远隔缺血预处理在成人二尖瓣置换术中的心肌保护作用及评价指标
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摘要
目的:远隔缺血预处理(Remote Ischemic Preconditioning,RIPC)是近十几年来提出并逐渐发展起来的减轻心肌缺血再灌注损伤的方法;然而,到目前为止,尚无证据显示RIPC在瓣膜置换手术中能否有心肌保护作用。本课题旨在观察通过右上肢的远隔缺血预处理能否对二尖瓣瓣膜置换术中心肌缺血再灌注损伤产生保护作用。本课题另一研究目的是观察缺血修饰白蛋白(Ischemia Modified Albumin,IMA)作为评判体外循环心脏手术导致的心肌缺血另一生化指标的可行性。
方法:因患风湿性心脏瓣膜病变需接受二尖瓣瓣膜置换术的成人患者70名,在全麻诱导后随机分为对照组(CONTROL GROUP)(n=35)和远隔缺血预处理组(RIPC GROUP)(n=35)。远隔缺血预处理组是利用一血压计袖囊充气到200mmHg或放气,对患者右上肢实施5分钟缺血/5分钟再灌注处理,连续重复该过程3次。对照组只绑血压计袖囊,不行充气/放气的缺血/再灌注处理。分别于麻醉诱导前,开主动脉后1,3,6,和24hr各时点抽取静脉血,检测肌酸激酶(CK)及其同工酶(CK-MB),心肌肌钙蛋白(cTnI),缺血修饰白蛋白(IMA),肿瘤坏死因子α(TNF-α)。术中记录体外循环时间、主动脉阻断时间;同时记录下术后各相应时间点正性肌力药物的用量;在ICU停留的时间及病人的住院时间及病人的死亡率。
结果:
(1)与对照组相比,远隔缺血预处理组患者体外循环后血清中CTnI浓度和CK-MB浓度均明显下降;血浆TNF-α水平也降低。
(2)与术前基础值相比,血清缺血修饰白蛋白浓度在开放主动脉后1,3,6小时三时点均明显增高,在24小时时,回到基础值水平;但是该指标在对照组和远隔缺血预处理组两组间没有明显差异(P=0.87)。
结论:
(1)本研究证明,作为远隔缺血预处理,短暂的上肢缺血预处理有利于成人心脏瓣膜置换术的心肌保护。
(2)本研究证明,缺血修饰白蛋白是一种心肌缺血/损伤的敏感标记物,然而,它并不能反映体外循环手术中心肌损伤的程度。
Objective: The present study is aimed to investigate whether remote ischaemic preconditioning (RIPC), an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing valve replacement surgery. Another objective of the present study is to evaluate the value of ischemia modified albumin (IMA) as a biomarker to reflect the cardiac injury in patients undergoing valve replacement.
Methods: 70 adult patients undergoing valvular replacement surgery were randomly assigned to either RIPC (n=35) or to a control group (n=35) after induction of anaesthesia. RIPC consisted of three 5-min cycles of right upper limb ischaemia, induced by a manual cuff-inflator placed on the upper arm and inflated to 200 mmHg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin I, CK, CK-MB, tumor necrosis factor-alpha (TNF-α) and IMA concentration were measured before surgery and at 1, 3, 6 and 24 hr after cardiopulmonary bypass (CPB). Analysis was by intention to treat.
Results: RIPC significantly reduced the overall serum troponin I and CK-MB levels after CPB. In addition, serum TNF-αlevel was also lower in patients with RIPC than the control patients. After surgery, the serum IMA level was dramatically increased at 1, 3 and 6 hr as compared with the basal level. At 24 hour, the serum IMA level returned to the basal level. However, there was not significant difference of IMA level between RIPC and control group (p=0.87).
Conclusion: The present study demonstrates that adult patients undergoing valvular replacement surgery could benefit from RIPC, using transient upper limb ischemia. The present study also shows that IMA is a sensitive marker of cardiac ishemia/injury, however, it is not a specific marker to reflect the extent of cardiac injury in patients undergoing CPB.
