INTESTINAL OBSTRUCTION : II. A STUDY OF A TOXIC SUBSTANCE PRODUCED BY THE MUCOSA OF CLOSED DUODENAL LOOPS.

The blood of closed duodenal loop dogs is not toxic to normal dogs. The blood of dogs that have been fatally poisoned with duodenal loop fluid is likewise non-toxic to normal dogs. The mucosa of closed or drained duodenal loops contains a toxic substance quite similar to the toxic material found in the lumen of the closed loops. This toxic substance is absorbed from the mucosa itself and not from the lumen of the drained loops. The same is probably true of the closed loops which have an intact mucosa. It seems highly probable that the poison is formed by the mucosa and is in great part absorbed directly from it by the blood. Normal intestinal mucosa contains no toxic substance nor can it neutralize in vitro the toxic substance produced in the closed loops. There is no evidence that the toxic material when given intravenously is excreted by the intestine or held by the intestinal mucosa in any demonstrable form. The toxic substance is not absorbed from the normal intestinal tract. Destruction of the mucosa in a closed loop by means of sodium fluoride prevents the formation of the toxic substance. This fact furnishes the final proof that the mucosa is the essential factor in the elaboration of the poisonous material.     

INTESTINAL OBSTRUCTION : AN EXPERIMENTAL STUDY OF THE INTOXICATION IN CLOSED INTESTINAL LOOPS.

1. Closed intestinal loops in which bacteria are first removed are compatible with life. 2. Closed intestinal loops in which bacteria are present but in which tissue necrosis is prevented, are compatible with life. 3. Closed aseptic intestinal loops in which the blood supply is completely occluded are compatible with life. 4. The normal secretions and bacterial products of the duodenum and jejunum are not sufficiently toxic to produce any symptoms when allowed to drain into the abdominal cavity. 5. Our results do not support the theory of Draper of a normal toxic secretion of the duodenal mucosa, neutralized by the jejunal mucosa, or the perverted secretion theory of Whipple. 6. Bacterial activity plus necrotic tissue, or the absorption of toxic products resulting from the action of putrefactive bacteria on necrotic tissue is the important factor in the rapid death in simple closed intestinal loops.     

INTESTINAL OBSTRUCTION : I. A STUDY OF A TOXIC SUBSTANCE PRODUCED IN CLOSED DUODENAL LOOPS.

Closed duodenal loops may be made in dogs by ligatures placed just below the pancreatic duct and just beyond the duodenojejunal junction, together with a posterior gastro-enterostomy. These closed duodenal loop dogs die with symptoms like those of patients suffering from volvulus or high intestinal obstruction. This duodenal loop may simulate closely a volvulus in which there has been no vascular disturbance. Dogs with closed duodenal loops which have been washed out carefully survive a little longer on the average than animals with unwashed loops. The duration of life in the first instance is one to three days, with an average of about forty-eight hours. The dogs usually lose considerable fluid by vomiting and diarrhea. A weak pulse, low blood pressure and temperature are usually conspicuous in the last stages. Autopsy shows more or less splanchnic congestion which may be most marked in the mucosa of the upper small intestine. The peritoneum is usually clear and the closed loop may be distended with thin fluid, or collapsed, and contain only a small amount of pasty brown material. The mucosa of the loop may show ulceration and even perforation, but in the majority of cases it is intact and exhibits only a moderate congestion. Simple intestinal obstruction added to a closed duodenal loop does not modify the result in any manner, but it may hasten the fatal outcome. The liver plays no essential role as a protective agent against this poison, for a dog with an Eck fistula may live three days with a closed loop. A normal dog reacts to intraportal injection and to intravenous injection of the toxic substance in an identical manner. Drainage of this loop under certain conditions may not interfere with the general health over a period of weeks or months. Excision of the part of the duodenum included in this loop causes no disturbance. The material from the closed duodenal loops contains no bile, pancreatic juice, gastric juice, or split products from the food. It can be formed in no other way than by the activity of the intestinal mucosa and the growth of the intestinal bacteria. This material after dilution, autolysis, sterilization, and filtration produces a characteristic effect when introduced intravenously. When in toxic doses it causes a profound drop in blood pressure, general collapse, drop in temperature, salivation, vomiting, and profuse diarrhea, which is often blood-stained. Splanchnic congestion is the conspicuous feature at autopsy and shows especially in the villi of the duodenal and jejunal mucosæ. Adrenalin, during this period of low blood pressure and splanchnic congestion, will cause the usual reaction when given intravenously, but applied locally or given intravenously it causes no bleaching of the engorged intestinal mucosa. Secretin is not found in the duodenal loop fluid, and the loop material does not influence the pancreatic secretion. Intraportal injection of the toxic material gives a reaction similar to intravenous injection. Intraperitoneal and subcutaneous injections produce a relatively slow reaction which closely resembles the picture seen in the closed duodenal loop dog. In both cases there is a relatively slow absorption, but the splanchnic congestion and other findings, though less intense, are present in both groups. There seems, therefore, to be no escape from the conclusion that a poisonous substance is formed in this closed duodenal loop which is absorbed from it and causes intoxication and death. Injection of this toxic substance into a normal dog gives intoxication and a reaction more intense but similar to that developing in a closed-loop dog.     

