Dopexamine can attenuate the inflammatory response and protect against organ injury in the absence of significant effects on hemodynamics or regional microvascular flow

Abstract

IntroductionThe effects of dopexamine, a β2-agonist, on perioperative and sepsis-related hemodynamic, microvascular, immune, and organ dysfunction are controversial and poorly understood. We investigated these effects in a rodent model of laparotomy and endotoxemia.MethodsIn two experiments, 80 male Wistar rats underwent laparotomy. In 64 rats, this was followed by administration of endotoxin; the remainder (16) underwent sham endotoxemia. Endotoxemic animals received either dopexamine at 0.5, 1, or 2 μg/kg/min or 0.9% saline vehicle (controls) as resuscitation fluid. The effects of dopexamine on global hemodynamics, mesenteric regional microvascular flow, renal and hepatic function and immune activation were evaluated.ResultsEndotoxin administration was associated with a systemic inflammatory response (increased plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, as well as cell-adhesion molecules CD11a and CD11b), and increased pulmonary myeloperoxidase (MPO) activity (indicating pulmonary leukocyte infiltration), whereas biochemical changes demonstrated lactic acidosis with significant renal and hepatic injury. Dopexamine administration was associated with less-severe lactic acidosis (pooled dopexamine versus controls, (lactate, 2.2 mM ± 0.2 mM versus 4.0 mM ± 0.5 mM; P < 0.001) and reductions in the systemic inflammatory response (pooled dopexamine versus control, 4 hour (TNF-α): 324 pg/ml ± 93 pg/ml versus 97 pg/ml ± 14 pg/ml, p < 0.01), pulmonary myeloperoxidase (MPO) activity, and hepatic and renal injury (pooled dopexamine versus control (ALT): 81 IU/L ± 4 IU/L versus 138 IU/L ± 25 IU/L; P < 0.05; (creatinine): 49.4 μM ± 3.9 μM versus 76.2 μM ± 9.8 μM; P < 0.005). However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow.ConclusionsIn this model, dopexamine can attenuate the systemic inflammatory response, reduce tissue leukocyte infiltration, and protect against organ injury at doses that do not alter global hemodynamics or regional microvascular flow. These findings suggest that immunomodulatory effects of catecholamines may be clinically significant when used in critically ill surgical patients and are independent of their hemodynamic actions.

A randomized controlled trial on the effects of goal-directed therapy on the inflammatory response open abdominal aortic aneurysm repair

“…In a mouse endotoxin model, levels of tumor necrosis factor (TNF)-α were lower in animals given dopexamine to improve global blood flow when compared with controls [ 15 ]. This decrease in TNF-α in the dopexamine group occurred despite similar SVI.…”

Monitoring Needs and Goal-directed Fluid Therapy Within an Enhanced Recovery Program

“…31 Positive outcomes may be caused by beta-agonist drugs having beneficial antiinflammatory and other metabolic effects. 53 A much larger multicentre RCT investigating this premise further is currently being set up by the OPTIMISE investigating group, but this will take at least 5 years to produce answers. Another interpretation of the results is that it is 6 postoperative hours of close attention that pays dividends.…”

Dopexamine: immunomodulatory, hemodynamic, or both?

“…Dopexamine reduced the systemic inflammatory response to endotoxin, including cytokine release, endothelial adhesion molecules, and oxidative stress, without substantially changing systemic hemodynamics, either blood pressure or stroke volume [1]. Regional flow, assessed by laser Doppler in the mesenteric circulation, was also not changed by dopexamine - yet lactate levels and organ function were improved [1]. The authors concluded that beneficial effects of dopexamine may result from immune modulation.…”

“…Animal studies are most useful when they illuminate clinical issues. The report in the previous issue of Critical Care by Bangash and colleagues is one such study [1]. …”