方法:因患风湿性心脏瓣膜病变需接受二尖瓣瓣膜置换术的成人患者70名,在全麻诱导后随机分为对照组(CONTROL GROUP)(n=35)和远隔缺血预处理组(RIPC GROUP)(n=35)。远隔缺血预处理组是利用一血压计袖囊充气到200mmHg或放气,对患者右上肢实施5分钟缺血/5分钟再灌注处理,连续重复该过程3次。对照组只绑血压计袖囊,不行充气/放气的缺血/再灌注处理。分别于麻醉诱导前,开主动脉后1,3,6,和24hr各时点抽取静脉血,检测肌酸激酶(CK)及其同工酶(CK-MB),心肌肌钙蛋白(cTnI),缺血修饰白蛋白(IMA),肿瘤坏死因子α(TNF-α)。术中记录体外循环时间、主动脉阻断时间;同时记录下术后各相应时间点正性肌力药物的用量;在ICU停留的时间及病人的住院时间及病人的死亡率。
结果:
(1)与对照组相比,远隔缺血预处理组患者体外循环后血清中CTnI浓度和CK-MB浓度均明显下降;血浆TNF-α水平也降低。
(2)与术前基础值相比,血清缺血修饰白蛋白浓度在开放主动脉后1,3,6小时三时点均明显增高,在24小时时,回到基础值水平;但是该指标在对照组和远隔缺血预处理组两组间没有明显差异(P=0.87)。
结论:
(1)本研究证明,作为远隔缺血预处理,短暂的上肢缺血预处理有利于成人心脏瓣膜置换术的心肌保护。
(2)本研究证明,缺血修饰白蛋白是一种心肌缺血/损伤的敏感标记物,然而,它并不能反映体外循环手术中心肌损伤的程度。
Objective: The present study is aimed to investigate whether remote ischaemic preconditioning (RIPC), an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing valve replacement surgery. Another objective of the present study is to evaluate the value of ischemia modified albumin (IMA) as a biomarker to reflect the cardiac injury in patients undergoing valve replacement.
Methods: 70 adult patients undergoing valvular replacement surgery were randomly assigned to either RIPC (n=35) or to a control group (n=35) after induction of anaesthesia. RIPC consisted of three 5-min cycles of right upper limb ischaemia, induced by a manual cuff-inflator placed on the upper arm and inflated to 200 mmHg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin I, CK, CK-MB, tumor necrosis factor-alpha (TNF-α) and IMA concentration were measured before surgery and at 1, 3, 6 and 24 hr after cardiopulmonary bypass (CPB). Analysis was by intention to treat.
Results: RIPC significantly reduced the overall serum troponin I and CK-MB levels after CPB. In addition, serum TNF-αlevel was also lower in patients with RIPC than the control patients. After surgery, the serum IMA level was dramatically increased at 1, 3 and 6 hr as compared with the basal level. At 24 hour, the serum IMA level returned to the basal level. However, there was not significant difference of IMA level between RIPC and control group (p=0.87).
Conclusion: The present study demonstrates that adult patients undergoing valvular replacement surgery could benefit from RIPC, using transient upper limb ischemia. The present study also shows that IMA is a sensitive marker of cardiac ishemia/injury, however, it is not a specific marker to reflect the extent of cardiac injury in patients undergoing CPB.
引文
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56. Schoemaker RG, van Heijningen CL. Bradykinin mediates cardiac preconditioning at a distance. Am J Physiol Heart Circ Physiol 2000; 278: H1571.
57. Liauw SK, Rubin BB, Lindsay TF, et al. Sequential ischemia/reperfusion results in contralateral skeletal muscle salvage. Am J Physiol 1996; 270:H1407.
58. Ren X, Wang Y, Jones WK. TNF-alpha is required for late ischemic preconditioning but not for remote preconditioning of trauma. J SurgRes 2004; 121: 120.
59. Chen YS, Chien CT, Ma MC, et al. Protection "outside the box" (skeletal remote preconditioning) in rat model is triggered by free radical pathway. J Surg Res 2005; 126: 92
60. Ferdinandy P, Csont T, Csonka C, et al. Capsaicin-sensitive local sensory innervation is involved in pacing-induced preconditioning in rat hearts: role of nitric oxide and CGRP? Naunyn Schmiedebergs Arch Pharmacol 1997; 356: 356.
61. Xiao L, Lu R, Hu CP, et al. Delayed cardioprotection by intestinal preconditioning is mediated by calcitonin gene-related peptide. Eur J Pharmacol 2001; 427: 131.
62. Wolfram S, Nienstedt J, Heidbreder M, et al. Calcitonin gene related peptide mediates cardioprotection by remote preconditioning. Regul Pept 2005; 127: 217.
