Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock

Satoshi Fukuda, Koji Ihara, Clark R. Andersen, Anita C. Randolph, Christina L. Nelson, Yaping Zeng, Jisoo Kim, Douglas S. Dewitt, Jose D. Rojas, Aristides Koutrouvelis, David N. Herndon, Donald S. Prough, Perenlei Enkhbaatar

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 [1.6-2.5×1011 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 (0.1mg/kg) was followed by a continuous infusion (0.04mg/kg/h). Titration of norepinephrine started at 0.05mcg/kg/min based on their mean arterial pressure. All animals were mechanically ventilated and monitored in the conscious state for 24h. The mean arterial pressure was well maintained in the PDC with significantly less norepinephrine requirement from 7 to 23h 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 18h postinjury were significantly lower in PDC compared with control. PDC improved survival rate at 24h (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.

Original languageEnglish (US)
Pages (from-to)E92-E99
JournalShock
Volume52
Issue number5
DOIs
StatePublished - Nov 1 2019

Fingerprint

Peroxynitrous Acid
Methicillin-Resistant Staphylococcus aureus
Septic Shock
Sheep
Norepinephrine
Reactive Nitrogen Species
Arterial Pressure
Smoke Inhalation Injury
Organ Dysfunction Scores
Resuscitation
Intravenous Injections
Blood Vessels
Sepsis
Therapeutics

Keywords

  • Norepinephrine
  • peroxynitrite decomposition catalyst
  • refractory shock
  • sepsis
  • shock
  • vascular hypo-responsiveness

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Fukuda, S., Ihara, K., Andersen, C. R., Randolph, A. C., Nelson, C. L., Zeng, Y., ... Enkhbaatar, P. (2019). Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock. Shock, 52(5), E92-E99. https://doi.org/10.1097/SHK.0000000000001297

Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock. / Fukuda, Satoshi; Ihara, Koji; Andersen, Clark R.; Randolph, Anita C.; Nelson, Christina L.; Zeng, Yaping; Kim, Jisoo; Dewitt, Douglas S.; Rojas, Jose D.; Koutrouvelis, Aristides; Herndon, David N.; Prough, Donald S.; Enkhbaatar, Perenlei.

In: Shock, Vol. 52, No. 5, 01.11.2019, p. E92-E99.

Research output: Contribution to journalArticle

Fukuda, S, Ihara, K, Andersen, CR, Randolph, AC, Nelson, CL, Zeng, Y, Kim, J, Dewitt, DS, Rojas, JD, Koutrouvelis, A, Herndon, DN, Prough, DS & Enkhbaatar, P 2019, 'Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock', Shock, vol. 52, no. 5, pp. E92-E99. https://doi.org/10.1097/SHK.0000000000001297
Fukuda S, Ihara K, Andersen CR, Randolph AC, Nelson CL, Zeng Y et al. Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock. Shock. 2019 Nov 1;52(5):E92-E99. https://doi.org/10.1097/SHK.0000000000001297
Fukuda, Satoshi ; Ihara, Koji ; Andersen, Clark R. ; Randolph, Anita C. ; Nelson, Christina L. ; Zeng, Yaping ; Kim, Jisoo ; Dewitt, Douglas S. ; Rojas, Jose D. ; Koutrouvelis, Aristides ; Herndon, David N. ; Prough, Donald S. ; Enkhbaatar, Perenlei. / Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock. In: Shock. 2019 ; Vol. 52, No. 5. pp. E92-E99.
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