PubMed1994
PURPOSE: In these investigations, three questions were addressed. First, to what extent did inhibition of endothelium-derived relaxation factor (EDRF) mimic the hemodynamic disturbances noted in a piglet model of neonatal group B streptococcal (GBS) sepsis? Second, to what extent would an attempt to augment EDRF production reverse the hemodynamic effects of continued GBS infusion in septic piglets? Third, to what extent would an attempt to augment EDRF production affect hemodynamics in piglets who were not septic. METHODS: Six experimental protocols were studied in a total of 25 piglets. The extent to which inhibition of EDRF resembled GBS sepsis was determined by comparing hemodynamic observations during (1) EDRF inhibition (using a competitive inhibitor of nitric oxide synthase, N-nitro-L-arginine [NNLA], 80 mg/kg) with (2) GBS infusion. Next, the extent to which an attempt to augment EDRF production would reverse hemodynamic effects of neonatal GBS sepsis was addressed by comparing hemodynamic observations during (3) administration of pharmacological doses (300 mg/kg) of the EDRF precursor L-arginine (L-ARG) in piglets receiving continuous GBS infusion with (4) continuous GBS infusion in piglets who did not receive L-ARG. Finally, to provide an additional comparison for the protocols described above, the effects of (5) L-ARG in piglets pretreated with NNLA were compared with (6) L-ARG infusion in normal piglets, who had received neither GBS nor NNLA. RESULTS: Both NNLA and GBS increased systemic and pulmonary vascular resistance and decreased systemic cardiac output. For equivalent reductions in cardiac output, GBS preferentially vasoconstricted the pulmonary versus systemic circulation, whereas NNLA produced equivalent vasoconstriction in both circulations. During continuous GBS infusion, L-ARG attenuated the progressive increase in systemic and pulmonary vascular resistance, pulmonary artery pressure, and pulmonary vascular resistance/systemic vascular resistance. L-ARG infusion in nonseptic, non-NNLA-treated piglets had no significant effect on any hemodynamic variable. L-ARG infusion in piglets pretreated with NNLA restored hemodynamic values towards those of piglets treated with L-ARG alone. CONCLUSIONS: EDRF inhibition with NNLA appeared to model GBS infusion partially but not completely. L-ARG appeared to produce desirable hemodynamic effects during GBS sepsis when compared with the consequences of ongoing GBS infusion without L-ARG. Given the constellation of increased pulmonary and systemic vascular resistance often observed during neonatal GBS sepsis in human infants, all these effects of L-ARG, if extrapolated from our piglets to the clinical arena, would appear to be beneficial. Particularly in the context of deleterious consequences resulting shunting or right ventricular decompensation from increased afterload), L-ARG administration might prove clinically useful.