脓毒症患者氧化应激水平与其预后关系
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摘要
目的:观察脓毒症患者氧化应激状态的变化,揭示氧化应激水平对判断脓毒症患者预后的临床意义。
方法:以天津医科大学总医院急救中心2007年8月～2007年12月连续5个月内收治的32例脓毒症患者和13例非脓毒症患者为研究对象。脓毒症患者均符合2001年美国危重病医学会/欧洲危重病医学会/美国胸科医师协会/美国胸科协会/美国外科感染学会(SCCM/ESICM/ACCP/AIS/SIS)联席会议提出的脓毒症诊断标准。两组患者近三个月来均未接受过抗氧化药物治疗。收集所有入选病例入院24小时内临床参数:年龄、性别、生命体征、血常规、电解质、血糖、肝功能、心肌酶、肾功能和血气分析,并计算其急性生理和慢性健康评分(acutephysiology and chronic health evaluationⅡscore,APACHEⅡ评分)。同时于24小时内检测研究对象的血清丙二醛(malondialdehyde,MDA)和总抗氧化力(totalantioxide capacity,T-AOC)水平,作为评价机体氧化应激状态的指标。将上述数据录入计算机采用SPSS13.0统计软件进行数据处理。定量资料进行正态性检验(K-S法)。正态分布的定量资料用均数±标准差表示,非正态分布的资料用中位数、最小值和最大值表示。对照组与脓毒症组间、脓毒症患者存活组和死亡组间:正态分布、方差齐的计量资料采用独立样本的t检验;正态分布、方差不齐的计量资料则采用t'检验;非正态分布的计量资料采用秩和检验;定性资料采用x~2检验。脓毒症组中,按患者存活或死亡的转归,先进行单因素分析,在单因素分析得出有意义指标的基础上进行多因素非条件Logistic回归分析,筛选出对判断预后有意义的指标,再以对判断预后有意义的指标绘制受试者工作特征曲线(receiver operator characteristic curve,ROC),分别计算各个指标的ROC曲线下面积,并比较其判断预后的价值。
结果:无论在脓毒症组,还是在对照组血清MDA和T-AOC水平均呈负相关,相关系数分别为-0.902(p＜0.01)和-0.793(p＜0.01)。对照组与脓毒症组患者在年龄、性别、APACHEⅡ评分、AST、ALT、氧合指数和功能不全器官数目间无统计学差异(p＞0.05)。脓毒症组患者血清MDA水平(9.52±1.69nmol/mL)高于对照组(7.48±0.71nmol/mL),差异有统计学意义(p＜0.01),脓毒症组患者血清T-AOC水平(9.79±1.72单位/mL)低于对照组血清(14.05±1.81单位/mL),差异有统计学意义(p＜0.01)。
脓毒症患者血清MDA水平和APACHEⅡ评分、血清C反应蛋白呈正相关,其相关系数分别为0.844(p＜0.05)和0.663(p＜0.05);而血清MDA和氧合指数呈负相关,相关系数为-0.409(p＜0.05)。对脓毒症患者血清MDA水平与功能不全器官数目进行Spearman等级相关分析,两者呈正相关,相关系数为0.717(p＜0.01)。
脓毒症患者中死亡组和存活组比较:年龄和性别无统计学差异(p＞0.05);APACHEⅡ评分、C反应蛋白、氧合指数和功能不全器官数目有统计学差异(p＜0.05);死亡组血清MDA水平(11.36±1.44 nmol/mL)高于存活组(8.91±1.29nmol/mL),差异有统计学意义(p＜0.01);死亡组血清T-AOC水平(7.86±1.38单位/mL)低于对照组(10.44±1.29单位/mL),差异有统计学意义(p＜0.01)。Logistic回归分析结果表明,脓毒症患者血清MDA水平是影响其预后的危险因素(B值=1.216 S.E值=0.439 p值=0.006 Exp值=3.372)。应用APACHEⅡ评分判断脓毒症患者预后的ROC曲线下面积为(0.888±0.061),应用血清MDA水平判断脓毒症患者预后的ROC曲线下面积为(0.891±0.057),两者比较无统计学差异(p＞0.05)。
结论:
1.脓毒症患者血MDA水平上升,T-AOC水平下降,体内处于严重的氧化应激状态。
2.脓毒症患者血MDA水平能反映其病情严重程度,血MDA水平高者病情严重。
3.脓毒症患者血MDA水平可帮助判断其预后,血MDA水平高者预后不良。
Objective:To observe the relationship between oxidative stress status and prognosis in the patients with sepsis,and to investigate the influence of oxidative stress status to the prognosis.
