Fritz B. Schweinburg

Host Resistance in Hemorrhagic Shock. IX. Demonstration of Circulating Lethal Toxin in Hemorrhagic Shock.

Summary and Conclusions I. Normal dogs tolerate an infusion of blood from dogs dying of advanced hemorrhagic shock without noticeable harm. Dogs in hemorrhagic shock recover rapidly and without signs of illness if transfused after 2 hours with normal donor blood, or with their own shed blood. But about 70% of such dogs die if the transfused blood is from dogs dying of prolonged hemorrhagic shock. Most of the recipients that survive, as well as all those that die, are prostrated, unable to stand, drink or take fluid after the transfusion, and display a bloody diarrhea until recovery or death. Only 37% of the 2 hour shock recipients of blood from dogs in prolonged shock die if the latter have been vigorously pretreated with non-absorbable antibiotics given orally and by rectum. The survivors, moreover, recover rapidly and disclose no signs of illness. Hence the blood of dogs in prolonged hemorrhagic shock contains a lethal toxin, which, for the reasons given, is considered to be an exogenous toxin derived from the intestinal flora. By the same token endogenous toxins, whether present or not, are not responsible for irreversibility to transfusion or death. II. The same findings are also true for the rabbit: The mortality rate of recipients of blood from untreated donors was 91%, while the mortality rate of recipients of blood from pretreated donors was only 7%. The greater tolerance to prolonged shock of animals pretreated with non-absorbable antibiotics appears to be due to the elimination of bacterial endotoxins by the antibiotics. III. The hemorrhagic lesion in the gut of shocked animals is produced by the toxin and not by the shock itself.

Transmural Migration of Intestinal Bacteria During Peritoneal Irrigation in Uremic Dogs.

Summary and Conclusions Repeated intraperitoneal infusion of the fluid used for peritoneal irrigation in uremic patients, administered aseptically to healthy rabbits and dogs for 11-16 days, produced a moderate leukocytic response, but the peritoneum remained free of bacteria or visible inflammatory reaction. In uremic dogs, however, bacterial contamination of the peritoneal fluid developed after the 4th day of irrigation. The micro-organisms found were E. coli alone or with A. aerogenes. Occasionally, several other species, normally found in the intestine, appeared; but Clostridia were never found. Preliminary oral administration of streptomycin and sulfathalidine prevented contamination of the peritoneal fluid. Blood cultures were uniformly sterile throughout the period of observation, It is concluded that irrigation of the peritoneal cavity of uremic dogs causes transmural migration of intestinal bacteria and that oral chemotherapy can prevent such contamination.

Resistance to Bacteria in Hemorrhagic Shock. II. Effect of Transient Vascular Collapse on Sensitivity to Endotoxin.

Summary and Conclusion Rabbits transfused after one to 2 hours in hemorrhagic shock nearly always recover. During the immediate post transfusion recovery phase the sensitivity to a purified E. colt toxin is increased 100,000 times normal. Return to normal tolerance to the endotoxin requires about 48 hours.

Bacteriology of the Healthy Experimental Animal

Conclusions 1) The organs of normal rats, guinea pigs and golden hamsters are sterile. Blood from vena cava, bile and urine of normal dogs and rabbits was always sterile. Most of the tissues of healthy dogs, and rabbits to a lesser degree, harbor Clostridia. The embryos of healthy dogs are sterile. 2) The great majority of the strains recovered from the tissues of dogs and rabbits show all the morphological and cultural characteristics of Cl. welckii (perfringens). Toxin production, though weak, was demonstrated.

Host resistance to bacteria in hemorrhagic shock. VI. Effect of endotoxin on antibacterial defense.

Summary and conclusions 1. The mortality rate from one intravenous MLD/100 of endotoxin was reduced from 100% to 40-60% by antibiotic therapy given prior to or at the time of injecting the endotoxin. This was true even if the antibiotic was given orally and was completely non-absorbable. Therefore, endotoxins from intraintestinal bacteria are involved in the death from an intravenous MLD/100 of endotoxin. Data are given to show that antibiotics act solely as antibacterial agents, and not as anti-endotoxic agents. 2. A sublethal intravenous dose of endotoxin promptly induced in rabbits an increased sensitivity to a supplementary fractional dose of endotoxin so that a second dose given one hour later increased the mortality from zero to 67%, even though the total of both doses, if given as a single initial dose, was not lethal. Recovery of nearly normal resistance to the second dose of endotoxin required about 4 hours. Antibiotics given with the initial dose rendered the second dose harmless; but the same antibiotics given with the second dose did not prevent death. Therefore, it is inferred that death from the second dose involved the production of additional endotoxin. 3. Reasons are given for inferring that similar phenomena operate in hemorrhagic shock and account for the development of irreversi-bility to transfusion.

