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米力农对心肺转流心内直视手术病人围术期炎性反应因子的影响

时间:2010-08-24 11:35:26  来源:  作者:

 

The effects of milrinone on serum level of CRP and cytokines in petients underwent cardiac surgery with CPB<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

张健  方能新  夏云  曾一平  钱梅  徐志荣 

ZHANG Jian,FANG Neng-xin,XIA Yun et al. Department of Anesthesiology,First Affiliated Hospital of Anhui Medical University,Hefei 230022,Anhui Province,China

 

Abstract

  Objective:To stady  the effects of milrinone on serum level of CRP,TNF-α,IL-8,and IL-10 in adults and children underwent cardiac surgery cardiopulmonary bypass (CPB).

  Methods:Prospective,randomized,double-blind study. Sixteen patients scheduled for cardiac surgery divided into 2 groups:(1)adults group(A),(2)children group (C). Patients received a loading dose of 50 microg/kg of milrinone followed by an introvenous infusion of 0.2 microg/kg/min immediately after aortic declamping. Blood samples for cytokines and CRP measurements were collected into EDTA-Vacutainers from central vein at the following time:just prior to induction of anesthesia (baseline,T0),5 min after aortic cross-clamp release (T1),5 min after weaning from CPB (end-CPB,T2),on completion of surgery (T3),24 hours (T4) and 48 hours(T5) after the operation. Concentrations of TNF-α,IL-8,and IL-10 were measured using a quantitative sandwich enzyme linked-immunosorbent assay (ELISA). The concentration of CRP on blood serum were measured by radio immunoassay (RIA).

  Results:There were no significant differences in the changes of TNF-α(P>0.05) in both groups . But CRP increased significantly at T0,T1 ,T2,T3,T5 in group A compared with those in group C and in both groups the level of CRP at T4 ,T5 were higher compared with their baseline. Compared with baseline a significant increase of IL-8 in the group A at T3,T5 and in the group C at T2,T3 (P<0.05). Significant reduce of IL-10 in group A at T1 ,T2,T3 was presented compared with group C (P<0.05) and significant increase in group A and C compared with the baseline at T3,T4,T5 and at T2,T3,T4,T5 respectively (P<0.05).

  Conclusions:Milrinone took different important roles in mediating systemic inflammation induced by cardiac surgery with CPB in adults and in children.

  Key Words:Milrinone;Cardiopulmonary Bypass;CRP;Cytokine

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  心肺转流(cardiopulmonary bypass,CPB)心脏手术这一应激刺激(stressor)能够诱发机体炎性反应,心肌细胞的缺血再灌注损伤使该反应进一步得到加强。如何调节机体炎性反应已成为目前研究的重要课题。米力农可产生正性变力和血管扩张的双重作用,对机体炎性反应因子也有调节功能。其对成人和小儿CPB心脏手术血浆中炎性反应因子的影响如何,国内外研究较少。本研究旨在观察米力农对该类患者围手术期血浆中C反应蛋白(C-reactive protein,CRP)、IL-10、TNF-α、IL-8水平的影响,以了解该药对调节成人和小儿炎性反应作用的异同,为指导临床用药提供依据。

 

资料与方法

  临床资料  16例择期行CPB心脏手术病人、ASA分级Ⅱ~Ⅳ,随机、双盲分为两组,即米力农成人组(adult group,A组)和小儿组(children group,C组),每组8例。其中A组F43例、左房粘液瘤2例、室缺伴重度肺高压2例、Ebstein畸形1例;C组均为F4根治术。A组和C组年龄分别为(33.750±22.626)和(6.125±2.300)岁;A组和C组体重分别为(53.000±5.210)、(16.750±3.955)千克。A 组和C组间年龄和体重差异均具有极大显著性(P值分别为P <0.0025、P<0.0005)。

  麻醉方法  所有患者均于术前半小时肌注东莨菪碱0.01 mg/kg,吗啡0.2 mg/kg。麻醉诱导为静脉注射咪唑安定0.1 mg/kg、芬太尼0.01mg/kg、维库溴铵0.1 mg/kg。麻醉维持药为咪唑安定0.1mg/kg/h、芬太尼0.01mg/kg/h、维库溴铵0.1mg/kg/h,以Graseby3500静脉输液泵连续静脉输注。两组均采用瑞典Jostra20-490型人工心肺机进行中低温非搏动性灌注,日本Terumo公司CAPIOX型人工肺进行血液氧合,用40C晶体高钾停跳液于主动脉根部或左右冠状动脉开口处灌注,使心电呈等电位线。心脏表面用冰屑降温。A组体外转流时间为97.546±56.329 min,主动脉阻断时间为73.468±47.251 min;C组体外转流时间为132.682±31.433 min,主动脉阻断时间为104.424±27.160 min。两组体外转流时间和主动脉阻断时间无明显差异(两组t值分别为t=1.541和t=1.606,P>0.05)。两组除颤次数和心脏自动复跳比较,差异无显著性。

  两组在主动脉钳开放后即刻使用Graseby3500静脉输液泵输注米力农负荷量0.05 mg/kg,10min内输完,继之以米力农0.0002mg/kg.min-1输注直至入心脏外科SICU。

  标本采集及处理  分别于全麻诱导前(T0)、主动脉开放后5min (T1)、心肺转流停机后5min (T2)、术毕(T3)、术后24h (T4)、术后48h (T5)抽取患者中心静脉血3ml,离心后取上清液送-800C深低温冰箱保存。用DFM-96型16管放射免疫γ计数器检测CRP及细胞因子。TNF-α、IL-8试剂盒由天津九鼎医学生物工程有限公司提供,检测采用顺序饱和法,即充分混匀静置15min,3600g离心20min,弃上清,测沉淀物放射性强度。IL-10试剂盒由北京北方生物技术研究所提供,采用双抗体放射免疫法测定。CRP试剂盒由北京市福瑞生物工程公司提供,放射免疫分析法(radio immunoassay,RIA)测定。