Methods:The 45 patients who were divided into sepsis group and non-sepsis group, were studied after they were admitted to emergency observation room and ICU of Tianjin Medical University General hospital from August 2007 to December 2007. The 32 patients with sepsis who met sepsis criteria according to 2001 SCCM/ESICM/ACCP/AIS/SIS International Sepsis Definition Conference were selected as sepsis group,other 13 patients were selected as non-sepsis group.Patients who used antioxidant in recent three months were excluded.We collected clinical variables of all patients after they were hospitalized within 24 hours,and calculated APACHEⅡscore.At the same time,in order to explore the oxidative stress status of patients,serum malondialdehyde(MDA)and total antioxidative capacity(T-AOC) were also measured in the first day.Based on a Single factor logistic regression analysis to define the risk factors,we performed the multinomial logistic regression analysis and found independent risk factors which had important effect on clinical. We divided the 32 patients with sepsis into non-survival group and survival group, according to the prognosis,and compare the clinical variable difference between the two groups.We also used receiver-operating-characteristic curve(ROC)analysis in serum MDA and APACHEⅡscore for prognosis in the patients with sepsis.
Results:There are negative correlation between the serum MDA and T-AOC both in sepsis group(r=-0.902)and non-sepsis group(r=-0.793).Between sepsis group and non-sepsis group,there are significant difference in serum MDA(sepsis group 9.52±1.69nmol/mL,non-sepsis group 7.48±0.71nmol/mL,p＜0.01),and T-AOC(sepsis group 9.79±1.72U/mL,non-sepsis group 14.05±1.81U/mL,p＜0.01).
We performed the bivariate correlations analysis between serum MDA and clinical variables which reflect the severity of sepsis,and found that there are positive correlation between serum MDA and APACHEⅡscore(r=0.844),the numbers of dysfunctional organ(r=0.717),C reactive protein(r=0.663),oxygenation index(r=-0.409).
There are also significant difference in serum MDA(non-survival group11.36±1.44nmol/mL,survival group 8.91±1.29nmol/mL,p＜0.01),and T-AOC(non-survival group 7.86±1.38U/mL,survival group 10.44±1.29U/mL,p＜0.01)between non-survival group and survival group of patients with sepsis.After performing the multinomial logistic regression analysis,we found that serum MDA is a independent risk factors for prognosis in the patients with sepsis.The area under ROC curve for serum MDA was 0.888±0.061,for the APACHEⅡscore was 0.891±0.057.
Conclusions:
1.In the patients with sepsis,serum MDA is increased,and serum T-AOC is decreased.Septic patients exist severe oxidative stress.
2.The serum MDA level can reflect the severity of sepsis.The higher level of serum MDA,the more severe sepsis.
3.According to the serum MDA level,we can predict the prognosis of the patients with sepsis effectively.The high serum MDA level is a predictor of poor prognosis in the septic patients.