Host resistance in hemorrhagic shock XV. Isolation of toxic factor from hemorrhagic shock plasma.

Summary 1) Previous observations on the toxicity of plasma from animals in irreversible hemorrhagic shock were confirmed and extended by the isolation of a toxic polysaccharide fraction from this plasma which cannot be isolated, under identical conditions, from normal plasma. The ability of this polysaccharide fraction to elicit responses characteristic of bacterial endotoxins, and to convert the reversible to the irreversible state of hemorrhagic shock has been demonstrated. The ability of bacterial endotoxins, in turn, to elicit the lesions characteristic of shock, was reviewed. 2) Although the entire quantity of toxic polysaccharide circulating in the irreversibly shocked animal is innocuous to a normal animal, only a fraction of the total is sufficient to inflict lethal injury to an animal with its defenses already depleted by reversible shock. The mounting evidence for the presence of endotoxemia in shock provides a logical basis for incriminating the loss of functional integrity of the R.E. system in the development of irreversibility to transfusion in hemorrhagic shock, and for an understanding of the phenomenon of variation in resistance to shock under different conditions. The development of irreversibility to transfusion in hemorrhagic shock in the germ-free animal is discussed in the light of these considerations.

Resistance to Bacteria in Hemorrhagic Shock. I. Decline in Phagocytosis-Promoting Capacity of Serum in Shock.

Summary During the course of severe hemorrhagic shock in dogs there is no change in the total and differential leucocytic count or in the hemolytic activity of complement in vitro. But the phagocytosis-promoting activity of the serum is considerably reduced.

Effect of Oral Neomycin on Normal Intestinal Flora of Dogs and Man

Summary 1. Ten random strains of each of the following species were sensitive in vitro (3 exceptions in 40 cultures) to 6.2 μg/cc or less of neomycin in a 48-hour nutrient broth culture: E. coli, A. aerogenes, Pseudomonas aeruginosa, B. proteus vulgaris, Hemolytic staphylococcus aureus and Hemolytic streptococcus. In 5 strains of enterococci the range of sensitivity was 25-3.2 μg neomycin/cc, while Clostridia were not sensitive at a concentration of 200 μg/cc or higher. When neomycin is effective, its antibacterial action is bactericidal and not bacteriostatic under the conditions of the test(8). 2. Oral administration of neomycin usually eliminates coliform bacilli from stool cultures in dogs and in man within 48 hours and frequently within 24 hours. Continuation of the drug for 5-6 days resulted in the appearance of resistant strains of E. coli in dogs. Such resistance was not observed in 25 humans. 3. The numbers of Enterococci, Ps. aeruginosa, and B. proteus vulgaris in the stool are reduced in most cases by oral neomycin therapy. 4. Clostridia are not noticeably affected by neomycin.

Aureomycin in urinary infections due to gram negative organisms.

Summary 1. Aureomycin is highly effective against many strains of gram-negative bacilli in vitro, including many which were found to be resistant to sulfonamides, penicillin, and streptomycin. The sensitivity of various strains of a given species, however, varies greatly. 2. Clinical trial in 10 patients with urinary infections which were refractory to previous treatment with other antibiotics, resulted in a clinical cure of all ten patients. Bacteriologically eight patients were cured, and 2 were markedly improved.

Effect of hemorrhagic shock on viability of invading bacteria.

Summary and Conclusions Gram-positive bacteria can be grown from the mesenteric nodes and liver of the normal rabbit and dog. Gram-negative bacteria can be grown from these tissues of the normal dog, but not of the normal rabbit. Gram-negative bacteria are found in the nodes and liver of the rabbit some hours after exposure of the rabbit to 2 hours of hemorrhagic shock. The incidence is higher 8 hours afterward than it is 4 hours afterward. These data confirm the view that bacteria are continuously invading from the intestine. Exposure for 2 hours to hemorrhagic shock so weakens the antibacterial defense that gram-negative as well as gram-positive bacteria can be grown out more readily than in the normal animal. However, the number of bacteria that can be recovered is judged too small to be a significant contribution to the endotoxemia of advanced hemorrhagic shock. Reasons are given for also excluding the bacteria normally found in the groin wound, made for cannulating the femoral vessels, from any significant role in the endotoxemia.