Gastric tubes, meals, acid, and analysis: rise and decline.
At a time when Roentgen rays were still a diagnostic novelty, gastric disorders were investigated with a wide variety of test meals. The test meal was a challenge to the patient's body to reveal a pathological state. The use of test meals was functional testing, a new approach to the chemical examination of the patient and represented an innovation in medical diagnosis. For centuries the stomach had been a mysterious organ. Doctors had to base their diagnoses largely on the vague and contradictory sensations described by their patients. The same therapy was not always effective in what appeared to be identical conditions. With the advent of the stomach tube (a flexible catheter and syringe), chemical analysis of digestive products of the test meal and the digestive juices removed could provide objective and scientific information.
The stomach tube was first used for its therapeutic potential rather than as an aid in diagnosis. Hermann Boerhaave (1668-1738) first suggested the use of a flexible stomach tube in cases of poisoning in individuals unable to swallow antidotes, but there is no evidence that he used it. In 1776, John Hunter (1728-1793) advised using a syringe with a flexible catheter long enough to reach into the stomach to transfer nourishment in cases of apparent drowning. In 1793 he published a paper (read in 1790) on the administration of food and medication through a hollow flexible eel skin tube passed into the stomach of a patient who was unable to swallow. This was the first published record of the successful practical use of the stomach pump. In 1797, Alexander Monro tertius (1773-1859) suggested the use of the tube and syringe for the extraction of poison from the stomach and for the introduction of food into the stomach in cases of dysphagia. He also noted that in 1767 his father, Alexander Monro secundus (1733-1817), had used a flexible tube to remove fermenting liquids and gases from the stomachs of cattle [1-3].
The use of the stomach tube for extracting poisons was introduced into American medicine in 1812 by Philip Syng Physick (1768-1837), professor of surgery at the University of Pennsylvania. Physick's report was the first authentic record anywhere of a stomach tube being used to remove noxious or poisonous substances from the human stomach. Hunter had used the tube only to introduce medicines and food into the stomach.
William Prout (1785-1850) is known for his discovery of the nature of the acid in the stomachs of animals. Prout read his report before the Royal Society of London on December 11, 1823, and it appeared in the Philosophical Transactions of the Royal Society the following year . He identified free muriatic acid (hydrochloric acid) in the gastric juice of various animals and humans after a meal and suggested that it was derived from the common salt of the blood by the force of galvanism (electricity). Before this finding, Prout favored phosphoric acid as responsible for the acidity of gastric juice.
Prout's results were confirmed by Army surgeon William Beaumont's (1785-1853) classic research on Alexis St. Martin, a Canadian with a permanent gastric fistula that remained after the wound from an accidental gunshot in 1822 had healed. Beaumont studied the appearance and function of the exposed living stomach over a number of years, and provided new information about the nature of gastric juice and the process of digestion in the stomach. He published his findings in Experiments and Observations on Gastric Juice and the Physiology of Digestion (1833).
Beaumont recognized the acid character of the gastric juice in response to food and alcohol. Its identity as muriatic acid was verified at the University of Virginia and at Yale University [5,6]. But old ideas die hard. Writers on gastric physiology continued to deny the presence of hydrochloric acid in gastric juice, or mentioned it merely as one of the acids present. Prout's discovery of hydrochloric acid in the gastric juice, and that none other was present in healthy people--a discovery of fundamental importance in the explanation of the chemistry of digestion--was not even mentioned in his obituaries.
Investigators considered that the hydrochloric acid was produced secondarily. They believed that the primary acid secreted was lactic acid, which then acted upon the sodium chloride present to produce the hydrochloric acid that Prout and others had found. Still others attributed gastric acidity primarily to the presence of acid phosphates in the juice. There was general reluctance to accept Prout's conclusions because no one had actually handled pure gastric juice, except Beaumont, and the material examined was usually mixed with other juices and food residues. Sometimes the juice stood for a while before it was analyzed, long enough for some lactic acid to be produced by fermentation of carbohydrates, especially with gastric contents of low acidity. Finally, some physiologists had difficulty accepting the idea that living cells could secrete acid as strong as hydrochloric acid . In 1850, Henry Bence Jones (1813-1873)  wrote: "This gastric juice, then, is a highly acid fluid secreted by the stomach ... What acid it is has not yet been determined. Hydrochloric, phosphoric, acetic, lactic, and butyric acids, have each been said to exist in the gastric juice" .