方法:以天津医科大学总医院急救中心2007年8月～2007年12月连续5个月内收治的32例脓毒症患者和13例非脓毒症患者为研究对象。脓毒症患者均符合2001年美国危重病医学会/欧洲危重病医学会/美国胸科医师协会/美国胸科协会/美国外科感染学会(SCCM/ESICM/ACCP/AIS/SIS)联席会议提出的脓毒症诊断标准。两组患者近三个月来均未接受过抗氧化药物治疗。收集所有入选病例入院24小时内临床参数:年龄、性别、生命体征、血常规、电解质、血糖、肝功能、心肌酶、肾功能和血气分析,并计算其急性生理和慢性健康评分(acutephysiology and chronic health evaluationⅡscore,APACHEⅡ评分)。同时于24小时内检测研究对象的血清丙二醛(malondialdehyde,MDA)和总抗氧化力(totalantioxide capacity,T-AOC)水平,作为评价机体氧化应激状态的指标。将上述数据录入计算机采用SPSS13.0统计软件进行数据处理。定量资料进行正态性检验(K-S法)。正态分布的定量资料用均数±标准差表示,非正态分布的资料用中位数、最小值和最大值表示。对照组与脓毒症组间、脓毒症患者存活组和死亡组间:正态分布、方差齐的计量资料采用独立样本的t检验;正态分布、方差不齐的计量资料则采用t'检验;非正态分布的计量资料采用秩和检验;定性资料采用x~2检验。脓毒症组中,按患者存活或死亡的转归,先进行单因素分析,在单因素分析得出有意义指标的基础上进行多因素非条件Logistic回归分析,筛选出对判断预后有意义的指标,再以对判断预后有意义的指标绘制受试者工作特征曲线(receiver operator characteristic curve,ROC),分别计算各个指标的ROC曲线下面积,并比较其判断预后的价值。
结果:无论在脓毒症组,还是在对照组血清MDA和T-AOC水平均呈负相关,相关系数分别为-0.902(p＜0.01)和-0.793(p＜0.01)。对照组与脓毒症组患者在年龄、性别、APACHEⅡ评分、AST、ALT、氧合指数和功能不全器官数目间无统计学差异(p＞0.05)。脓毒症组患者血清MDA水平(9.52±1.69nmol/mL)高于对照组(7.48±0.71nmol/mL),差异有统计学意义(p＜0.01),脓毒症组患者血清T-AOC水平(9.79±1.72单位/mL)低于对照组血清(14.05±1.81单位/mL),差异有统计学意义(p＜0.01)。
脓毒症患者血清MDA水平和APACHEⅡ评分、血清C反应蛋白呈正相关,其相关系数分别为0.844(p＜0.05)和0.663(p＜0.05);而血清MDA和氧合指数呈负相关,相关系数为-0.409(p＜0.05)。对脓毒症患者血清MDA水平与功能不全器官数目进行Spearman等级相关分析,两者呈正相关,相关系数为0.717(p＜0.01)。
脓毒症患者中死亡组和存活组比较:年龄和性别无统计学差异(p＞0.05);APACHEⅡ评分、C反应蛋白、氧合指数和功能不全器官数目有统计学差异(p＜0.05);死亡组血清MDA水平(11.36±1.44 nmol/mL)高于存活组(8.91±1.29nmol/mL),差异有统计学意义(p＜0.01);死亡组血清T-AOC水平(7.86±1.38单位/mL)低于对照组(10.44±1.29单位/mL),差异有统计学意义(p＜0.01)。Logistic回归分析结果表明,脓毒症患者血清MDA水平是影响其预后的危险因素(B值=1.216 S.E值=0.439 p值=0.006 Exp值=3.372)。应用APACHEⅡ评分判断脓毒症患者预后的ROC曲线下面积为(0.888±0.061),应用血清MDA水平判断脓毒症患者预后的ROC曲线下面积为(0.891±0.057),两者比较无统计学差异(p＞0.05)。
结论:
1.脓毒症患者血MDA水平上升,T-AOC水平下降,体内处于严重的氧化应激状态。
2.脓毒症患者血MDA水平能反映其病情严重程度,血MDA水平高者病情严重。
3.脓毒症患者血MDA水平可帮助判断其预后,血MDA水平高者预后不良。
Objective:To observe the relationship between oxidative stress status and prognosis in the patients with sepsis,and to investigate the influence of oxidative stress status to the prognosis.
Methods:The 45 patients who were divided into sepsis group and non-sepsis group, were studied after they were admitted to emergency observation room and ICU of Tianjin Medical University General hospital from August 2007 to December 2007. The 32 patients with sepsis who met sepsis criteria according to 2001 SCCM/ESICM/ACCP/AIS/SIS International Sepsis Definition Conference were selected as sepsis group,other 13 patients were selected as non-sepsis group.Patients who used antioxidant in recent three months were excluded.We collected clinical variables of all patients after they were hospitalized within 24 hours,and calculated APACHEⅡscore.At the same time,in order to explore the oxidative stress status of patients,serum malondialdehyde(MDA)and total antioxidative capacity(T-AOC) were also measured in the first day.Based on a Single factor logistic regression analysis to define the risk factors,we performed the multinomial logistic regression analysis and found independent risk factors which had important effect on clinical. We divided the 32 patients with sepsis into non-survival group and survival group, according to the prognosis,and compare the clinical variable difference between the two groups.We also used receiver-operating-characteristic curve(ROC)analysis in serum MDA and APACHEⅡscore for prognosis in the patients with sepsis.
Results:There are negative correlation between the serum MDA and T-AOC both in sepsis group(r=-0.902)and non-sepsis group(r=-0.793).Between sepsis group and non-sepsis group,there are significant difference in serum MDA(sepsis group 9.52±1.69nmol/mL,non-sepsis group 7.48±0.71nmol/mL,p＜0.01),and T-AOC(sepsis group 9.79±1.72U/mL,non-sepsis group 14.05±1.81U/mL,p＜0.01).
