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连续性血浆滤过吸附对重症急性胰腺炎细胞因子的调节作用

2019-04-04周恒杰刘思伯舒姣洁

中国医药导报 2019年4期
关键词:重症急性胰腺炎细胞因子

周恒杰 刘思伯 舒姣洁

[摘要] 目的 探討连续性血浆滤过吸附(CPFA)治疗重症急性胰腺炎的效果及其对肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)的影响。 方法 选择2014年10月~2018年6月大连市中心医院重症医学科收治的40例重症急性胰腺炎患者,根据治疗方法将其分为对照组(n = 20)和治疗组(n = 20)。对照组在常规治疗基础上行连续性静脉静脉血液滤过(CVVH)治疗72 h,治疗组在对照组基础上加用CPFA治疗。治疗前及治疗3、7 d后,测量血液中的TNF-α、IL-6、IL-10水平;比较治疗前后两组患者的生命体征、腹腔内压力、急性生理与慢性健康(APACHEⅡ)评分等,评估脏器功能,观察不良反应及预后。 结果 两组患者治疗前各临床指标比较,差异无统计学意义(P > 0.05)。治疗3 d后,两组心率、氧合指数、腹腔内压力及APACHEⅡ评分均较治疗前降低,平均动脉压、白细胞计数较治疗前升高,差异有统计学意义(P < 0.05);治疗组心率、腹腔内压力低于对照组,平均动脉压高于对照组,差异有统计学意义(P < 0.05)。治疗7 d后,两组心率、白细胞计数、腹腔内压力及APACHEⅡ评分均较治疗前降低,平均动脉压、氧合指数较治疗前升高,差异有统计学意义(P < 0.05);治疗组心率、腹腔内压力及APACHEⅡ评分低于对照组,平均动脉压高于对照组,差异有统计学意义(P < 0.05)。治疗前两组的TNF-α、IL-6、IL-10水平差异无统计学意义(P > 0.05)。血液净化治疗3 d,两组的促炎性细胞因子TNF-α、IL-6均较治疗前下降,且治疗组的TNF-α及IL-6水平低于对照组,差异有统计学意义(P < 0.05);两组的抗炎性细胞因子IL-10均升高,治疗组IL-10水平高于对照组,差异有统计学意义(P < 0.05)。治疗7 d后,两组的促炎性细胞因子水平进一步下降,且治疗组低于对照组,差异有统计学意义(P < 0.05);而抗炎性细胞因子水平进一步升高,且治疗组高于对照组,差异有统计学意义(P < 0.05)。治疗组的平均住院天数及需要继续血液净化治疗的时间明显短于对照组,差异有统计学意义(P < 0.05),但两组的病死率差异无统计学意义(P > 0.05)。 结论 CPFA可以更好地调节血液中的细胞因子水平,从而改善临床症状,缩短治疗时间,治疗重症急性胰腺炎。

[关键词] 重症急性胰腺炎;连续性血浆滤过吸附;连续性血液滤过;细胞因子

[中图分类号] R459.5;R576          [文献标识码] A          [文章编号] 1673-7210(2019)02(a)-0092-05

