右美托咪定抑制脓毒症患者炎症反应的可能机制及剂量相关性研究

Possible mechanism and dose correlation of dexmedetomidine in inhibiting inflammatory response in patients with sepsis

目的探讨右美托咪定镇静治疗脓毒症患者炎症反应的可能机制及剂量相关性。方法选择2017年11月至2018年10月在大连医科大学附属第二医院ICU入住的75例脓毒症需要机械通气治疗的患者,将其分为低剂量组、高剂量组和对照组,每组25例。低剂量组和高剂量组患者起始分别给予0.5μg/kg和1.5μg/kg右美托咪定镇静负荷剂量后,持续以0.2μg·kg^(-1)·h^(-1)和0.6μg·kg^(-1)·h^(-1)的剂量进行镇静治疗;而对照组患者15 min内予1 mg/kg丙泊酚负荷剂量进行镇静治疗,而后以1~3 mg·kg^(-1)·h^(-1)的剂量持续镇静治疗。记录所有患者的一般资料,采用酶联免疫吸附测定法测定3组患者用药前(T0)、用药后12 h(T1)、用药后24 h(T2)肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)、核因子κB(NF-κB)的表达水平。采用Pearson相关分析探讨NF-κB与TNF-α、IL-6的相关性。结果3组患者T0、T1、T2时间点TNF-α、IL-6、NF-κB表达水平比较,差异均有统计学意义(F=3.501、3.258、12.218,P均<0.05)。进一步两两比较发现,高剂量组患者T1时间点TNF-α[(14±6)、(29±18)、(27±16)ng/L]、IL-6[(49±26)、(178±110)、(180±115)ng/L]表达水平均较低剂量组和对照组显著降低,NF-κB[(2.84±0.71)μg/L vs.(3.89±0.51)μg/L]表达水平较对照组显著降低(P均<0.05);高剂量组患者T2时间点TNF-α[(7±5)ng/L vs.(19±9)ng/L]表达水平较对照组显著降低,IL-6[(19±11)、(91±53)、(96±57)ng/L]、NF-κB[(1.91±0.94)、(2.67±0.70)、(3.25±0.58)μg/L]表达水平均较低剂量组和对照组显著降低(P均<0.05);而低剂量组与对照组患者T1、T2时间点TNF-α、IL-6、NF-κB表达水平比较,差异均无统计学意义(P均>0.05)。Pearson相关分析结果显示,NF-κB水平与血清TNF-α(r=0.456,P<0.001)、IL-6(r=0.309,P=0.007)均呈正相关。结论右美托咪定可以通过抑制胆碱能抗炎通路中NF-κB降低脓毒症患者TNF-α、IL-6的水平发挥抗炎作用,其抗炎作用与剂量相关。

Objective To investigate the possible mechanism and dose correlation of dexmedetomidine sedation in treating the inflammatory response of patients with sepsis.Methods From November 2017 to October 2018,75 patients with sepsis requiring mechanical ventilation were selected from the ICU of the Second Hospital of Dalian Medical University.They were divided into a low dose group,a high dose group and a control group,with 25 patients in each group.Patients in the low dose group and high dose group were initially given 0.5μg/kg and 1.5μg/kg of dexmedetomidine respectively,and continued sedation treatment with 0.2μg·kg^(-1)·h^(-1) and 0.6μg·kg^(-1)·h^(-1) of dexmedetomidine.Patients in the control group were treated with 1 mg/kg of propofol within 15 min,and then sustained sedation with doses of 1~3 mg·kg^(-1)·h^(-1).The general data of all patients were recorded,and the expression levels of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6)and nuclear factor-kappa B(NF-κB)at pre-medication(T0),12 h after medication(T1)and 24 h after medication(T2)were measured by enzyme-linked immunosorbent assay in these three groups.Pearson correlation analysis was used to explore the correlation between NF-κB and TNF-α,IL-6.Results The expression levels of TNF-α,IL-6 and NF-κB at T0,T1 and T2 were statistically significantly different in the three groups(F=3.501,3.258,12.218;all P<0.05).A further pairwise comparison found that at T1,the expression levels of TNF-α[(14±6),(29±18),(27±16)ng/L]and IL-6[(49±26),(178±110),(180±115)ng/L]in the high dose group were significantly lower than those in the low dose group and control group,and the expression level of NF-κB[(2.84±0.71)μg/L vs.(3.89±0.51)μg/L]in the high dose group was significantly lower than that in the control group(all P<0.05).At T2,the expression level of TNF-α[(7±5)ng/L vs.(19±9)ng/L]in the high dose group was significantly lower than that in the control group,and the expression levels of IL-6[(19±11),(91±53),(96±57)ng/L]and NF-κB[(1.91±0.94),(2.67±0.70),(3.25±0.58)μg/L]in the high dose group were significantly lower than those in the low dose group and control group(all P<0.05).No significant difference was noted in the expression levels of TNF-α,IL-6 and NF-κB at T1 and T2 between the low dose group and control group(all P>0.05).Pearson correlation analysis showed that NF-κB was positively correlated with serum TNF-α(r=0.456,P<0.001)and IL-6(r=0.309,P=0.007).Conclusion Dexmedetomidine can reduce the levels of TNF-αand IL-6 in patients with sepsis by inhibiting NF-κB in the cholinergic anti-inflammatory pathway,and its anti-inflammatory effect is positively correlated with its dose.