七氟醚预处理对体外循环心内直视手术期间心肌缺血/再灌注损伤的保护作用
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摘要
目的研究七氟醚(sevoflurane,Sevo)预处理对风湿性心脏病患者在体外循环(cardiopulmonary bypass,CPB)下行瓣膜置换术围手术期缺血/再灌注损伤(ischemia-reperfusion injury,IRI)心肌的保护作用;评价心肌缺血三项生化指标的可靠程度。
方法选择20例风湿性心脏病行瓣膜置换术患者,患者ASAⅡ～Ⅳ级,年龄29～54岁。随机分为对照组(C组)和Sevo预处理组(S组),每组10例。两组患者均相继静脉注射咪唑安定(0.08～0.12mg·kg~(-1))、芬太尼(5～10μg·kg~(-1))、哌库溴铵(0.1mg·kg~(-1))行麻醉诱导,3min后经口明视气管内插管。连接麻醉机施行控制呼吸,呼吸参数根据年龄、体重进行调整,维持P_(ET)CO_2在35～40mmHg之间。术中按需追加咪唑安定、芬太尼及哌库溴铵维持麻醉,手术中双频谱指数(Bispectral Index,BIS)维持在40～60之间。S组于劈开胸骨后持续吸入1%Sevo,至CPB开始后结束;C组不用任何吸入性麻醉药。分别于麻醉后切皮前(T_1)、主动脉阻断即刻(T_2)、主动脉开放即刻(T_3)、主动脉开放30min(T_4)、CPB停机后2h(T_5)、6h(T_6)、12h(T_7)和24h(T_8)8个时间点抽取桡动脉血样,测定血浆心肌肌钙蛋白I(cardiac troponin I,cTnI)、肌酸磷酸激酶(creatine phosphokinase,CK)及肌酸磷酸激酶同工酶(creatine phosphokinaseisoenzyme,CK-MB)浓度。主动脉阻断前和开放后5min取左室后壁心肌,电镜观察两组患者的心肌超微结构变化。记录CPB时间、主动脉阻断时间、手术时间、围CPB期间心血管活性药物的使用情况、心脏复跳情况以及术后24h创面引流量。
结果两组患者的年龄、体重、性别比、术前心功能、心胸比、麻醉药用量、CPB时间、主动脉阻断(aortic cross-clamp,ACC)时间以及手术时间差异无显著性(P＞0.05)。
两组患者术前(T_1)血浆cTnI、CK和CK-MB浓度均在正常范围内,组间比较无差异。
C组血浆cTnI浓度于T_2时点开始升高,T_3时点显著升高(P＜0.05),但仍在正常范围内;于T_4～T_8时点继续升高(P＜0.001),并于T_6时点达峰值(均值约为T_1值的66倍,P＜0.001);于T_7时点开始回降,但于T_8时点仍显著高于T_1值(均值约为T_1值的20倍,P＜0.001)。S组血浆cTnI浓度同样于T_2时点开始升高,T_3时点继续升高,但与T_1值比较无统计学差异(P＞0.05);于T_4和T_5时点显著升高(P＜0.001),于T_6时点达到峰值(均值约为T_1值的27倍,P＜0.001);同样于T_7时点开始回降,但于T_8时点已回降至接近正常水平(P＜0.05)。组间比较,血浆cTnI浓度在T_4～T_8时点S组明显低于C组(P＜0.05～0.01),于T_6时点血浆cTnI浓度峰值S组约只有C组的35%(P＜0.01),于T_8时点血浆cTnI浓度S组约只有C组的20%(P＜0.01)。
C组血浆CK浓度于T_2时点开始升高,于T_3时点显著升高(P＜0.01),并超过正常范围;于T_4～T_7时点继续升高(P＜0.001),于T_8时点仍继续升高(均值约为T_1值的14倍,P＜0.001)。S组血浆CK浓度于T_3～T_7时点也显著升高(P＜0.01～0.001),但于T_8时点升高趋势趋于平缓(均值约为T_1值的9倍,P＜0.001)。两组血浆CK浓度变化于T_1～T_7时点的组间比较无显著性差异(P＞0.05);但于T_8时点S组低于C组(P＜0.05)。
C组血浆CK-MB浓度于T_2时点开始升高,于T_3时点显著升高(P＜0.05),但仍在正常范围内;于T_4时点继续升高(P＜0.001),并于T_6时点升高达峰值(均值约为T_1值的9.1倍,P＜0.001);于T_7时点开始回降,但T_8时点仍高于T_1时点水平(P＜0.001)。S组血浆CK-MB浓度于T_3和T_4时点也显著升高(P＜0.05～0.001),于T_6时点升高达峰值(均值约为T_1值的9.2倍,P＜0.001);同样于T_7时点开始回降,T_8时点血浆CK-MB浓度虽仍高于T_1时点水平(P＜0.001),但有接近正常范围的趋势。两组血浆CK-MB浓度于T_1～T_7时点组间比较无显著性差异(P＞0.05)。但于T_8时点,S组血浆CK-MB浓度明显低于C组(P＜0.05),且有接近正常范围的趋势。
