Detrimental Hemodynamic Effects of Nitric Oxide Synthase Inhibition in Septic Shock

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Abstract
Objective: To investigate the physiologic effects of nitric oxide synthase inhibition with N-nitro-l-arginine methyl ester in an acute resuscitated model of porcine septic shock. Design: Randomized control trial. Setting: Animal research facility. Study Subjects: Domestic Yorkshire swine. Interventions: Twenty-four animals were randomly divided into one of four treatment groups as follows: normal saline resuscitation (NSR) (control group); NSR plus 200 μg/kg of lipopolysaccharide (LPS) at 1 hour after baseline (LPS group); NSR, LPS, and a continuous infusion of 50 μg/kg per minute of N-nitro-l-arginine methyl ester (NAME) at 1 hour after baseline (LPS/NAME group); and NSR and NAME (NAME group). All animals received NSR at 1 mL/kg per minute starting at baseline. Main Outcome Measures: Mean arterial pressure (MAP), systemic vascular resistance index (SVRI), mean pulmonary arterial pressure (MPAP), and pulmonary vascular resistance index (PVRI) were measured at baseline and hourly for 4 hours. Values at baseline and 3 hours are given below as mean (±SE). Results: All variables remained unchanged in the control group. The administration of LPS produced a systemic hyperdynamic response characterized by a decrease in MAP and SVRI from 66.0±3.9 to 55.0±2.8 mm Hg (P<.05) and from 422.0±22.0 to 272.0±29.0 mm Hg.min.kg/L (P<.05), respectively. The administration of LPS produced an increase in MPAP and PVRI from 16.3±0.8 to 30.0±1.3 mm Hg (P<.05) and from 37.0±5.3 to 119.0±13.0 mm Hg.min.kg/L (P<.05), respectively. In the LPS/NAME group, NAME infusion normalized MAP and increased SVRI from 506.0±40.0 to 642.0±72.0 mm Hg.min.kg/L (P<.05). Infusion of NAME potentiated LPS-induced pulmonary hypertension, increasing MPAP and PVRI from 16.8±0.6 to 36.0±2.8 mm Hg (P<.05) and from 59.0±3.5 to 319.0±64.0 mm Hg.min.kg/L (P<.05), respectively. Infusion of NAME alone increased MAP from 74.0±1.3 to 100.0±4.1 mm Hg (P<.05) and had no significant effect on MPAP and PVRI. Conclusions: The potentiation of LPS-induced pulmonary hypertension following NAME infusion suggests that inhibition of nitric oxide synthase may have a limited role in the treatment of septic shock. (Arch Surg. 1994;129:149-156)