INTESTINAL OBSTRUCTION : III. THE DEFENSIVE MECHANISM OF THE IMMUNIZED ANIMAL AGAINST DUODENAL LOOP POISON.

Dogs may be immunized against lethal doses of the duodenal loop poison by means of small doses of the loop fluid from dog or cat and by material obtained from human cases of intestinal obstruction. The immunity is transient and may disappear within a few weeks. Dogs immunized by repeated doses of loop fluid show a definite resistance against the intoxication of a closed duodenal loop and may survive twice the usual period. A dog that recovers from simple intestinal obstruction may possess a strong resistance to the intoxication of a closed duodenal loop, thus indicating a similar type of intoxication in the two conditions. The sera of immune dogs are inactive when incubated with duodenal loop fluid. The organ extracts and emulsions (liver, spleen, lung) of immune dogs rapidly destroy the loop poison during incubation in vitro. This destructive property is possessed by a clear filtrate of the digested immune organs, excluding adsorption, and is lost after long periods of incubation (twelve weeks). We are investigating the action of this immune organ extract to determine whether it can destroy the closed-loop poison in vivo and perhaps be of value in treatment.     

INTESTINAL OBSTRUCTION : II. A STUDY OF THE FACTORS INVOLVED IN THE PRODUCTION AND ABSORPTION OF TOXIC MATERIAIS FROM THE INTESTINE.

1. It is impossible to sterilize the intestine by the use of chemical antiseptics even when these are applied directly to the mucosa of isolated segments. 2. The mucosa of the alimentary tract does not elaborate an internal secretion which is necessary to life, or a secretion which could be disturbed by the conditions of acute obstruction so as to account for the symptom complex of that condition. 3. The substances responsible for the toxemia in acute obstruction are produced by the action of intestinal bacteria on proteins or their split products. 4. An injury to the intestinal mucosa, particularly that resulting from disturbances of the blood supply to the intestine, greatly facilitates the absorption of these poisons. The work of Hartwell and his associates and that of Murphy and Brooks on this point are confirmed.     

PROTEOSE INTOXICATIONS AND INJURY OF BODY PROTEIN : II. THE METABOLISM OF DOGS WITH DUODENAL OBSTRUCTION AND ISOLATED LOOPS OF INTESTINE.

