轻症全身炎症反应综合征患儿体内促炎细胞因子的变化及其意义
摘要
前言
全身炎症反应综合征(SIRS)指机体对感染或非感染性损害的全身炎症反应。SIRS的发病是由于炎症介质的大量、失控性释放，形成复杂的级联反应网络从而造成损害，这种反应一旦启动，并不会因致病因素的解除而停止，如果病理过程不被及时阻断的话，可导致多器官功能不全(MODS)甚至多器官衰竭(MOF)。故了解SIRS发病机理，从而早期监测、诊断、治疗SIRS对改善疾病预后有重要意义。
许多研究已表明SIRS时的细胞因子显著升高，升高水平与病情严重程度及预后有关，但目前SIRS的研究主要集中在严重全身炎症反应的病人上，对病情相对较轻的SIRS病人体内细胞因子变化的研究不多。本研究利用小儿危重病例评分选取轻症SIRS病人，测定血中IL-1β、IL-6、IL-8、TNF-α水平，旨在了解促炎因子在轻症SIRS病人中的变化及意义，并探讨小儿危重病例评分在SIRS病情判断中的作用。
对象与方法
一、研究对象的选取
1．实验组：广州市儿童医院2001年1～12月间在PICU及普通病房住院的符合SIRS诊断标准且小儿危重病例评分大于80分的病儿43例，其中＜1岁15例，1～3岁10例，3～7岁10例，＞7岁8例，男24例，女19例。
诊断标准：根据1996年第二届儿科ICU大会Hayden提出的小儿SIRS四项诊断标准，具有两项或两项以上指标者可诊断SIRS。
小儿危重病例评分根据1995年第四届全国小儿急救医学研讨会上提出的草案及1996年小儿危重病例评分试用协作组对草案的调整意见进行，评分＞80为病情非危重状态。
2．对照组：同期在广州市儿童医院保健科进行抽血体检的健康儿童48人，其中＜1岁7例，1～3岁26例，3～7岁11例，＞7岁4例，男29例，女
19例。
二、方法
(一)主要仪器及试剂:
离心机，一70℃冰箱，IMMUH亚，一1000全自动酶放大化学发光免疫分
析系统及IL一l日、IL石、IL名、TNF一a试剂盒。
(二)标本采集:
实验组在诊断评分后的24小时内抽血3nil，以3500甲m的速度离心5
分钟，取上清夜，保存于一70℃冰箱中备用，将对照组体检抽血作常规检查
后所剩的血清保存于一70℃冰箱中备用。
(三)检测:
1.从冰箱中取出标本，解冻后加50一100微升到标本杯中。
2.从冷藏室中取出试剂盒，复温至室温。
3.启动全自动酶放大化学发光免疫分析仪，分别放人相应的标本试剂
锲、标本杯、测试杯，再分别用IL一1日、][L石、IL一8及TNF一a试剂在全自动化学
发光免疫分析仪上检测各指标。
(四)统计学分析:
部分数据以均数(标准差表示，计数资料用t检验，计量资料用(才检
验，P>0.05表示无显著性差异，P<0.05表示有显著性差异。
实验结果
一、实验组43例病人及正常对照.组43例儿童IL一lp全部 二、IL石水平检测:实验组25例病人IL石水平 而;正常对照组35例 05，有显著性差异。
三、IL一8水平检测:实验组22例病人IL一8水平 耐;正常对照组20例0.