63. Huda R, Chung DH, Mathru M. Ischemic preconditioning at a distance: Altered gene expression in mouse heart and other organs following brief occlusion of the mesenteric artery. Heart Lung Circ 2005; 14: 36.
64. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, et al. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: Role of the autonomic nervous system. J Am Coll Cardiol 2005; 46: 450.
65. Wang YP, Maeta H, Mizoguchi K, et al. Intestinal ischemia preconditions myocardium: Role of protein kinase C and mitochondrial K(ATP) channel. Cardiovasc Res 2002; 55: 576.
66. Wolfrum S, Schneider K, Heidbreder M, et al. Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform. Cardiovasc Res 2002; 55: 583.
67. Pagliaro P, Gattullo D, Rastaldo R, Losano G. Involvement of nitric oxide in ischemic preconditioning. Ital Heart J 2001; 2: 660.
68. Kristiansen SB, Henning O, Kharbanda RK, et al. Remote preconditioning reduces ischemia-reperfusion injury in the explanted heart by a KATP channel-dependent mechanism. Am J Physiol Heart Circ Physiol 2005; 288: H1252.
69. Moses MA, Addison PD, Neligan PC, et al. Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: Efficacy and mechanism.AmJ Physiol Regul Integr Comp Physiol 2005; 289:R1609.
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56. Schoemaker RG, van Heijningen CL. Bradykinin mediates cardiac preconditioning at a distance. Am J Physiol Heart Circ Physiol 2000; 278: H1571.
57. Liauw SK, Rubin BB, Lindsay TF, et al. Sequential ischemia/reperfusion results in contralateral skeletal muscle salvage. Am J Physiol 1996; 270:H1407.
58. Ren X, Wang Y, Jones WK. TNF-alpha is required for late ischemic preconditioning but not for remote preconditioning of trauma. J SurgRes 2004; 121: 120.
59. Chen YS, Chien CT, Ma MC, et al. Protection "outside the box" (skeletal remote preconditioning) in rat model is triggered by free radical pathway. J Surg Res 2005; 126: 92
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61. Xiao L, Lu R, Hu CP, et al. Delayed cardioprotection by intestinal preconditioning is mediated by calcitonin gene-related peptide. Eur J Pharmacol 2001; 427: 131.
62. Wolfram S, Nienstedt J, Heidbreder M, et al. Calcitonin gene related peptide mediates cardioprotection by remote preconditioning. Regul Pept 2005; 127: 217.
63. Huda R, Chung DH, Mathru M. Ischemic preconditioning at a distance: Altered gene expression in mouse heart and other organs following brief occlusion of the mesenteric artery. Heart Lung Circ 2005; 14: 36.
64. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, et al. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: Role of the autonomic nervous system. J Am Coll Cardiol 2005; 46: 450.
65. Wang YP, Maeta H, Mizoguchi K, et al. Intestinal ischemia preconditions myocardium: Role of protein kinase C and mitochondrial K(ATP) channel. Cardiovasc Res 2002; 55: 576.
66. Wolfrum S, Schneider K, Heidbreder M, et al. Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform. Cardiovasc Res 2002; 55: 583.
67. Pagliaro P, Gattullo D, Rastaldo R, Losano G. Involvement of nitric oxide in ischemic preconditioning. Ital Heart J 2001; 2: 660.
68. Kristiansen SB, Henning O, Kharbanda RK, et al. Remote preconditioning reduces ischemia-reperfusion injury in the explanted heart by a KATP channel-dependent mechanism. Am J Physiol Heart Circ Physiol 2005; 288: H1252.
69. Moses MA, Addison PD, Neligan PC, et al. Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: Efficacy and mechanism.AmJ Physiol Regul Integr Comp Physiol 2005; 289:R1609.
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71. O'Rourke B. Myocardial K(ATP) channels in preconditioning. Circ Res 2000; 87: 845.
72. Murata M, Akao M, O'Rourke B, Marban E. Mitochondrial ATPsensitive potassium channels attenuate matrix Ca(2+) overload during simulated ischemia and reperfusion: Possible mechanism of cardioprotection. Circ Res 2001; 89: 891.
73. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol 2001; 280: H649.
74. Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284: G15.
75.Konstantinov IE, Arab S, Li J, et al. The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg 2005; 130: 1326.