.9 53.9
1.26 2.34 7.61 9.39 9.32 29.29 9.91 8.94 8.44 7.99 35.28 21.64 4.0 53.7
24
42
10 10 .Ol .05 .05 .Ol .Ol .Ol .Ol .Ol .Ol .Ol NS NS
0.27 0.67 0.94 2.98 4.05 4.70 12.92 4.41 3.65 3.41 3.03 14.49 9.59 3.8 67.9
0.35 1.20 2.12 5.60 6.91 7.73 23.21 7.58 7.36 7.06 6.50 28.51 17.62 4.1 69.1
34
57
NS .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol NS NS
* No significance.
duodenal ulcer, the difference was not statistically significant. The Hollander test is used to determine vagal integrity after operation. The gastric acid response to insulin hypoglycemia is complex. (Fig. 2.) Approximately twenty to forty minutes after the administration of insulin, blood sugar and acid output simultaneously decrease from basal levels. The depressed gastric response does not appear to be related to the insulin but to the hypoglycemia [5]. The acid output then increases sharply in the normal subject and returns gradually to near basal levels at the end of three hours. A more modest late rise in acid output occurs four to six hours after the insulin is administered. Present evidence indicates that the initial phase of gastric acid stimulation is dependent upon intact vagal nerves, whereas the second phase of gastric stimulation can be modified by adrenalectomy [6]. A postoperative Hollander test was carried out in 198 patients. (Fig. 3.) On the basis of the acid response found in these patients, they have been placed in three groups: (1) those in whom no increase in gastric secretion occurs after insulin hypoglycemia; these patients are Vol. 114, August 1967
judged to have a complete vagotomy; (2) those in whom an increase over basal levels occurs in the first hour, which indicates an incomplete vagotomy; and (3) those in whom a modest increase in acid secretion over basal levels occurs during the second or third hour after stimulation. The significance of the response in this latter group is not clear. At present, we have considered these patients as having an incomplete vagotomy. Thirty-two patients had an incomplete vagotomy by these criteria, despite histologic evidence of both ?
FIG. 3. Results of postoperative patients.
Hollander
test in 198
336
and Gordon contents were removed by gastric lavage. An upper gastrointestinal series showed a duodenal ulcer and gastric retention. On continuous nasogastric suction, 3,000 ml. of juice, containing approximately 110 mEq. of acid per L., was removed daily. A pancreatic adenoma was suspected preoperatively. Before additional studies could be performed, the patient started to hemorrhage. At operation a posterior duodenal ulcer was found and a 3 cm. mass was removed from the uncinate process of the pancreas. A frozen section confirmed the diagnosis of an islet cell tumor. The postoperative basal secretion was 0.6 mEq.; hr.
Gastric secretory tests in twenty-two patients with chronic pancreatitis.
FIG. 4.
vagal trunks having been excised in twentytwo patients. In the remaining ten, the left nerve was missed twice and neither nerve was excised in eight. These thirty-two patients have been carefully followed up from one to four years. Evidence of marginal ulceration has been obtained in five. Secretory tests have been used to evaluate pathophysiologic relationships in a variety of diseases. The secretory response in twentytwo patients with histologic evidence of chronic pancreatitis is given in Figure 4. The response of this group was not significantly different from that of the control group. These patients came to operation because of complications of their disease, and in many instances their cases represent the extremes in pancreatic destruction. No patient had hypersecretion. The importance of gastric secretory data in establishing the diagnosis in cases of the Zollinger-Ellison syndrome has been amply documented. We have studied five patients who, on the basis of clinical history and secretory data, were suspected of having gastrin-secreting islet cell tumors. Their basal secretions ranged from 32 to 110 mEq. per hour. The importance of secretory data, whether obtained by a formal test or not, is shown in the following case: A forty-four year old man was admitted to the hospital with a six month history of epigastric “distress and burning” relieved in part by alkalis. He noted abdominal swelling after meals and occasionally vomited partially digested food. He had had three to four formed bowel movements daily “for years.” More than 700 ml. of gastric
Four patients with parathyroid adenomas have had gastric secretory studies. The level of secretion was well within the normal range in each patient. Of particular interest, however, was the decrease in gastric secretion after removal of a parathyroid adenoma in a patient with multiple endocrine adenopathies. (Fig. 5.) Although removal of the pancreatic adenomas caused a decrease in basal secretion, a more pronounced decrease occurred after removal of the parathyroid adenoma. COMMENTS
The twelve hour overnight secretory test reputedly differentiates more clearly patients with and without ulcers [7]. Difficulties in120_ PRE-
op:
EXCISION PANCREATIC AOENOYATA
EXCWON PARATHIROIO AOENOMA
100. I
t
0
0 HOURS
n 2
5. Alterations in basal gastric secretion levelsin patient with multiple endocrine adenopathies. FIG.
Gastric Secretory Tests herent in the test, however, have lead others to the opposite opinion [8]. In most studies the range of secretion in control subjects overlaps that of patients with duodenal ulcer so that a distinction cannot be made with an individual patient’s secretory test. Differences in results may be explained in part by several factors. Age has been demonstrated as an important variable. Sex also influences basal gastric secretion since female subjects in all age groups have lower amounts of secretion than male patients have. Systematic standardization of the evening meal prior to an overnight collection has not been done. The major difficulty is that of maintaining a patent functioning nasogastric tube. Recently a plastic gastric sump tube has been introduced which we have found insures more complete collection of gastric juice. A water-seal system has been proposed to make monitoring of the gastric tube easier for hospital personnel [9]. The test almost always entails hospitalization of the patient. A standard Histalog test performed on the awake patient for three hours is safe, practical, gives highly reproducible results, and is easy to perform. The test can be carried out readily on an outpatient basis. Unfortunately our studies and those of others show that the test has only limited application to the diagnosis of peptic ulcer. With the older patient, however, the test may serve to differentiate patients with duodenal ulcer from those without ulcer. With increasing age, there is a fall in the level of gastric secretion as well as a higher incidence of achlorhydria in nonulcer patients. Elderly patients with duodenal ulcer do not appear to show a decrease in acid secretion in contradistinction to their peers. Achlorhydria is best determined by a standard Histalog test. A comparison of the basal rate to the maximal rate of secretion in response to Histalog aids in the diagnosis of the Zollinger-Ellison syndrome. The basal rate in these patients is characteristically half or more of the maximal rate. The Hollander test is an exhausting one and deaths associated with its use have been reported. It should not be performed on patients with a history of severe heart disease, strokes, seizures, or general debilitation. The patient is most comfortable if kept in the recumbent position. Glucose may be given intravenously after the onset of the hypoglycemia without affecting the gastric response. Interpretation of the test is based on the basal secretion and the changes in Vol. 114,August 1967
secretion during the first two hours after the administration of insulin [IO]. If the basal rate is greater than 1 mEq./hr., vagal integrity can be assumed. Important exceptions to this may be the presence of endocrine factors. If the basal secretion is low and does not rise at least 0.5 to 1 mEq. in the next hour or two, the stomach is effectively denervated. Difficulty exists in interpreting the results in patients who show a late rise in gastric secretion after three hours or more. At present we consider this to indicate that some vagal innervation of the stomach remains. In our series 16 per cent (32 of 198) of the patients operated on showed an incomplete vagotomy by the Hollander test. Histologic evidence of at least portions of each vagal trunk was obtained in twenty-two of these patients. Ross and Kay reported similar results [11]. This would suggest that anatomic variations will not permit a higher rate of complete vagotomy performed by the transabdominal route. In the dog chronic pancreatitis produced by ligation of the pancreatic duct leads to gastric hypersecretion [12]. The stimulus for this hypersecretion has been avidly sought but not found. Our studies in patients with severe pancreatic disease would indicate that such hypersecretion does not occur in man. Similar results have been reported by others [13,14]. Hypercalcemia has been shown recently to stimulate gastric secretion in man [15]. Although most of our patients with hyperparathyroidism did not show increased levels of acid secretion, one patient with multiple endocrine adenopathies had a pronounced decrease in basal secretion after parathyroidectomy. Acknowledgment: We wish to thank Mr. Earle Herbert for this expert technical assistance in conducting these tests and to express our appreciation for the aid of the Western Research Support Center, Sepulveda, California in providing statistical studies of the data. REFERENCES 1. WARD, S., GILLESPIE, I.,
PASSARO, E., JR., and GROSSMAN, M. I. Comparison of histalog and histamine as stimulants for maximal gastric secretion in human subjects and in dogs. Gastroenterology, 44: 620,1963. 2. LEVIN. E.. KIRSNER.._1. B.. and PALMER, W. L. A simple measure of gastric secretion in man. Gastroenterology, 19: 88, 1951. 3. BARON, J. H. Studies of basal and peak acid output with an augmented histamine test. Gut, 4: 136, 1963.