05，无显著性差异。
四、实验组和对照组各一例TNF一a浓度<4p扩耐，实验组平均水平为
n.4o士6.45p群d，对照组平均水平为13.32士7.26p群nil。两组数值经t
检验，P>0，05，无显著性差异。
讨论
SIRS的发病机制有三种假说:细胞因子假说、正反馈学说和促炎/抗炎
失衡学说。这三种学说的共同点是sIRS过程中炎症介质大量、失控性释
放，并相互刺激、诱导、调节，形成复杂的级联反应网络，从而造成病理损害。
在众多炎症介质中，TNF一a、IL一1日、IL石、几名等主要参与过度炎症反应，称
为促炎细胞因子，其中TNF一a是网络的初级细胞因子，起启动、触发级联反
应网络的作用。IL一lp产生较早，与TNF一a有协同作用，可进一步刺激IL石
的产生，是细胞因子级联反应过程:TNF一a*IL一1日*IL石的中间环节。lL石
由TNF一。、IL一1刺激产生，通常认为它的产生和到达高峰时间比TNF一a晚，
在SIRS阶段升高，浓度与疾病严重程度相关。
关于促炎细胞因子水平在SIRS病人中的临床意义，研究很多。大多数
对SIRS的研究显示，促炎因子水平与疾病严重度及预后呈正相关关系。许
多研究表明TNF一a在全身炎症反应时升高，产生早，到达高峰快，其升高程
度与疾病严重程度有关。对于SIRS病人血IL一lp水平，测定结果不一，有
实验显示SIRS早期IL一lp已有明显升高，提示IL一1日是早期炎症因子，而也
有实验显示SIRS时几芍、lL一8升高，IL一，甲未升高，或仅在较重的病人才明
显升高。至于IL石的作用，HauPt的研究表明IL石>275n群L可证实为
SIRS，方步武则提出>25On岁L可诊断为SIRS。
在我们的实验中，与对照组相比，s]:RS病人IL石升高，，rNF一a、IL一lp、
IL一8无升高。这个结果显示人选的轻症SIRS病人体内已出现细胞因子的
过量释放，只是水平升高的IL石，其升高幅度与HauPt或方步武提出的水平
相比要低很多;其次，本实验SIRS病人的血TNF一a、IL一lp、IL一没有升高，
说
Preface
SIRS is the systemic inflammatory response to a variety insults, independent of its causes. It is induced by uncontrolled release of inflammatory mediators , these mediators interact with each other, and form a cytokine cascades network , result in tissue and organ injuries. Once the inflammatory response is initiated, it would continue and enlarge, regarding of its cause, MODS or even MOF would develop. Many studies have showed that cytokines in patients with SIRS increase significantly, high level of cytokines imply poor prognosis. Detecting and diagnosis of SIRS in early stage is significant to interrupt the pathophys-iologic process.
Up to now, less researches were reported on less severe SIRS patients. We chose less severe SIRS patients according to pediatric severity score, and determined their plasma level of IL-1,IL-6 IL-8 TNF-, and analyzed the changes of the cytokines in these patients.
Patients and Methods
1. Patients
The study was conduced from January to December 2001 in Guangzhou Children' s Hospital. We prospectively studied 43 SIRS patients with the score of severity less than 80, ageing from 1 month to 11 years old. Among them, 24 were boys and 19 girls.
Meanwhile, we chose 48 healthy children as control group.
2. Diagnoses
SIRS was defined using a modification of the guidelines developed by Hay-den in 1996. (1) temperature >38 C or <36 C; (2) heart rate higher than 2SD upon normal for age; (3) respiratory rate higher than 2SD upon normal for
age orPaC02 < 32mmHg ; (4) WBC count > 12000/mm3or <4000/mm3 or 10% immature forms on the peripheral blood smear. When two or more of these manifestations manifests the patient, SIRS can be diagnosed.
A severity score was calculated according to pediatric severity score criteria proposed in 1995 and modified in 1996.
3. Blood Collection and Laboratory Processing
Blood samples of SIRS patients and normal controls, 3ml blood each person , were collected within 24 hours after admission or on normal physical examination respectively. Blood samples were centrifuged at 1500g for 5min, and plasma was aspirated and stored at -70t.
The plasma was warmed in the lab, the levels of IL-lpxIL-6^IL-8xTNF-a were determined.