Dogs with isolated loops of small intestine show many evidences of intoxication. A study of the total nitrogen elimination shows a great rise above the normal base-line minimum of the fasting period (Table II). This means that the intoxication is associated with a great destruction of body protein, and explains the high non-protein nitrogen of the blood which was observed and reported previously (2). Injection of a proteose obtained from a closed intestinal loop will cause a similar rise in the nitrogen elimination curve. This furnishes more evidence that the intoxication observed in association with a closed intestinal loop is in reality a proteose intoxication. Dogs injected with sublethal doses of proteose will show a definite tolerance to subsequent injection, and will show much less acute intoxication after the isolation of a closed intestinal loop (Table 1). These immune or tolerant dogs show a much less pronounced rise in the nitrogen elimination curve during proteose intoxication of any type. This indicates that the tolerance or immunity to proteose gives more protection for the body proteins against the injury which these toxic proteoses inflict upon the body cells. Complete duodenal obstruction combined with a gastrojejunostomy gives a chronic type of intestinal obstruction associated with little vomiting, which is peculiarly suited to metabolism study (Table IV). Such duodenal obstructions show a definite and sustained rise in the curve of nitrogen elimination above the normal base-line level. These dogs, too, are tolerant to injections of standard toxic proteoses. Control ether anesthesia experiments show little if any rise in the curve of nitrogen elimination (Table VI). Control laparotomy experiments show a definite rise in the curve of nitrogen elimination, but a rise which is small compared with the rise noted in the intoxication of duodenal obstruction or of isolated intestinal loops. It is probable that the tissue injury and disintegration associated with the wound reaction are responsible for the general reaction. We may assume that protein split products from the wound area are absorbed and are responsible for the general reaction observed. We propose to assume that the intoxications here studied are associated with a definite proteose intoxication, which is capable of initiating and continuing a profound injury of tissue protein. One index of this protein injury is the great and sustained rise in the curve of total nitrogen elimination.     

THE INFLUENCE OF X-RAY LESIONS OF THE INTESTINAL MUCOSA ON ABSORPTION OF GLUCOSE AND OTHER SUGARS

A sublethal dose of x-rays was applied over the abdomen of rats and over the thorax for control purposes. 20 and 40 hours after radiation (i.e. during the "latent period") the rate of absorption of glucose, fructose and mannose was markedly diminished. Simultaneously definite histological changes were observed in the intestinal mucosa. In spite of the decrease in the absolute amount absorbed, the relative rate of absorption of the three sugars mentioned remained nearly unchanged, indicating that the epithelial cells retained their selective action on sugars.     

ENDOMETRIOSIS – THE PROBLEMS OF INTESTINAL OBSTRUCTION

Endometriosis is a relatively common condition in women of child-bearing age, and coincidental intestinal serosal involvement is frequently recognised. However, intestinal obstruction, although reported, is rare. We report what we believe is the first case with synchronous ileo-caecal and rectosigmoid obstructing endometriomas. Endometriosis as a cause of bowel obstruction is discussed and in particular the differential diagnosis from Crohn's disease and malignancy.     

INTESTINAL OBSTRUCTION : VI. A STUDY OF NON-COAGULABLE NITROGEN OF THE BLOOD.

Intestinal obstruction, as a rule, is associated with an increasing amount of non-coagulable nitrogen in the blood. With acute intoxication the rise in non-coagulable nitrogen may be rapid and reach as high as three or even ten times normal. With more chronic intoxication there may be little or no rise in the blood non-coagulable nitrogen. Closed intestinal loops show exactly the same picture, and, when combined with obstruction, may give very high nitrogen readings. Acute proteose intoxication due to injection of a pure proteose will show a prompt rise in blood non-coagulable nitrogen, even an increase of 100 per cent within 3 or 4 hours. These intoxications also show a high blood content of creatinine and urea. The residual or undetermined nitrogen may be very high. A human case of intestinal obstruction with autopsy presents blood findings exactly similar to those observed in many animal experiments. Clinically the non-coagulable nitrogen of the blood may give information of value in intestinal obstruction. A high reading means a grave intoxication, but a low reading may be observed in some fatal cases and gives no assurance that a fatal intoxication may not supervene. The kidneys in practically all these experiments are normal in all respects. It is possible that protein or tissue destruction rather than impaired eliminative function is responsible for the rise in non-coagulable nitrogen of the blood in these acute intoxications. Transfusions of dextrose solutions often benefit intestinal obstruction, and may depress the level of the non-coagulable nitrogen in the blood. Some cases show no change in non-coagulable nitrogen following transfusions and diuresis, and, as a rule, such cases present the most severe intoxication.     

THE SODIUM CONTENT OF THE BLOOD OF THE DOG AFTER EXPERIMENTAL INTESTINAL OBSTRUCTION

Sodium determinations on the blood of ten dogs after experimental obstruction of the jejunum are reported. The average sodium content of the plasma of the normal dog is 336 mg. per 100 cc. There is relatively little change in the sodium content of the blood plasma after the intestine is obstructed, even with marked changes in the chloride and bicarbonate. The whole blood sodium tends to rise after intestinal obstruction. The increase in bicarbonate ions does not fully compensate for the decrease in chloride ions. After intestinal obstruction there is a larger amount of sodium in some unknown combination than in the normal dog. These findings throw no definite light on the mechanism of the increased protein destruction characteristic of intestinal obstruction.     