We performed the bivariate correlations analysis between serum MDA and clinical variables which reflect the severity of sepsis,and found that there are positive correlation between serum MDA and APACHEⅡscore(r=0.844),the numbers of dysfunctional organ(r=0.717),C reactive protein(r=0.663),oxygenation index(r=-0.409).
There are also significant difference in serum MDA(non-survival group11.36±1.44nmol/mL,survival group 8.91±1.29nmol/mL,p＜0.01),and T-AOC(non-survival group 7.86±1.38U/mL,survival group 10.44±1.29U/mL,p＜0.01)between non-survival group and survival group of patients with sepsis.After performing the multinomial logistic regression analysis,we found that serum MDA is a independent risk factors for prognosis in the patients with sepsis.The area under ROC curve for serum MDA was 0.888±0.061,for the APACHEⅡscore was 0.891±0.057.
Conclusions:
1.In the patients with sepsis,serum MDA is increased,and serum T-AOC is decreased.Septic patients exist severe oxidative stress.
2.The serum MDA level can reflect the severity of sepsis.The higher level of serum MDA,the more severe sepsis.
3.According to the serum MDA level,we can predict the prognosis of the patients with sepsis effectively.The high serum MDA level is a predictor of poor prognosis in the septic patients.
引文
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[48] Zeitz O, Maass AE, Nguyen PV, et al. Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode[J].Circ Res,2002,90:988-995.
[49]Sakaguchi S,Furusawa S.Oxidative stress and septic shock:metabolic aspects of oxygen-derived free radicals generated in the liver during endotoxemia[J].FEMS Immunol Med Microbiol,2006,47:167-177.
[50]Osakabe N,Yasuda A,Natsume M,et al.Rosmarinic acid,a major polyphenolic component of perilla frutescens,reduces lipopolysaccharide(LPs)-induced liver injury in d-galactosamine(d-galn)-sensitized mice[J].Free Radic BiolMed,2002,33:798-806.
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[52]Kolgazi M,Sener G,Cetinel S,et al.Resveratrol reduces renal and lung injury caused by sepsis in rats[J].J Surg Res,2006,134:315-21.
[53]Jung SE,Youn YK,Lim YS,et al.Combined administration of glutarnine and growth hormone synergistically reduces bacterial translocation in sepsis[J].Korean Med Sci,2003,18:17-22.
[54]Sener G,Arbak.S,Kurtaran P,et al.Estrogen protects the liver and intestines against sepsis-induced injury in rats[J].Surg Res,2005,128:70-78.
[55]姚咏明,林洪远,柴家科.现代脓毒症理论与实践[M].北京:科学出版社,2005:203-204.
[56]Fehsei K,Kroncke KD,Meyer KL,et al.Nitric oxide induces apoptosis in mouse thymocytes[J].Immunol,1995,155:2858-2865.
[57]Bornstein SR,Licinio J,Tauchnitz R,et al.Plasma Leptin Levels Are Increased in Survivors of Acute Sepsis:Associated Loss of Diurnal Rhythm in Cortisol and Leptin Secretion[J].J.Clin.Endocrinol.Metab,1998,83:280-283.
[58]Chuang CC,Shiesh SC,Chi CH,ea al.Serum total antioxidant capacity reflects severity of illness in patients with severe Sepsis.Crit Care,2006,10:R36.
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[60] Kapoor K, Basu S, BK Das, et al. Lipid Peroxidation and Antioxidants in Neonatal Septicemia [J]. J Trop Pediatr, 2006, 52: 372 - 375.
[61] Hsu DZ, Chien SP, Li YH, et al. Sesame Oil Attenuates Hepatic Lipid Peroxidation by Inhibiting Nitric Oxide and Superoxide Anion Generation in Septic Rats [J]. JPEN J Parenter Enteral Nutr, 2008, 32: 154 -159.
[62] Victor VM, Rocha M, Esplugues JV, et al. Role of free radicals in sepsis:antioxidant therapy [J]. Curr Pharm Des, 2005, 11: 3141-3158.
[63] Sica V, Slutsky AS, Zhang H, et al. Role of oxidative stress in experimental sepsis and multisystem organ dysfunction [J]. Free Radic Res, 2006,40: 665-672.
[1] Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis [J]. N Engl J Med, 2003, 348:138-150.
[2] Angus DC, Linde-Zvi-irble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associatedcosts of care[J].Crit Care Med, 2001, 29:1303-1310.
