中华急诊医学杂志  2016, Vol. 25 Issue (3): 356-361
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蒋舒玉, 吕菁君, 魏捷, 孙胜男, 王蕊, 杨卫泽, 田丹. 血清肾上腺髓质素前体在闭合性小肠破裂患者预后评估中的作用[J]. 中华急诊医学杂志, 2016, 25(3): : 356-361.
Xiang Yawei, Xiang Heping, Gao Ming, Li He, Wang Wei. The value of serum pro-adrenomedullin for assessing prognosis of patients with closed rupture of small intestine[J]. Chin J Emerg Med, 2016, 25(3): : 356-361.
血清肾上腺髓质素前体在闭合性小肠破裂患者预后评估中的作用
相亚伟, 项和平 , 高明, 李贺, 王伟     
230601 合肥，安徽医科大学第二附属医院急诊外科
收稿日期：2015-08-30
通信作者：项和平，Email: xhping1968@aliyun.com
摘要： 目的 通过动态监测闭合性小肠破裂患者血清肾上腺髓质素前体(pro-adrenomedullin, pro-ADM)水平，探讨此类患者术前血清pro-ADM水平与术后继发腹腔感染之间的关系；以及术后血清pro-ADM水平对其术后腹腔感染严重程度的评估价值。 方法 选取安徽医科大学第二附属医院急诊外科2014年6月至2015年5月收治的85例闭合性小肠破裂患者；并依据患者术后是否发生腹腔感染，分感染组及无感染组；感染组依据其感染严重程度分为SIRS，脓毒症，严重脓毒症，脓毒症休克四组。分别于患者入院时及患者术后第1、3、5天检测血清pro-ADM、白细胞介素-6(IL-6)、C-反应蛋白(CRP)水平并行急性生理学与慢性健康状况评分系统Ⅱ(APACHE Ⅱ)评分。比较患者入院时各组指标之间的差异性及相关性，并通过对各指标预测患者术后发生腹腔感染进行ROC曲线阈值分析，比较各指标对此类患者术后发生腹腔感染预测价值。并对术后血清pro-ADM水平及APACHE Ⅱ评分结果进行相关性分析，比较两者对患者术后腹腔感染严重程度的评估价值。 结果 入院时及术后感染组血清pro-ADM(P=0.03，P＜0.01)、IL-6(P=0.02，P＜0.01)水平及APACHE Ⅱ评分(均P＜0.01)显著高于无感染组(P＜0.05)；感染组术后血清pro-ADM水平及APACHE Ⅱ评分随感染严重程度增加而升高(r=0.924)，且各组之间差异具有统计学意义(P＜0.05)，而各组IL-6及CRP水平差异无统计学意义。 结论 (1)闭合性小肠破裂患者术前血清pro-ADM水平对预测患者术后继发腹腔感染有一定的预测价值。(2)患者术后血清pro-ADM水平对患者术后腹腔感染严重程度有一定的评估作用。
关键词： 闭合性小肠破裂     肾上腺髓质素前体     白细胞介素-6     C-反应蛋白     感染    
The value of serum pro-adrenomedullin for assessing prognosis of patients with closed rupture of small intestine
Xiang Yawei, Xiang Heping , Gao Ming, Li He, Wang Wei     
Emergency Department, Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
Corresponding author: Xiang Heping, Email: xhping1968@aliyun.com
Abstract: Objective To explore the relationship between preoperative serum pro-adrenomedullin (pro-ADM) in the patients with closed rupture of small intestine, and postoperative secondary abdominal infection, and to study the value of postoperative serum pro-ADM in assessment of severity of postoperative secondary abdominal infection of this patients. Methods Eighty-five patients with closed rupture of small intestine treated in the emergency surgery from June 2014 to May 2015 were selected. According to the presence of postoperative abdominal infection or not, these patients were divided into infection group and non-infection group. The infection group was further divided into SIRS, sepsis, severe sepsis, septic shock subgroups as per the severity of infection. The levels of serum pro-ADM, interleukin-6 (IL-6), C- reactive protein (CRP) were determined and the acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score was calculated at admission and the first day、the second day and the third day after operation. Comparisons of these biomarkers were carried out to find out the factors associated with postoperative abdominal infection. In addition, ROC curve was used to verify the factors for predicting the abdominal infection of these patients after operation. The relationship between serum levels of pro-ADM and APACHEⅡ score after operation was analyzed. The severity of abdominal infection after operation was assessed with laboratory findings. Results Compared with non-infection group, preoperative and postoperative serum pro-ADM(P=0.03，P<0.01),IL-6(P=0.02，P<0.01) levels and APACHEⅡ scores (P<0.01，P< 0.01)were significantly higher in infection group (P<0.05). In the infection groups, the postoperative levels of serum pro-ADM and APACHEⅡscores were increased with the severity of infection increased (r=0.924), and the difference between the groups was statistically significant (P<0.05), but there were no significant differences in IL-6 and CRP levels between two groups. Conclusion (1)The serum levels of pro-ADM before operation has value in predicting the genesis of abdominal infection in these patients after operation. (2) The serum levels of pro-ADM after operation has value in severity assessment of abdominal infection in these patients after operation.
Key words: Closed rupture of small intestine     Pro-adrenomedullin     Interleukin -6     C-reactive protein     Infection    

