Clinical study of Modified Xiaochengqi Decoction in Perioperative Period of Cholelithiasis: A Randomised Controlled Trial


 Background Modified Xiaochengqi Decoction is a new prescription designed by the author to add astragalus, frankincense and myrrh on the basis of the classic Xiaochengqi Decoction based on the characteristics of biliary tract surgery, and it has been used for clinical differentiation.Therefore, in order to evaluate the clinical effect of Modified Xiaochengqi Decoction in perioperative period of cholelithiasis, this study conducted a prospective randomized controlled study. Methods A total of 162 patients with cholelithiasis were randomly divided into three groups. Modified Xiaochengqi Decoction group: ERAS process + Modified Xiaochengqi decoction. Xiaochengqi Decoction group: ERAS process + Xiaochengqi decoction. Control group: ERAS process + warm boiled water 50ml.Compare the clinical indicators, immune indicators and acute inflammatory stress response indicators between the three groups, and observe the adverse reactions of traditional Chinese medicine. Results Clinical indicators In the Modified Xiaochengqi Decoction group, the postoperative VAS pain scores was decreased, the postoperative activity time and activity distance was increased, the feeding time was advanced, the recovery of gastrointestinal function was advanced, the postoperative cost and postoperative hospital stay was reduced and the incidence of nausea and vomiting was reduced (P <0.05).There was no serious adverse reaction in Modified Xiaochengqi Decoction. Immune indicators On the 1st and 2nd day after operation, the expression of CD3+,CD4+,CD19+ and the ratio of CD4 + / CD8 + in the Modified Xiaochengqi Decoction group was higher than that in the Xiaochengqi Decoction group and the control group.The expression of CD8+ and NK cell was not statistically different between the three groups (P>0.05). A cute inflammatory stress response indicators On the 1st and 2nd day after the operation, the expression of IL-6, CRP and SAA in the Modified Xiaochengqi Decoction group was lower than that in the control group, and the expression of substance P was higher than that in the control group (P<0.05).There was no significant difference in IL-10 expression between the three groups (P>0.05). Conclusions Modified Xiaochengqi Decoction relieved the inflammatory response and improved the immune function in the perioperative period, and promoted postoperative rehabilitation. Moreover, there was no serious adverse reaction in Modified Xiaochengqi Decoction.Trial registration This study is registered at Chinese Clinical Trial Registry.The registration identification number is ChiCTR2000033125.Registered 25 May 2015 Retrospectivelyregistered,http://www.medresman.org.cn/ChiCTR2000033125.


Background
Surgical trauma can lead to the imbalance of pro-inflammatory and anti-inflammatory response, causing a series of pathophysiological changes including immune dysfunction [1][2][3][4] .Correcting immune dysfunction and reducing inflammatory stress response are the key and difficult points in the perioperative period of biliary surgery [5] , and also the basis for early postoperative recovery of patients [6] .Modified Xiaochengqi Decoction is a new prescription designed by the author to add astragalus, frankincense and myrrh on the basis of the classic Xiaochengqi Decoction based on the characteristics of biliary tract surgery, and it has been used for clinical differentiation.Therefore, in order to evaluate the clinical effect of Modified Xiaochengqi Decoction in the perioperative period of cholelithiasis and its effect on immune function and acute inflammatory stress response, this study conducted a prospective randomized controlled study, and the results are reported as follows.

Study design
This was a prospective, randomised, placebo-controlled trial to evaluate the clinical  Bitter Orange 12g,Astragalus 20g ,Frankincense 6g and Myrrh 6g. Appropriate increase or decrease according to the patient's symptoms.Control group: ERAS process + warm water 50ml.Dosing process: Dissolve the above Chinese medicine granules in 100ml water, 50ml was taken orally 14-16 hours before surgery, and 50ml was taken orally 6-8 hours before surgery.50 ml was taken orally 6-8 h after surgery, and 50 ml was taken orally 14-16 h after surgery.On the 1st and 2nd postoperative 7 days, 50ml was taken orally every 8-12 hours.
The ERAS process was as follows: (1) Preoperative preparation: admission education, nutritional risk screening, disease assessment, detailed introduction of the treatment plan, preemptive analgesia, and Visual analogy score (VAS) pain score, etc.

