修回日期: 2008-08-26
接受日期: 2008-09-01
在线出版日期: 2008-09-28
胰腺继发感染是重症急性胰腺炎(severe acute pancreatitis, SAP)最严重的并发症. 防治胰腺感染已成为进一步降低SAP病死率的关键. 对血-胰屏障结构和功能的认识和不同抗生素在胰腺局部浓度和渗透力的研究, 促进防治SAP胰腺感染时抗生素的合理选择. 研究能够提高抗生素在胰腺组织浓度、增强抗生素疗效的治疗方法与药物, 有望进一步阐明某些药物治疗SAP的作用机制, 有助于SAP继发感染的预防与治疗.
引文著录: 邓力珲, 夏庆. 胰腺抗生素浓度在防治重症急性胰腺炎继发感染中的作用. 世界华人消化杂志 2008; 16(27): 3077-3082
Revised: August 26, 2008
Accepted: September 1, 2008
Published online: September 28, 2008
Secondary pancreatic infection represents the most serious complication with fatal outcome in severe acute pancreatitis (SAP). Preventing and curing secondary infection of pancreas is the key obstacle to minimize the mortality of these patients. The studies on blood-pancreatic juice barrier as well as penetration and pancreatic tissue concentration of antibiotics have improved the antibiotic prophylaxis or treatment of pancreatic infection. In the future, potential therapeutics that can enhance the antibiotic concentration and efficacy may help to prevent and treat the secondary infection of SAP.
- Citation: Deng LH, Xia Q. Value of pancreatic antibiotic concentration in treatment of secondary infection of serve acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2008; 16(27): 3077-3082
- URL: https://www.wjgnet.com/1009-3079/full/v16/i27/3077.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v16.i27.3077
急性胰腺炎(acute pancreatitis, AP)是临床常见的急腹症, 20%-30%的AP发展为重症急性胰腺炎(severe acute pancreatitis, SAP)[1-4], 30%-50% SAP继发感染[5-6]. 一旦继发感染, SAP死亡率将由30%[7-9]上升至40%-80%[10-17]. 合理使用抗生素, 防治胰腺炎感染已成为进一步降低SAP病死率的关键问题[18]. 临床上选择抗生素遵循覆盖SAP常见感染菌群和能穿透血-胰屏障在胰腺组织保持较高浓度的原则.
目前, 对SAP继发感染发病机制的研究中, 肠道细菌移位学说已得到认同[19-20]. 促进肠道细菌移位的因素有如下几个方面: (1)细菌过度生长和菌群失调. SAP时胃肠功能障碍, 胃肠蠕动功能减弱造成细菌过度生长和肠道微生态失调, 使细菌易黏附于肠上皮细胞表面, 细菌可以穿过结肠壁直接到达胰腺引起胰腺感染, 这在实验研究中已得到证实[21-22]; (2)宿主免疫防御功能削弱. SAP急性期, 过度释放的细胞因子及炎性介质诱发全身炎症反应, 随后产生代偿性抗炎反应综合征, IL-2等具有保护作用的细胞因子水平下降, 网状内皮系统功能受到削弱等因素导致机体免疫抑制是导致胰腺感染的全身性发病基础[23-26]. (3)肠黏膜屏障的破坏. AP时炎症介质的释放破坏了肠黏膜屏障; 肠液的大量聚集以及肠内容物被细菌分解后产生的大量气体, 使肠腔内压力增加肠管扩张, 肠壁血液循环障碍肠血流量显著减少, 加重了黏膜缺氧损伤, 促进细菌移位; 谷氨酰胺、精氨酸等维持肠道免疫功能、微生态环境、保护黏膜屏障功能的作用营养物质的缺乏, 导致胃肠黏膜屏障和免疫屏障受损, 从而促进肠道菌群移位和胰腺感染[27-29]. (4)腹腔内胰腺坏死及胰周腔隙积液, 尤其是增强CT提示胰腺坏死大于30%者, 亦为感染提供了良好的培养基, 增加感染的风险[30]. 上述任何一方面均可增加细菌移位的可能性. 此外, 胆道细菌以及AP治疗过程中的各种诊疗措施(导尿、气管插管、各种穿刺等)可使细菌从呼吸道、泌尿道、皮肤黏膜侵入血液, 也是引起胰腺感染的重要途径.
