指導教授：余忠仁臺灣大學：臨床醫學研究所鄭廣華Cheng, Kuang-HuaKuang-HuaCheng2014-11-302018-07-062014-11-302018-07-062014http://ntur.lib.ntu.edu.tw//handle/246246/264387研究背景： 外科手術後併發細菌感染的情況，必須及時診斷並給予適當抗生素的治療。但是因外科手術本身造成組織器官的損傷，可以引起人體發炎反應而出現發燒以及白血球增加的情況。這些症狀同時也是病菌感染的最常見臨床表徵，臨床醫師變得難以決定何時進行抽血檢驗、細菌培養或抗生素治療。手術後感染及敗血症的診斷變得令人混淆與困難。本研究嘗試探討發炎性感染指標：介白素17A (Interleukin-17A, IL-17A)在重大手術後的變化，以及能否運用於診斷手術後感染併發症。 研究方法： 本研究為前瞻性觀察研究，研究地點是台北馬偕紀念醫院外科加護病房。目標是接受胸部、腹部以及腦部手術的成年病人。收集手術前後的血液檢體以及手術後第一天每四個小時從引流管中收集胸水、腹水或腦脊髓液引流檢體。以Bio-RadR bead-based Multiplex assay測量IL-17A與相關介白素（IL-17A偵測界限0.1-24512pg/ml)。同時記錄臨床資料包括血液白血球、發燒天數、手術出血量、感染併發症等。如果手術後48小時再次發燒，再次留取檢體進行血液以及引流液體的介白質濃度分析。 研究結果： 資料收集從2013年6月至2014年4月間，總共收集90位病人檢體。其中48位接受胸腔手術；1位接受腦室引流手術和41位接受腹部手術。平均年齡61.8±12.5歲（範圍27-89歲）。 手術前沒有感染的病人，手術前血液中肺癌、肝癌或食道癌病人可在血液測得微量IL-17A(範圍:0-7.06 pg/ml)。手術後回到加護病房12小時內追蹤血液IL-17A濃度皆下降(p=0.0487)。手術後一天內引流體液中表現少量IL-17A（範圍：0-21.33pg/ml）多在8-12小時達到濃度高峰之後下降。但是發生感染併發症的病人其第24小時的IL-17A濃度多高於第12小時。48小時之後發生腹內吻合處滲漏感染而發燒的病人，則其腹水的IL-17Ａ在發燒之際明顯高於因其他原因發燒的病人（中位數23.45 (n=7) vs. 10.41pg/ml(n=6), p=0.0066)。體液中IL-17A濃度與開刀時間長短、出血量、血液中IL-17A以及手術後白血球數目並無顯著相關。手術後48小時發燒時病人手術引流液體IL-17A濃度與IL-1s顯著正相關(rho=0.686, p=0.0004)，也與IL-22呈顯著正相關(rho=0.739, p=0.0003)。以腹腔引流液IL-17A高於14.4pg/ml為標準則可以幫助診斷腹腔內感染（敏感性100%；特異性83.33%）。 結論： 外科手術後在引流液中可測到少量IL-17A，若是24小時之際腹水IL-17A增加則暗示發生手術後併發症。以腹腔引流液IL-17A高於14.4pg/ml為標準則可以幫助診斷腹腔內感染，及早發現腸道或膽道吻合處滲漏感染。IL-17A的表現與IL-1s和IL-22有關。癌症病人血液中可以檢測出IL-17A，且在手術腫瘤切除後IL-17A呈現下降趨勢Purpose: Timely identification of septic complication is important for post-surgery patients. However, systemic inflammatory response syndrome secondary to surgical tissue damage can induce fever and leukocytosis. Thus trigger of infection workup and diagnosis of post-operation sepsis are difficult and confusing. In this study, we investigated the change and diagnostic value of pro-inflammatory interleukin-17A (IL-17A) in patients with major operations. Methods: This is a prospective observatory study in surgical intensive care unit. Patients’ plasmas were collected before and after the major operations. Body fluids from drainage tube, including pleural, peritoneal or cerebral-spinal fluid were collected every 4 hours on the first day after the operation. The IL-17A and relative interleukin were measured by Bio-RadR bead-based Multiplex assay (detection limit of IL-17A:0.1-24512pg/ml). Clinical data such as white blood cell count、fever days、and infectious complication were recorded. Plasma and drainage fluid were checked again when fever was noted 48 hours after the surgery. Results: Ninety patients with informed consent were enrolled, and their mean age was 61.8±12.5 years-old(range:27-89). 