4. Statistical Analysis
Data were expressed as means SD. T test or x2 test were applied to compare the difference between two groups. Statistical significance was considered at the 5% level.
Results
1. IL-1 could not be detected in all of the 43 patients and 43 healthy children.
2. IL-6 could be detected in 18 patients of 43 SIRS patients and 2 among 37 healthy children. Significant difference was found between two groups, P < 0.01.
3. IL-8 could be detected in 21 out of 43 patients and in 17 out of 37 healthy children. There was no significant difference between two groups, P >0. 05.
4. Compared TNF- levels in the patients and healthy children with t test, there was no significant difference between them, p >0.05.
Discussion
There are three hypotheses about SIRS as following: cytokines hypothesis, positive feedback hypothesis and immunologic dissonance hypothesis. The same opinion of these hypotheses is that inflammatory mediators release uncontrollably ; the mediators interact and induce with each other, and form a complex cascade network, then tissues or organ injury develops. TNF- , IL-1 , IL-6 and IL-8 are proinflammatory cytokines among them. TNF is considered to be primary mediator, which initiates the systemic inflammatory response and induces the release of other cytokines, its level is related to the severity of disease. IL-1 pis also produced quiet earlier, it cooperate with TNF-. IL-6 release under the stimulation of TNF- and IL-1 , in general, its release is later than TNF-a and IL-1 .
Many studies have been performed on proinflammoty cytokines in SIRS. Many of them showed that TNF-, increase in the early stage of SIRS, its level is related to the severity. The level of IL-1 is quiet different in patients with SIRS, the trials by Wangtao and Huxiaomin suggested t
全身炎症反应综合征(SIRS)指机体对感染或非感染性损害的全身炎症反应。SIRS的发病是由于炎症介质的大量、失控性释放，形成复杂的级联反应网络从而造成损害，这种反应一旦启动，并不会因致病因素的解除而停止，如果病理过程不被及时阻断的话，可导致多器官功能不全(MODS)甚至多器官衰竭(MOF)。故了解SIRS发病机理，从而早期监测、诊断、治疗SIRS对改善疾病预后有重要意义。
许多研究已表明SIRS时的细胞因子显著升高，升高水平与病情严重程度及预后有关，但目前SIRS的研究主要集中在严重全身炎症反应的病人上，对病情相对较轻的SIRS病人体内细胞因子变化的研究不多。本研究利用小儿危重病例评分选取轻症SIRS病人，测定血中IL-1β、IL-6、IL-8、TNF-α水平，旨在了解促炎因子在轻症SIRS病人中的变化及意义，并探讨小儿危重病例评分在SIRS病情判断中的作用。
对象与方法
一、研究对象的选取
1．实验组：广州市儿童医院2001年1～12月间在PICU及普通病房住院的符合SIRS诊断标准且小儿危重病例评分大于80分的病儿43例，其中＜1岁15例，1～3岁10例，3～7岁10例，＞7岁8例，男24例，女19例。
诊断标准：根据1996年第二届儿科ICU大会Hayden提出的小儿SIRS四项诊断标准，具有两项或两项以上指标者可诊断SIRS。