电镜观察心肌超微结构,两组主动脉阻断前心肌纤维排列整齐,肌节清晰,线粒体正常,或线粒体轻度水肿,肌丝存在轻度疏松、水肿。主动脉开放后5min,C组心肌纤维排列疏松,肌丝排列紊乱,肌节缩短,线粒体肿胀较明显,出现空泡化和峭断裂现象;S组心肌纤维排列整齐,线粒体水肿程度较轻,线粒体嵴相对完整。
临床观察中,C组4例自动复跳,6例除颤复跳;复跳后有2例出现室性心动过速,1例出现室性早搏,1例复跳后再次出现室颤;复跳后使用多巴胺和/或多巴酚丁胺者有6例。S组8例自动复跳,2例除颤复跳,未出现心律失常,全部病例均未使用血管活性药物。S组自动复跳率高于C组(P＜0.05)。术后24h创面引流量C组明显多于S组(P＜0.05)。
结论风湿性心脏病瓣膜置换术患者围CPB期,心肌细胞和心脏功能受到一定程度的损害。而在主动脉阻断前吸入一定浓度和一定时间的Sevo(预处理),能有效抑制心肌缺血/再灌注损伤,对保护心肌功能有一定疗效。cTnI可视为心肌损伤的标志物,与CK、CK-MB比较,其时效性更强、敏感性和特异性更高,是心内直视手术围术期监测心肌损伤的可靠指标。
Objective To study the protective effects of sevoflurane-induced preconditioning on myocardial ischemia-reperfusion injury in open heart surgery with cardiopulmonary bypass (CPB).
Methods Twenty patients (ASAⅡ～Ⅳ) scheduled for elective cardiac valve replacement with CPB were randomly divided into two groups: control group (group C, n=10) and sevoflurane preconditioning group (group S, n=10). Anesthesia was induced with intravenous injection of midazolam (0.08～0.12mg·kg~(-1)), fentanyl (5～10μg·kg~(-1)) and pipecuronium (0.1mg·kg~(-1)) and was maintained with intermittent i.v. boluses of midazolam, fentanyl and pipecuronium. In group S, 1vol% sevoflurane was continuously inhaled from the beginning of operation to the beginning of CPB, and no anesthetic was inhaled in group C. Plasma levels of cardiac troponin I (cTnI), creatine phosphokinase (CK) and creatine phosphokinase isoenzyme (CK-MB) were measured after induction of anesthesia (T_1), immediate after aorta clamping (T_2), immediate after (T_3) and 30min after (T_4) aorta unclamping, 2h (T_5), 6h (T_6), 12h (T_7) and 24h (T_8) after discontinuation of CPB, respectively. Myocardial samples of left ventricle for electronic microscopy were obtained before aorta clamping and 5 minutes after aorta unclamping.