General anesthesia
After the patient entered the operating room, the peripheral vein was opened, and the ECG, heart rate and blood oxygen saturation were monitored routinely.Anesthesia induction: Propofol 1.5-2.5 mg / kg, fentanyl 2-3 μ g / kg and atracurium besylate 0.3-0.6 mg / kg were injected intravenously.Mechanical ventilation was performed after tracheal intubation. Tidal volume was maintained at 8-12 ml / kg, positive end expiratory pressure ventilation (PEEP) was 2-4 cmH2O (1 cmH2O = 0.098 kPa), ventilation frequency was 12-20 times / min, inspiratory oxygen concentration was 30% -60%, gas flow rate was 2 L / min ,and partial pressure of carbon dioxide in end expiratory gas(PETCO2 ) 35 ～45 mmHg ( 1mmHg=0.133kPa) .The nasopharyngeal temperature probe was placed to monitor the patient's intraoperative temperature, and the thermal insulation blanket and infusion heater were used to keep the patient warm 8 during the operation.Anesthesia maintenance: Remifentanil (0.25-0.5μg· kg-1· min-1) was infused intravenously and sevoflurane was inhaled. The inhalation concentration was adjusted according to the vital signs of patients. Atracurium besylate 0.05 mg / kg was injected intravenously during the operation.Anesthesiologists perform radial artery catheterization to contin uously monitor invas ive blood pressure.
Anesthesiologists perform right central venous catheterization to continuously monitor the pressure of the central vein, guide fluid input, maintain hemodynamic stability, and apply vasoactive drugs when necessary.Respiratory parameters were adjusted or medicated according to the results of blood gas analysis.

Operation mode
Biliary tract surgery was performed by one of four trained Surgeon, each with at least 5 years of experience. Check client, routinely disinfect,and lay sterile sheet.A small arc-shaped incision with a length of about 1.5 cm was made under the umbilicus, and a pneumoperitoneum needle was used to enter the abdominal cavity, and carbon dioxide gas was injected into the pneumoperitoneum to 15mmgh.Entered the abdominal cavity with a 10mm Trocar puncture, inserted a laparoscope, and explored the abdominal cavity.Two more cannulas were punctured under the xiphoid process,

Statistical analysis
SPSS17.0 software package was used to analyze the experimental data.Single factor analysis of variance was used in preoperative baseline data, and repeated measurement of variance was used in preoperative and postoperative indicators.The difference was statistically significant with P < 0.05.

Biliary perioperative pain score
Compared with the group before operation, the VAS pain score of Modified Xiaochengqi Decoction group decreased at 12 hour (h) and 1day (D) after operation (P < 0.05); the VAS pain score of Xiaochengqi Decoction group and control group increased at 4h, 8h, 12h and 16h after operation (P < 0.05).There was no significant difference in VAS scores between the three groups 2h before surgery, 0h after surgery (P>0.05).At 4h, 8h, 12h, 16h and 1D after operation, the VAS pain score of Modified Xiaochengqi Decoction group was lower than that of Xiaochengqi Decoction group and control group (P < 0.05).At 16h after operation,the VAS score of xiaochengqi decoction group was lower than that of control group (P<0.05)( Table 1).

Activity after biliary surgery
On the 1st and 2nd day after the operation, the activity time and activity distance in the Modified Xiaochengqi Decoction group were more than those in the Xiaochengqi Decoction group and the control group (P<0.05).On the third day after operation, the activity time of Modified Xiaochengqi Decoction group was more than that of the control group, and the activity distance was more than that of Xiaochengqi Decoction group and the control group (P < 0.05).On the 4th day after operation, the activity time of Modified Xiaochengqi Decoction group was longer than that of the control group (P < 0.05).On the second day after operation, the activity time and activity distance in the Xiaochengqi Decoction group were more than those in the control group (P < 0.05).On the third day after operation, the activity time of Xiaochengqi Decoction group was more than that of the control group (P < 0.05).On the 5th day after operation, there was no statistical difference between the three groups ( Table 2).

Diet after biliary surgery
Compared with the control group, the time of drinking water, entering liquid diet and entering half liquid diet were shortened (P < 0.05).After the operation, the half-liquid diet time in the Modified Xiaochengqi Decoction group was shorter than the Xiaochengqi Decoction group (P <0.05).After operation, the time of normal diet in the three groups was no significant difference (P>0.05)( Table 3).