48 patients underwent video-assisted thoracoscopic surgery, 1 had external ventricular drain after intracranial hemorrhage, and 41 patients had abdominal operations. For patients with malignancy of lung, liver or esophagus, IL-17A was detected in plasma before the operation (range: 0-7.06 pg/ml), and the concentration decreased after the cancer resection (p=0.0487). IL-17A in the drainage fluid (range: 0-21.33pg/ml) was noted on the first day after the major operation, and reached peak concentration at 8-12 hours. For patients had septic complications, their IL-17A in the drainage fluid tended to increase rather than decrease at 12-24 hours after the operation. After abdominal operations 48 hours, the febrile patients complicated with intra-abdominal infection following bile or intestine leak had significant higher IL-17A in the drainage fluid compared to patients with extra-abdominal infections such as ventilator-associated pneumonia or catheter-related blood stream infection (median 23.45 vs. 10.41pg/ml, p=0.0066). Peritoneal drainage IL-17A >14.4pg/ml helped diagnosis of gastro-intestine leak and sepsis (sensitivity: 100%, specificity: 83.33%). Concentration of IL-17A in the drainage fluid did not correlate significantly with serum IL-17A、 operation duration、 blood loss or post-operation white cell count. For patients with recurred fever 48 hours after operations, their IL-17A in the drainage fluid correlated significantly with concentration of IL-1s(rho=0.686, p=0.0004) and IL-22(rho=0.739, p=0.0003)。 Conclusion: Minimal concentration of IL-17A in the drainage fluid was detected in patients with major operation. From 12 to 24 hours after the operation, increasing IL-17A in the drainage fluid inferred septic complications Monitoring IL-17A in drainage fluid is non-invasive and aid early identification of focal infections. IL-17A >14.4 pg/ml in the peritoneal drainage fluid helps diagnosis of intra-abdominal infections. Secretion of IL-17A after operation correlated with IL-1s and IL-22. IL-17A was detectable in serum of patients with malignancy, and the concentration decreased after the resection of cancer.口試委員會審定書……………………………………………………………… 2 誌謝……………………………………………………………………………… 4 中文摘要………………………………………………………………………… 5-6 英文摘要………………………………………………………………………… 7-9 碩士論文內容 第一章 緒論 ………………………………………………………………… 10 (1) 背景 ……………………………………………………………… 10-14 (2) 研究假說 …………………………………………………………… 15 (3) 研究方法與材料 …………………………………………………… 15-17 (4) 統計方法 …………………………………………………………… 17 第二章 結果 …………………………………………………………… 18-23 第三章 討論 ……………………………………………………………… 24-30 第四章 結論與展望 ……………………………………………………… 31-32 參考文獻……………………………………………………………………… 33-39 表1 …………………………………………………………………………… 40 表2 …………………………………………………………………………… 41 圖 1 …………………………………………………………………………… 42 圖 2 …………………………………………………………………………… 43 圖 3 …………………………………………………………………………… 44 圖 4 …………………………………………………………………………… 45 縮寫對照表…………………………………………………………………… 46 附錄：個人在碩博士班修業期間所發表之相關論文清冊 ………………… 47637552 bytesapplication/pdf論文使用權限：同意有償授權(權利金給回饋學校)外科手術敗血症全身發炎反應介白素17A介白素1s介白素22[SDGs]SDG3thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/264387/1/ntu-103-P01421004-1.pdf