引起SAP继发感染的病原菌多为肠源性革兰阴性杆菌, 病原菌出现的频率依次为大肠杆菌(35%)、克雷伯杆菌(25%)、肠球菌(24%), 其他感染菌为葡萄球菌(14%)、假单孢菌(11%)、变形杆菌(8%)、链球菌(7%)、肠杆菌(7%)、类杆菌(6%)、厌氧菌(6%)[31]. Isenmann et al[32-33]对77例感染性坏死的病原学检查结果, 单菌感染占69%, 以大肠杆菌、金黄色葡萄球菌居多; 多菌感染占31%, 以大肠杆菌、肠球菌居多. Widdison et al[19]研究发现常见胰腺感染的病原菌出现的频率依次为: 大肠埃希杆菌、肺炎克雷伯杆菌、粪肠球菌、金黄色葡萄球菌、表皮葡萄球菌、链球菌、绿脓杆菌、奇异假单孢菌、产气肠杆菌、脆弱类杆菌等. 近年来真菌(念珠菌)感染有所增加, 主要见于长期使用多种抗生素的患者.
20世纪50年代开始研究抗生素在胰腺中的分布, 结果发现抗生素在胰腺中的分布发现胰腺组织不同于其他器官[34-36]. 动物实验及临床实践使用区域动脉灌注(regional arterial infusion, RAI)能提高胰腺及胰周的药物浓度, 防治SAP继发感染, 降低胰腺感染率[37-38]. Burns et al[39]总结抗生素在胰腺组织中的渗透率与抗生素的极性和脂溶性高低、抗生素的血清蛋白结合率、作为载体的结合蛋白分子质量大小、抗生素pH值等因素有关后, 首次提出血-胰屏障(blood-pancreatic juice barrler)的概念, 描述血-胰屏障为一种类似脑组织血-脑屏障的结构, 并认为血-胰屏障为影响抗生素渗透入胰腺组织最主要的因素.
血-胰屏障主要在于毛细血管缺少小孔, 并可能存在实质细胞间的"紧密连接", 这些连接进一步限制药物在间质中通过, 从而对不同的抗生素有选择性的通透作用. 因此, 抗生素的药效与他们通过血-胰屏障的能力有关, 从而直接影响药物对胰腺组织作用的发挥. 实验证明, 正常胰腺的血流灌注很丰富, 血液中的抗生素必先依次透过腺泡周围的毛细血管内皮细胞层和基底层, 然后透过胰腺腺泡细胞层、泡心细胞层、闰管等结构而进入胰液, 随后渗透入胰腺组织. 而在AP时, 胰腺的血流量明显减少, 坏死组织的功能性毛细血管密度降低62%, 非坏死区域减低43%[40]. 此外, AP时炎症影响细胞膜通透性改变, 亦在很大程度上影响了抗生素向胰液的透入.