Results Plasma cTnI, CK and CK-MB levels were within normal range before CPB and there were no significant differences in cTnI, CK and CK-MB between both groups at T_1. In group C, plasma levels of cTnI at T_4, T_5, T_6, T_7 and T_8 were higher than that at T_1 (P<0.001), and reach the peak level at T_6, then declined at T_7. In group S plasma level of cTnI at T_4, T_5 and T_6 was higher than that at T_1 (P<0.001), and declined to normal range at T_8. Increasing amplitude of plasma cTnI was lower at T_4, T_5, T_6, T_7 and T_8 in group S than that in group C (P<0.05～0.01). Plasma levels of CK and CK-MB at T_3, T_4, T_5, T_6, T_7 and T_8 were higher than that at T_1 (P<0.05～0.001) in both two groups. There were no significant differences in plasma levels of CK and CK-MB between two groups at T_3, T_4, T_5, T_6 and T_7, but the values were lower in group S than that in group C at T_8 (P<0.05). Ischemic and hypoxic changes in myocardial biopsy were obviously observed with electric microscope 5min after aorta unclamping in group C. No distinct changes were found in group S. In group C, the heart beat conversed automatically in four patients and conversed electrically in six cases, and ventricular tachycardia occurred in two patients, ventricular premature beat appeared in one patient and ventricular fibrillation happened in one case, and six patients were supported with inotropic drugs. In group S, heart beat conversed automatically in eight patients and was conversed electrically in two cases, and no arrhythmia appeared and no inotropic drugs were used in all patients. The rate of automatic conversion was higher in group S than that in group C (P<0.05). The volume of wound drainage in first postoperative day was less in group S than that in group C (P<0.05).
Conclusion The findings of the present study demonstrated that during peri-CPB stage for patients undergoing cardiac valve replacement, myocardium and cardiac function was damaged. Sevoflurane-induced preconditioning is able to effectively relieve myocardial ischemia-reperfusion injury in open heart surgery with CPB. As a marker of myocardial injury, cTnI is more sensitive and more specific than CK and CK-MB. cTnI is a reliable detecting parameter for the diagnosis of myocardial injury during open heart surgery.