[Abstract] Objective To investigate the effect of continuous plasma filtration adsorption (CPFA) on severe acute pancreatitis and its effects on tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10). Methods A total of 40 patients with severe acute pancreatitis were selected from October 2014 to June 2018 in the Department of Severe Medicine of Dalian Central Hospital. They were divided into control group (n = 20) and treatment group (n = 20) according to the treatment method. The control group was treated with continuous venovenous hemofiltration (CVVH) for 72 hours on the basis of routine treatment, while the treatment group was treated with CPFA on the basis of the control group. The levels of TNF-α, IL-6 and IL-10 in blood were measured before and after treatment for 3 and 7 days. The vital signs, intra-abdominal pressure, acute physiology and chronic health (APACHEⅡ) scores were compared between the two groups before and after treatment, and the organ function was evaluated, adverse reactions and prognosis were observed. Results There was no significant difference in the clinical indexes between the two groups before treatment (P > 0.05). After 3 days of treatment, the heart rate, oxygenation index, intra-abdominal pressure and APACHE Ⅱ scores of the two groups were lower than those before treatment, and the average arterial pressure and white blood cell count were higher than those before treatment (P < 0.05); the heart rate and intra-abdominal pressure of the treatment group were lower than those of the control group, and the average arterial pressure was higher than that of the control group (P < 0.05). After 7 days of treatment, the heart rate, white blood cell count, intra-abdominal pressure and APACHE Ⅱ scores of the two groups were lower than those before treatment, and the average arterial pressure and oxygenation index were higher than those before treatment (P < 0.05); the heart rate, intra-abdominal pressure and APACHE Ⅱ scores of the treatment group were lower than those of the control group, and the average arterial pressure was higher than that of the control group, with significant differences (P < 0.05). There was no significant difference in the levels of TNF-α, IL-6 and IL-10 between the two groups before treatment (P > 0.05). After 3 days of treatment, the levels of pro-inflammatory cytokines TNF-α, IL-6 in the two groups decreased, the levels of TNF-α and IL-6 in the treatment group were lower than those in the control group (P < 0.05), and the levels of anti-inflammatory cytokines IL-10 in both groups were increased (P < 0.05), and the level of IL-10 in the treatment group was higher than that in the control group (P < 0.05). After 7 days of treatment, the levels of pro-inflammatory cytokines in the two groups decreased further, and the treatment group was lower than the control group, the difference was statistically significant (P < 0.05); while the anti-inflammatory cytokine levels were further increased, and the treatment group was higher than the control group, the difference was statistically significant (P < 0.05). The average hospitalization days and the time needed to continue blood purification treatment in the treatment group were significantly shorter than those in the control group (P < 0.05), but there was no significant difference in mortality between the two groups (P > 0.05). Conclusion CPFA can better regulate the levels of cytokines in the blood, thereby improving clinical symptoms, shortening treatment time and treating severe acute pancreatitis.

[Key words] Severe acute pancreatitis; Continuous plasma filtration adsorption; Continuous veno-venous hemofiltration; Cytokine

重症急性胰腺炎(SAP)是常见的外科重症,其起病急、进展快、并发症多、病死率高,可导致多器官功能障碍综合征(MODS)进而危及生命[1]。细胞因子对该疾病的发生起着重要的作用,大量的促炎因子和抗炎因子的相互作用导致胰腺局部损害、胰腺外脏器功能损害以及全身炎性反应[2]。连续性血液滤过治疗(CVVH)可以清除细胞因子,从而达到治疗SAP的目的[3],但吸附对炎性细胞因子的清除能力远远强于CVVH[4-5]。连续性血浆滤过吸附(CPFA)结合了CVVH与血浆吸附的特点[6],在有效清除血液中的细胞因子的同时,还可以调整容量平衡,稳定机体内环境。然而,作为一种新型的血液净化方式,CPFA在SAP救治中的相关研究较少。本研究旨在深入了解CPFA对SAP的治疗效果,以期为其临床治疗提供参考。

1 资料与方法

1.1 一般资料

选取2014年10月~2018年6月大连市中心医院(以下简称“我院”)收治的SAP患者40例,均符合重症胰腺炎诊断标准[3]。纳入标准:①年龄18~70岁;②发病时间<72 h。排除标准:①年龄<18岁或>70岁;②发病时间>72 h。根据治疗方法将其分为治疗组和对照组,每组20例。其中,研究组男12例,女8例;平均年龄(43.4±8.7)岁;急性生理与慢性健康评分(APACHEⅡ评分)(22.1±4.3)分;发病至血液净化时间(41.2±6.1)h。对照组男11例,女9例;平均年龄(44.2±6.3)岁;APACHEⅡ评分(21.4±3.5)分;发病至血液净化时间(41.2±8.7)h。两组性别、年龄等一般资料比较,差异无统计学意义(P > 0.05),具有可比性。本研究经医院伦理学委员会批准,所有研究对象或委托人知晓病情并签署知情同意书。