Passaro and Gordon
33%
4. WORMSLEY, K. and GROSSMAN, M. I. Maximal histalog test in control subjects and patients with peptic ulcers. Gut, 6: 427, 1965. 5. BACHRACH, W. H. On the question of a pituitary adrenal component in the gastric secretory response to insulin hypoglycemia. Gastroenterology, 44: 178, 1963. 6. FRENCH, J. D., LONGMIRE, R. L., PORTER, R. W., and MOVITJS, H. J. Extravagal influences on gastric hydrochloric acid secretion induced by stress stimuli. Surgery, 34: 621,1953. 7. LEVIN, E., KIRSNER, J. B., PALMER W. L. A comparison of the nocturnal gastric secretion in patients with duodenal ulcer and in normal individuals. Gastroenterology 10: 952, 1948. 8. VOEGTLIN, W. L. Gastric acidity in normal individuals and those with uncomplicated duodenal ulcer: an attempt to influence the nocturnal secretion. Gastroenterology, 9: 125, 1947. 9. HUGHES, R. K. and WOOTTON, D. G. Gastric sump drainage with a water seal monitor. Surgery, in press. 10. STEMPIEN, S. J. Insulin gastric analysis: technic and interpretations. Am. J. Digest. Dis., 7: 138, 1962. 11. Ross, B. and KAY, A. W. The insulin test after vagotomy. Gastroenterology, 46: 379, 1964. 12. ELLIOTT, D. W., TAFT, D. A., PASSARO, E., JR., and ZOLLINGER, R. M. Pancreatic influences on gastric secretion. Surgery, 50: 126, 1961. 13. BANK, S., MARKS, I. N., and GROIN, A. Gastric acid studies in pancreatic disease. Gastroenterology, 51: 649,1966. 14. KRAVETZ, R. E. and SPIRO, H. H. Gastric secretion in chronic pancreatitis. Ann. Int. Med., 63: 776, 1965. 15. MURPHY, D. L., GOLDSTEIN, H., BOYLE, J. D., and WARD, S. Hypercalcemia and gastric secretion in man. J. A#. Physiol., 21: 1607, 1966. DISCUSSION DAVID B. HINSHAW (Loma Linda, Calif.): The authors have described a very extensive experience with gastric secretory tests in a wide range of conditions and disease states. Their data would appear to challenge the generally accepted concept that the chief physiologic characteristic of duodenal ulcers is a significantly elevated secretion of gastric acid. In this study only one fifth of the patients had a peak rate of secretion above the range of the control group but the mean secretory rate was significantly higher than that in the control group and became more pronounced in older patients. These findings do serve to remind us that duodenal ulcers represent an interplay of at least three factors, rather than being simply a function of gastric hypersecretion. These factors are (1) the level of the gastric acid secretion; (2) the volume and quality of the alkaline buffering secretions present in the duodenum; (3) the local tissue resistance to peptic ulceration. The current therapeutic approach to peptic ulceration is primarily aimed at controlling the first
of these factors, that is, the acid secretory level, but with increased information this may not always be the case. It is particularly important to recognize, for example, the recent significant work relating to gastric mucin and its local protective effect relative to peptic ulceration. We certainly agree with the authors that the Hollander test is very rigorous and may be dangerous in elderly people or in those with cardiac disease. It is disconcerting to note the rather high incidence of incomplete vagotomy which the authors report. HARRY A. OBERHELMAN, JR. (Palo Alto, Calif.): It may be questioned whether the gastric secretory response to maximal histamine or Histalog stimulation should be used as a test to differentiate the secretory pattern in patients with duodenal ulcer and in normal subjects. The hypersecretion of gastric juice which occurs in patients with duodenal ulcers is of vagal origin and is best measured by studying the basal or fasting gastric secretion. Have the authors made such a comparison of the fasting secretion of normal patients and those with duodenal ulcers? I think it is also important when measuring basal gastric secretion to consider the sex of the patient as well as the age since it has been shown that secretory rates, both in normal subjects and those with duodenal ulcers, decline with increasing age and are lower in female than male subjects. We have not found the response to the Hollander insulin test an accurate prognostic study with regard to ulcer recurrence after vagotomy. It may be shown that 20 to 25 per cent of the patients six months after vagotomy exhibit a positive response to insulin stimulation. However, it has also been observed that the majority of these patients have a persistent reduction in secretion levels to normal or below normal after a twelve hour nocturnal secretion test and remain free of recurrent ulcer disease. It has been suggested that this discrepancy is due to the fact that insulin hypoglycemia is a stronger stimulus than the physiologic stimuli of vagal function and in the presence of any remaining vagal fibers is capable of eliciting a positive response. We have found that the measurements in the basal gastric secretion are more reliable in predicting the success of vagotomy. WILLIAM W. KRIPPAEHNE (Portland, Ore.): A note of warning concerning Hollander tests in some patients seems warranted. Starved patients or patients with hepatic disease are prone to the development of severe hypoglycemia with even small doses of insulin. Some pre-diabetic patients also may have hypoglycemia without exogenous insulin. We have observed the conditions of patients given as little as 8 to 10 units of insulin to progress rapidly to convulsions or coma. If Hollander tests seem necessary, they must be used with caution and there must be preparation for immediate infusion of glucose in these and other instances when
Gastric Secretory Tests patients have or are prone to the development of severe hypoglycemia. H. EARL GORDON (closing): The results of our studies are not meant to convey the impression that acid secretion is unimportant in the pathogenesis of peptic ulcer. Rather, we are trying to emphasize the limitations of gastric secretory tests as a diagnostic aid. In our series, neither the one hour basal test nor the level of stimulated secretion served to distinguish the normal patient from the patient with peptic ulcer in the majority of instances. Our 15 per cent incidence of incomplete vagotomy is, of course, disturbing. However, a number of other investigators here and in England have reported a similar incidence on the basis of the postoperative Hollander test. Fortunately, recurrent ulcers will
Vol.114. August 1967
339
not develop in all of these patients. In our series, in only five of thirty-two patients with a Hollander test giving positive results did recurrent ulceration develop during a follow-up period of one to four years. My comments in regard to the twelve hour nocturnal secretory test were made to emphasize the inherent difficulties of the procedure and not to imply that it lacked potential value. However, we have been unable to obtain reproducible results with the test. This is most likely due to the difficulty in obtaining a complete collection during the twelve hour period. We are currently trying a double lumen tube with a simple monitoring device in an attempt to insure a continuous patency of the gastric tube.
