NITRIC-OXIDE INHIBITION IN THE TREATMENT OF THE SEPSIS SYNDROME IS DETRIMENTAL TO TISSUE OXYGENATION

The manifestations of the septic syndrome are thought to be mediated b y cytokines through their role in the production of nitric oxide (NO). It is hypothesized that the inhibition of NO production with an inhib itor such as N-G-monomethyl-L-arginine (L-NMMA) may be beneficial in t he treatment of septic shock. Sepsis was induced by the intravenous ad ministration of Escherichia coli endotoxin (60 mu g/kg) in six conditi oned mongrel dogs (20-24 kg). Mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and pulmonary artery pressure (P AP) were continuously monitored. Cardiac output (CO), pulmonary capill ary wedge pressure (PCWP), and arterial and mixed venous blood gases w ere obtained every 10 min. When the MAP decreased below 60 mm Hg, NO i nhibitor L-NMMA was given by intravenous injection (25 mg/kg). Physiol ogic parameters were then measured at 2 and 5 min after L-NMMA injecti on. Subsequently, L-arginine (400 mg/kg), the substrate for the NO syn thase enzyme, was administered and measurements were repeated at simil ar intervals. L-NMMA in septic canines produced a significant increase in MAP and SVR with a significant decrease in CO and tissue oxygenati on (DO2 and VO2). These changes were reversed with the administration of L-arginine. There were no significant differences in the PCWP, CVP, PAP, or HR throughout the entire study. These results suggest that th e inhibition of NO production by L-NMMA in a septic model produces ele vated MAP and SVR at the expense of tissue oxygenation. Thus, its use, as a principal means of therapy for the septic syndrome, may not be a ppropriate because of detrimental effects on tissue oxygenation. (C) 1 994 Academic Press, Inc.