All doubt was finally dispelled by the publication in 1852 of "Gastric Juice and Metabolism. A PhysiologicalChemical Investigation," by Friedrich Bidder (1810-1894) and Carl Schmidt (1822-1894) of the University of Dorpat. From their quantitative analyses of the gastric juice collected by means of a fistula created in different species of live animals, Bidder and Schmidt proved that the acid of gastric juice is exclusively hydrochloric acid .
In 1869, Adolf Kussmaul (1822-1902) pioneered the treatment of stomach diseases by use of the stomach pump and tube. He aspirated the stomachs of patients who had gastric retention and dilatation produced by pyloric stricture due to a duodenal ulcer. This procedure gave symptomatic relief and prolonged the lives of many of the patients. However, Kussmaul's interests were therapeutic, and although he described the gross physical characteristics of the fluid, he did not examine the gastric juice chemically. His work renewed clinical interest in the stomach tube and led to its widespread therapeutic application.
Finally, in 1871, it occurred to Wilhelm Otto Leube (1842-1922), assistant to Kussmaul, that the chemical analysis of stomach contents had diagnostic possibilities. Leube used Kussmaul's stomach pump to aspirate specimens at 4 to 6 h after ingestion of a meal of soup, steak, potatoes, and white bread. He was primarily interested in the degree of digestion of the test meal, and also in the concentration of acid and pepsin. Although Leube's gastric tube was large and not very flexible, the procedure was quickly adopted as other test meals were developed. Because of the buffering properties of a solid meal and the difficulties in titrating the acidity of mixtures of a meal and gastric juice, fluid meals were introduced in 1895.
Gastric analysis quickly became an important laboratory procedure. George Dock related that after his arrival at the University Hospital in Ann Arbor in 1891, almost all patients on admission had examinations of stomach contents and stools in addition to urine and blood tests. Everyone looked for evidence of cancer X10].
In 1899, Jaksch  described the following procedure recommended by Schutz (1884) for obtaining gastric juice:
"A pliable gum-elastic sound, perforated at the end with a number of apertures not larger than a pins head, and furnished with a lacquered handle, is introduced into the stomach, and pushed on until a slight resistance is encountered. A collar of horn is then slipped over its upper part, and grasped between the teeth of the person experimented upon, so as to keep the sound in position. After the lapse of about half a minute the handle is removed and the sound connected with a stomach-pump. The piston is now drawn out, and the projecting extremity of the tube being grasped with the fingers, the sound is withdrawn, and its contents discharged by the movement of the piston into a glass vessel." Danger of the procedure "may be entirely obviated by introducing a mercurial manometer between the sound and the pump, and estimating beforehand the amount of pressure (as indicated by the position of the mercury) which may be employed without applying any considerable suction force to the mucous membrane of the stomach."
Jaksch  also described 12 chemical color reactions of varying reliability and sensitivity for the detection of free hydrochloric acid in gastric juice and classified them into four groups: (a) Mohr's tests, (b) aniline-dye tests, (c) Uffelmann s tests, and (d) ultramarine and zinc sulfide. Two of the more sensitive procedures are the methylaniline-violet reaction and the tropaeolin test. In the presence of a large quantity of free hydrochloric acid, the aniline dye is bleached; with a moderate quantity of acid, the color becomes green; if there is very little acid, the color is blue. Tropaeolin in alcoholic or watery solution yields a ruby-red or dark-brown red color in the presence of free acids. Uffelmann used the coloring matter of claret in testing for free acids in gastric contents. In a modified version, the almost colorless mixture of claret, 900 mL/L ethanol, and ether was rendered a rose color by the presence of a minute quantity of hydrochloric acid. Ultramarine, a test used for free acids in general, is decomposed by them even in dilute solutions, with the release of hydrogen sulfide and precipitation of silicic acid and sulfur. Zinc sulfide is dissolved in dilute acids, with the evolution of hydrogen sulfide. However, zinc sulfide is insoluble in acetic acid.