Secretory
Tests*
Pro and Con EDWARDPASSARO,JR., M.D. AND H. EARL GORDON,M.D., Los Angeles,
From the Surgical Service, Wadsworth Hospital, Veterans Administration Center, Los Angeles, California 90073, and the Department of Surgery, UCLA School of Medicine, Los Angeles, California 90024.
HE role of the gastric secretory test in clinical practice is poorly defined A variety of tests are employed and a variety of interpretations are given to the results. The purpose of this paper is to discuss some of the pros and cons of gastric secretory tests in view of the work carried out in our laboratory. It is hoped that a more rational approach to the clinical use of these tests will result. Gastric secretory tests serve to indicate a patient’s level of secretion, to determine completeness of vagotomy, to aid in the diagnosis of gastroduodenal disease, and to investigate pathophysiologic relationships. Various tests have been employed in order to evaluate these factors, the two commonly used types being (1) basal secretion followed by a stimulant and (2) a nocturnal twelve hour collection. Stimulants for the various tests include a test meal, caffeine, insulin, 2-desoxy-D-glucose, histamine, histamine in combination with antihistamines and, more recently, betazole hydrochloride (His&Jog). Histalog has been shown to have advantages over other stimulants; it produces no side effects, the maximal acid response achieved is greater than that produced by histamine, and it is safe and simple to administer [I]. Histalog has become the standard stimulant in our laboratory. The nocturnal secretory test has long enjoyed a reputation as being diagnostic in peptic ulcer disease. Proponents of the test
T
Culi$wniu
claim it gives a more meaningful evaluation of the patient’s basal secretion than shorter tests performed during waking hours [2]. Admittedly, the test is more cumbersome for the patient and difficult to monitor to assure good collection. To obviate some of the problems with adequate collection, we have employed a plastic double lumen gastric sump tube (Bardi@ Andersen tube). A total of 1,134 gastric secretory tests have been conducted in the surgical gastric secretory laboratory at Wadsworth Hospital over the past four years. These studies have all been carried out in male patients. A group of 105 “normal patients” were included for control purposes; this group was composed of patients awaiting inguinal herniorraphy who, on the basis of history and laboratory tests, gave no indication of having peptic ulcers or other serious illnesses. A Histalog secretory test was carried out in 665 patients as follows: in 285 before operation and 105 after operation for peptic ulcer, in 170 patients with miscellaneous diagnoses, and in 105 “normal” patients. A Hollander test was performed in 359 patients as follows: in 144 before operation and 198 after operation for peptic ulcer and in 47 patients with miscellaneous diagnoses. MATERIALAND METHODS The patient arrives in the laboratory in the morning after an overnight fast. The patient is seated and a plastic nasogastric tube is passed to a level approximately 60 cm. from the nares and the residuum is aspirated by hand and collected. Although placement of the nasogastric tube under fluoroscopic control may possesscertain advantages,
* Presented at the Thirty-Eighth Annual Meeting of the Pacific Coast Surgical Association, Monterey, California, February 19-22, 1967. Vol. 114, August
1967
333
Passaro and Gordon
334 .. . .
RESULTS
.
:9 t
0% 080 8 ,@ 02,
0
x
FIG. 1. Peak acid response in patients with two types of ulcers and control patients after administration of Histalog.