随着交通及建筑行业的发展，创伤患者呈逐渐增加趋势，严重创伤已成为我国城市人口第5位死因，农村人口第4位死因[1]。 其中腹部损伤占整个创伤的比重亦逐渐增加。由于解剖关系，小肠损伤在闭合性腹部损伤中占有很大比例[2, 3]。小肠破裂后小肠液大量漏入腹腔，术后腹腔残余感染发生率极高，而腹腔感染引起的脓毒症又是患者死亡的主要原因之一。肾上腺髓质素(adrenomedullin，ADM)具有抗炎及炎症调节作用，可参与炎症感染时的病理生理过程[4, 5, 6, 7]。相关研究表明ADM可减缓脓毒症的发生和发展，并可作为脓毒症患者预后独立的预测因素[8, 9],但其检测较为困难。而肾上腺髓质素前体(pro-ADM)较ADM稳定，且pro-ADM可直接反映ADM活性水平，血清pro-ADM水平测定较简单[10, 11, 12]。本研究旨在通过动态检测血清pro-ADM水平，探讨闭合性腹部损伤致小肠破裂患者术前血清pro-ADM水平对其术后继发腹腔感染的预测价值以及患者术后血清pro-ADM水平对其所继发腹腔严重程度的评估意义。

1 资料与方法 1.1 一般资料

选取的安徽医科大学第二附属医院急诊科2014年6月至2015年5月收治的闭合性腹部损伤致使小肠破裂患者85例。排除标准：1)并存如下基础疾病者，消化道疾病如消化性溃疡、消化道肿瘤；严重腹腔外感染性疾病如尿路感染、肺部感染、丹毒等；免疫系统性疾病；2)患者早期死亡致使资料收集不全；3)开放性腹部损伤；4)合并其余腹腔脏器损伤如膀胱破裂、脾破裂、肝脏破裂及胰腺损伤等。实际纳入本次研究患者85例。根据术后是否出现腹腔感染分为无感染组30例，感染组55例，出现以下情况之一者考虑患者出现腹腔感染：1)有发热、腹痛、腹胀、腹膜炎体征；2)腹腔穿引流或穿刺液细菌培养阳性；3)再次手术有化脓性渗出、脓肿形成、组织坏死等腹腔内感染病变存在。将55例感染组患者根据1991年美国胸科医师协会/危重病医学会(ACCP/SCCM)关于脓毒症的定义[13]分为SIRS、脓毒症、严重脓毒症、脓毒症休克4组；SIRS须具备以下4点中的至少2点:1)体温>38.3 ℃或＜36.0 ℃；2)心率＞90次/min；3)呼吸>30次/min或过度通气,PaCO2＜32 mmHg(1 mmHg=0.133 kPa)；4)血白细胞计数＞12×109 L-1或＜4×109 L-1 或未成熟粒细胞＞10%；或者患者微生物培养有细菌生长、X线胸片发现新生浸润影。

1.2 患者基本情况

其中男性患者55例，女性30例；年龄18~65岁；行肠破裂修补+部分小肠切除+小肠吻合术57例；小肠造瘘28例，其中死亡14例。

1.3 标本采集及分析

分别于入院时，术后第1、3、5天采集静脉血5 mL(每次两管)；一管离心分离血浆，-70 ℃保存待测，一管用于测定IL-6、CRP(由本院检验科完成)；并于每次采血时对患者进行APACHEⅡ评分。共采集血标本241份，pro-ADM用新型夹心免疫荧光测量法检测，试剂盒由德国Brahms公司提供，操作按说明书进行，完成pro-ADM检测。

1.4 统计学方法

使用SPSS 19.0软件进行统计学处理。计数资料以构成比表示，非正态分布计量资料以中位数(M)及四分位数(P25，P75)表示，正态分布计量资料以均数±标准差(x±s)表示；两组间比较采用两独立样本的非参数U检验,多组间比较采用多个独立样本的非参数检验;两因素相关分析用Spearman秩相关分析；以P＜0.05为差异具有统计学意义。

