Peroxynitrite decomposition catalyst reduces vasopressin requirement in ovine MRSA sepsis

Abstract

Background: Sepsis is one of the most frequent causes of death in the intensive care unit. Host vascular hypo-responsiveness to vasopressors during septic shock is one of the challenging problems. This study tested the hypothesis that adjunct therapy with peroxynitrite decomposition catalyst (WW-85) would reduce arginine vasopressin (AVP) requirements during sepsis resuscitation, using ovine sepsis model.

Methods: Thirteen adult female Merino sheep, previously instrumented with multiple vascular catheters, were subjected to "two-hit" (cotton smoke inhalation and intrapulmonary instillation of live methicillin-resistant Staphylococcus aureus; 3.5 × 10¹¹ colony-forming units) injury. Post injury, animals were awakened and randomly allocated to the following groups: (1) AVP: injured, fluid resuscitated, and titrated with AVP, n = 6 or (2) WW-85 + AVP: injured, fluid resuscitated, treated with WW-85, and titrated with AVP, n = 7. One-hour post injury, a bolus intravenous injection of WW-85 (0.1 mg/kg) was followed by a 23-h continuous infusion (0.02 mg/kg/h). Titration of AVP started at a dose of 0.01 unit/min, when mean arterial pressure (MAP) decreased by 10 mmHg from baseline, despite aggressive fluid resuscitation, and the rate was further adjusted to maintain MAP. After the injury, all animals were placed on a mechanical ventilator and monitored in the conscious state for 24 h.

Results: The injury induced severe hypotension refractory to aggressive fluid resuscitation. High doses of AVP were required to partially attenuate the sepsis-induced hypotension. However, the cumulative AVP requirement was significantly reduced by adjunct treatment with WW-85 at 17-24 h after the injury (p < 0.05). Total AVP dose and the highest AVP rate were significantly lower in the WW-85 + AVP group compared to the AVP group (p = 0.02 and 0.04, respectively). Treatment with WW-85 had no adverse effects. In addition, the in vitro effects of AVP on isolated artery diameter changes were abolished with peroxynitrite co-incubation.

Conclusions: The modulation of reactive nitrogen species, such as peroxynitrite, may be considered as a novel adjunct treatment option for septic shock associated with vascular hypo-responsiveness to vasopressors.

Keywords: Arginine vasopressin; Peroxynitrite decomposition catalyst; Refractory shock; Septic shock; Vascular hypo-responsiveness; WW-85.

Fig. 1

Mean arterial pressure (MAP) and cumulative requirement of arginine vasopressin (AVP) with or without peroxynitrite decomposition catalyst (WW-85) treatment on MRSA-induced septic shock. a Changes in MAP in the two groups. b Cumulative requirement of AVP to maintain MAP in the two groups. Closed circles represent the AVP group animals. Open circles represent the WW-85 + AVP group animals. Data are expressed as mean ± SEM (*p < 0.05 vs. AVP group)

Fig. 2

Effects of peroxynitrite decomposition catalyst (WW-85) on requirement of arginine vasopressin (AVP) in MRSA-induced septic shock. a The highest AVP rate (unit/min) in the two groups (p = 0.04 between the two groups). b Total AVP requirement (unit/BW kg) in the two groups (p = 0.02 between the two groups). Data are expressed as mean ± SEM

Fig. 3

Cardiac output, left atrial pressure, and systemic vascular resistance index changes from the baseline in the two groups. a Cardiac output had significant differences between the two groups from 18 to 24 h post-injury (*p < 0.05 vs. AVP group). b Left atrial pressure had significant differences between the two groups at 24 h post-injury (*p < 0.05 vs. AVP group). c Systemic vascular resistance index changes from the baseline had significant differences between the two groups at 24 h post-injury (*p < 0.05 vs. AVP group). Closed circles represent the AVP group animals. Open circles represent the WW-85 + AVP group animals. Data are expressed as mean ± SEM

Fig. 4

Total fluid input, total urine output, and net fluid balance in the two groups. a Total fluid input and b total urine output at 24 h had no significant differences between the two groups. c Net fluid balance had significant differences between the two groups at 24 h post-injury (p < 0.05). Closed circles represent the AVP group animals. Open circles represent the WW-85 + AVP group animals. Data are expressed as mean ± SEM

Fig. 5

Plasma protein concentration and blood lactate concentration in two groups. a Plasma protein concentration had significant differences between two groups at 15 h and 21–24 h post-injury (p < 0.05). b Blood lactate concentration had significant differences between the two groups at 18 h post-injury (p < 0.05). Closed circles represent the AVP group animals. Open circles represent the WW-85 + AVP group animals. Data are expressed as mean ± SEM

Fig. 6

Isolated small artery diameter measurement. The contraction rate of small arteries (isolated from healthy sheep mesentery) after arginine vasopressin (AVP) administration was significantly reduced after peroxynitrite exposure compared to no peroxynitrite exposure (p = 0.03). Data are expressed as mean ± SEM