由于血-胰屏障对不同的抗生素有选择性通透作用, 目前经研究的30多种抗生素能够进入胰腺且能达到有效浓度的仅1/3; 有的抗生素如青霉素G和一些头孢类抗生素不能进入胰组织; 有的抗生素如四环素、庆大霉素、氨苄青霉素进入胰组织很少, 不能形成有效的浓度[41-43]. Büchler et al[44]研究了10种不同的抗生素在正常胰腺组织的渗透性及其对常见胰腺感染细菌的临床疗效, 结果将抗生素分为以下3组: A组, 胰腺组织浓度低, 不能达到大多数细菌的最小抑菌浓度(MIC), 如耐替米星、妥布霉素等; B组, 胰腺组织浓度足以抑制一些细菌, 但不能覆盖所有的病原菌, 如氧哌嗪青霉素、头孢噻肟等; C组, 胰腺组织浓度高且对大多数胰腺感染的病菌有效, 如环丙沙星、氧氟沙星、亚胺培南. 虽然甲硝唑在胰腺组织渗透力强, 但考虑其抗菌谱狭窄, 此研究未将其列为研究对象. 随后的研究发现静脉用药后, 培氟沙星和甲硝唑在胰腺坏死组织中的浓度能持续超过大多数细菌MIC, 而亚胺培南浓度不能持续超过MIC, 连续应用亚胺培南可以提高其在胰腺坏死组织中的浓度. 其余研究发现环丙沙星在胰腺组织与胰液中均有高浓度[45]. 由此, 血-胰屏障的结构和功能使得人们认识到有些抗生素不能有效到达胰腺组织起到杀菌作用, 从而指导了临床对抗生素的选择.
目前, 对于AP患者是否预防性使用抗生素仍存在争议[46-48], 但多数学者主张胆源性轻症AP(mild acute pancreatitis, MAP)或SAP应常规使用抗生素[49-53]. 根据SAP继发感染的机制、致病菌谱、血-胰屏障等特点, 2005年英国循证指南推荐在胰腺坏死范围大30%时预防性使用能有效穿透胰腺血液屏障的广谱抗菌药7-14 d[9]. 中华医学会外科学分会胰腺外科学组制定了《重症急性胰腺炎诊治指南》[54]及中华医学会消化病学分会胰腺疾病学组制定了《中国急性胰腺炎诊治指南(草案)》[55]指出, 对于胆源性MAP或SAP常规使用抗生素应遵循以下原则: (1)抗菌谱应以革兰阴性菌和厌氧菌为主, 能有效抑制胰腺感染的常见致病菌; (2)脂溶性强, 能充分穿透胰腺组织; (3)能够通过血-胰屏障, 在局部达到有效浓度. 指南推荐在胰腺组织中具有较好的穿透力的喹诺酮类联合甲硝唑药物为一线用药. 而2007年一项治疗AP的多中心研究显示亚胺培南(43.1%)是最常使用的预防胰腺坏死感染的抗生素[56]. 夏庆 et al[57]评价: 当前证据更倾向于推荐对胰腺坏死面积>30%或胆源性SAP患者早期开始预防性使用碳青酶烯类抗生素, 一般使用不超过3 wk.
胰液的细胞学、分子生物学、外分泌功能测定等已在胆胰疾病的基础与临床研究占有重要地位[58-62], 研究胰液中的抗生素浓度能够反映抗生素在胰腺组织中的浓度. 动物实验中的胰液主要是通过对胰总管的插管或通过制备胰瘘来获取. 在人体, 逆行胰胆管造影(endoscopic retrograde cholangiopancreatography, ERCP)下ENPD为目前收集胰液作细胞学、组织学、胰液和胆汁生化、肿瘤标志物检测以及基因诊断等现代诊断技术的主要方法[63-64]. 李兆申 et al[65]认为ERCP后行ENPD方法简单, 可获取足量的胰液, 胰管引流可预防ERCP术后高淀粉酶血症和胰腺炎. 陈保华 et al[66]认为ENPD可将胰液经鼻孔引至体外, 由于胰管减压以及术后强化预防治疗, 有利于SAP的治疗. Quan et al[67]报道了ENPD治疗SAP的经验, 认为该法保持胰液引流通畅在SAP的治疗中具有重要地位. 该方法还涉及胰腺假性囊肿、与胰管相通的胰腺脓肿、其他胰管良、恶性梗阻的过渡性引流等诸多方面.
