Effect of Xiangbin Prescription in Gastrointestinal Function After Gynecological Abdominal Surgery: a Randomized Controlled Trial

Background: Recovery of gastrointestinal function after gynecological abdominal surgery is a major clinical problem. An effective intervention to promote the rapid recovery of gastrointestinal function postoperatively is lacking. This randomized trial investigated whether Xiangbin prescription (XBP) was feasible in terms of efficacy and safety on gastrointestinal function recovery in patients after gynecological abdominal surgery. Methods: A randomized controlled study was conducted, in which 190 patients with gynecological abdominal surgery who met the inclusion and exclusion criteria were enrolled. They were assigned randomly to XBP group, chewing gum group or blank control group, and respectively received the following treatments: took the XBP twice a day, chewed a piece of gum for about 15 minutes each 4 hours, or received conventional western basic treatment, starting on postoperative day 1 until defecation. Three groups were compared in terms of primary outcomes including the time of the first defecation and the time of the first flatus and secondary outcomes including the level of Ghrelin (GHRL) and the incidence of postoperative complications. Meanwhile, the safety of this trial was evaluated. Results: There was no statistical difference in baseline characteristics among the three groups. For the time of the first flatus, XBP group ( 22.33 ± 6.68 h ) showed less time compared with the chewing gum group ( 23.06 ± 7.37 h ), while it was shorter than that in the blank control group ( 25.86 ± 7.93 h ) with significant difference ( P < 0.05). As for the time of the first defecation, XBP group ( 38.65 ± 12.96 h ) showed shorter time significantly compared with both the chewing gum group ( 47.29 ± 14.50 h ) and the blank control group ( 54.01 ± 20.32 h ) ( P < 0.05). For the postoperative GHRL levels, XBP group was higher than that in the chewing gum group with no significant difference and had more significant improvement of the GHRL levels at postoperative day 3 compared with the blank control group ( P < 0.05). For postoperative complications, XBP group had lower incidence than the other two groups but with no significant difference. For safety evaluations, no serious adverse events occurred in the three groups. Conclusions: XBP could promote the recovery of gastrointestinal function after gynecological abdominal surgery and it is overall safe. Trial registration: This trial was retrospectively registered by Chinese Clinical Trial Registry with the identifier number, ChiCTR1900026327, at September 30, 2019.

previous study has shown that XBP may show significant effects in promoting gastrointestinal motility in healthy individuals 9 . To evaluated the efficacy and safety of XBP for patients who underwent gynecological surgery, this randomized controlled trial was designed and completed.

Study design
This study was designed as a randomized controlled trial which was registered by Chinese Clinical Trial Registry with the identifier number, ChiCTR1900026327.  Table 1. This study was approved by the ethical committee of Guangdong Provincial Hospital of Traditional Chinese Medicine(NO.B2017-153-01). All patients signed the informed consent form.

Randomization
The random cards were prepared according to the output random distribution by the PEMS 3.1 software and put into opaque envelopes, on the surface of which we coded numbers. The order of enrolled patients corresponded to the numbers on the envelops. Each enrolled patient was intervened according to the random number.
The randomization was coded numerically with 1 for XBP group, 2 for chewing gum group, and 0 for blank control group. The random card was kept by the research team while the random number was issued by the specific person.
Professional training was provided to all researchers, including filling Case Report Forms normatively, research work manual and research program. We gained the trust and cooperation of patients to improve clinical compliance. We established record cards, one for each person,which were recorded and checked timely by the chief doctor, chief nurse and the patient, so as to ensure the integrity and accuracy of the research report and the quality of clinical research. All the authors vouch for the veracity and completeness of the data and analyses.

Blinding
Due to the different interventions in this study, one was oral traditional Chinese medicine and the other was chewing gum, so the blinding methods was not suitable for patients and evaluators.

Intervention
Eligible patients were randomly assigned to the XBP group, chewing gum group and the blank control group. In the XBP group, on the basis of conventional therapies XBP should be taken 2 packs a day and 150ml each time at 9:00 am and 4:00 pm from the first postoperative day until defecation. In the chewing gum group, each patient was given a packet of sugar-free mint gum, chewing once every 4 hours when awake after surgery, and one tablet each time for about 15 minutes, until defecation.
In the blank group, patients only accepted basic therapies without other intervention.

Primary outcomes
The primary outcomes of the study were time to first defecation and flatus after the surgery. Time to first defecation and flatus was from the time when the surgery was completed until the first observed passage of stool and the first observed passing of flatus, respectively. Patients were monitored daily until the 7th postoperative day (or the day of discharge).

Secondary outcomes
The secondary outcomes included GHRL and the incidence of complications related to PGID such as nausea, vomiting, abdominal pain and abdominal distention, etc. Patient compliance was also evaluated.

