Effects of tempol, a free radical scavenger, on long-term hyperdynamic porcine bacteremia.
OBJECTIVE
Pretreatment with tempol, a membrane-permeable radical scavenger, has been shown to be protective in rodent models of endotoxic and Gram-positive shock. However, neither the pretreatment design nor hypodynamic endotoxic shock in rodents mimics the clinical scenario. Therefore, we investigated the effects of tempol in a posttreatment model of long-term, volume-resuscitated, hyperdynamic porcine bacteremia.


METHODS
Prospective, randomized, controlled experimental study.


METHODS
University animal laboratory.


METHODS
Sixteen anesthetized, mechanically ventilated, and instrumented pigs.


METHODS
Sepsis was induced and maintained for 24 hrs with continuous infusion of live Pseudomonas aeruginosa. After 12 hrs of hyperdynamic sepsis, animals were randomized to receive either vehicle (control, n = 8) or continuous infusion of tempol (n = 8, 30 mg/kg/hr).


RESULTS
Systemic and hepatosplanchnic hemodynamics, oxygen exchange, metabolism, ileal mucosal microcirculation, and tonometry as well as oxidative stress and coagulation variables were assessed before and after 12, 18, and 24 hrs of P. aeruginosa infusion. Tempol significantly attenuated reduction in mean arterial pressure. Despite comparable mesenteric macrocirculation, tempol attenuated the otherwise progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. By contrast, treatment with tempol failed to influence the P. aeruginosa-induced derangements of hepatosplanchnic redox state, liver lactate clearance, and regional acidosis but prevented the development of renal dysfunction. In addition, tempol reduced nitrosative stress without significant effect on the gradual increase in plasma 8-isoprostanes. Finally, tempol attenuated sepsis-induced endothelial (von Willebrand factor) and hemostatic dysfunction (thrombin-antithrombin complexes, plasminogen activator inhibitor-type 1).


CONCLUSIONS
The radical scavenger tempol partially prevented live bacteria from causing key features of hemodynamic and metabolic derangements in porcine hyperdynamic sepsis and beneficially affected surrogate markers of sepsis-induced endothelial and coagulation dysfunction. Incomplete reduction of oxidative stress because of dilutional effects and/or missed optimal therapeutic window for antioxidant treatment when used in posttreatment approach may account for the only partial protection by tempol in this model.
Matejovic
Martin
M
Intensive Care Unit, First Medical Department, Charles University Medical School and Teaching Hospital, Plzen, Czech Republic.
Krouzecky
Ales
A
Martinkova
Vendula
V
Rokyta
Richard
R
Radej
Jaroslav
J
Kralova
Hana
H
Treska
Vladislav
V
Radermacher
Peter
P
Novak
Ivan
I
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001777:Blood Coagulation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D004734:Energy Metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D013113:Spin Labels; D013552:Swine
D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; C001803:tempol