The single-specimen test gradually developed into the fractional test. Repeated single aspirations with stiff tubes were difficult, and multiple sampling of the gastric contents became practical only with the development of more flexible tubes that could be swallowed easily and kept in the stomach for long intervals. Over a few years, the tube and overall procedure were improved, resulting in less discomfort to the patient and more information for the clinician. By 1912, Ehrenreich, using a thin flexible tube, could sample gastric contents at 10-min intervals and plot curves of acidity for as long as 3.5 h after a meal .
The fractional test was introduced into the US in 1914 by Martin Rehfuss, who used a thin, flexible, rubber tube fitted with a metal tip  (Fig. 1). The tip is slotted with large perforations, the diameter of each being equivalent to the maximum bore of the tubing. After gastric stimulation by a simplified carbohydrate test meal of toast, rolls, or crackers, and water or plain tea, first proposed in 1886 by Karl Anton Ewald (1845-1915) and Boas in Berlin, samples were removed by syringe every 15 min for 2 h and titrated for acidity. This combination of test meal and Rehfuss tube marked the start of modern gastric analysis and made following the full cycle of the changes during digestion possible. In England, Ryle  later popularized a similar small-bore rubber tube ending in a brass bulb containing numerous perforations (Fig. 2). Levin  advocated a newly designed catheter, thin like a urethral catheter, for gastric analysis and duodenal intubation by the nasal route. These tubes helped make the fractional test a routine procedure.
[FIGURE 1 OMITTED]
The primary objective in the titration of gastric acidity is to determine the amount of unneutralized hydrochloric acid ("free") present, in the possible presence of other acids that, while titratable, are nevertheless so much less highly ionized than hydrochloric acid that they contribute little or nothing to the hydrogen ion concentration of the solution. The hydrogen ion concentration of the gastric contents largely determines whether or not the physiological functions of the gastric secretion will be served; the appropriate concentration can come only from a highly ionized acid such as hydrochloric acid. Thus gastric function can be evaluated in terms of the presence and amount of free hydrochloric acid.
Titration of free hydrochloric acid in the presence of other titratable acids is based on the fact that hydrochloric acid is completely dissociated in solution and reacts with the hydroxide ions being added before any undissociated acid present can ionize and so react. Therefore, the amount of alkali added up to the point of practically complete neutralization of the hydrochloric acid present should be distinguishable from that necessary for the remaining acid or acids. At about pH 3.5, all of the acid has been reacted and the titration at this point gives a value for the hydrochloric acid present.
[FIGURE 2 OMITTED]
When titratiog weak acids, i.e., acetic acid, the solution has a pH of ~3.0-corresponding to the relatively small ionization of the acid molecules--before any alkali has been added. As titration continues, all the acid is eventually neutralized. However, the end point is not pH 7.0, but ~8.5, and requires an indicator that changes color at pH ~8.5, e.g., phenolphthalein. Hence, in titration of a mixture of hydrochloric acid and some weak acid or acids with alkali, the volume added to reach pH 3.5 is a measure of the hydrochloric acid present, while the burette reading at pH 8.5 will be a measure of the total acidity of the solution. Quantitative distinction between these two types of acidity can be made by pH meter or more commonly with an indicator whose color change lies at the pH range desired. Topfer's reagent (dimethylaminoazobenzene) and phenolphthalein are almost universally used. Topfer's reagent changes color from red to yellow over the pH range 2.9 to 4.0. The intermediate color of salmon pink is noticeable at pH ~3.3, and titration with alkali to this color gives a measure of the free hydrochloric acid present, uninfluenced by any weak acids present. Titration continued to color change with phenolphthalein gives the total acidity.