CHEMICAL CHANGES IN THE BLOOD OF THE DOG AFTER INTESTINAL OBSTRUCTION

A study of the non-protein nitrogen, urea nitrogen, uric acid, creatinine, amino-acid nitrogen, sugar, and chlorides of the blood and the CO₂-combining power of the plasma in normal dogs, and in dogs after different types of intestinal obstruction, is reported. Following ligation of the duodenum, ligation of the duodenum with gastroenterostomy, and ligation of the upper half of the ileum, a fall in chlorides and a rise in the non-protein nitrogen and urea nitrogen of the blood and in the CO₂-combining power of the plasma occur. The uric acid, creatinine, amino-acid nitrogen, and sugar show no significant changes. The fundamental change is a fall in chlorides followed by an alkalosis. The degree of alkalosis depends upon the rate of formation of carbonate, rate of excretion by the kidneys, and extent of neutralization of the carbonate by acid bodies formed during the intoxication. The fall in chlorides is probably due to a utilization of the chlorine ion in the course of the intoxication. It is suggested that this use of chlorine is a protective measure on the part of the body. There are indications that high intestinal obstruction should not be treated by the administration of alkalies. The urea nitrogen is a good index of the protein destruction. Ligation of the ileum at the ileocecal valve is followed by little increase in nitrogen and no change in the chlorides or CO₂-combining power of the plasma. The close similarity of the blood findings in intestinal obstruction, acute lobar pneumonia, and serum disease suggests that these widely different conditions may have a common chemical basis.     

THE DISTRIBUTION OF CHLORIDES IN THE BLOOD OF THE DOG AFTER EXPERIMENTAL INTESTINAL OBSTRUCTION

The results of simultaneous chloride determinations in whole blood, in plasma, and in cells of the dog after experimental intestinal obstruction are presented, and the chloride content of whole blood and of plasma is compared by two methods of estimation: the iodometric titration on protein-free filtrate, and the digestion technique of Van Slyke. The chloride as determined on protein-free filtrate checks closely with that as determined by the digestion procedure. The iodometric determination shows accurately the level of chlorides in the blood. The total change in the chloride store of the body is best reflected in determinations on whole blood. In intestinal obstruction the retained chloride is not present in the blood in some undetermined form.     

INTESTINAL OBSTRUCTION : V. PROTEOSE INTOXICATION.

A definite intoxication develops as a result of a closed intestinal loop and toxic material accumulates in the closed loops. Much evidence has been submitted to show that this loop poison causes the intoxication observed after producing a closed intestinal loop. Sufficient evidence has been presented to prove that the essential poison is present in these closed intestinal loops, and usually in concentrated form. Chemical study of the contents of closed intestinal loops shows that a single substance or group of substances possesses toxic properties. This resists autolysis and pancreatic and ereptic digestion. It is thrown out of solution by five volumes of alcohol or by half saturation with ammonium sulphate. It is readily soluble in water and is not injured by boiling. It is not removed by dialysis. The method of isolation excludes practically all substances except primary proteoses. The characteristic resistance to digestive enzymes suggests a heteroproteose. Proteose intoxication in dogs gives a picture identical with that described after poisoning with intestinal loop fluid: early salivation and vomiting, followed by diarrhea and prostration, fall in temperature and blood pressure, and finally death in collapse. Autopsy shows essentially a splanchnic paralysis and remarkable engorgement of liver and spleen, but especially of the mucosa of the duodenum and small intestine. The blood shows great concentration due to loss of fluid and may remain incoagulable because of an excess production of antithrombin. Proteoses escaping from the blood are excreted in the urine. This toxic proteose concerned in intestinal obstruction has not yet been isolated in the urine, but may be excreted by the kidneys. This probably explains the clinical improvement and lessened intoxication noted after transfusion. Experimental evidence points to a primary proteose as the essential poison concerned in the intoxication of closed intestinal loops and intestinal obstruction.