DELAYED ADMINISTRATION OF INHALED NITRIC-OXIDE PRESERVES ALVEOLAR-CAPILLARY MEMBRANE INTEGRITY IN PORCINE GRAM-NEGATIVE SEPSIS

Objective: To determine the effect of delayed administration of inhale d nitric oxide (NO) on acute lung injury after the onset of gram-negat ive sepsis. Design: Nonrandomized controlled study. Setting: Universit y medical center laboratory. Subjects: Yorkshire swine. Interventions: Five groups of swine were anesthetized, mechanically ventilated, and studied for 5 hours. After surgical preparation, control (n=10) and NO -treated control (n=6) animals received a 1-hour infusion of sterile s aline solution. Sepsis was induced with a 1-hour intravenous infusion of live Pseudomonas aeruginosa. Untreated animals with sepsis (n=10) r eceived no treatment. Inhaled NO at 20 ppm was administered to NO30-tr eated animals with sepsis (n=7) and NO60-treated animals with sepsis ( n=8) beginning at 30 and 60 minutes after bacterial infusion was begun , respectively. Main Outcome Measures: Systemic and pulmonary hemodyna mics, arterial blood gas determination, bronchoalveolar lavage protein and neutrophil content, neutrophil oxidant burst, lung myeloperoxidas e content, and scanning electron micrographic studies. Results: A prog ressive, significant (P<.05) decline in PaO2 developed in untreated an imals with sepsis, which was prevented in NO30- and NO60-treated anima ls with sepsis. A significant (P<.05) increase in bronchoalveolar lava ge protein and neutrophil counts compared with baseline values was obs erved in untreated animals with sepsis, indicating acute lung injury. These variables exhibited no notable increase in NO30- and NO60-treate d animals with sepsis and were significantly (P<.05) reduced compared with untreated animals with sepsis. The lung myeloperoxidase content w as significantly (P<.05) elevated at 5 hours in all groups with sepsis compared with baseline values and the control and NO-treated control groups. The total phorbol myristate acetate-induced polymorphonuclear leukocyte oxidant burst at 5 hours was significantly (P<.05) decreased in the NO30- and NO60-treated animals with sepsis compared with untre ated animals with sepsis. Untreated and NO30- and NO60-treated animals with sepsis showed a significant (P<.05) increase in pulmonary artery pressure at 30 minutes, followed by a progressive decline. These chan ges were significant (P<.05) compared with baseline values and the con trol groups. No significant (P<.05) difference in pulmonary artery pre ssure or systemic arterial pressure was found at any time between untr eated and NO30- and NO60-treated animals with sepsis. Conclusions: The delayed administration of inhaled NO preserves alveolar-capillary mem brane integrity in this porcine model of gram-negative sepsis. The inh ibition of neutrophil transendothelial migration, rather than neutroph il rolling or tight adhesion, may be a critical mechanism by which inh aled NO produces this effect. Decreased oxidant production by activate d neutrophils may be a secondary mechanism by which inhaled NO reduces acute lung injury.