小儿危重病例评分根据1995年第四届全国小儿急救医学研讨会上提出的草案及1996年小儿危重病例评分试用协作组对草案的调整意见进行，评分＞80为病情非危重状态。
2．对照组：同期在广州市儿童医院保健科进行抽血体检的健康儿童48人，其中＜1岁7例，1～3岁26例，3～7岁11例，＞7岁4例，男29例，女
19例。
二、方法
(一)主要仪器及试剂:
离心机，一70℃冰箱，IMMUH亚，一1000全自动酶放大化学发光免疫分
析系统及IL一l日、IL石、IL名、TNF一a试剂盒。
(二)标本采集:
实验组在诊断评分后的24小时内抽血3nil，以3500甲m的速度离心5
分钟，取上清夜，保存于一70℃冰箱中备用，将对照组体检抽血作常规检查
后所剩的血清保存于一70℃冰箱中备用。
(三)检测:
1.从冰箱中取出标本，解冻后加50一100微升到标本杯中。
2.从冷藏室中取出试剂盒，复温至室温。
3.启动全自动酶放大化学发光免疫分析仪，分别放人相应的标本试剂
锲、标本杯、测试杯，再分别用IL一1日、][L石、IL一8及TNF一a试剂在全自动化学
发光免疫分析仪上检测各指标。
(四)统计学分析:
部分数据以均数(标准差表示，计数资料用t检验，计量资料用(才检
验，P>0.05表示无显著性差异，P<0.05表示有显著性差异。
实验结果
一、实验组43例病人及正常对照.组43例儿童IL一lp全部
三、IL一8水平检测:实验组22例病人IL一8水平
05，无显著性差异。
四、实验组和对照组各一例TNF一a浓度<4p扩耐，实验组平均水平为
n.4o士6.45p群d，对照组平均水平为13.32士7.26p群nil。两组数值经t
检验，P>0，05，无显著性差异。
讨论
SIRS的发病机制有三种假说:细胞因子假说、正反馈学说和促炎/抗炎
失衡学说。这三种学说的共同点是sIRS过程中炎症介质大量、失控性释
放，并相互刺激、诱导、调节，形成复杂的级联反应网络，从而造成病理损害。
在众多炎症介质中，TNF一a、IL一1日、IL石、几名等主要参与过度炎症反应，称
为促炎细胞因子，其中TNF一a是网络的初级细胞因子，起启动、触发级联反
应网络的作用。IL一lp产生较早，与TNF一a有协同作用，可进一步刺激IL石
的产生，是细胞因子级联反应过程:TNF一a*IL一1日*IL石的中间环节。lL石
由TNF一。、IL一1刺激产生，通常认为它的产生和到达高峰时间比TNF一a晚，
在SIRS阶段升高，浓度与疾病严重程度相关。
关于促炎细胞因子水平在SIRS病人中的临床意义，研究很多。大多数
对SIRS的研究显示，促炎因子水平与疾病严重度及预后呈正相关关系。许
多研究表明TNF一a在全身炎症反应时升高，产生早，到达高峰快，其升高程
度与疾病严重程度有关。对于SIRS病人血IL一lp水平，测定结果不一，有
实验显示SIRS早期IL一lp已有明显升高，提示IL一1日是早期炎症因子，而也
有实验显示SIRS时几芍、lL一8升高，IL一，甲未升高，或仅在较重的病人才明
显升高。至于IL石的作用，HauPt的研究表明IL石>275n群L可证实为
SIRS，方步武则提出>25On岁L可诊断为SIRS。
在我们的实验中，与对照组相比，s]:RS病人IL石升高，，rNF一a、IL一lp、
IL一8无升高。这个结果显示人选的轻症SIRS病人体内已出现细胞因子的
过量释放，只是水平升高的IL石，其升高幅度与HauPt或方步武提出的水平
相比要低很多;其次，本实验SIRS病人的血TNF一a、IL一lp、IL一没有升高，
说
Preface
SIRS is the systemic inflammatory response to a variety insults, independent of its causes. It is induced by uncontrolled release of inflammatory mediators , these mediators interact with each other, and form a cytokine cascades network , result in tissue and organ injuries. Once the inflammatory response is initiated, it would continue and enlarge, regarding of its cause, MODS or even MOF would develop. Many studies have showed that cytokines in patients with SIRS increase significantly, high level of cytokines imply poor prognosis. Detecting and diagnosis of SIRS in early stage is significant to interrupt the pathophys-iologic process.
Up to now, less researches were reported on less severe SIRS patients. We chose less severe SIRS patients according to pediatric severity score, and determined their plasma level of IL-1,IL-6 IL-8 TNF-, and analyzed the changes of the cytokines in these patients.