方法选择20例风湿性心脏病行瓣膜置换术患者,患者ASAⅡ～Ⅳ级,年龄29～54岁。随机分为对照组(C组)和Sevo预处理组(S组),每组10例。两组患者均相继静脉注射咪唑安定(0.08～0.12mg·kg~(-1))、芬太尼(5～10μg·kg~(-1))、哌库溴铵(0.1mg·kg~(-1))行麻醉诱导,3min后经口明视气管内插管。连接麻醉机施行控制呼吸,呼吸参数根据年龄、体重进行调整,维持P_(ET)CO_2在35～40mmHg之间。术中按需追加咪唑安定、芬太尼及哌库溴铵维持麻醉,手术中双频谱指数(Bispectral Index,BIS)维持在40～60之间。S组于劈开胸骨后持续吸入1%Sevo,至CPB开始后结束;C组不用任何吸入性麻醉药。分别于麻醉后切皮前(T_1)、主动脉阻断即刻(T_2)、主动脉开放即刻(T_3)、主动脉开放30min(T_4)、CPB停机后2h(T_5)、6h(T_6)、12h(T_7)和24h(T_8)8个时间点抽取桡动脉血样,测定血浆心肌肌钙蛋白I(cardiac troponin I,cTnI)、肌酸磷酸激酶(creatine phosphokinase,CK)及肌酸磷酸激酶同工酶(creatine phosphokinaseisoenzyme,CK-MB)浓度。主动脉阻断前和开放后5min取左室后壁心肌,电镜观察两组患者的心肌超微结构变化。记录CPB时间、主动脉阻断时间、手术时间、围CPB期间心血管活性药物的使用情况、心脏复跳情况以及术后24h创面引流量。
结果两组患者的年龄、体重、性别比、术前心功能、心胸比、麻醉药用量、CPB时间、主动脉阻断(aortic cross-clamp,ACC)时间以及手术时间差异无显著性(P＞0.05)。
两组患者术前(T_1)血浆cTnI、CK和CK-MB浓度均在正常范围内,组间比较无差异。
C组血浆cTnI浓度于T_2时点开始升高,T_3时点显著升高(P＜0.05),但仍在正常范围内;于T_4～T_8时点继续升高(P＜0.001),并于T_6时点达峰值(均值约为T_1值的66倍,P＜0.001);于T_7时点开始回降,但于T_8时点仍显著高于T_1值(均值约为T_1值的20倍,P＜0.001)。S组血浆cTnI浓度同样于T_2时点开始升高,T_3时点继续升高,但与T_1值比较无统计学差异(P＞0.05);于T_4和T_5时点显著升高(P＜0.001),于T_6时点达到峰值(均值约为T_1值的27倍,P＜0.001);同样于T_7时点开始回降,但于T_8时点已回降至接近正常水平(P＜0.05)。组间比较,血浆cTnI浓度在T_4～T_8时点S组明显低于C组(P＜0.05～0.01),于T_6时点血浆cTnI浓度峰值S组约只有C组的35%(P＜0.01),于T_8时点血浆cTnI浓度S组约只有C组的20%(P＜0.01)。
C组血浆CK浓度于T_2时点开始升高,于T_3时点显著升高(P＜0.01),并超过正常范围;于T_4～T_7时点继续升高(P＜0.001),于T_8时点仍继续升高(均值约为T_1值的14倍,P＜0.001)。S组血浆CK浓度于T_3～T_7时点也显著升高(P＜0.01～0.001),但于T_8时点升高趋势趋于平缓(均值约为T_1值的9倍,P＜0.001)。两组血浆CK浓度变化于T_1～T_7时点的组间比较无显著性差异(P＞0.05);但于T_8时点S组低于C组(P＜0.05)。
C组血浆CK-MB浓度于T_2时点开始升高,于T_3时点显著升高(P＜0.05),但仍在正常范围内;于T_4时点继续升高(P＜0.001),并于T_6时点升高达峰值(均值约为T_1值的9.1倍,P＜0.001);于T_7时点开始回降,但T_8时点仍高于T_1时点水平(P＜0.001)。S组血浆CK-MB浓度于T_3和T_4时点也显著升高(P＜0.05～0.001),于T_6时点升高达峰值(均值约为T_1值的9.2倍,P＜0.001);同样于T_7时点开始回降,T_8时点血浆CK-MB浓度虽仍高于T_1时点水平(P＜0.001),但有接近正常范围的趋势。两组血浆CK-MB浓度于T_1～T_7时点组间比较无显著性差异(P＞0.05)。但于T_8时点,S组血浆CK-MB浓度明显低于C组(P＜0.05),且有接近正常范围的趋势。
电镜观察心肌超微结构,两组主动脉阻断前心肌纤维排列整齐,肌节清晰,线粒体正常,或线粒体轻度水肿,肌丝存在轻度疏松、水肿。主动脉开放后5min,C组心肌纤维排列疏松,肌丝排列紊乱,肌节缩短,线粒体肿胀较明显,出现空泡化和峭断裂现象;S组心肌纤维排列整齐,线粒体水肿程度较轻,线粒体嵴相对完整。
临床观察中,C组4例自动复跳,6例除颤复跳;复跳后有2例出现室性心动过速,1例出现室性早搏,1例复跳后再次出现室颤;复跳后使用多巴胺和/或多巴酚丁胺者有6例。S组8例自动复跳,2例除颤复跳,未出现心律失常,全部病例均未使用血管活性药物。S组自动复跳率高于C组(P＜0.05)。术后24h创面引流量C组明显多于S组(P＜0.05)。
结论风湿性心脏病瓣膜置换术患者围CPB期,心肌细胞和心脏功能受到一定程度的损害。而在主动脉阻断前吸入一定浓度和一定时间的Sevo(预处理),能有效抑制心肌缺血/再灌注损伤,对保护心肌功能有一定疗效。cTnI可视为心肌损伤的标志物,与CK、CK-MB比较,其时效性更强、敏感性和特异性更高,是心内直视手术围术期监测心肌损伤的可靠指标。
Objective To study the protective effects of sevoflurane-induced preconditioning on myocardial ischemia-reperfusion injury in open heart surgery with cardiopulmonary bypass (CPB).