1.2 治疗方法

所有患者均在右侧颈内静脉建立临时性血管通路,且入院后均给予禁食、胃肠减压、抑酸、抑酶、肠外营养和对症治疗。在此基础上,治疗组采用CPFA+CVVH治疗,对照组采用CVVH治疗。

1.2.1 治疗组  将日本旭化成公司生产的IQ21血液净化机与百特公司生产的AQUARIUS血滤机串联,IQ21机选择血浆吸附模式,AQUARIUS血滤机选择连续性静脉静脉血液滤过(CVVH)模式,血浆分离器选用日本旭化成公司生产的OP-08,血液吸附器选用健帆公司生产的HA330-Ⅰ型血液吸附器,血滤器选用Fresenius生产的AV-600滤器。血浆吸附在前,CVVH在后,两台机器串联,并利用串联的2个三通管形成循环短路以避免无谓的压力报警,连接方式如图1所示。

前后血泵转速保持一致,血流速度150 mL/min,血浆分离速度30~40 mL/min,采用青山利康商品化置换液(批准文号:国药准字H20080452),置换液速度2000 mL/h,前后稀释各1000 mL/h,治疗10 h,中间更换吸附器1次。10 h后撤下IQ21机器,继续CVVH治疗14 h,上述治疗持续3 d后,停止血液净化治疗。如患者仍需要肾脏替代,则改为CVVH治疗。采用普通肝素抗凝,置换液钾、钙的浓度根据生化结果随时调整,滤器根据使用情况24~48 h更换一次。

图1   CPFA组成模式

1.2.2 对照组  CVVH治疗方法及参数同治疗组。连续治疗3 d后,根据情况停血液净化治疗或继续CVVH治疗。

1.3 检测指标与方法

于血液净化治疗前及治疗3、7 d后,监测并记录患者的生命体征,测量腹腔内压力,检测血白细胞、血气分析等,计算APACHEⅡ评分;留取全血1 mL,4℃ 1000 r/min低温离心15 min,提取上层血浆,采用酶联免疫吸附试剂盒(Elabscience公司)检测肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6、10)、白细胞介素-10(IL-10);记录患者血液净化治疗的时间和住院天数,并观察因血液净化引起的并发症,如出血、低血压、血膜反应等,观察病情转归情况。

1.4 统计学方法

采用SPSS 24.0统计学软件进行数据分析,计量资料用均数±标准差(x±s)表示,两组间比较采用t检验,以P < 0.05为差异有统计学意义。

2 结果

2.1 两组并发症及病情转归比较

40例患者均置管顺利,治疗过程未出现凝血、出血、过敏、血小板减少等并发症。治疗组死亡1例,对照组死亡1例,放弃治疗出院1例,两組差异无统计学意义(P > 0.05),其余均治愈出院。经过3 d的血液净化后,治疗组有2例(10%)仍需要继续肾脏替代,少于对照组(6例,30%)(P < 0.05)。治疗组的平均住院时间为(21.7±4.7)d,明显低于对照组的(26.5±6.8)d,差异有统计学意义(P < 0.05)。

2.2 两组临床指标比较

两组患者治疗前各临床指标比较,差异无统计学意义(P > 0.05)。治疗3 d后,两组心率、氧合指数、腹腔内压力及APACHEⅡ评分均较治疗前降低,平均动脉压、白细胞计数较治疗前升高,差异有统计学意义(P < 0.05);且治疗组心率、腹腔内压力低于对照组,平均动脉压高于对照组,差异有统计学意义(P < 0.05)。治疗7 d后,两组心率、白细胞计数、腹腔内压力及APACHEⅡ评分均较治疗前降低,平均动脉压、氧合指数较治疗前升高,差异有统计学意义(P < 0.05);且治疗组心率、腹腔内压力及APACHEⅡ评分低于对照组,平均动脉压高于对照组,差异有统计学意义(P < 0.05)。见表1。

