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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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Stroke volume index 4 hours after laparotomy and endotoxemia, experiment 2. Stroke volume index decreased significantly throughout the experiment, but no differences were observed between controls and dopexamine-treated animals. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests **P < 0.01, ***P < 0.001 sham compared with controls).
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Figure 7: Stroke volume index 4 hours after laparotomy and endotoxemia, experiment 2. Stroke volume index decreased significantly throughout the experiment, but no differences were observed between controls and dopexamine-treated animals. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests **P < 0.01, ***P < 0.001 sham compared with controls).

Mentions: No statistically significant differences were found between groups in terms of animal weight, dose of anesthetic administered, or volumes of fluid infused at baseline (see Additional file 6, Table S3). Baseline MAP, HR, CI, SVI, and lactate were not significantly different between groups (see Additional file 7, Table S4; Additional file 8, Figure S4; and Additional file 9, Figure S5; Figure 7). In the sham group, CI and SVI increased progressively (Figure 7 and Additional file 9, Figure S5), whereas ileal flux decreased to a mean of 82% of baseline over a 4-hour period (P < 0.05 versus baseline) (Figure 8). In control-group animals, ileal flux also decreased over time, but more rapidly and to levels below those observed in sham animals (P < 0.05 minimum, from 30 minutes onward) (Figure 8). This was associated with a moderate but significant decrease in CI over 4 hours (P < 0.05 versus baseline) and a more-marked decrease in SVI over the same period (P < 0.0005 versus baseline), possibly reflecting the importance of compensatory tachycardia in this model. By 4 hours, control-group plasma lactate (P < 0.01) and base deficit (P < 0.05) were significantly increased compared with sham animals (Additional file 7, Table S4). With regard to organ dysfunction, endotoxemia in experiment 2 also resulted in organ injury, although the changes did not reach statistical significance for AST (see Additional file 10, Table S5).


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)

Stroke volume index 4 hours after laparotomy and endotoxemia, experiment 2. Stroke volume index decreased significantly throughout the experiment, but no differences were observed between controls and dopexamine-treated animals. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests **P < 0.01, ***P < 0.001 sham compared with controls).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Stroke volume index 4 hours after laparotomy and endotoxemia, experiment 2. Stroke volume index decreased significantly throughout the experiment, but no differences were observed between controls and dopexamine-treated animals. Data presented as mean (SEM). Two-way ANOVA (Bonferroni posttests **P < 0.01, ***P < 0.001 sham compared with controls).
Mentions: No statistically significant differences were found between groups in terms of animal weight, dose of anesthetic administered, or volumes of fluid infused at baseline (see Additional file 6, Table S3). Baseline MAP, HR, CI, SVI, and lactate were not significantly different between groups (see Additional file 7, Table S4; Additional file 8, Figure S4; and Additional file 9, Figure S5; Figure 7). In the sham group, CI and SVI increased progressively (Figure 7 and Additional file 9, Figure S5), whereas ileal flux decreased to a mean of 82% of baseline over a 4-hour period (P < 0.05 versus baseline) (Figure 8). In control-group animals, ileal flux also decreased over time, but more rapidly and to levels below those observed in sham animals (P < 0.05 minimum, from 30 minutes onward) (Figure 8). This was associated with a moderate but significant decrease in CI over 4 hours (P < 0.05 versus baseline) and a more-marked decrease in SVI over the same period (P < 0.0005 versus baseline), possibly reflecting the importance of compensatory tachycardia in this model. By 4 hours, control-group plasma lactate (P < 0.01) and base deficit (P < 0.05) were significantly increased compared with sham animals (Additional file 7, Table S4). With regard to organ dysfunction, endotoxemia in experiment 2 also resulted in organ injury, although the changes did not reach statistical significance for AST (see Additional file 10, Table S5).

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