  统计学处理  各参数均用x±s表示。小样本均数比较,采用t检验。样本的方差齐性检验,采用F检验。取P<0.05为统计学有显著性差异。

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结 果

  两组TNF-α、CRP、IL-8、IL-10的各时点测定值见表1。

 

讨 论

  CPB心脏手术能够导致机体产生炎性反应综合症(systemic inflammatory response syndrome,SIRS),这可能会引起多脏器功能障碍甚至衰竭,使术后并发症发生率和和患者死亡率大幅度上升[1]。探寻减轻机体炎性反应的有效方法和合理途径是手术者和麻醉医师共同面临的难题。米力农(milrinone)是一种双嘧啶类药,是磷酸二脂酶Ⅲ(enzyme phosphodiesterase type Ⅲ,PDEⅢ)抑制剂。它通过抑制磷酸二脂酶Ⅲ,提高心肌内cAMP含量而发挥作用[2]

  cAMP是第一个被发现的第二信使,是上世纪50年代由Sutherland在研究肾上腺素激活磷酸化酶,促进糖原分解机制时发现。Sutherland提出第二信使假说,对于细胞信息的研究起了极为重要的作用。配体与受体结合后,通过鸟苷三磷酸结合蛋白(guanosine triphosphate-binding protein,G蛋白)激活腺苷酸环化酶,使cAMP生成增加。G蛋白是由α、β、γ三种亚基构成的不均一三聚体。α亚基除了有鸟苷酸结合位点,还有GTP酶活性。βγ亚基结合紧密,起着调节α亚基的作用,且在脑组织或一些受体的磷酸化过程中,其对效应蛋白也直接起调节作用。G蛋白又根据其生理效应的不同分为激活型(Gs)和抑制型(Gi)[3]。cAMP激活了依赖cAMP的蛋白激酶A(protein kinase A,PKA)。PKA是四聚体,由2个催化亚基和2个调节亚基。每个调节亚基上有2个结合cAMP的位点。当调节亚基结合cAMP后,调节亚基和催化亚基解离,游离的催化亚基表现出其催化活性。PKA催化细胞内蛋白质的磷酸化,磷酸化钙通道,引起钙离子内流[4]。cAMP浓度升高引起一些基因表达水平升高。这些基因的转录控制区都有一个共同的DNA序列TGACGTCA,称为cAMP反应元件(cAMP response element,CRE)。CRE与能与之结合的转录因子(CRE binding protein,CREB)共同作用,引起基因的表达。

  米力农使磷酸二酯酶活性降低,细胞内cAMP浓度升高。而cAMP浓度升高可以通过上述蛋白激酶和磷酸化途径影响炎症反应多个环节,主要表现为:抑制肥大细胞释放组胺,抑制淋巴细胞的活化、增生和炎性介质的生成和释放,抑制嗜酸性细胞的趋化和聚集,从而抑制炎性反应。反之,磷酸二酯酶活性增高,cAMP降解增加,将减弱对炎性反应因子释放的抑制。用相同的方式于术中静脉使用米力农时,理论上其对成人和小儿血浆中炎性反应因子产生的影响是不同的,因为对CPB的炎性反应在小儿可能比成人更为严重,这是由于前者有更多比例的血液暴露于机械管道的表面和更多的心内吸引,但其结果有待进一步证实[5]

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参考文献

1. Brix-Christensen V. The systemic inflammatory response after cardiac surgery with cardiopulmonary bypass in children. Acta Anaesthesiol Scand,2001,45:671-679

2. Mutafova-Yambolieva VN,Smyth L,Bobalova J. Involvement of cyclic AMP-mediated pathway in neural release of noradrenaline in canine isolated mesenteric artery and vein. Cardiovasc Res,2003,57:217-224

3. Chanani NK,Cowan DB,Takeuchi K,et al. Differential effects of amrinone and milrinone upon myocardial inflammatory signaling. Circulation,2002,106(12 Suppl 1):I284-1289

4. Hiramatsu N,Kageyama K. Anti-thrombotic effect of milrinone is caused by inhibition of calcium release from the dense tubular system in human platelets. Acta Anaesthesiol Scand,2003,47:53-57

5. Azuma M,Yamane M,Tachibana K,et al. Effects of epinephrine and phosphodiesterase III inhibitors on bupivacaine-induced myocardial depression in guinea-pig papillary muscle.Br J Anaesth,2003,90:66-71

6. Meng X,Ao L,Shames BD,et al. Inhibition of cyclic-3',5'-nucleotide phosphodiesterase abrogates the synergism of hypoxia with lipopolysaccharide in the induction of macrophage TNF-alpha production. Surg Res,2001,101:210-215

7. Kalfin RE,Engelman RM,Rousou JA,et al. Induction of interleukin-8 expression during cardiopulmonary bypass. Circulation,1993,88(5 Pt 2):II401-406

8. Brix-Christensen V,Petersen TK,Ravn HB,et al. Cardiopulmonary bypass elicits a pro- and anti-inflammatory cytokine response and impaired neutrophil chemotaxis in neonatal pigs. Acta Anaesthesiol Scand,2001,45:407-413

9. Fernando R,Chan R. Anti-inflammatory pre-treatment and the resultant effects of interleukin-10:adjuncts to multi-therapeutical strategies. Perfusion,2000,15:501-505

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