Recovery of gastrointestinal function after biliary surgery
At 0h, 6h, 12h and 24h after surgery, the frequency of bowel sounds in the three groups was statistically different from that at 2h before surgery (P<0.05).There was no statistical difference in the frequency of bowel sounds between the three groups of patients at 2h before surgery (P> 0.05).The frequency of bowel sounds in the Modified Xiaochengqi Decoction group and the Xiaochengqi Decoction group was more than that in the control group at 6 h, 12 h, and 24 h after operation (P <0.05).At 0h after the operation, the frequency of bowel sounds in the Modified Xiaochengqi Decoction group was more than that in the control group, and the frequency of bowel

Perioperative hospitalization expenses and hospitalization time
Compared with the control group, the postoperative cost, hospital stay and postoperative hospital stay in the Modified Xiaochengqi Decoction group was reduced (P<0.05)(

Complications after biliary tract surgery
Compared with the control group, the incidence of nausea, vomiting, and abdominal distension in the Modified Xiaochengqi Decoction group and the Xiaochengqi Decoction group was reduced(P <0.05).There was no significant difference in incision complications, infection, thrombosis, bile leakage, secondary bile duct stones and other complications among the three groups (P > 0.05)( Table 6). increased fecal frequency (>3 times /d), increased fecal volume (>200g/d), thin fecal quality (>85%) ,without abdominal pain (>75%) [6,7] .According to the above symptoms, the number of diarrhea cases was counted.Diarrhea is relieved after stopping taking Chinese medicine.The incidence of diarrhea of the Modified Xiaochengqi Decoction group and the Xiaochengqi Decoction group was significantly higher than that of the control group at 1day before surgery, 1day and 2day after surgery (P<0.05).The incidence of diarrhea in the Modified Xiaochengqi Decoction group was lower than that in the Xiaochengqi Decoction group at 1day before surgery (P<0.05).There was no statistical difference between the three groups at 3d, 4d and 5d after operation (P> 0.05)( Table 7). There was no statistically significant difference in alanine aminotransferase, aspartate aminotransferase, creatinine, and urea nitrogen during the perioperative period of biliary tract between the three groups (P> 0.05)( Table 8).

Acute inflammatory stress response indicators
On the 1st, 2nd, and 5th postoperative days, the expression of IL-6 in the Modified Xiaochengqi Decoction group, Xiaochengqi Decoction group, and control group increased compared with 1d before surgery (P <0.05).On the 1st day after the operation, the expression of IL-6 in the Modified Xiaochengqi Decoction group and the Xiaochengqi Decoction group was lower than that in the control group. On the 2nd day after the operation, the expression of IL-6 in the Modified Xiaochengqi Decoction group was lower than that in the Xiaochengqi Decoction group and control group (P<0.05).There was no statistical difference between the three groups on 1d before operation and 5d after operation (P> 0.05)( Table 10).
Compared with 1d before the operation, there was no statistical difference in the expression of il-10 in the Modified Xiaochengqi Decoction group, Xiaochengqi Decoction group and control group on the 1st, 2nd and 5th day after the operation (P>0.05).There was no statistical difference between the three groups on 1d before surgery, 1d, 2d and 5d after surgery (P>0.05)( Table 10).
On the 1st and 2nd day after operation, the expression of CRP and SAA in Modified Xiaochengqi Decoction group, Xiaochengqi Decoction group and control group was higher than that on 1 day before operation (P < 0.05).On the 5th day after operation, the expression of CRP in the control group was higher than that on 1 day before operation, and the expression of SSA in Modified Xiaochengqi Decoction group and Xiaochengqi Decoction group was higher than that on 1 day before operation. On the first day after operation, the expression of CRP and SAA in Modified Xiaochengqi Decoction group and Xiaochengqi Decoction group was lower than that in the control group, and the expression of SAA in Modified Xiaochengqi Decoction group was lower than that in Xiaochengqi Decoction group (P < 0.05).On the second day after operation, the expression of CRP and SAA in the group of Modified Group n Time IL-6(pg.mL-1) IL-10(pg.mL-1) CRP(ng.mL-1) SAA(ng.mL-1) Substance P(pg.mL-1) Xiaochengqi Decoction group was lower than that in the group of Xiaochengqi Decoction and the control group, and the expression of SAA in the group of Xiaochengqi decoction was lower than that in the control group (P < 0.05).There was no statistical difference between the three groups on 1d before operation and 5d after operation (P> 0.05)( Table 10).

