ROBERT C. REISINGER, D.V.M., M.S.
SUDDEN DEATH SYNDROME
There are striking similarities between the Sudden Death Syndrome (SDS) of the human infant and the young of other mammalian species. The young calf, piglet, foal, rabbit and monkey are similarly afflicted, (17, 33, 34, 45, 66, 67, 92, 98) as are the young of other, perhaps all, mammalian species. It is postulated, that the final cause of death, an endotoxemia, is the same in all. This endotoxemia may be precipitated by a variety of adverse contributing factors, including viruses and various environmental stressors.
The basis of this hypothesis is the well-documented, but generally ignored fact that endotoxin is absorbed from the gastrointestinal tract of all mammalian species (28, 29, 30, 33, 51, 61, 64, 66, 67, 98). Absorbed endotoxin is normally detoxified in the liver. Endotoxemia results when one or more of many and varied "adverse contributing factors" interferes with normal liver functions, and/or results in increased endotoxin production within an increased absorption from the gastrointestinal tract so the detoxication is incomplete.
If incomplete detoxification occurs free endotoxin is carried via the inferior vena cava into the right side of the heart and by the pulmonary artery into the lungs. Lesser amounts are carried into the left side of the heart and by the way of the arterial circulation into all parts of the body, but in decreasing amounts. Extremely small quantities of endotoxin absorbed over several hours time exert adrenergic action in the lungs, and reduction of thrombocytes and fibrinogen. Alternating vasoconstriction and dilatation, and increased capillary permeability, with drastically decreased thrombocytes and fibrinogen levels, result in varying amounts of edema and hemorrhage by diapedesis, primarily in the lungs, where the greatest concentration of endotoxin occurs, and death (8).
Infants, who have succumbed to the sudden Death Syndrome have varying degrees of edema and hemorrhage of the lungs and unclotted blood in the heart and large vessels (2, 7). Decrease of platelets and fibrinogen following initial vasoconstriction and then dilatation and increased permeability of capillaries, all of which are known reactions to endotoxin (29, 30, 72, 73) can cause such changes.
The intestinal microflora of the normal breast-fed infant consists largely of Bacteroides and Lactobacillus spp., which may in the early weeks of life constitute 90 percent or more of the total bacterial organisms in the feces (35, 36, 58, 83). Relatively few toxin producing Escherichia coli are present in the digestive tract of the normal breast-fed infant, usually totaling no more than one percent of the total bacteria in the feces.
Substitution of breast feeding by bottle feeding with cow's milk results in a dramatic and immediate hundred fold or greater increase in E. coli, so that they may equal or exceed numbers of Bacteroides and Lactobacilli, and a rise in pH from approximately 5.8 for the breast-fed infant to 7.4 in infants fed cow's milk. Also, because of it's high casein and high calcium content, cow's milk forms larger and firmer curds and takes longer to pass through the bowel (99). Thus, cow's milk interferes with two basic defense mechanisms of the infant's digestive tract - acidity and adequate intestinal motility. Human milk has a lactose:protein-ratio of 6:1 and cow's milk a lactose:protein-ratio of 1.5:1 (54). Various commercial infant feeding formulas available in this country have lactose:protein-ratios from 5:1 to 2:1 (26). Experiments in the human infant and other mammalian species have demonstrated that, to establish or maintain a predominantly lactobacilli intestinal microflora it is essential that a quantity of lactose sufficient to produce approximately the same quantitative lactose:protein ratio, that exists in human milk be present (35, 99). Theobald Smith and Marion Orcutt (80) described the mechanism of diarrhea in calves as "a great increase in the number of E. coli in the lowest third of the small intestine with a spreading of the invasion towards the duodenum as the disease gains headway. Under these conditions, a general intoxication results......
Escherichia coli in the digestive tract has not been in general regarded as significant. This significance appears when the quantitative factor, obtained before natural death, is determined." Thus, Smith and Orcutt explained and documented the key importance of quantitative and location factors in the role of E. coli in the diarrhea syndrome of calves and the fact that such changes occur antemortem.