Safety evaluation
Safety observation items included recording of adverse events, such as rash, headache, dizziness, and testing of general safety indicators, electrocardiogram, blood routine, urine routine, liver and kidney function include. Adverse events were recorded truthfully at any time. For all adverse events, patients were withdrawn from the study if necessary.

Statistical analysis
SPSS 18.0 was used for statistical analysis of the data. The statistical analyses were performed on an intention-to-treat (ITT) basis. All analyses were based on the ITT population. The enumeration data were described by proportion and rate, while the measurement data were described by x s  , Median and interquartile range.
Pearson's Chi-square or Fisher's exact tests was performed to compare the qualitative parameters between groups. Using ANOVA or Kruskal-wallis test to compare between groups of continuous variable. P < 0.05 was considered to be statistically significant. All statistical tests were two-tailed with a significance level set at α = 0.05.  Table 2.

Patient demographic and baseline characteristics
There was no statistically significant difference between groups (P > 0.05), which showed that three groups were comparable in patient demographic and baseline characteristics.

Primary outcomes
Overall comparison(

Secondary outcomes
Compared the GHRL levels with three groups of different detection point (preoperative, postoperative day 1 and postoperative day 3), the GHRL levels of three groups of postoperative patients were lower than before operation, and elevated at postoperative day 3. The difference of GHRL levels among three groups was statistically significant (P < 0.05). Comparison among three groups manifested that the GHRL levels in the XBP group was significantly higher than that in the blank control group at postoperative day 3, and the difference was statistically significant (P < 0.05). The improvement in the XBP group was more efficiency than chewing gum group, but no significant difference was found (P > 0.05). (Fig. 2)

Fig. 2 GHRL levels
For the incidence of postoperative complications, the morbidity in the XBP group was similar to the chewing gum group and decreased compared with the blank control group, but it was not statistically significant. In conclusion, XBP can reduce the incidence of postoperative complications to a certain extent ( Table 4).

Safety evaluation
There was no local or systemic adverse reactions such as headache, dizziness or rash occurred in the three groups during the treatment. Compared with pretreatment, it is nothing abnormal for the liver and kidney function, electrocardiogram, blood routine and urine routine of the three groups after surgery.
XBP is safe to use. To prevent POI, many efforts have been taken. In modern medicine, antibiotics, restricted fluids, early activity and nutrition are used to promote rapid postoperative recovery after abdominal gynecologic surgery [16][17][18] . Generally the common gastrointestinal motility drugs, such as morbutoline, cisapride, metoclopramide and alvimopan, are restricted in clinical use by the cardiac system adverse reactions and extrapyramidal reactions, which are mainly used for internal medicine treatment 19,20 .

DISCUSSION
However, none of these measures has been completely successful 5 . As an alternative to sham feeding, chewing gum had been proved to be an effective measure to Alkaloids are believed to be the main active components. An animal trial showed that Lindera radix ethanol extract treatment can significantly reduce NF-kB and LPS levels, suppress the inflammatory response and ameliorate intestinal ultrastructure injury 24 .
As a kind of Chinese medicine with high medicinal value, ginseng has been shown to improve the symptoms of intestinal mucosa atrophy, reduce the effect of intestinal mucosa secretions, and protect the intestinal mucosa 25 . As a M receptor agonist, Arecoline can promote the secretion of gastrointestinal glands, especially enhance gastric emptying 26 . Taoren has been confirmed to promote blood circulation, removes blood stasis, and moistens and loosens the bowels. Sharen can promote the release of motilin and substance P in the body so as to improve gastrointestinal function after gastric surgery 27 . Our previous research also showed that alkaloids may be the main substances in promoting gastrointestinal motility of XBP 28 .
There were some limitations in our study that should be mentioned. First of all, the sample size is not large enough so that some data did not have significant statistical differences as expected or skewed in some extent.In addition, due to the obvious difference in the intervention methods, blind design was not adopted in this study, which may lead to differential misclassification bias. Besides, too few research indicators. Summing up the above, in the later study, we will expand the sample size and carry out the trial by using the method of randomized double-blind control with placebo to improve the authenticity and credibility of the research results.
Furthermore, later studies can add indicators like electroencephalogram observations of patients and in terms of mechanism research, animal experiments, cell experiments or muscle strip experiments can be designed to further explore the mechanism in multiple ways.

CONCLUSION
XBP was verified to be benefit to promote the recovery of gastrointestinal function after gynecological surgery, whose mechanism may be through the regulation of GHRL level. Further more, XBP can reduce the incidence of postoperative complications to a certain extent, which is worthy of promotion and application in clinical practice.