Effects Of Ulinastatin On Cellular Immunity And Hepatorenal Function In Patients Undergoing Laparoscopic Surgery For Colorectal Cancer

[Bacground]Colorectal cancer(CRC) is one of the most common types of malignant tumors worldwide.In China,CRC is the fourth leading cause of cancer-related mortality. Radical resection is the preferred treatments for colorectal cancer. Laparoscopic surgery, as a low invasive surgery, has more advantages including tiny incision, quick recovery, fewer complications, early activities off the bed and food available, and better recovery of gastrointestinal function.But as a result of the surgery with general anesthesia, CO2pneumoperitoneum, and the use of ultrasonic knife, odd-or-even electrocoagulation and so on, the laparoscopic surgery will certainly change the physiological and immunologic organic function. Surgical trauma may restrain the immunologic function for malignant tumor patient, whose preoperative immunologic function has been inhibited by the tumor itself. It will further result in the change of the metastasis and recurrence of tumor, putting impact on the prognosis of the tumor patient. It is necessary to take some measures for perioperative malignant tumor patients in order to protect and rebuild the immunologic function. Thus improve the immunologic function, restrain and alleviate the nociceptive stimulus of stress reaction. It has important significance to promote the postoperative rehabilitation of malignant tumor patients.The tumor immunity include cellular immunity and humoral immunity. Among them, T cell-mediated cellular immunity is more important. It directly influence the tumor’s occurrence, development and prognosis. CD3+-positive is the key marker of mature T lymphocyte in peripheral blood, which represents the overall condition of cellular immunity. Human mature T lymphocyte phenotype can be divided into CD4+and CD8+lymphocytes according to their different phenotype. CD4+T cells, the helper and inducer lymphocyte, assist the organism to complete anti-immune response. CD8+T cells, the cytotoxic and inhibitory T lymphocyte, have the virus removal and adhesion function. It keeps balance with CD4+cells on the immunity function each other. CD4+/CD8+ratio keeps dynamic balance, in order to maintain the stability of the cellular immune function. When the ratio is down, it shows a trend of immunosuppression, which will be helpful for tumor proliferation and infection.Ulinastatin is a broad spectrum protease inhibitors, which can inhibit the release and the activity of variety of hydrolytic enzyme, stabilize cell membrane and lysosome membrane, inhibit inflammatory medium and oxygen radicals and reduce myocardial depressant factor, improve microcirculation and tissue perfusion. UTI break down into low molecular weight ingredients in vivo which was proteinase inhibitor with a wide spectrum too.UTI have been widely used for the treatment of acute pancreatitis,acute lung injury,acute respiratory distress syndrome and multiple organ dysfunction syndrome,etc. With the development of medicine,human being come to realize that it is more important to take protection for the surgical patients’ immunologic function and visceral organ function. To use UTI for the operationcan reduce tissue damage and destruction by operation,reduce organ damage by stress reaction,improve the ability for resist the attack of operation,enhance the immune function of patients.The research found that UTI had a protective effect in esophageal cancer radical surgery-induced immunosuppression and low hepatorenal function.The using of UTI shorten the recover time of the T cell subsets(CD3+, CD4+, CD4+/CD8+)and NK cell,attenuated the elevation of ALT,BUN and Cr postoperation.Research have indicated that laparoscopic colorectal cancer surgery significantly inhibited immunity function, which presents as postoperative decrease of total of T lymphocyte, significant reduce of the CD3+、CD4+and CD8+T lymphocyte subsets, down CD4+/CD8+ratio, the elevation of ALT and AST. Even the joint use of fast track surgery (FTS) concept such as short-term use of antibiotics and unconventional preoperational bowel preparation, CD3+, CD4+and CD4+/CD8+at the third day postoperative still declined obviously compared to preoperative baseline value. Study found that UTI protected hepatorenal function of laparoscopic rectal tumor resection patients. These studies have shown that immune protection and organ protective effect of UTI used in the digestive tract tumor surgery,but was not oberved in the dose-effect relationship or the effect of laparoscopic colorectal cancer surgery on patients’T cell subsets.[Objective]To investigate the effects of ulinastatin on cellular immunity and hepatorenal function in patients undergoing laparoscopic surgery for colorectal cancer and the dose-effect relationship of ulinastatin by observing the change of perioperative peripheral blood T cell subsets and hepatorenal function.