Patients and Methods
1. Patients
The study was conduced from January to December 2001 in Guangzhou Children' s Hospital. We prospectively studied 43 SIRS patients with the score of severity less than 80, ageing from 1 month to 11 years old. Among them, 24 were boys and 19 girls.
Meanwhile, we chose 48 healthy children as control group.
2. Diagnoses
SIRS was defined using a modification of the guidelines developed by Hay-den in 1996. (1) temperature >38 C or <36 C; (2) heart rate higher than 2SD upon normal for age; (3) respiratory rate higher than 2SD upon normal for
age orPaC02 < 32mmHg ; (4) WBC count > 12000/mm3or <4000/mm3 or 10% immature forms on the peripheral blood smear. When two or more of these manifestations manifests the patient, SIRS can be diagnosed.
A severity score was calculated according to pediatric severity score criteria proposed in 1995 and modified in 1996.
3. Blood Collection and Laboratory Processing
Blood samples of SIRS patients and normal controls, 3ml blood each person , were collected within 24 hours after admission or on normal physical examination respectively. Blood samples were centrifuged at 1500g for 5min, and plasma was aspirated and stored at -70t.
The plasma was warmed in the lab, the levels of IL-lpxIL-6^IL-8xTNF-a were determined.
4. Statistical Analysis
Data were expressed as means SD. T test or x2 test were applied to compare the difference between two groups. Statistical significance was considered at the 5% level.
Results
1. IL-1 could not be detected in all of the 43 patients and 43 healthy children.
2. IL-6 could be detected in 18 patients of 43 SIRS patients and 2 among 37 healthy children. Significant difference was found between two groups, P < 0.01.
3. IL-8 could be detected in 21 out of 43 patients and in 17 out of 37 healthy children. There was no significant difference between two groups, P >0. 05.
4. Compared TNF- levels in the patients and healthy children with t test, there was no significant difference between them, p >0.05.
Discussion
There are three hypotheses about SIRS as following: cytokines hypothesis, positive feedback hypothesis and immunologic dissonance hypothesis. The same opinion of these hypotheses is that inflammatory mediators release uncontrollably ; the mediators interact and induce with each other, and form a complex cascade network, then tissues or organ injury develops. TNF- , IL-1 , IL-6 and IL-8 are proinflammatory cytokines among them. TNF is considered to be primary mediator, which initiates the systemic inflammatory response and induces the release of other cytokines, its level is related to the severity of disease. IL-1 pis also produced quiet earlier, it cooperate with TNF-. IL-6 release under the stimulation of TNF- and IL-1 , in general, its release is later than TNF-a and IL-1 .
Many studies have been performed on proinflammoty cytokines in SIRS. Many of them showed that TNF-, increase in the early stage of SIRS, its level is related to the severity. The level of IL-1 is quiet different in patients with SIRS, the trials by Wangtao and Huxiaomin suggested t
引文
1. Bone RC, Balk RA, Cerra FB, et al. Definition for sepsis and organ failure and guidelines for the use of irmovative therapies in sepsis [J]. Chest. 1991; 101: 1644-1655.,
2．蒋建新、田昆仑、陈惠新等．严重创伤患者血浆细胞因子变化及其与器官功能损害的关系．中华外科杂志，1997，37(7)：
3．王丽杰、刘春峰、袁壮等．危重患儿全身炎症反应综合征血清细胞因子的动态变化及其意义．中华急诊医学杂志，2003，12(5)：298-300．
4. Baue AE. A debate on the subject "Are SIRS and MODS important entities in the clinic evaluation of patients?" The con position. Shock. 2000; 14 (6): 590-593.
5. Marshall JC. SIRS and MODS: what is their relevance to the science and practice of intensive care.9 Shock. 2000 ; 14 (6): 586-589.