The weak acids in gastric contents include protein hydrochloride ("combined hydrochloric acid"), acid phosphates, and various organic acids such as lactic and citric acids, after fermentation or the ingestion of certain foods. The difference between free and total acid is more a measure of the buffering power of the gastric juice than anything else. Therefore, from a practical point of view, gastric acid is measured either by free acid or by the pH.
Initially, quantitative estimations of acidity were made by titration with 0.1 mol/L sodium hydroxide and litmus as indicator, and reported in "degrees," a unit introduced by Jaworski and Gluzinski in 1886. The name was later changed to "clinical units." The unit was defined as the number of cc of 0.1 mol/L sodium hydroxide needed to neutralize 100 cc of specimen . The procedure at present determines the concentration of acid (free or total) by titration of 1.0 mL of gastric fluid with 0.01 mol/L sodium hydroxide. At end point, the milliliters of 0.01 mol/L alkali are multiplied by 10 to obtain the volume of 0.1 mol/L alkali that would neutralize the acid in 100 mL of gastric fluid. This value corresponds to the concentration of acid expressed as milliequivalents per liter.
The proper choice of indicators was a difficult problem that could be resolved only with a clear understanding of the significance of acid-base titration curves and the effect upon them of various buffers. Although the early titration work was done with the same indicators being used for the qualitative tests, gradually all of these were discarded, with the exception of Topfer's reagent--introduced in 1894--for free hydrochloric acid, and were replaced by phenolphthalein. Litmus for total acidity was also discarded. With the introduction of the pH concept of acidity in 1909 by Soren Peter Lauritz Sorensen (1868-1939), the end points could be defined in terms of those pH units that correspond exactly to whatever definitions of free and total acidity might be adopted.
Ethyl alcohol (<100 mL/L) as a test meal was suggested by Kast in 1906. In 1914, 200 mL of 50 mL/L ethyl alcohol was first used . Histamine stimulation was introduced in 1922, and caffeine in 1925. One problem common to all tube methods is that the size and nature of the sample of gastric contents depends largely on where the end of the tube lies. Gastric residue may be removed under fluoroscopic guidance.
Gastric stimulation with histamine, its analog (betazole, histalog), or a synthetic gastrin (pentagastrin)--currently the stimulus of choice--may be administered subcutaneously, intramuscularly, or by intravenous infusion. Pentagastrin is a more potent and highly reproducible stimulus that is practically free of the undesired side effects of histamine, e.g., drowsiness, headache, nausea, tachycardia, and erythema. Gastric residue is collected by oral or nasal intubation.
A tendency toward high acidities may be found, though not constantly, in cases of gastric and duodenal ulcers, especially those in the neighborhood of the pylorus and inducing some degree of obstruction. In the early years of this test, clinicians looked for the absence of hydrochloric acid as evidence of stomach cancer. It is now known that anacidity occurs in a minority of cases and then usually only in advanced stages of the disease, and anacidity of itself does not necessarily have pathological significance.
Approximately 4% of young healthy persons may have no free hydrochloric acid in the fasting stomach. This percentage increases with age and is ~25% in individuals at age 60. Absence of free hydrochloric acid in gastric residue is considered abnormal only if the condition persists after maximal stimulation with pentagastrin . Anacidity is also associated with other clinical conditions, e.g., pernicious anemia and rheumatoid arthritis. In only ~40% of patients with duodenal ulcer is the upper limit of the normal range of acidity exceeded. The use of gastric analysis decreased as more precise and informative diagnostic procedures became generally available, especially gastroscopy, improved roentgenographic techniques, exfoliative cytology, and newer laboratory procedures, such as gastrin by RIA .