Perhaps the greatest source of confusion regarding secretory tests concerns their value in the diagnosis of duodenal ulcer disease. In Figure 1, the peak acid responses in a group of patients with duodenal ulcer are compared to those in a control group. It can be seen that although there is a difference in the mean level of secretion, the secretory values of the patients with duodenal ulcer greatly overlap those of the control group. Only one fifth of the patients with duodenal ulcer have a peak rate of secretion beyond the range of the control group. Popular opinion to the contrary, the secretory response of most patients with duodenal ulcer falls within the normal range. Neither volume of juice, nor acid concentration, nor rate of secretion serves to separate these two groups further [4]. If a comparison is made between the group with duodenal ulcer and the control group in each decade of life, however, a statistically significant difference is seen. (Table I.) Thus, older patients with duodenal ulcer tend to have a level of gastric secretion which is significantly higher than their peers in the control group. The results in patients with gastric ulcer were more variable. Although the average level of secretion in this group was lower than that in the control group or the group of patients with
it is seldom practicable. As a test for correct placement of the tube, 50 ml. of saline solution is instilled through the tube and then immediately aspirated. Recovery of 45 to 50 ml. is taken as an indication of a dependent positioning of the tube.* If a smaller volume is collected, the position of the tube is changed until an adequate amount can be recovered. A pump, applying intermittent low suction, is used to collect gastric juice over the next hour as a basal measurement (B). The pump is disconnected at fifteen minute intervals throughout the test and hand aspiration performed to insure complete recovery and patency of the tube. Histalog, in the dose of 1.5 mg./kg. of body weight, is given intramuscularly at the end of the basal period and collections are made during the next two hours. A 2 ml. sample from each collection is titrated with 0.1 NaOH to pH 7.0 with an automatic titrator. * A Hi&dog secretory test was repeated in seventeen patients from three to fourteen days after the initial study. Excellent reproducibility (r = 0.7 to 0.9) of the results was achieved during all collection periods, verifying this simple technic for tube placement. The most reproducible part of the secretory curve was the “peak acid output,” defined as the highest output in any two consecutive fifteen minute periods [S] .
INSULIN !O u. 1.v 4 -*---._..
R
8
12
I
16
15 4MIN. PE&ODS FIG. 2. Gastric acid response to Hollander test. American Journal
of Surgery
Gastric Secretory Tests
335
TABLE I MEANS AND SIGNIFICASCE
LEVELS
OF DIFFERENCES AND
Patients Thirty-Nine Years Old or Less
BETWEEN
IN THOSE
GASTRIC
WITH
SECRETORY
RESPONSE
IN
NORMAL
PATIENTS
ULCERS
Patients Forty through Patients Fifty through Forty-Nine Years Old Fifty-Nine Years Old
Patients Sixty Years or More
Variable
1. Response 2. Basal 3. 1 4. 2 5. 3 6. 4 7. Total 1 8. 5 9. 6 10. 7 11. 8 12. Total 2 13. Peak 14. Location 15. Age SampleSize
0.14 0.91 1.70 4.72 6.02 7.20 19.91 7.58 5.66 5.67 4.83 23.74 15.66 4.2 32.1 19
0.70 1.49 2.42 6.73 8.14 8.75 26.89 8.75 8.87 7.67 6.89 32.30 19.58 3.9 33.7 37
.05
10 NS* .05 .Ol NS .05 NS .Ol .05 .05 .05 .05 NS NS
0.16 0.92 2.11 5.47 6.63 7.21 21.70 7.29 6.73 6.67 5.23 25.92 15.68 4.3 44.9
0.53 1.39 2.39 7.07 8.53 9.18 27.63 9.55 8.88 8.09 7.17 33.83 20.78 4.1 44.6
22
63
.05
10 NS .05 .05 .05 .05 .05 .05
.10 .Ol .Ol .Ol NS NS
NS
0.25 0.77 1.53 4.90 6.82 7.40 21.01 7.28 6.10 5.85 5.15 24.39 15.62 3.9 53.9
1.26 2.34 7.61 9.39 9.32 29.29 9.91 8.94 8.44 7.99 35.28 21.64 4.0 53.7
24
42
10 10 .Ol .05 .05 .Ol .Ol .Ol .Ol .Ol .Ol .Ol NS NS
0.27 0.67 0.94 2.98 4.05 4.70 12.92 4.41 3.65 3.41 3.03 14.49 9.59 3.8 67.9
0.35 1.20 2.12 5.60 6.91 7.73 23.21 7.58 7.36 7.06 6.50 28.51 17.62 4.1 69.1
34
57
NS .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol .Ol NS NS
* No significance.