Theobald Smith and Ralph B. Little (81) described the action of E. coli filtrates inoculated intravenously in the calf and cow. Their description of the resulting pathology - primarily edema, congestion and hemorrhages affecting the lungs and other organs, is very similar to the pathology described by Adelson (2) and others (7) in the Sudden Death Syndrome. Reisinger (66, 67) confirmed the findings of Smith and co-workers regarding the role of E. coli in the pathogenesis of calf diarrhea. He also reported that two of his series of 65 calves died suddenly and unexpectedly, without evidence of diarrhea or struggle, within several hours after having been observed to appear healthy and normal. "-- in most of the early deaths, grossly evident inflammation of the intestinal tract was conspicuous by it's absence, and the most consistent gross pathological finding was varying amounts of edema of the mesenteric lymph glands." Septicemia was not necessary for death to occur, but as many as 100-500 million E. Coli organisms per ml of intestinal contents were demonstrated in the upper ileum and jejunum which in the healthy animal contain few or none of these organisms.
Gay (33) has described the "enteric-toxemic form of colibacillosis" associated with sudden death of calves up to one month of age. In his experience, "the calf usually died before scouring (diarrhea) was evident." Arnold and Brody (4) found the normal pH of the duodenum and upper jejunum of dogs to be between 5.5. and 6.3. "The slightly acid reaction of the content of this part of the intestinal tract is to a large extent dependent upon the gastric secretory function, and under these conditions the contents of the upper half of the small intestine are practically free of bacteria. When the reaction is neutral or slightly alkaline (pH 7 to 8) the bacterial flora resembles that of the cecum, i.e., there is a predominance of the coli-aerogenes type of flora. This can be produced by injecting alkaline-buffered solutions into the lumen of the duodenum, by feeding alkaline salts, or by elevation of the temperature of the animals (dogs)."
Digestion and absorption of carbohydrates, fats and proteins occurs primarily in the upper portion of the small intestine (10, 76). This portion of the digestive tract normally contains few or no toxin-producing organisms (20, 66, 67, 80) -- if toxin is produced in appreciable amounts in this portion of the digestive tract, the individual is either ill or dead, depending on the amount and rate of toxin absorption and relative resistance or susceptibility to the toxin. (12, 25, 43, 53, 66, 67, 80).
Dubos et al. (24) in a review relating to the composition, alteration and effects of the intestinal flora suggest that the enterobacteria and especially E. coli, the Proteus and Pseudomonas bacilli, the enterococci and the clostridia are accidental inhabitants of the intestine rather than part of it's normal flora. They have developed and maintained a colony of mice (NCS) practically free of E. coli in which the largest percentage of intestinal flora cultivable both aerobically and anaerobically consists of organisms commonly classified as Lactobacillus and Bacteroides spp. NCS mice grow faster, are more resistant to lethal effects of endotoxin and have less exacting nutritional requirements than control mice. However, administration per os of even small quantities of penicillin brings about a sudden disappearance of lactobacilli from the fecal flora of NCS mice accompanied by an explosive and lasting increase in enterococci and gram negative enterobacilli. E. coli, which is not normally found in the stool cultures of the NCS mice, became abundant following treatment with penicillin. These findings are similar to those of De Somer et al. (21) in the guinea pig which also normally has a primarily gram positive intestinal microflora. Schaedler and Dubos (74) found that in the mouse "the composition of the bacterial flora could be rapidly and profoundly altered by a variety of unrelated disturbances, such as sudden changes in environmental temperature, crowding in cages, handling, administration of antibacterial drugs, etc. The first effect of the change was a marked decrease in the numbers of lactobacilli and commonly an increase in the numbers of gram negative bacilli and enterococci. When tested three weeks after these disturbances some NCS animals, normally relatively resistant, were found to have become susceptible to the lethal effect of endotoxin."
Dubos et al. (24) reported that the numbers of lactobacilli recovered from stools of mice fed diets of natural materials were much larger than in those mice fed a casein semi-synthetic diet.
Dubos et al. (24) and Ravin et al. (64) have shown, that endotoxin is being continually absorbed into the circulatory system of animals which have appreciable numbers of E. coli in their digestive tracts. Fine and co-workers (28, 29, 30) have stated that endotoxins are always at hand ready to destroy peripheral vascular integrity, and to kill the moment the endotoxin detoxifying power is lost. They have shown that irreversible shock resulting from prolonged blood loss is due to the inability of the damaged reticuloendothelial system to adequately detoxify endotoxin being continually absorbed from the intestinal tract. They have also shown that blocking the reticuloendothelial system of the rabbit with thorotrast (a sterile colloidal suspension of 25% thorium dioxide in dextrins) makes this animal exquisitely susceptible to the effects of endotoxin.
