Vascular hypo-responsiveness to vasopressors during
septic shock is a challenging problem. This study is to test the hypothesis that
reactive nitrogen species (RNS), such as
peroxynitrite, are major contributing factors to vascular hypo-responsiveness in
septic shock. We hypothesized that adjunct
therapy with
peroxynitrite decomposition catalyst (PDC) would reduce
norepinephrine requirements in
sepsis resuscitation. Fourteen female Merino sheep were subjected to a "two-hit"
injury (smoke inhalation and endobronchial instillation of live methicillin-resistant Staphylococcus aureus [1.6-2.5 × 10 CFUs]). The animals were randomly allocated to control: injured, fluid resuscitated, and titrated
norepinephrine, n = 7; or PDC: injured, fluid resuscitated, titrated
norepinephrine, and treated with PDC, n = 7. One-hour postinjury, an
intravenous injection of PDC (0.1 mg/kg) was followed by a continuous infusion (0.04 mg/kg/h). Titration of
norepinephrine started at 0.05 mcg/kg/min based on their mean arterial pressure. All animals were mechanically ventilated and monitored in the conscious state for 24 h. The mean arterial pressure was well maintained in the PDC with significantly less
norepinephrine requirement from 7 to 23 h after injury compared with control. Total
norepinephrine dose, the highest
norepinephrine rate, and time on
norepinephrine support were also significantly lower in PDC. Modified sheep organ failure assessment scores at 6 to 18 h postinjury were significantly lower in PDC compared with control. PDC improved survival rate at 24 h (71.4% vs. 28.6%). PDC treatment had no adverse effects. In conclusion, the modulation of RNS may be considered an effective adjunct
therapy for
septic shock, in the case of hypo-responsiveness to
norepinephrine.