duodenal ulcer, the difference was not statistically significant. The Hollander test is used to determine vagal integrity after operation. The gastric acid response to insulin hypoglycemia is complex. (Fig. 2.) Approximately twenty to forty minutes after the administration of insulin, blood sugar and acid output simultaneously decrease from basal levels. The depressed gastric response does not appear to be related to the insulin but to the hypoglycemia [5]. The acid output then increases sharply in the normal subject and returns gradually to near basal levels at the end of three hours. A more modest late rise in acid output occurs four to six hours after the insulin is administered. Present evidence indicates that the initial phase of gastric acid stimulation is dependent upon intact vagal nerves, whereas the second phase of gastric stimulation can be modified by adrenalectomy [6]. A postoperative Hollander test was carried out in 198 patients. (Fig. 3.) On the basis of the acid response found in these patients, they have been placed in three groups: (1) those in whom no increase in gastric secretion occurs after insulin hypoglycemia; these patients are Vol. 114, August 1967
judged to have a complete vagotomy; (2) those in whom an increase over basal levels occurs in the first hour, which indicates an incomplete vagotomy; and (3) those in whom a modest increase in acid secretion over basal levels occurs during the second or third hour after stimulation. The significance of the response in this latter group is not clear. At present, we have considered these patients as having an incomplete vagotomy. Thirty-two patients had an incomplete vagotomy by these criteria, despite histologic evidence of both ?
FIG. 3. Results of postoperative patients.
Hollander
test in 198
336
and Gordon contents were removed by gastric lavage. An upper gastrointestinal series showed a duodenal ulcer and gastric retention. On continuous nasogastric suction, 3,000 ml. of juice, containing approximately 110 mEq. of acid per L., was removed daily. A pancreatic adenoma was suspected preoperatively. Before additional studies could be performed, the patient started to hemorrhage. At operation a posterior duodenal ulcer was found and a 3 cm. mass was removed from the uncinate process of the pancreas. A frozen section confirmed the diagnosis of an islet cell tumor. The postoperative basal secretion was 0.6 mEq.; hr.
Gastric secretory tests in twenty-two patients with chronic pancreatitis.
FIG. 4.
vagal trunks having been excised in twentytwo patients. In the remaining ten, the left nerve was missed twice and neither nerve was excised in eight. These thirty-two patients have been carefully followed up from one to four years. Evidence of marginal ulceration has been obtained in five. Secretory tests have been used to evaluate pathophysiologic relationships in a variety of diseases. The secretory response in twentytwo patients with histologic evidence of chronic pancreatitis is given in Figure 4. The response of this group was not significantly different from that of the control group. These patients came to operation because of complications of their disease, and in many instances their cases represent the extremes in pancreatic destruction. No patient had hypersecretion. The importance of gastric secretory data in establishing the diagnosis in cases of the Zollinger-Ellison syndrome has been amply documented. We have studied five patients who, on the basis of clinical history and secretory data, were suspected of having gastrin-secreting islet cell tumors. Their basal secretions ranged from 32 to 110 mEq. per hour. The importance of secretory data, whether obtained by a formal test or not, is shown in the following case: A forty-four year old man was admitted to the hospital with a six month history of epigastric “distress and burning” relieved in part by alkalis. He noted abdominal swelling after meals and occasionally vomited partially digested food. He had had three to four formed bowel movements daily “for years.” More than 700 ml. of gastric
Four patients with parathyroid adenomas have had gastric secretory studies. The level of secretion was well within the normal range in each patient. Of particular interest, however, was the decrease in gastric secretion after removal of a parathyroid adenoma in a patient with multiple endocrine adenopathies. (Fig. 5.) Although removal of the pancreatic adenomas caused a decrease in basal secretion, a more pronounced decrease occurred after removal of the parathyroid adenoma. COMMENTS
The twelve hour overnight secretory test reputedly differentiates more clearly patients with and without ulcers [7]. Difficulties in120_ PRE-
op:
