Effect of phenytoin on acute lung injuries in unanesthetized sheep

To determine if the intravenous administration of phenytoin attenuates or prevents acute experimental lung injury.

Placebo-controlled, longitudinal animal investigative study.

University research laboratory.

Sixteen yearling female lambs weighing 30 +/- 3 kg.

After administration of anesthesia, the animals were endotracheally intubated and mechanically ventilated. Using sterile techniques, four thoracotomies were performed. Through the left fourth intercostal space, cannulas for pressure measurements were inserted directly into the main pulmonary artery and left atrium. An ultrasound flow cuff for determination of cardiac output was placed around the main pulmonary artery. Through the left tenth intercostal space, the diaphragmatic and mediastinal parietal pleura were widely cauterized. Through the right tenth intercostal space, the caudal mediastinal lymph node was identified and divided at the caudal margin of the right pulmonary ligament, and a 1- to 2-cm portion of the node distal to the ligament was resected. The diaphragmatic and mediastinal parietal pleura were widely cauterized. Through the right sixth intercostal space, the efferent duct (or ducts) was identified, ligated at the site of entry into the thoracic duct, and cannulated. The lymph cannula was brought to the outside of the thorax through a separate stab wound.

Unanesthetized sheep were studied 7 to 10 days after surgery. Hemodynamic, lung fluid balance, and arterial blood variables were measured in uninjured sheep and in sheep injured by intravenous infusions of Escherichia coli endotoxin (1 microgram/kg iv over 30 mins), air bubbles (0.056 to 0.074 mL/kg/min over 4 hrs), or oleic acid (0.06 mL/kg over 1 hr). The sheep were studied when untreated and after pretreatment with phenytoin. We found that the expected increase in protein-rich lung lymph flow with injuries, resulting from increased microvascular permeability in the lungs, was attenuated by phenytoin when the lungs were injured by endotoxin or air bubbles. In contrast, phenytoin had no effect on oleic acid-induced lung injury or on uninjured lungs.

Phenytoin attenuates acute lung injuries in sheep that are thought to be caused by stimulation of host inflammatory responses (e.g., endotoxin and air bubbles), but has no effect on direct injuries to the lungs (e.g., oleic acid). A plausible mechanism for this finding is phenytoin inhibition of polymorphonuclear leukocyte function.