2.3 两组细胞因子水平比较

两组治疗前TNF-α、IL-6、IL-10水平比较,差异无统计学意义(P > 0.05)。血液净化治疗3 d后,两组促炎性细胞因子TNF-α、IL-6水平均较治疗前下降,抗炎性细胞因子IL-10水平均较治疗前升高,且治疗组TNF-α、IL-6水平低于对照组,IL-10水平高于对照组,差异有统计学意义(P < 0.05)。治疗7 d后,两组促炎性细胞因子TNF-α、IL-6水平均较治疗前下降,抗炎性细胞因子IL-10水平均较治疗前升高,且治疗组的TNF-α、IL-6水平低于对照组,IL-10水平高于对照组,差异有统计学意义(P < 0.05)。见表2。

3 讨论

SAP的发病机制目前尚未阐述清楚。目前认为细胞因子在其发病中起着重要作用[7-8]。TNF-α、IL-6等促炎性细胞因子通过启动所谓的“瀑布式炎症级联反应”,参与组织细胞损伤,参与创伤后的高代谢以及激活凝血系统和补体系统,从而在全身炎性反应的发生发展中起重要作用[7]。下调TNF-α、IL-6等促炎性细胞因子水平,可显示出对局部胰腺损伤的保护作用以及对系统性炎症反应综合征和疾病预后的显著改善作用[9-10]。抗炎性细胞因子IL-10对SAP有保护作用,可以显著降低死亡风险[11]。

血液净化可以清除血液中的细胞因子,CVVH在过往的20年被用于SAP的治疗,并显示出一定的治疗效果[12-13]。然而,CVVH并不能降低血浆中的TNF-α、IL-6水平[14-15],许多炎性细胞因子的分子量均超出了透析膜的截留分子量,难以实现有效清除,而CVVH中细胞因子主要通过吸附清除,其清除效果受到透析膜饱和的限制[16]。CPFA在CVVH的基础上引入血浆吸附装置,强化了吸附机制对炎症介质的清除,在MODS等炎性疾病的救治中显示了良好的应用前景[17-19]。

本研究对收入重症监护病房的SAP患者进行早期CPFA治疗,发现促炎性细胞因子TNF-α、IL-6在血液净化治疗后明显下降,治疗的不同时点治疗组的下降程度均优于对照组;抗炎性细胞因子IL-10在治疗后均明显升高,且治疗组优于对照组。该结果提示,与CVVH比较,CPFA对细胞因子的调节作用更强,与既往文献报道[20]一致。停止血液净化治疗后,促炎性细胞因子继续下降,而抗炎性细胞因子仍在缓慢升高,这一现象提示早期进行CPFA治疗可以阻断SAP的“瀑布式炎症级联反应”。因此,即使3 d后停止CPFA治疗,在其他保守治疗干预下,体内细胞因子仍会趋于正常化。

治疗后,两组患者的心率、平均动脉压、APACHEⅡ评分、腹腔内压力等指标均有不同程度改善;与对照组比较,治疗组的心率、平均动脉压、APACHEⅡ评分及腹腔内压力的改善更为显著(P < 0.05)。临床症状与细胞因子水平的變化具有一致性,即当促炎性细胞因子下降而抗炎性细胞因子升高时,患者的临床症状得到改善。由于CPFA对细胞因子具有强大的调节作用,治疗组患者的临床症状改善更为显著。

本研究中治疗组的住院天数及需要继续血液净化治疗的时间明显短于对照组,但死亡情况无明显差别,考虑可能与样本量较少及血液净化干预是否及时有关。可以明确的是,CPFA可以更好地调节体内细胞因子水平,从而提供更好的临床疗效,为SAP的救治提供了良好的前景。

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(收稿日期:2018-04-07  本文编辑:王   蕾)

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