Dose-related effects of dexmedetomidine on immunomodulation and mortality to septic shock in rats

Abstract

Background: Dexmedetomidine has already been used in septic patients as a new sedative agent, few studies have examined its effects on immunomodulation. Therefore, the authors have designed a controlled experimental study to characterize the immunomodulation effects of dexmedetomidine in the cecal ligation and puncture (CLP) model in rats.

Methods: After CLP, 48 Wistar rats were randomly allocated into four groups: (1) CLP group; (2) small-dose treatment group (2.5 μg·kg-1·h-1); (3) medium-dose treatment group (5.0 μg·kg-1· h-1); and (4) large-dose treatment group (10.0 μg·kg-1·h-1). HLA-DR and plasma cytokine (IL-4, IL-6, IL-10 and TNF-α) levels were measured, and the mean arterial blood pressure (MAP), heart rate (HR), arterial blood gases, lactate concentrations and mortality were also documented.

Results: The HLA-DR level, inflammatory mediator levels, MAP and HR had no obvious changes among Dexmedetomidine treatment groups (DEX groups). Compared with the CLP group, the DEX groups exhibited decreased HLA-DR levels (Pgroup=0.0202) and increased IL-6 production, which was increased at 3 h (P= 0.0113) and was then attenuated at 5 h; additionally, the DEX groups exhibited decreased HR (P<0.001) while maintaining MAP (Pgroup=0.1238), and remarkably improving lactate (P<0.0001). All of these factors led to a significant decrease in the mortality, with observed rates of 91.7%, 66.7%, 25% and 18% for the CLP, DEX2.5, DEX5.0, DEX10.0 groups, respectively.

Conclusion: Dexmedetomidine treatment in the setting of a CLP sepsis rat model has partially induced immunomodulation that was initiated within 5 h, causing a decreased HR while maintaining MAP, remarkably improving metabolic acidosis and improving mortality dose-dependently.

Keywords: Dexmedetomidine; Immunomodulation; Septic shock.

Conflict of interest statement

Conflicts of interests: The authors declare that they have no competing interests. The funders had no role in the design, conduct, analysis, or interpretation of data or in writing the manuscript.

Figures

Figure 1

HLA-DR during the experimental period. Note that a significant difference was observed between four groups (Pgroup=0.0202). HLA-DR values (given as means±SD) were measured at 1 hour (1 h), 3 hours (3 h) and 5 hours (5 h) of normal saline or dexmedetomidine infusion. CLP: cecal ligation and puncture, normal saline treated (n=12); DEX2.5: cecal ligation and puncture, dexmedetomidine treated, 2.5 mg·kg-1·h-1 infusion (n=12); DEX5.0: cecal ligation and puncture, dexmedetomidine treated, 5.0 mg·kg-1·h-1 infusion (n=12); DEX10.0: cecal ligation and puncture, dexmedetomidine treated, 10.0 mg·kg-1·h-1 infusion (n=12).

Figure 2

Levels of interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-6 (IL-6) and plasma tumor necrosis factor α (TNF-α) at diffrents time points (1 h, 3 h and 5 h) after normal saline or dexmedetomidine infusion (means±SD). CLP: cecal ligation and puncture, normal saline treated (n=12); DEX2.5: cecal ligation and puncture, dexmedetomidine treated, 2.5 mg·kg-1·h-1 infusion (n=12); DEX5.0: cecal ligation and puncture, dexmedetomidine treated, 5.0 mg·kg-1·h-1 infusion (n=12); DEX10.0: cecal ligation and puncture, dexmedetomidine treated, 10.0 mg·kg-1·h-1 infusion (n=12). #P<0.05 as compared with CLP groups at 3 h.

Figure 3

Heart rate (HR) and mean arterial blood pressure (MAP) evolution during the experimental period. Values (given as means±SD) were measured at 1 hour (1 h), 3 hours (3 h) and 5 hours (5 h) of normal saline or dexmedetomidine infusion. CLP: cecal ligation and puncture, normal saline treated (n=12); DEX2.5: cecal ligation and puncture, dexmedetomidine treated, 2.5 mg·kg-1·h-1 infusion (n=12); DEX5.0: cecal ligation and puncture, dexmedetomidine treated, 5.0 mg·kg-1·h-1 infusion (n=12); DEX10.0: cecal ligation and puncture, dexmedetomidine treated, 10.0 mg·kg-1·h-1 infusion (n=12). ΔP<0.001 as compared with 3h, *P<0.001 as compared with CLP groups in 5 h, #P<0.01 as compared in 1 h.

Figure 4

Arterial blood gases and lactate analysis during the experimental period. Values (given as means±SD) were measured at 3 hours (3 h) and 5 hours (5 h) of normal saline or dexmedetomidine infusion. CLP: cecal ligation and puncture, normal saline treated (n=12); DEX2.5: cecal ligation and puncture, dexmedetomidine treated, 2.5 mg·kg-1·h-1 infusion (n=12); DEX5.0: cecal ligation and puncture, dexmedetomidine treated, 5.0 mg·kg-1·h-1 infusion (n=12); DEX10.0: cecal ligation and puncture, dexmedetomidine treated, 10.0 mg·kg-1·h-1 infusion (n=12). *P<0.001 as compared with CLP groups, ΔP<0.0001 as compared with CLP groups.

Figure 5

Survival curve for CLP, DEX2.5, DEX5.0, DEX10.0 groups at 24 hours. CLP: cecal ligation and puncture, normal saline treated (n=12); DEX2.5: cecal ligation and puncture, dexmedetomidine treated, 2.5 mg·kg-1·h-1 infusion (n=12); DEX5.0: cecal ligation and puncture, dexmedetomidine treated, 5.0 mg·kg-1·h-1 infusion (n=12); DEX10.0: cecal ligation and puncture, dexmedetomidine treated, 10.0 mg·kg-1·h-1 infusion (n=12).