2 结果 2.1 单因素分析

无感染组及感染组两组患者临床资料比较，两组患者术前血清pro-ADM、IL-6水平及APACHEⅡ评分差异具有统计学意义(P＜0.05)；血清CRP水平差异无统计学意义(P＞0.05)；两组患者术后血清pro-ADM、IL-6、CRP水平及APACHEⅡ评分差异具有统计学意义(P＜0.05)(表 1、表 2)。无感染组术前与术后血清pro-ADM、IL-6、CRP、APACHEⅡ评分比较差异无统计学意义(P＞0.05)；感染组术前与术后血浆pro-ADM、IL-6、APACHEⅡ评分比较差异无统计学意义(P＜0.05)，血浆CRP 差异具有统计学意义(P＞0.05)。

表 1 入院时无腹腔感染组及腹腔腔感染组血浆pro-ADM、IL-6、CRP及APACHEⅡ评分比较[M(P25，P75)] Table 1 The comparisons of pro-ADM，IL-6，CRP and APACHEⅡscores between non-abdominal infection group and abdominal infection group at admission of patients [M(P25，P75)]
        指标 无腹腔感染组(n=30) 腹腔感染组(n=55) P值
年龄(岁， x±s) a 39.8±11.5 42.3±10.7 0.22
性别(例，%) b
  男 18(60) 37(67.3) 0.15
  女 12(40) 18(22.7) 0.17
pro-ADM(μg/L) c 0.10(0.06,0.13) 0.53(0.45,0.63) 0.03
IL-6(ng/L) c 54.19(44.21，64.09) 137.78(110.48,161.98) 0.02
CRP(mg/L) c 46.04(39.15,53.68) 50.49(36.87，75.27) 0.13
APACHEⅡ评分(分) c 3(2,4) 10(8,11) ＜0.01
注：aχ2检验； bANOVA；c U检验
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表 2 无腹腔感染组及腹腔感染组术后临床资料比较[M(P25，P75)] Table 2 The comparisons of clinical data between non-abdominal infection group and abdominal infection group after surgery[M(P25，P75)]
        指标 无腹腔感染组(n=30) 腹腔感染组(n=55) U值 P值
pro-ADM(μg/L) 0.12(0.09,0.14) 0.51(0.42,0.59) 11.54 ＜0.05
IL-6(ng/L) 60.19(50.15,68.93) 137.78(152.35,187.83) 15.65 ＜0.05
CRP(mg/L) 46.04(46.14,60.67) 110.49(90.56,130.43) 21.21 ＜0.05
APACHEⅡ评分(分) 2(1,3) 5(4,6) 11.45 ＜0.05
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2.2 腹腔感染组患者术后血浆pro-ADM、IL-6、CRP、APACHEⅡ评分结果

血清pro-ADM水平及APACHEⅡ评分感染严重程度的增加呈逐渐升高趋势，且pro-ADM浓度在脓毒症休克组中最高，各组之间差异具有统计学意义(P＜0.05)，见表 3。相关性分析发现血清pro-ADM水平及APACHEⅡ评分呈正相关性，pro-ADM水平(Y)关于APACHEⅡ评分线性方程式为Y=1.43+0.002 45X，Pearson相关系数r=0.924，P＜0.05，APACHEⅡ评分越高，血清pro-ADM水平越高，见图 1。

表 3 腹腔感染患者各分组间患者术后血浆pro-ADM、IL-6、CRP、APACHEⅡ评分比较[M(P25，P75)] Table 3 The comparisons of pro-ADM,IL-6,CRP and APACHEⅡscores after surgery between groups with different severities of abdominal infection[M(P25，P75)]
        指标 SIRS组(n=33) 脓毒症组(n=11) 严重脓毒症组(n=6) 脓毒症休克组(n=5)
标本数 90 32 16 13
pro-ADM(μg/L) 0.47(0.34，0.57) 1.36(0.85，1.76) a 3.35(2.41，4.37) ab 6.65(5.21，7.99) abc
IL-6(ng/L) 152.63(127.23，178.34) 128.65(124.25，171.37) 215.34(180.21，254.35) a 167.34(140.15，195.61)
CRP(mg/L) 104.35(82.21，125.35) 100.21(80.15，121.31) 133.24(110.21，148.78) 121.57(96.25，144.86)
APACHEⅡ评分(分) 4(3,5) 9(9,10.5) a 14(12,15) ab 19(18,21) abc
注：与SIRS组比较，aP＜0.05；与脓毒症组比较，bP＜0.05；与严重脓毒症组比较，cP＜0.05
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图 1 术后腹腔感染患者血浆pro-ADM水平及APACHEⅡ评分相关性分析(n=55) Fig 1 The correlation analysis of plasma levels of pro-ADM in infected patients and APACHEⅡ score in the abdominal infection patient after operation(n=55)
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2.3 阈值分析

