Effect Of Intravenous Ulinastatin On Postoperative Delirium In Elderly Patients With Hip Fracture

Objective:This study aimed to explore the effect of ulinastatin treatment on postoperative delirium?POD?in elderly patients receiving hip fracture surgery and to disclose the underlying mechanism.Methods:The study protocol was approved by the Research Ethics Committee of Qilu Hospital of Shandong University?Qingdao?.The written informed consent were obtained from all patients before the study.96 elderly patients who were scheduled for elective hip fracture surgery from October 2015 to May 2016?age:greater than 70 years;ASA:?-??were enrolled in the study.One patient was excluded because of receiving extra analgesia after surgery,one was excluded due to a failure in spinal anesthesia.Two patients were excluded because of being admitted to the intensive care unit?ICU?after surgery.The remaining ninety-two patients completed the blood sample collection and the laboratory tests finally.Ninety-two elderly patients were randomly divided into 2 groups using a random number table:ulinastatin group?group U?and control group?group C?,n=46.There were no preoperative benzodiazepine and anticholinergic agent administration in the two groups.No else sedative?such as benzodiazepine?or anticholinergic agent was administered during the operative period.Each patient was admitted to the orthopedic ward after surgery.There was no patient controlled analgesia?PCA?after surgery.Oxygen was given for all patients through the mask?2L/min?during the operation.The basic monitoring including electrocardiogram,heart rate,pulse oximetry,noninvasive blood pressure,end-tidal carbon dioxide pressures(P_ETCO₂),hemoglobin oxygen saturation?SpO₂?and temperature?T?were continuously performed and recorded during surgery.All patients were anesthetized using spinal-epidural anesthesia combined with fascia iliaca compartment block,as follows:0.375%ropivacaine?volume 20 ml?for fascia iliaca compartment block was injected before spinal-epidural anesthesia,which was guided by the ultrasound and then the patients were placed in the lateral decubitus position.The epidural space was identified at the L3-L4level.After free flow of the cerebral spinal fluid was obtained,2.0-2.5ml of 0.5%ropivacaine solution was injected within 20-30s.After the spinal anesthesia and fascia iliaca compartment block,ulinastatin 5000 U/kg diluted with normal saline to a volume of50ml?group U?was administered intravenously over 10 min before surgical incision and the equal doses on post-operative days 1-2.The equal volume of normal saline was administered intravenously in group C at the same time.Postoperative delirium was evaluated twice daily?in the morning from 0700h to 0900h and in the afternoon from1600h to 1800h?at 1,2,3 days postoperatively in a quiet room of ward at the bedside by an experienced psychiatrist using the Confusion Assessment Method?CAM?.The CAM algorithm is based on four features:?a?the acute onset of mental status changes and fluctuating course,?b?inattention,?c?disorganised thinking,and?d?altered level of consciousness.The diagnosis of delirium requires the presence of features a and b plus c or d.Both the psychiatrist and patients were blinded to the treatment and group.Venous blood samples?5ml?were withdrawn to measure the concentrations of IL-6,IL-10 and S100?before anesthesia and drug administration?T0?,at the end of surgery?T1?and three days after surgery?T2?.Venous blood samples was centrifuged at 3600 rpm for 10min at 4?and the serum fraction was removed and stored at-80?for further analysis.The concentrations of serum IL-6,IL-10 and S100?were measured using an Enzyme-linked immunosorbent assay?ELISA?kit.Statistical analyses were performed using SPSS software,version 20.0?SPSS 20.0 inc,Chicago,IL,USA?.GraphPad Prism7was used for drawing the figures in the manuscript.The data involved in this study included measurement data and counting data.Normal distribution of measurement data were expressed as the means x±SD.Normal distribution was performed before our analysis.Difference of measurement data with normal distribution between the two groups was compared with the Student's t-test.The biochemical variables,including IL-6,IL-10 and S100?concentrations in the group?before anesthesia,at the end of surgery and three days after surgery?were analyzed using repeated measures analysis of variance?ANOVA?.The non-normal distribution measurement data were compared with the Mann-Whitney U nonparametric test.The counting data were analyzed usingc2 test.P<0.05?both sides?was considered statistically significant.Results:There were no significant differences in any of the baseline characteristics examined including age,gender,weight and operation time et al.between the ulinastatin group and control group.The trial profile was seen in Figure 1.The result of the baseline characteristics between the two groups was seen in Table 1.There were 13 patients in the group C and 2 patients in the group U diagnosed to have postoperative delirium.The incidence of POD in group C was 28.2%and the incidence of POD in group U was 4.3%.The incidence of POD in group U was significantly lower than that in group C?Table 2and Figure 2,P<0.05?.Serum samples were tested in the levels of IL-6,IL-10 and S100?at three time points:before anesthesia?T0?,at the end of surgery?T1?and 3 days after surgery?T2?.In the control group,serum IL-6 concentration increased at T1 and T2.However,the ulinastatin group had lower serum IL-6 concentration than those in the control group?Table 3 and Figure 3,P<0.05?.Serum levels of IL-10 were higher at T1and T2 when compared with preoperative levels in the two groups but there were no significant differences between groups at T1 and T2?Table 4 and Figure 4,P>0.05?.Serum S100?concentration was higher at the end of surgery when compared with preoperative concentration in the control group.However,the elevated S100?concentration was significantly alleviated by ulinastatin pretreatment?P<0.05?.There was no statistically significant differences in the serum S100?concentration between the two groups at T2?Table 5 and Figure 5,P>0.05?.The results of our research showed that ulinastatin could inhibit the excessive release of serum proinflammatory factor,IL-6 and neural apoptosis related proteins,S100?,but not influencing the expression of serum anti-inflammatory factor,IL-10.Conclusion:Ulinastatin can significantly reduce the incidence of POD in elderly patients undergoing hip fracture surgery.Serum IL-6,IL-10 and S100?may be involved in the mechanism underlying the therapeutic and preventative effect of intravenous ulinastatin on POD in elderly patients.Therefore,the study conducted by us showed that ulinastatin may be considered as an effective neuroprotective agent for the prevention and treatment of POD.