Xiaochengqi Decoction is selected from "Treatise on Febrile and Miscellaneous
Disease" by Zhang Zhongjing, a famous doctor of Han Dynasty.Its drug composition is Rhubarb 12g ,Magnolia officinalis6g and Immature Bitter Orange 9g [8] .Modified Xiaochengqi Decoction added Astragalus, Frankincense, Myrrh and other drugs on the basis of Xiaochengqi decoction.Modern research has confirmed that Rhubarb, Astragalus, Magnolia officinalis and other drugs have the effects of immune protection and reducing inflammatory stress response [9][10][11][12] .
Biliary tract surgery can lead to postoperative immunosuppression and acute inflammatory stress.Preventive application of antibiotics, intraoperative thermal insulation, minimally invasive surgery, nutritional support and other perioperative measures to reduce stress and inflammation and improve immune suppression [13][14][15] .Rossaint et al [16] found that there was time-dependent immunosuppression after surgery, and NK cell amplification and reduction of CD4 + and CD8 + appeared in the early stage after surgery, which was immunosuppression caused by the stimulation of surgical trauma.Walker et al [17] compared the immune At the same time, moderate inflammatory stress in perioperative period participates in the defense response and protects the body [18] .However, in excessive inflammatory response, a large number of inflammatory cells activated, continuous inflammatory response and immune activation, a large number of pro-inflammatory mediators released, and the imbalance between pro-inflammatory mediators and anti-inflammatory mediators can eventually lead to systemic inflammatory response syndrome, which can develop into multi-organ dysfunction [19] .Wang et al [20] confirmed by randomized controlled experiment that IL-6 was significantly higher after operation than before, but laparoscopic operation and ERAS measures could significantly inhibit the release of IL-6 and other inflammatory factors.Li et al [21] compared ERAS measures with the traditional treatment measures by hepatectomy, and found that the expression level of CRP after ERAS measures was significantly lower than that of the traditional treatment measures, which proved its safety and effectiveness.Jung et al [22] found that the expression of SAA in laparoscopic assisted gastric cancer radical operation was significantly lower than that in open gastric cancer radical operation at 2hours, 1 and 4 days after operation by comparing laparoscopic assisted gastric cancer radical operation with that in open gastric cancer radical operation, which indicated that laparoscopic assisted gastric cancer radical operation reduced the stress response.In this experiment, on the first day and the second day after the operation, the expression of IL-6, CRP and SAA in the Modified Xiaochengqi Decoction group were lower than that in the control group, which proved that it could reduce the inflammatory stress response.
Modified Xiaochengqi Decoction can promote the recovery of gastrointestinal function on the physiological basis of reducing postoperative inflammatory stress response.The frequency of bowel sounds in the Modified Xiaochengqi Decoction was significantly higher than that in the control group at 4h, 8h, 12h, 16h and 1D after operation, and the first time of exhaust and defecation was significantly earlier than that in the control group, which confirmed that the recovery of gastrointestinal function in the Modified Xiaochengqi Decoction group was significantly earlier.At the same time, it has been confirmed that substance P can increase Ca2 + transfer of 27 Cajal interstitial cells in the small intestine, enhance excitatory neuron response and promote gastrointestinal peristalsis [23] .Zhang et al [24] confirmed through the animal experiment that the level of substance P in serum increased significantly after the application of Betel nut, thus promoting gastrointestinal activity.In this experiment, Substance P in the Modified Xiaochengqi Decoction group was significantly higher than that in the control group on the first and second day after surgery.This indicates that Modified Xiaochengqi Decoction increases the secretion of substance P, thereby increases the gastrointestinal smooth muscle contractility and enhances gastrointestinal motility, and promotes the recovery of gastrointestinal function.
In recent years, more researches have been carried out on the treatment of gastrointestinal dysfunction with traditional Chinese medicine.Gastrointestinal dysfunction is mostly caused by severe inflammation.Wang et al [25] found that Rhubarb, Magnolia officinalis and Immature Bitter Orange reduce inflammation and promote the recovery of gastrointestinal function.Wang et al [26] found through a randomized controlled study that Modified Huanglian Jiedu Decoction may promote the recovery of gastrointestinal motor function and shorten the time of mechanical ventilation in patients with severe abdominal surgery.Guo et al [27] found that Chenxia Sijunzi Decoction can promote the recovery of gastrointestinal function in severe patients.All of these confirmed the role of traditional Chinese medicine in promoting the recovery of gastrointestinal function.At the same time, traditional Chinese medicine has analgesic effect.Hu et al [28] confirmed through animal experiments that the water extracts of Frankincense and Myrrh relieve neuropathic pain in mice by regulating TRPV1.Bagheri et al [29] found that Astragalus induce analgesia through the adrenergic system.Shojaii et al [30] also confirmed in animal models that Astragalus extract produce anti-inflammatory and analgesic effects.The patient's early exhaust, defecation, early recovery of gastrointestinal peristalsis, postoperative pain relief, and then promote the patient's early diet, thereby reduce the incidence of nausea, vomiting, abdominal distension and other complications.

Corresponding author
Correspondence to Qiangpu Chen.