The pulmonary and systemic response to recurrent endotoxemia in the adult sheep.

The pulmonary and systemic hemodynamic effects of recurrent endotoxemia were studied in the adult sheep with lung lymph fistulas. Six sheep were given 1 mu/kg Escherichia coli endotoxin every 12 hours for 5 days, after which animals were monitored for another 3 days. The pulmonary response to the first three injections was characterized by an initial severe pulmonary hypertension, hypoxia, and a two- to threefold increase in lymph flow, QL. Lymph and plasma thromboxane A2 (TxB2) and prostacyclin (6-keto-PGF1 alpha) levels increased from baseline values of nearly 200 pg/ml to values exceeding 2000 pg/ml. The systemic response to initial doses was characterized by an increase in systemic vascular resistance, a decrease in cardiac index, and a transient 20% increase in oxygen consumption. With later endotoxin doses, the pulmonary response was markedly attenuated, with only modest changes in pulmonary artery pressure, lymph flow, and arterial oxygen tension noted. TxB2 increases were less than 800 pg/ml, and 6-keto-PGF1 alpha levels remained unchanged. However, we noted the progressive onset of a hyperdynamic state characterized by a sustained increase in cardiac index and body temperature, and a 50% increase in oxygen consumption, whereas systemic vascular resistance decreased by 45%. Three days after endotoxin injections were discontinued, the hyperdynamic state (including leukocytosis) was still present, whereas pulmonary variables returned to baseline levels. We conclude that a hyperdynamic state can be produced by repeated doses of endotoxin that will present even after the endotoxin insult is discontinued, which is a characteristic of the multisystem organ failure syndrome.

Endotoxin-induced prostanoid production by the burn wound can cause distant lung dysfunction.

We injected Escherichia coli endotoxin, 2 micrograms/kg, beneath the eschar of sheep with 25% total body surface full-thickness burns to determine whether burn tissue in the presence of endotoxin releases prostanoids, particularly thromboxane A2, (TxA2), and if increased local TxA2 production can lead to distant lung dysfunction. We compared this response to the lung injury produced by the same dose given intravenously. We noted a marked increase in burn tissue TxA2 production after subeschar endotoxin as reflected in significant increases in burn lymph and pulmonary artery TxB2 levels. Pulmonary artery pressure increased from 22 to 38 mm Hg and PaO2 decreased from 89 to 71 torr while lung lymph flow (QL) increased only modestly with no evidence of increased lung permeability. The TxA2 production and the lung response were prevented by the subeschar injection of ibuprofen, 12.5 mg/kg. Circulating endotoxin was noted in only one of five sheep. After intravenous (endotoxin), a significant increase in lung TxA2 production was noted and a characteristic two-phase lung injury was seen with an initial phase basically identical to that seen with the subeschar injection followed by an increase in lung protein permeability. Burn tissue endotoxin can stimulate local TxA2 production leading to distant lung dysfunction without the need for circulating endotoxin. The source of the TxA2 is the burn, while with endotoxemia the source is the lung.