EFFECT OF PHENYTOIN ON ACUTE LUNG INJURIES IN UNANESTHETIZED SHEEP

Objective. To determine if the intravenous administration of phenytoin attenuates or prevents acute experimental lung injury. Design: Placeb o-controlled, longitudinal animal investigative study. Setting. Univer sity research laboratory. Subjects: Sixteen yearling female lambs weig hing 30 +/- 3 kg. Intervention: After administration of anesthesia, th e animals were endotracheally intubated and mechanically ventilated. U sing sterile techniques, four thoracotomies were performed. Through th e left fourth intercostal space, cannulas for pressure measurements we re inserted directly into the main pulmonary artery and left atrium. A n ultrasound flow cuff for determination of cardiac output was placed around the main pulmonary artery. Through the left tenth intercostal s pace, the diaphragmatic and mediastinal parietal pleura were widely ca uterized. Through the right tenth intercostal space, the caudal medias tinal lymph node was identified and divided at the caudal margin of th e right pulmonary ligament, and a 1- to 2-cm portion of the node dista l to the ligament was resected. The diaphragmatic and mediastinal pari etal pleura were widely cauterized. Through the right sixth intercosta l space, the efferent duct (or ducts) was identified, ligated at the s ite of entry into the thoracic duct, and cannulated. The lymph cannula was brought to the outside of the thorax through a separate stab woun d. Measurements and Main Results: Unanesthetized sheep were studied 7 to 10 days after surgery. Hemodynamic, lung fluid balance, and arteria l blood variables were measured in uninjured sheep and in sheep injure d by intravenous infusions of Escherichia coli endotoxin (1 mug/kg iv over 30 mins), air bubbles (0.056 to 0.074 mL/kg/min over 4 hrs), or o leic acid (0.06 mL/kg over 1 hr). The sheep were studied when untreate d and after pretreatment with phenytoin. We found that the expected in crease in protein-rich lung lymph flow with injuries, resulting from i ncreased microvascular permeability in the lungs, was attenuated by ph enytoin when the lungs were injured by endotoxin or air bubbles. In co ntrast, phenytoin had no effect on oleic acid-induced lung injury or o n uninjured lungs. Conclusions. Phenytoin attenuates acute lung injuri es in sheep that are thought to be caused by stimulation of host infla mmatory responses (e.g., endotoxin and air bubbles), but has no effect on direct injuries to the lungs (e.g., oleic acid). A plausible mecha nism for this finding is phenytoin inhibition of polymorphonuclear leu kocyte function.