85例闭合性腹部损伤致使小肠破裂患者入院时血清pro-ADM、IL-6、CRP水平及APACHEⅡ评分结果预测患者术后继发腹腔感染的阈值的受试者工作特征曲线(ROC曲线)分析见图 2，统计各种指标的曲线下面积(AUC)、阈值、敏感度、特异度见表 4。

图 2 术前血浆pro-ADM、IL-6、CRP水平及APACHEⅡ评分结果预测患者术后继发腹腔感染的ROC曲线比较 Fig 2 The ROC curve analysis of preoperative plasma pro-ADM, IL-6, CRP levels and APACHEⅡ score results to predict postoperative abdominal infection
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表 4 术前血浆pro-ADM、IL-6、CRP水平及APACHEⅡ评分结果预测患者术后继发腹腔感染的ROC曲线评估结果 Table 4 The assessment results of ROC curve analysis for preoperative plasma pro-ADM, IL-6, CRP levels and APACHEⅡ score results to predict postoperative abdominal infection
        指标 AUC 阈值 敏感度(%) 特异度(%)
pro-ADM 0.88 0.79 μg/L 85 72
IL-6 0.72 164.00 ng/L 74 69
CRP 0.54 110.00 mg/L 53 59
APACHEⅡ评分 0.81 13 81 76
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3 讨论

急性闭合性腹部损伤是常见的急腹症之一，且其发生率逐年升高[14]；在腹部损伤中，空场脏器较容易受伤，造成腹腔污染。对腹部损伤而言，有文献提示腹部损伤继发腹腔感染患者，其病死率可达60%[15, 16]。对于腹部外伤致肠破裂患者，术后腹腔感染致患者病死率较高，预后较差[17]。因此，如何在腹部损伤致肠管破裂患者术后早期的评估其腹腔感染的发生及其严重程度，对腹部损伤致肠破裂患者术后治疗尤为重要。

机体在感染时，尤其在严重感染时，内皮屏障功能出现降低甚至丧失，相关实验表明，肾上腺素(ADM)有对上述的屏障功能有稳定作用[17, 18]，且具有调节免疫、代谢和血管活性作用，不仅有助于保持器官的血液供应且通过调节补体活性使其以及加强抗菌能力[4, 5, 6, 7]。pr-ADM可降解为ADM，参与炎症反应，目前国内外对pro-ADM研究主要在获得性肺炎领域及新生儿感染领域。有相关研究表明，血清pro-ADM水平对获得性肺炎患者脓毒症严重程度有一定评估价值[19, 20, 21, 22, 23]，对早期发现新生儿发生重度感染及感染严重程度有一定价值[24]，而在闭合性腹部损伤致小肠破裂患者术后继发感染领域研究较少。本研究发现，对于腹腔感染组患者术前血清pro-ADM明显高于无腹腔感染组，差异具有统计学意义(P＜0.05)，术前各指标ROC曲线分析当设定血浆pro-ADM阈值在0.79 μg／L时，对预测腹部损伤致肠管破裂患者术后发生腹腔感染的敏感度为85％，特异度为72％。其预测的准确性与APACHE Ⅱ评分相当，比IL-6、CRP更精确，目前也有类似研究结果[12, 22]；因此本研究认为血清pro-ADM对此类患者术后继发腹腔感染有一定的预测价值。对于腹腔感染组，患者血清pro-ADM水平及APACHE Ⅱ评分随着感染严重程度的增加而上升，并对二者进行相关性分析发现，pro-ADM水平与APACHE Ⅱ评分呈显著正相关性；对SIRS组、脓毒症组、严重脓毒症组及脓毒症休克组进行各组之间比较，发现各组之间血清pro-ADM水平差异具有统计学意义(P＜0.05)，因此本研究认为血清pro-ADM对患者术后腹腔感染严重程度的评估具有一定的价值。APACHE Ⅱ评分被认为是评估疾病严重程度的指标，并与预后密切相关，但因其涉及到患者预定的12项急性生理学和慢性健康状况参数，在实际操作中比较费时、操作不便。本次研究结果认为，血清pro-ADM对闭合性腹部损伤致小肠破裂患者术后发生腹腔感染的预测以及感染严重程度的评估价值与APACHE Ⅱ评分相当，但血清pro-ADM水平测定方法简单，便于操作，且更加精确，因此pro-ADM对闭合性小肠破裂患者的预后评估有一定的临床价值。

此次研究由于时间及条件限制，实验样本量较少，仍需进大样本实验研究，进一步证明其作为临床常规指标的可行性。此外，因腹部损伤致肠破裂患者术后常规加强抗感染、血液净化治疗，促炎因子及细胞因子类物质生成受到影响，导致患者血清IL-6及CRP水平与以往大量实验研究中数据有所差异[25]。

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