EXCISION PANCREATIC AOENOYATA
EXCWON PARATHIROIO AOENOMA
100. I
t
0
0 HOURS
n 2
5. Alterations in basal gastric secretion levelsin patient with multiple endocrine adenopathies. FIG.
Gastric Secretory Tests herent in the test, however, have lead others to the opposite opinion [8]. In most studies the range of secretion in control subjects overlaps that of patients with duodenal ulcer so that a distinction cannot be made with an individual patient’s secretory test. Differences in results may be explained in part by several factors. Age has been demonstrated as an important variable. Sex also influences basal gastric secretion since female subjects in all age groups have lower amounts of secretion than male patients have. Systematic standardization of the evening meal prior to an overnight collection has not been done. The major difficulty is that of maintaining a patent functioning nasogastric tube. Recently a plastic gastric sump tube has been introduced which we have found insures more complete collection of gastric juice. A water-seal system has been proposed to make monitoring of the gastric tube easier for hospital personnel [9]. The test almost always entails hospitalization of the patient. A standard Histalog test performed on the awake patient for three hours is safe, practical, gives highly reproducible results, and is easy to perform. The test can be carried out readily on an outpatient basis. Unfortunately our studies and those of others show that the test has only limited application to the diagnosis of peptic ulcer. With the older patient, however, the test may serve to differentiate patients with duodenal ulcer from those without ulcer. With increasing age, there is a fall in the level of gastric secretion as well as a higher incidence of achlorhydria in nonulcer patients. Elderly patients with duodenal ulcer do not appear to show a decrease in acid secretion in contradistinction to their peers. Achlorhydria is best determined by a standard Histalog test. A comparison of the basal rate to the maximal rate of secretion in response to Histalog aids in the diagnosis of the Zollinger-Ellison syndrome. The basal rate in these patients is characteristically half or more of the maximal rate. The Hollander test is an exhausting one and deaths associated with its use have been reported. It should not be performed on patients with a history of severe heart disease, strokes, seizures, or general debilitation. The patient is most comfortable if kept in the recumbent position. Glucose may be given intravenously after the onset of the hypoglycemia without affecting the gastric response. Interpretation of the test is based on the basal secretion and the changes in Vol. 114,August 1967
secretion during the first two hours after the administration of insulin [IO]. If the basal rate is greater than 1 mEq./hr., vagal integrity can be assumed. Important exceptions to this may be the presence of endocrine factors. If the basal secretion is low and does not rise at least 0.5 to 1 mEq. in the next hour or two, the stomach is effectively denervated. Difficulty exists in interpreting the results in patients who show a late rise in gastric secretion after three hours or more. At present we consider this to indicate that some vagal innervation of the stomach remains. In our series 16 per cent (32 of 198) of the patients operated on showed an incomplete vagotomy by the Hollander test. Histologic evidence of at least portions of each vagal trunk was obtained in twenty-two of these patients. Ross and Kay reported similar results [11]. This would suggest that anatomic variations will not permit a higher rate of complete vagotomy performed by the transabdominal route. In the dog chronic pancreatitis produced by ligation of the pancreatic duct leads to gastric hypersecretion [12]. The stimulus for this hypersecretion has been avidly sought but not found. Our studies in patients with severe pancreatic disease would indicate that such hypersecretion does not occur in man. Similar results have been reported by others [13,14]. Hypercalcemia has been shown recently to stimulate gastric secretion in man [15]. Although most of our patients with hyperparathyroidism did not show increased levels of acid secretion, one patient with multiple endocrine adenopathies had a pronounced decrease in basal secretion after parathyroidectomy. Acknowledgment: We wish to thank Mr. Earle Herbert for this expert technical assistance in conducting these tests and to express our appreciation for the aid of the Western Research Support Center, Sepulveda, California in providing statistical studies of the data. REFERENCES 1. WARD, S., GILLESPIE, I.,
PASSARO, E., JR., and GROSSMAN, M. I. Comparison of histalog and histamine as stimulants for maximal gastric secretion in human subjects and in dogs. Gastroenterology, 44: 620,1963. 2. LEVIN. E.. KIRSNER.._1. B.. and PALMER, W. L. A simple measure of gastric secretion in man. Gastroenterology, 19: 88, 1951. 3. BARON, J. H. Studies of basal and peak acid output with an augmented histamine test. Gut, 4: 136, 1963.
Passaro and Gordon
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4. WORMSLEY, K. and GROSSMAN, M. I. Maximal histalog test in control subjects and patients with peptic ulcers. Gut, 6: 427, 1965. 5. BACHRACH, W. H. On the question of a pituitary adrenal component in the gastric secretory response to insulin hypoglycemia. Gastroenterology, 44: 178, 1963. 6. FRENCH, J. D., LONGMIRE, R. L., PORTER, R. W., and MOVITJS, H. J. Extravagal influences on gastric hydrochloric acid secretion induced by stress stimuli. Surgery, 34: 621,1953. 7. LEVIN, E., KIRSNER, J. B., PALMER W. L. A comparison of the nocturnal gastric secretion in patients with duodenal ulcer and in normal individuals. Gastroenterology 10: 952, 1948. 8. VOEGTLIN, W. L. Gastric acidity in normal individuals and those with uncomplicated duodenal ulcer: an attempt to influence the nocturnal secretion. Gastroenterology, 9: 125, 1947. 9. HUGHES, R. K. and WOOTTON, D. G. Gastric sump drainage with a water seal monitor. Surgery, in press. 10. STEMPIEN, S. J. Insulin gastric analysis: technic and interpretations. Am. J. Digest. Dis., 7: 138, 1962. 