Methods Twenty patients (ASAⅡ～Ⅳ) scheduled for elective cardiac valve replacement with CPB were randomly divided into two groups: control group (group C, n=10) and sevoflurane preconditioning group (group S, n=10). Anesthesia was induced with intravenous injection of midazolam (0.08～0.12mg·kg~(-1)), fentanyl (5～10μg·kg~(-1)) and pipecuronium (0.1mg·kg~(-1)) and was maintained with intermittent i.v. boluses of midazolam, fentanyl and pipecuronium. In group S, 1vol% sevoflurane was continuously inhaled from the beginning of operation to the beginning of CPB, and no anesthetic was inhaled in group C. Plasma levels of cardiac troponin I (cTnI), creatine phosphokinase (CK) and creatine phosphokinase isoenzyme (CK-MB) were measured after induction of anesthesia (T_1), immediate after aorta clamping (T_2), immediate after (T_3) and 30min after (T_4) aorta unclamping, 2h (T_5), 6h (T_6), 12h (T_7) and 24h (T_8) after discontinuation of CPB, respectively. Myocardial samples of left ventricle for electronic microscopy were obtained before aorta clamping and 5 minutes after aorta unclamping.
Results Plasma cTnI, CK and CK-MB levels were within normal range before CPB and there were no significant differences in cTnI, CK and CK-MB between both groups at T_1. In group C, plasma levels of cTnI at T_4, T_5, T_6, T_7 and T_8 were higher than that at T_1 (P<0.001), and reach the peak level at T_6, then declined at T_7. In group S plasma level of cTnI at T_4, T_5 and T_6 was higher than that at T_1 (P<0.001), and declined to normal range at T_8. Increasing amplitude of plasma cTnI was lower at T_4, T_5, T_6, T_7 and T_8 in group S than that in group C (P<0.05～0.01). Plasma levels of CK and CK-MB at T_3, T_4, T_5, T_6, T_7 and T_8 were higher than that at T_1 (P<0.05～0.001) in both two groups. There were no significant differences in plasma levels of CK and CK-MB between two groups at T_3, T_4, T_5, T_6 and T_7, but the values were lower in group S than that in group C at T_8 (P<0.05). Ischemic and hypoxic changes in myocardial biopsy were obviously observed with electric microscope 5min after aorta unclamping in group C. No distinct changes were found in group S. In group C, the heart beat conversed automatically in four patients and conversed electrically in six cases, and ventricular tachycardia occurred in two patients, ventricular premature beat appeared in one patient and ventricular fibrillation happened in one case, and six patients were supported with inotropic drugs. In group S, heart beat conversed automatically in eight patients and was conversed electrically in two cases, and no arrhythmia appeared and no inotropic drugs were used in all patients. The rate of automatic conversion was higher in group S than that in group C (P<0.05). The volume of wound drainage in first postoperative day was less in group S than that in group C (P<0.05).
Conclusion The findings of the present study demonstrated that during peri-CPB stage for patients undergoing cardiac valve replacement, myocardium and cardiac function was damaged. Sevoflurane-induced preconditioning is able to effectively relieve myocardial ischemia-reperfusion injury in open heart surgery with CPB. As a marker of myocardial injury, cTnI is more sensitive and more specific than CK and CK-MB. cTnI is a reliable detecting parameter for the diagnosis of myocardial injury during open heart surgery.
引文
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