Rabbits so blockaded can be killed with one one-hundred-thousandth of the normally lethal dose of endotoxin (28). Guinea pigs, whose intestinal tracts usually contain very few coliforms, are consistently killed with penicillin or the tetracyclines, which destroy the normal gram positive flora and allow overgrowth of E. coli (21).
Viruses, various immunization procedures,and any of the many and varied other stressors which may interfere with, or occupy, the RE system may make the infant even more normally sensitive to the effects of endotoxin.
Administration of Diphteria-Pertussis-Tetanus toxoid (DPT) can cause temporary liver disfunctions in infants similar to those resulting from viral hepatitis (14), and inoculations of killed Bordetella pertussis organisms makes some strains of mice 200 times more sensitive to histamine (1) and 3 to 5 times as sensitive to Brucella and Salmonella endotoxins for approximately 14 days (1, 3).
These facts are well documented and when assembled make a reasonable pattern supporting the critical importance of the effects of these various stressors, particularly in the young infant absorbing relatively more endotoxin from the intestinal tract than the more mature, and having less resistance to it.
An infant absorbing abnormally large quantities of endotoxin from the intestinal tract may be "up to the mouth", almost drowning in endotoxin and yet appear apparently normal until the critical threshold is reached. He is able to handle relatively large amounts of endotoxin within limits as long as his reticuloendothelial system is functioning properly and detoxifying adequately. However, when viruses or other stressing factors interfere with the detoxifying process or actions of the RE system, and/or interfere with the normal defense mechanisms of the digestive system to the extent that tremendously increased amounts of endotoxin are being produced in and absorbed from the digestive tract, he is overwhelmed. The result may be a less acute syndrome manifested by diarrhea and the symptoms associated therewith, or by the peracute form manifested by the Sudden Death Syndrome. In both conditions the mechanisms, are the same - they differ only in degree.
Since we can never hope to protect an infant from the many viruses and other environmental stressors with which in the normal course of events he must come in contact, the most practical approach to prevention of the SDS would seem by appropriate diet to maintain him as coliform-free as possible during the period of greatest risk - at least through the first six months of age. This can best be done by breast feeding.OTHER CLINICAL MANIFESTATIONS OF ENDOTOXIN SHOCK:
It is postulated that endotoxemia is the ultimate cause of a large proportion of cases of not only Sudden Death Syndrome, but also of Hyaline Membrane Disease, Infant Diarrhea, Pneumonias of "Obscure" Etiology and Toxemia of Pregnancy. Each of these syndromes is a varying manifestation of endotoxin action resulting from exposure to varying amounts of endotoxin over varying periods of time in hosts of varying susceptibilities.
There is an abundance of experimental and clinical evidence in other mammalian species, as well as in man, to indicate the occurrence and importance of endotoxin absorption. While recognizing the need for further research in this area, perhaps of equal importance is the need to objectively examine presently available evidence. It is difficult to believe that all positive evidence developed in the past is invalid. It is equally difficult to believe that endotoxin absorption, proven so important in the pathogenesis of many diseases of various other mammalian species, does not occur in man. The stakes are too high to continue to ignore this possibility. For if endotoxin absorption is an important factor in the pathogenesis of human disease, knowledge of this fact makes amenable to prevention and treatment of many important diseases now considered obscure.
With the extensive background of information and evidence available, controlled clinical studies may offer the most logical and fruitful area for confirmation and development of further information. Only when persons engaged in the many different areas of disease studies begin to consider it's possible involvement will the full role of endotoxin absorption begin to be adequately assessed. All that is "known" in medicine, and all that is unknown, should be reassessed from the standpoint of this possible involvement.
Since it will probably never be possible to prevent, or even to know, all of the many "adverse contributing factors" which may result in or contribute to the state of endotoxemia, the best hope for prevention and therapy of the various diseases in which endotoxemia is involved would seem by appropriate dietary and chemotherapeutic means to limit amounts of endotoxin produced in and absorbed from the digestive tract.
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