11. Ross, B. and KAY, A. W. The insulin test after vagotomy. Gastroenterology, 46: 379, 1964. 12. ELLIOTT, D. W., TAFT, D. A., PASSARO, E., JR., and ZOLLINGER, R. M. Pancreatic influences on gastric secretion. Surgery, 50: 126, 1961. 13. BANK, S., MARKS, I. N., and GROIN, A. Gastric acid studies in pancreatic disease. Gastroenterology, 51: 649,1966. 14. KRAVETZ, R. E. and SPIRO, H. H. Gastric secretion in chronic pancreatitis. Ann. Int. Med., 63: 776, 1965. 15. MURPHY, D. L., GOLDSTEIN, H., BOYLE, J. D., and WARD, S. Hypercalcemia and gastric secretion in man. J. A#. Physiol., 21: 1607, 1966. DISCUSSION DAVID B. HINSHAW (Loma Linda, Calif.): The authors have described a very extensive experience with gastric secretory tests in a wide range of conditions and disease states. Their data would appear to challenge the generally accepted concept that the chief physiologic characteristic of duodenal ulcers is a significantly elevated secretion of gastric acid. In this study only one fifth of the patients had a peak rate of secretion above the range of the control group but the mean secretory rate was significantly higher than that in the control group and became more pronounced in older patients. These findings do serve to remind us that duodenal ulcers represent an interplay of at least three factors, rather than being simply a function of gastric hypersecretion. These factors are (1) the level of the gastric acid secretion; (2) the volume and quality of the alkaline buffering secretions present in the duodenum; (3) the local tissue resistance to peptic ulceration. The current therapeutic approach to peptic ulceration is primarily aimed at controlling the first
of these factors, that is, the acid secretory level, but with increased information this may not always be the case. It is particularly important to recognize, for example, the recent significant work relating to gastric mucin and its local protective effect relative to peptic ulceration. We certainly agree with the authors that the Hollander test is very rigorous and may be dangerous in elderly people or in those with cardiac disease. It is disconcerting to note the rather high incidence of incomplete vagotomy which the authors report. HARRY A. OBERHELMAN, JR. (Palo Alto, Calif.): It may be questioned whether the gastric secretory response to maximal histamine or Histalog stimulation should be used as a test to differentiate the secretory pattern in patients with duodenal ulcer and in normal subjects. The hypersecretion of gastric juice which occurs in patients with duodenal ulcers is of vagal origin and is best measured by studying the basal or fasting gastric secretion. Have the authors made such a comparison of the fasting secretion of normal patients and those with duodenal ulcers? I think it is also important when measuring basal gastric secretion to consider the sex of the patient as well as the age since it has been shown that secretory rates, both in normal subjects and those with duodenal ulcers, decline with increasing age and are lower in female than male subjects. We have not found the response to the Hollander insulin test an accurate prognostic study with regard to ulcer recurrence after vagotomy. It may be shown that 20 to 25 per cent of the patients six months after vagotomy exhibit a positive response to insulin stimulation. However, it has also been observed that the majority of these patients have a persistent reduction in secretion levels to normal or below normal after a twelve hour nocturnal secretion test and remain free of recurrent ulcer disease. It has been suggested that this discrepancy is due to the fact that insulin hypoglycemia is a stronger stimulus than the physiologic stimuli of vagal function and in the presence of any remaining vagal fibers is capable of eliciting a positive response. We have found that the measurements in the basal gastric secretion are more reliable in predicting the success of vagotomy. WILLIAM W. KRIPPAEHNE (Portland, Ore.): A note of warning concerning Hollander tests in some patients seems warranted. Starved patients or patients with hepatic disease are prone to the development of severe hypoglycemia with even small doses of insulin. Some pre-diabetic patients also may have hypoglycemia without exogenous insulin. We have observed the conditions of patients given as little as 8 to 10 units of insulin to progress rapidly to convulsions or coma. If Hollander tests seem necessary, they must be used with caution and there must be preparation for immediate infusion of glucose in these and other instances when
Gastric Secretory Tests patients have or are prone to the development of severe hypoglycemia. H. EARL GORDON (closing): The results of our studies are not meant to convey the impression that acid secretion is unimportant in the pathogenesis of peptic ulcer. Rather, we are trying to emphasize the limitations of gastric secretory tests as a diagnostic aid. In our series, neither the one hour basal test nor the level of stimulated secretion served to distinguish the normal patient from the patient with peptic ulcer in the majority of instances. Our 15 per cent incidence of incomplete vagotomy is, of course, disturbing. However, a number of other investigators here and in England have reported a similar incidence on the basis of the postoperative Hollander test. Fortunately, recurrent ulcers will
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not develop in all of these patients. In our series, in only five of thirty-two patients with a Hollander test giving positive results did recurrent ulceration develop during a follow-up period of one to four years. My comments in regard to the twelve hour nocturnal secretory test were made to emphasize the inherent difficulties of the procedure and not to imply that it lacked potential value. However, we have been unable to obtain reproducible results with the test. This is most likely due to the difficulty in obtaining a complete collection during the twelve hour period. We are currently trying a double lumen tube with a simple monitoring device in an attempt to insure a continuous patency of the gastric tube.