高效液相色谱法(high performance liquid chromatography, HPLC), 是20世纪70年代急剧发展起来的一项高效、快速的分离分析技术, 是以液体为流动相的色谱法称为液相色谱法. HPLC法具有柱效高、灵敏度高、分离速度快、分离效能高、检测灵敏度高、检测自动化、适用范围广、组分易回收、样品处理较简单、重复性好和操作方便(样品不需气化, 只需制成溶液即可)、仪器已较成熟、普及、色谱柱可反复使用等优点. HPLC法已发展为集分离和测定为一体, 广泛应用于药物的含量测定、组成分析、质量控制、药代动力学等方面[68-70]. 姚有贵 et al[71]运用HPLC法分别对8种抗生素透入急性出血坏死性胰腺犬血清和胰组织能力进行了研究, 实验提示静脉推注环丙沙星后, 其血清浓度下降较快, 而胰组织浓度下降却较慢, 以致于胰腺组织浓度逐渐高于血清浓度, 胰组织渗透率有增高趋势. 目前, HPLC能够同时测定生物样品中二种或二种以上[71-74]抗生素含量, 可在保证足够的灵敏度、精密度和准确度的前提下, 达到操作简便、节约有机溶剂、节省人力和时间的目的.
对血-胰屏障结构和功能的认识和不同抗生素在胰腺局部浓度和渗透力的研究, 促进了防治SAP胰腺感染时抗生素的合理选择. 研究具有协同提高胰腺炎时胰腺组织抗生素浓度、增强抗生素疗效的药物, 有望进一步阐明某些药物治疗SAP的作用机制, 促进SAP继发感染的预防与治疗.
重症急性胰腺炎(SAP)病情凶险, 病死率高. 随着重症监护及治疗措施的进步, 早期休克和多器官功能衰竭所致死亡率的下降, 中后期胰腺继发感染成为SAP病死率发生的主要原因. 合理使用抗生素防治胰腺继发感染是进一步降低SAP死亡率的关键环节之一.
崔云甫, 教授, 哈尔滨医科大学第二附属医院普外一科; 宋振顺, 教授, 中国人民解放军第四军医大学西京医院肝胆外科
血-胰屏障概念的确立, 使针对胰腺感染的选择用药有了明确的方向. 目前研究证据推荐对胰腺坏死面积>30%或胆源性SAP患者早期开始预防性使用有效抑制胰腺感染的常见致病菌、能充分穿透胰腺组织、能够通过血-胰屏障, 在局部达到有效浓度的抗生素.
研究已证实氨苄青霉素治疗胰腺炎继发感染被认为是无效的, 原因是氨苄青霉素无法通过血胰屏障, 连续应用亚胺培南可以提高其在胰腺坏死组织中的有效浓度, 培氟沙星、环丙沙星、甲硝唑等在胰腺组织与胰液中均有高浓度, 从而指导了临床对抗生素的选择.
目前胰腺感染的机制和其可能的感染途径已基本阐明,大多数学者致力于研究SAP继发感染的防治方法和策略. 本文着重阐述抗生素在胰腺组织及胰液中有效治疗浓度的研究及其方法学.
本文综述SAP继发感染的机制和血-胰屏障对预防性选用抗生素降低感染率和死亡率的影响, 进一步阐述了研究抗生素在胰液和胰腺组织中浓度及穿透率的方法学.
急性胰腺炎(AP):指多种病因引起的胰酶激活,继以胰腺局部炎症反应为主要特征,伴或不伴有其他器官功能改变的疾病. 在AP临床表现和生化改变的基础上,且具下列之一者为SAP:局部并发症(胰腺坏死,假性囊肿,胰腺脓肿); 器官衰竭; Ranson评分≥3; APACHEⅡ评分≥8; CT 分级为D、E.
本综述选题较好, 对SAP后继发感染之预防意义深远, 若加上胰周动脉区域注射抗生素相关论点会更好.
编辑: 李军亮 电编: 何基才
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