6. Vincent J-L. Dear SIRS, I'm sorry to say that I don't like you. Intensive Care Med. 2000;26(9): 1170-1171.
7．袁壮，刘春峰．危重患儿全身炎症反应综合征与临床应用评价．小儿急救医学，2000，7(4)：173-175．
8. Takala A, J0usela I, et al. Systemic inflammatory response syndrome without systemic inflammatory in acutely ill patients admitted to hospital in a medical emergency. Clin Sci (Lond). 1999; 96 (3): 287-295.
9. Levy MM, Fink MD, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003;29 (4): 530-583.
10．中华急诊医学会儿科学会急救学组．第四届全国小儿急救医学研讨会纪要[J]．中华儿科杂志，1995；33(6)：371～373．
11．小儿危重病例评分试用协作组．小儿危重病例评分法(草案)临床应用的评价[J]．中华儿科杂志，1998；36(10)：579～582．
12. Headley AS, Tolley E, et al. Infections and the inflammatory response in acute respiratory distress syndrome. Chest, 1997, 111 (5): 1306-1321.
13. Moggi C, Memmini G, et al. Severe inflammatory disease in children. Ra-
tionale for corticosteroid immunomodulating therapy: pathogenic therapy. Pediatr Med Chir, 1996,18 (4): 395-401.
14. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med, 1996; 24 (7): 1125-1128.
15．许国根、陈雯、张万光等．全身炎症反应综合征患者致炎因子与抗炎因子的变化和相关性研究．中国急救医学，2002，22(6)：320-321．
16．虎晓岷、尹文等．危重病患者多器官功能障碍综合征细胞因子变化的意义．中国急救医学，2001，21(12)：683-685．
17．王涛，文亮等．全脑再灌注损伤后：炎性细胞因子的变化及其意义．中国危重病急救杂志，2000，12(5)：290-292．
18. Sablotzki A, Mann V, Simm A, et al. Changes in the network through escalaling SIRS after heart disease. Anasthesiol Itensivmed Notfallmed Schmerzther,2001,36(9): 552-559.
19. Sablotzki A,Friedrich I, et al. The systemic inflammatory response syndrom following cardiac surgery:different expression of proinflammatory cytokines and procalcitonin in patients with and without multiorgan dysfunction. Perfusion, 2002,17 (2): 103-109.
20. Haupt W, Zirngibl H, et al. Depression of tumor necrosis factor-alpha, interleukin-6, and interleukin-10 production: a reaction to the initial systemic hyperactivation in septic shock. J Invest Surg. 1997; 10(6):349-55.
21．方步武、邱奇、崔乃强等．急腹症全身炎症反应综合征阶段细胞因子及炎症介质的变化特点．中国危重病急救医学，2001，13(9)：542-544．
22. Taniguchi T, koido Y, et al. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrom. Crit Care Med, 1999,27 (7): 1262-1264.
23. Gogos CA, Giali s, et al. nterleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis. Diabetologia. 2001; 44(8):1011-4.
24. Du B, Pan J, et al. Serum procalcitonin and intedeukin-6 levels may help to differentiate systemic inflammatory response of infectious and non-infectious origin. Chin Med J (Engl). 2003;116(4):538-42.
25. Bone. RC. Immunologic Dissonance:A continuing Evolution in Our Under-
standing of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple Organ Dysfunction Syndrome (MODS). Ann Intern Med. 1996; 125 (8): 680-7.
26. Salgado A, Boveda JL, Monasterio J, et al. Inflammatory mediator and their influence on haemostasis. Haemostasis, 1994,24(2): 132-138.
2．蒋建新、田昆仑、陈惠新等．严重创伤患者血浆细胞因子变化及其与器官功能损害的关系．中华外科杂志，1997，37(7)：
3．王丽杰、刘春峰、袁壮等．危重患儿全身炎症反应综合征血清细胞因子的动态变化及其意义．中华急诊医学杂志，2003，12(5)：298-300．
4. Baue AE. A debate on the subject "Are SIRS and MODS important entities in the clinic evaluation of patients?" The con position. Shock. 2000; 14 (6): 590-593.