[Methods] 1.General Information Sixty ASA Ⅰ or Ⅱ (aged32-78yr, weighing42-77kg,male36and female24) patients undergoing laparoscopic colorectal cancer surgery between February to August2012were chosen.All patients did not have any endocrine and immune system disease, not ever received preoperative immune inhibitors or blood and blood product treatment.And remove the patients with abdominal surgery history previous, serious heart and lung disease for can’t accept pneumoperitoneum,malignant tumor history previous, distant metastasis had been proved by auxiliary examination (including chest X-ray, B ultrasonic of abdomen, and CT, etc.)preoperative,tumor can’t be resect intraoperative for fixed or infringement of surrounding tissues and organs,emergency surgery for acute intestinal obstruction,bleeding or perforation. All of them have been diagnosed preoperative by colonoscopy and histologic.The patients were randomly divided into group Ⅰ, Ⅱ,Ⅲ and group C. Before anesthesia induction,ulinastatin0.5×104u/kg(group Ⅰ),1.0×104u/kg(group Ⅱ),1.5×104u/kg(groupⅢ)and the same volume of saline(group C) were intravenously infused respectively.2.Anesthesia and operation methods Prepare four groups of patients the same according to routine preoperative preparation.Dilute ulinastatin to100ml with saline for group Ⅰ, Ⅱ,Ⅲ, while just100ml saline for the control group.Pump them into vivo about30minutes through the open access vein before induction of anesthesia with infusion pump.The drug of anesthesia induction consist of midazolam(0.05-0.1mg/kg), propofol(1.5-2mg/kg), fentanyl(3-5ug/kg), vecuronium(0.1mg/kg), while maintain anesthesia with sevoflurane intraoperative, vecuronium and fentanyl,keep the Narcotrend idex at the level of D2, blood pressure in the basic between the plus20%and minus20%.All of anesthesia for the patients are managed by the same responsibility anesthesiologist.And they have the same postoperative patient controlled intravenous analgesia(analgesia pump recipe is sufentanil (2 ug/kg),flurbiprofen (2mg/kg),saline, total liquid is150m1.3ml load dose,3ml/h background dose,3ml/time additional dose,15min lock time, maintain VAS score<3points). All surgery for the patients were performed by the same group surgeon, and had the same postoperative treatment regimen.3.Sample collection Venous blood samples were taken at30minutes before anesthesia induction(T0)and6o’clock on the morning the first day (T1), third day(T2),fifth day (T3)and seventh day(T4) after operation.4.Detection index The detection index consist of T lymphocyte subsets (CD3+, CD4+, CD8+and CD4+/CD8+), Hepatic function (aspartate aminotransferase and alanine aminotransferase)and kidney function(blood urea nitrogen and serum creatinine).5.Statistical analysis Using SPSS13.0statistical analysis software, Values are expressed as mean±SD. The measurement data were analyzed using repeated measure analysis of variance, the multiple comparison were analyzed using Dunnett method, the inter-group comparison were analyzed using LSD method.Demographic data in four groups were analyzed using one-way analysis of variance. Enumeration datd were analyzed using Chi-square test. Differences were considered to be statistically significant if the P value was<0.05.[Results]1. General Data in four groupsThere was no statistically significant differences in gender, age, weight, duration of surgery, and postoperative VAS score between four groups of patients (P>0.05)。2.Narcotrend idexThere was no significant difference in Narcotrend idex between four groups(F=0.255, P=0.998). There was no significant difference between the four groups at the same time points (F=0.175, P=0.913) 3.T lymphocyte subsetsNo significant difference were found in CD3+、CD4+、CD8+and CD4+/CD8+between four groups at T0(P>0.05). Compared to T0, CD3+and CD4+in group C and CD4+in group Ⅰ, Ⅱ and Ⅲ at T1,CD3+,CD4+and CD4+/CD8+in group C at T2were significantly decreased (P<0.05).CD3+、CD4+and CD4+/CD8+at T2in group Ⅰ, Ⅱ and Ⅲ returned to TO level. CD3+at T2and CD4+at T2and T3in group Ⅰ and Ⅱ, CD3+, CD4+and CD4+/CD8+at T2and T3in group Ⅲ were significantly higher than in group C at the same time (P<0.05). There were no significant difference in CD3+, CD4+, CD4+/CD8+between group Ⅰ, Ⅱ, Ⅲ and CD8+between the four groups at the same time (P>0.05).4.Hepatorenal functionNo significant difference were found in AST、ALT、BUN and Cr(P>0.05). AST、 ALT、BUN and Cr of four groups were with the normal range.The difference at different time in the same group and between the four groups at the same time were not significant (P>0.05).[Conclusions]1. The cellular immune function is reduced as the tendency of CD3+、CD4+、 CD4+/CD8+descended on1-3days after laparoscopic colorectal cancer surgery.2. Ulinastatin0.5～1.5×104u/kg improve cellular immunity by shorten the recover time of the T cell subsets,and better at dose of1.5×104u/kg.3. Ulinastatin0.5～1.5×104u/kg have no significant effect on hepatorenal function in patients undergoing laparoscopic surgery for colorectal cancer.