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

Bangash MN, Patel NS, Benetti E, Collino M, Hinds CJ, Thiemermann C, Pearse RM - Crit Care (2013)

Bottom Line: However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow.In 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.

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ABSTRACT

Introduction: The 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.

Methods: In 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.

Results: Endotoxin 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.

Conclusions: In 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.

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Circulating neutrophil surface CD11b mean fluorescent intensity (MFI) at baseline and 4 hours after laparotomy and endotoxemia (n = 6 controls, n = 8 all others), experiment 1. No significant differences were found between groups at baseline. Dopexamine was associated with smaller increases in D1 and D2 groups compared with controls. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests, **P < 0.01, ***P < 0.001 compared with controls).
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Figure 2: Circulating neutrophil surface CD11b mean fluorescent intensity (MFI) at baseline and 4 hours after laparotomy and endotoxemia (n = 6 controls, n = 8 all others), experiment 1. No significant differences were found between groups at baseline. Dopexamine was associated with smaller increases in D1 and D2 groups compared with controls. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests, **P < 0.01, ***P < 0.001 compared with controls).

Mentions: No statistically significant differences were found between control and other animals in terms of weight, anesthetic dose, volume of fluid administered, HR, MAP, base deficit, or lactate at baseline (see Additional file 1, Table S1). Compared with sham animals, control animals had a significantly higher HR (P < 0.05) at 4 hours and a lower MAP (P < 0.01) compared with baseline at this time (see Additional file 2, Table S2). At this point, plasma lactate (P < 0.001) and base deficit (P < 0.01), neutrophil cell surface CD11b expression (P < 0.001), pulmonary tissue MPO activity (P < 0.01), and plasma TNF-α (P < 0.01), IL-1β (P < 0.01), IL-6 (P < 0.001), and IL-10 (P < 0.05) were also significantly higher in control animals when compared with sham animals (Figures 1, 2, 3, and 4 and Additional file 3, Figure S1). Levels of plasma TNF-α at 1 hour (that is, peak levels) were also significantly higher in control animals (P < 0.001).


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

Bangash MN, Patel NS, Benetti E, Collino M, Hinds CJ, Thiemermann C, Pearse RM - Crit Care (2013)

Circulating neutrophil surface CD11b mean fluorescent intensity (MFI) at baseline and 4 hours after laparotomy and endotoxemia (n = 6 controls, n = 8 all others), experiment 1. No significant differences were found between groups at baseline. Dopexamine was associated with smaller increases in D1 and D2 groups compared with controls. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests, **P < 0.01, ***P < 0.001 compared with controls).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672538&req=5

Figure 2: Circulating neutrophil surface CD11b mean fluorescent intensity (MFI) at baseline and 4 hours after laparotomy and endotoxemia (n = 6 controls, n = 8 all others), experiment 1. No significant differences were found between groups at baseline. Dopexamine was associated with smaller increases in D1 and D2 groups compared with controls. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests, **P < 0.01, ***P < 0.001 compared with controls).
Mentions: No statistically significant differences were found between control and other animals in terms of weight, anesthetic dose, volume of fluid administered, HR, MAP, base deficit, or lactate at baseline (see Additional file 1, Table S1). Compared with sham animals, control animals had a significantly higher HR (P < 0.05) at 4 hours and a lower MAP (P < 0.01) compared with baseline at this time (see Additional file 2, Table S2). At this point, plasma lactate (P < 0.001) and base deficit (P < 0.01), neutrophil cell surface CD11b expression (P < 0.001), pulmonary tissue MPO activity (P < 0.01), and plasma TNF-α (P < 0.01), IL-1β (P < 0.01), IL-6 (P < 0.001), and IL-10 (P < 0.05) were also significantly higher in control animals when compared with sham animals (Figures 1, 2, 3, and 4 and Additional file 3, Figure S1). Levels of plasma TNF-α at 1 hour (that is, peak levels) were also significantly higher in control animals (P < 0.001).

Bottom Line: However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow.In 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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: The 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.

Methods: In 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.

Results: Endotoxin 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.

Conclusions: In 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.

Show MeSH
Related in: MedlinePlus