5. Marshall JC. SIRS and MODS: what is their relevance to the science and practice of intensive care.9 Shock. 2000 ; 14 (6): 586-589.
6. Vincent J-L. Dear SIRS, I'm sorry to say that I don't like you. Intensive Care Med. 2000;26(9): 1170-1171.
7．袁壮，刘春峰．危重患儿全身炎症反应综合征与临床应用评价．小儿急救医学，2000，7(4)：173-175．
8. Takala A, J0usela I, et al. Systemic inflammatory response syndrome without systemic inflammatory in acutely ill patients admitted to hospital in a medical emergency. Clin Sci (Lond). 1999; 96 (3): 287-295.
9. Levy MM, Fink MD, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003;29 (4): 530-583.
10．中华急诊医学会儿科学会急救学组．第四届全国小儿急救医学研讨会纪要[J]．中华儿科杂志，1995；33(6)：371～373．
11．小儿危重病例评分试用协作组．小儿危重病例评分法(草案)临床应用的评价[J]．中华儿科杂志，1998；36(10)：579～582．
12. Headley AS, Tolley E, et al. Infections and the inflammatory response in acute respiratory distress syndrome. Chest, 1997, 111 (5): 1306-1321.
13. Moggi C, Memmini G, et al. Severe inflammatory disease in children. Ra-
tionale for corticosteroid immunomodulating therapy: pathogenic therapy. Pediatr Med Chir, 1996,18 (4): 395-401.
14. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med, 1996; 24 (7): 1125-1128.
15．许国根、陈雯、张万光等．全身炎症反应综合征患者致炎因子与抗炎因子的变化和相关性研究．中国急救医学，2002，22(6)：320-321．
16．虎晓岷、尹文等．危重病患者多器官功能障碍综合征细胞因子变化的意义．中国急救医学，2001，21(12)：683-685．
17．王涛，文亮等．全脑再灌注损伤后：炎性细胞因子的变化及其意义．中国危重病急救杂志，2000，12(5)：290-292．
18. Sablotzki A, Mann V, Simm A, et al. Changes in the network through escalaling SIRS after heart disease. Anasthesiol Itensivmed Notfallmed Schmerzther,2001,36(9): 552-559.
19. Sablotzki A,Friedrich I, et al. The systemic inflammatory response syndrom following cardiac surgery:different expression of proinflammatory cytokines and procalcitonin in patients with and without multiorgan dysfunction. Perfusion, 2002,17 (2): 103-109.
20. Haupt W, Zirngibl H, et al. Depression of tumor necrosis factor-alpha, interleukin-6, and interleukin-10 production: a reaction to the initial systemic hyperactivation in septic shock. J Invest Surg. 1997; 10(6):349-55.
21．方步武、邱奇、崔乃强等．急腹症全身炎症反应综合征阶段细胞因子及炎症介质的变化特点．中国危重病急救医学，2001，13(9)：542-544．
22. Taniguchi T, koido Y, et al. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrom. Crit Care Med, 1999,27 (7): 1262-1264.
23. Gogos CA, Giali s, et al. nterleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis. Diabetologia. 2001; 44(8):1011-4.
24. Du B, Pan J, et al. Serum procalcitonin and intedeukin-6 levels may help to differentiate systemic inflammatory response of infectious and non-infectious origin. Chin Med J (Engl). 2003;116(4):538-42.
25. Bone. RC. Immunologic Dissonance:A continuing Evolution in Our Under-
standing of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple Organ Dysfunction Syndrome (MODS). Ann Intern Med. 1996; 125 (8): 680-7.
26. Salgado A, Boveda JL, Monasterio J, et al. Inflammatory mediator and their influence on haemostasis. Haemostasis, 1994,24(2): 132-138.