Tubeless Gastric Tests
In 1950, a carboxylic cation-exchange resin (Amberlite IRC-50 or XE-96), in which quinine replaces part of the hydrogen ions, became the basis of an indirect and simple rapid tubeless gastric test for free hydrochloric acid X21, 221. The resin (Diagnex; Squibb, New York, NY) was taken by mouth after gastric secretion was stimulated by caffeine sodium benzoate taken orally, or by histamine injected subcutaneously. At pH 3.0 or lower, quinine is displaced by the hydrogen ions in the gastric juice and is absorbed into the circulation and excreted in the urine where it is determined fluorometrically in a 2-h collection. To avoid the need for a fluorometer, a new resin combination incorporating the dye azure A (Diagnex Blue, Squibb) was used . The dye is displaced from the resin by the free hydrogen ions of gastric juice, is absorbed in the small intestine, and appears in the urine, where its concentration can be determined by visual comparison with color standards or by photometric measurement. The amount of dye excreted is proportional to the total gastric acidity. Since tubeless gastric analysis requires the functional integrity of the liver and kidneys, discrepancies between the two techniques can occur, resulting in numerous false positives and false negatives. This procedure was eventually abandoned in the late 1980s.
Current Role of Gastric Analysis
Intermittently since Beaumont's observation that the stomach contained hydrochloric acid, the clinicians inter est in testing gastric contents has waxed and waned. It is clearly on the wane at this time. Surgeons no longer operate on patients with peptic ulcer on the basis of acid secretion. Interest in secretory studies declined when it became evident that one could not tell with any certainty, on the basis of acid secretion, whether a given individual was likely to develop a gastric or duodenal ulcer or a gastric cancer .
Although tests of gastric secretion have decreased in importance, they are helpful in specific instances and may even be necessary to make an appropriate clinical decision. Examples include the need to determine the status of acid secretion in patients who have hypergastrinemia or who are being treated for a gastrinoma. Gastrointestinal intubation is necessary for invasive pancreatic function tests to collect samples for measuring pancreatic enzyme or bicarbonate secretion into the duodenum. The gastric tube is necessary to aspirate gastric secretions constantly, because acid in the duodenum stimulates exocrine pancreatic secretion but may also inactivate pancreatic enzyme activity. Tests of gastric acid secretion have aided in the diagnosis of many upper gastrointestinal lesions, in helping select the type of surgical procedure for gastric and duodenal ulcers, and in determining postoperatively the completeness of a vagotomy .
Historically, tests of gastric secretion were performed to aid the clinician in diagnosing pernicious anemia, distinguishing between benign and malignant gastric ulcers, evaluating patients with ulcer dyspepsia and normal x-ray films, selecting appropriate operations in patients with duodenal ulcers, and evaluating and assessing the type of reoperation needed for patients who developed recurrent ulceration after surgery for duodenal ulcer. Today, most of these clinical problems can be satisfactorily addressed without performing secretory tests. Measurement of serum vitamin [B.sub.12] is the preferred screening test for pernicious anemia. Differentiation between benign gastric ulcer and gastric carcinoma (20% of gastric carcinomas are accompanied by gastric anacidity) is now made with confidence by endoscopy with biopsy and cytology. Even in patients with recurrent ulceration after gastric surgery, the frequency and importance of gastric analysis have declined because the ulcers can often be healed with drugs .
Before the availability of fiberoptic endoscopy, gastric secretory tests were used in patients who had nonulcer dyspepsia and normal upper gastrointestinal x-ray films, because gastric acid hypersecretion in this situation could indicate a duodenal ulcer. Today, endoscopy, not gastric analysis, is used to exclude peptic ulceration in these patients. In many institutions, endoscopy is replacing radiologic examination of the upper gastrointestinal tract as a first-line test for the evaluation of patients with dyspepsia. The use of gastric secretory tests has decreased dramatically over the past decade but continue to be performed to determine whether patients who have undergone surgery for ulcer disease and who have complications are secreting acid .
Received October 15, 1996; revised December 5, 1996; accepted December 5, 1996.
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LOUIS ROSENFELD New York University Medical Center, Department of Pathology, 530 First Ave., New York, NY 10016.
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|Date:||May 1, 1997|
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