[3] Awad SS. State-of-the-art therapy for severe sepsis and multisystem organ dysfunction [J]. Am J Surg, 2003, 186:23S- 30S.
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[53]Jung SE,Youn YK,Lim YS,et al.Combined administration of glutarnine and growth hormone synergistically reduces bacterial translocation in sepsis[J].Korean Med Sci,2003,18:17-22.
[54]Sener G,Arbak.S,Kurtaran P,et al.Estrogen protects the liver and intestines against sepsis-induced injury in rats[J].Surg Res,2005,128:70-78.
[55]姚咏明,林洪远,柴家科.现代脓毒症理论与实践[M].北京:科学出版社,2005:203-204.
[56]Fehsei K,Kroncke KD,Meyer KL,et al.Nitric oxide induces apoptosis in mouse thymocytes[J].Immunol,1995,155:2858-2865.
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[61] Hsu DZ, Chien SP, Li YH, et al. Sesame Oil Attenuates Hepatic Lipid Peroxidation by Inhibiting Nitric Oxide and Superoxide Anion Generation in Septic Rats [J]. JPEN J Parenter Enteral Nutr, 2008, 32: 154 -159.
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[1] Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis [J]. N Engl J Med, 2003, 348:138-150.
[2] Angus DC, Linde-Zvi-irble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associatedcosts of care[J].Crit Care Med, 2001, 29:1303-1310.
[3] Awad SS. State-of-the-art therapy for severe sepsis and multisystem organ dysfunction [J]. Am J Surg, 2003, 186:23S- 30S.
[4] Crimi E, Sica V, Slutsky AS, et al. Role of oxidative stress in experimental sepsis and multisystem organ dysfunction [J]. Free Radic Res, 2006, 40: 665-72.
[5] Sener G, H Toklu, Kapucu C, et al. Melatonin protects against oxidative organ injury in a rat model of sepsis [J]. Surg Today, 2005, 35:52-59.
[6] Hsu DZ, Liu MY. Effects of sesame oil on oxidative stress after the onset of sepsis in rats [J]. Shock, 2004, 22: 582-585.
[7] Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis [J]. Br J Anaesth, 2003, 90: 221-232.
[8] Khadour FH, Panas D, Ferdinandy P, et al. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats [J]. Am J Physiol Heart Circ Physiol, 2002,283: H1108-H1115.
[9] Lancel S, Tissier S, Mordon S, et al. Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats [J]. J Am Coll Cardiol, 2004,43: 2348 - 2358.
[10] Steendijk P. The role of nitric oxide signaling in sepsis-induced myocardial dysfunction [J]. Crit Care Med, 2006, 34: 255-257.
[11] Harsdorf RV, Li PF, Dietz R. Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis [J]. Circulation, 1999, 99: 2934-2941.
[12] Aikawa R, Nagai T, Tanaka M, et al. Reactive oxygen species in mechanical stress-induced cardiac hypertrophy [J]. Biochem Biophys Res Commun, 2001, 289:901-907.
[13] Roelofsen H, Schoemaker B, Bakker C, et al. Impaired hepato-canalicular organic anion transport in endotoxemic rats[J].Am j Physiol,1995,269:G427-G434.
[14]Kirshenbaum LA,Moissac D.The bcl-2 gene product prevent programmed cell death of ventricular myocytes[J].Circulation,1997,96:1580-1585.
[15]Carlson D,Maass DL,White DJ,et al.Antioxidant vitamin therapy alters sepsis related apoptotic myocardial activity and inflammatory responses[J].Am J Physiol Heart Circ Physiol,2006,291:H2779-H2789.
[16]Fujishima S,Aikawa H.Neutrophil-mediated tissue injury and its modulation [J].Intens Care Med,1995,21:277-285.
[17]Vogelmeier C,Biedermann T,Maier K,et al.Comparative loss of activity of recombinant secretory leukoprotease inhibitor and alpha 1-protease inhibitor caused by different forms of oxidative stress[J].Ear Respir,1997,10:2114-2119.
[18]Gibot S,Levy B,Neviere R,et al.Myocardial dysfunction and septic shock[J].Med Sci(Paris),2004,20:1115-118.
[19]Mink SN,Bose R,Roberts DE,et al.Lysozyme binding to endocardial endothelium mediates myocardial depression by the nitric oxide guanosine 3',5'monophosphate pathway in sepsis[J].Mol Cell Cardiol,2005,39:615-625
[20]Zeitz O,Maass AE,Nguyen PV,et al.Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode[J].Circ Res,2002,90:988-995.
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