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The administration of small dosages of endotoxin to sheep results in cardiopulmonary changes characterized by an elevation in pulmonary lymph flow, vascular resistance, and hemoconcentration, and a reduction in cardiac output. These changes are not as great when the narcotic antagonist, naloxone (2 mg/kg/h for 5 h), is infused prior to and during the endotoxin response. The present study evaluates the ovine response to endotoxin when naloxone is administered 1 h after the endotoxin infusion. Sheep were prepared by implanting cardiopulmonary and lung lymphatic catheters. One week following the last surgical procedure, the sheep, in the awake state, were given 0.75 micrograms/kg of endotoxin and the variables were measured. Three days later, a second dose of endotoxin was administered and variables were again measured. An infusion of naloxone was given with one of the dosages of lipopolysaccharide. Two dosages of the narcotic antagonist were used. One group received 2 mg/kg bolus + 2 mg/kg/h for 5 h; another group was given twice this amount. Both dosages were started 1 h after endotoxin. The response to endotoxin was essentially the same whether or not the sheep were treated with naloxone. If naloxone pretreatment is effective and posttreatment is not, then it is possible that an opiatelike substance might be released by endotoxin which in turn results in the ultimate release of the lesion-producing substance.

Endotoxin (0.75 micrograms/kg) was administered to unanesthetized sheep with and without premedication with ibuprofen, a cyclooxygenase inhibitor, and diphenhydramine, an antihistamine. The effect of the endotoxin on cardiopulmonary and lung lymph data and their alteration by the drug regimen was assessed. The cardiopulmonary responses to endotoxin can be defined into two phases. In phase I there is an elevation in protein-poor lung lymph flow, in pulmonary artery pressure (PA), and in hematocrit, and a reduction in cardiac index and leukocyte count. Phase II occurs late and shows much the same changes as phase I except that the PA is not as high and the lymph protein is increased. The drug combination (ibuprofen and diphenhydramine) virtually eliminates the phase I response. The phase II changes in lymph flow and protein content are affected by diphenhydramine but not ibuprofen. The cardiovascular changes which occur during this period are not affected by either agent.

Acute burn wound sepsis is a common clinical entity resulting from a showering of the circulation with gram-negative organisms which grow abundantly in the burn. We duplicate this state in our laboratory by creating 40%, third degree burns (anesthetic burns) in chronically instrumented sheep. Three days following the thermal insult, the burn wound is infected by injecting gram-negative organisms (3 X 10(10)) into it. Cardiopulmonary variables and pulmonary lymph flux data are monitored two hours prior to the injection of organisms and for three hours following it. Three different organisms were used in this study; Pseudomonas aeruginosa (N = 12), Escherichia coli (N = 9), and Klebsiella pneumoniae (N = 2). The injection of all three organisms resulted in a similar response; an early marked pulmonary hypertension and a late increase in microvascular permeability. These changes occur concomitantly with an elevation in hematocrit and an early marked fall in neutrophils. The cardiac output gradually falls over the period of observation despite vigorous body shivering associated with a febrile response. The data from the sheep were compared to similarly instrumented animals (N = 12) which were not burned, but received a very small dosage of E coli endotoxin (0.75 micrograms/kg). The cardiopulmonary response was qualitatively identical to that seen with live organisms. However, the quantitative changes in several of the cardiopulmonary variables were much more marked with endotoxin. It is concluded that the cardiopulmonary response noted with burn wound sepsis is produced by endotoxin.

This study compares qualitative and quantitative differences between the cardiopulmonary responses to Salmonella typhimurium and Escherichia coli 055:B5 endotoxins (Difco) in the same sheep model. Lipopolysaccharides, 0.75 micrograms/kg, were infused into chronically instrumented sheep over 30 min. Cardiopulmonary and pulmonary lymph flux data were collected for 2 h prior to and 6 h following this. One week later the sequence was repeated with another endotoxin. The administration of the two endotoxins was varied: some received S. typhimurium first; others received E. coli. A total of 13 animals were studied; 8 had intact pulmonary lymphatic catheters. Following each injection of endotoxin these animals showed a typical response of early high pressure-mediated increase in pulmonary lymph flow and later lymph flow elevation associated with a very mild increase in microvascular pressure and lymph with normal protein levels. These changes were associated with hemoconcentration, lowered arterial oxygen partial pressure, cardiac index, and blood neutrophil count. It is concluded that Difco S. typhimurium and E. coli endotoxins are similar in their mechanism of action and potency and can be studied in the same animal.