Gastroenterology

Effect of Guo Qing Yi Tang combined with Western medicine cluster therapy on acute pancreatitis

a b s t r a c t

Background: This study evaluated the effect of Guo Qing Yi Tang (GQYT) combined with Western medicine clus- ter therapy on acute pancreatitis (AP).

Methods: A total of 138 AP patients were recruited and divided into the observation group (68 patients) and con- trol group (70 patients). The control group was treated with cluster therapy alone, while the observation group was treated with trans-jejunum feeding of GQYT combined with cluster therapy. Blood samples were taken be- fore the treatment and 24 h, 72 h, and 1 week after the treatment. The serum concentrations of Di amine oxidase (DAO), Endotoxin(ET), D-lactic acid, Intestinal trefoil factor(ITF), MFG-E8, TNF-?, IL-1?, IL-6, and IL-8 were deter- mined by using spectrophotometry and enzyme-linked immunosorbent assay. The concentrations of urinary lactulose and mannitol (L/M) were determined by high-performance liquid chromatography, and the urinary L/M value was calculated.

Results: Compared with the control group, the observation group had shorter hospital stay, faster recovery, sig- nificantly lower APACHE II score, and higher complete response rate (94.12%) after 1 week of treatment (P < 0.05). Moreover, the indicators related to Intestinal mucosal barrier function (DAO, MFG-8, L/M) and inflam- matory cytokines (TNF-?, IL-6, IL-8) were significantly reduced in the observation group after 1 week of treat- ment (P < 0.05).

Conclusion: GQYT combined with cluster therapy for the treatment of AP has definite curative effect and rapid onset, reduces the level of inflammatory factors, and improves intestinal mucosal barrier function and APACHE II score. Thus, it has obvious clinical therapeutic advantages and can be used as a new therapeutic regimen for AP.

(C) 2021 Published by Elsevier Inc.

  1. Introduction

Acute pancreatitis (AP) is one of the most common gastrointestinal diseases. It is caused by infection, hyperlipidemia, gallstones, and trauma. The mortality rate of severe AP (SAP) is 40%. AP is one of the most intractable diseases in Surgical emergencies, and its incidence rate has been increasing annually [1]. AP has a rapid onset and develop- ment, which can lead to sudden and persistent upper abdominal pain, accompanied by nausea and vomiting and other symptoms, and even threaten the patient’s life in serious cases. Therefore, effective treatment measures are needed [2]. At present, Western medicine and surgical treatment are routinely used in the treatment of this disease, but pa- tients can still relapse after the initial treatment of the disease, resulting in recurrent AP. If recurrent AP occurs repeatedly, it can lead to Chronic pancreatitis [3], which is a clinical problem that needs to be solved urgently.

* Corresponding author.

E-mail addresses: [email protected] (Y.-J. Chen), [email protected] (M.-Z. Chen).

Compared with Western medicine, accumulating evidence suggests the beneficial effects of plants used in Traditional Chinese Medicine (TCM) and compounds isolated therein [4,5]. The utilization of TCM shows good prospects in AP therapy because of its extensive pharmaco- logical effects and fewer adverse effects [6-8]. In a retrospective study, the Chinese herbal decoction, Huoxue Qingyi Decoction (HQD), was found to be effective, safe, and economic for reducing the complications; for achieving early recovery from systemic inflammation; and for pro- moting earlier rehabilitation from SAP [9]. The study found that the number of patients with pancreatic pseudo cyst was much higher in the control group than in the HQD group. Borneol, which is a US-FDA- approved food adjustment, has the potential to attenuate cerulein- induced AP by reducing oxidative damage and pancreatic inflammation by modulating the Nrf2/NF-?B pathway [10]. Studies have shown that combining TCM and Western medicine can create synergies and im- prove clinical Curative effects. In recent years, more and more studies have combined TCM with Western medicine to treat pancreatitis with remarkable curative effect. The Qingyi Chengqi Decoction (QCD) can re- lieve inflammatory response; lower the mortality; increase the curative rate; and improve the prognosis of SAP [11]. The Chaishao Chengqi

https://doi.org/10.1016/j.ajem.2021.07.004 0735-6757/(C) 2021 Published by Elsevier Inc.

Decoction combined with LMWH can effectively relieve the clinical signs and symptoms of HLP patients, shorten the course of disease, in- hibit the release of inflammatory mediators in vivo, and improve the co- agulation function [12].

Guo Qing Yi Tang (GQYT) is composed of 13 TCMs such as raw rhu- barb, sodium sulfate, senna leaf, hawthorn, Magnolia officinalis, and Bupleurum. It is an empirical prescription created by Guo Senren, chief physician of our hospital (National famous experts in traditional Chi- nese Medicine), which has been proved to be effective in the treatment of AP through long-term clinical practice. In our previous studies, we found that trans-jejunum feeding is a new route of administration that enables rapid absorption of drug components [13]. However, to our knowledge, no study has combined GQYT with Western medicine cluster therapy in the treatment of pancreatitis. Thus, the present study explored the effect of GQYT combined with cluster therapy in the treatment of AP.

  1. Methods
    1. AP patients

A total of 138 AP patients were recruited from the Jinjiang Hospital of Traditional Chinese Medicine, Fujian Province (Jinjiang Hospital of Traditional Chinese Medicine Affiliated to Fujian University of Tradi- tional Chinese Medicine) in September 2017 to December 2019. Ac- cording to the random number table method, the patients were divided into the control group (n = 70) and observation group (n = 68). The study was approved by the Ethical Committee of Jinjiang Hospital of Traditional Chinese Medicine Affiliated to Fujian University of Tradi- tional Chinese Medicine. All patients were informed of the study details before admission. No additional treatment was given to the patients be- fore surgery.

    1. Peripheral venous blood

About 5 ml of peripheral venous blood was collected from each indi- vidual before the treatment and 24 h, 72 h, and 1 week after treatment. The samples were added with 35 ul of 10% EDTA for anticoagulation and then centrifuged (Ortho BioVue, Shanghai) for 10 min at 3000 rpm and 4 ?C. The supernatant (serum) was obtained and stored at -80 ?C for follow-up tests.

    1. Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) patients who met the di- agnostic criteria of moderate AP or SAP in the Chinese Guidelines for the Diagnosis and Treatment of Acute Pancreatitis (Shanghai, 2013) is- sued by the Pancreatic Diseases Group of Gastroenterology Society of Chinese Medical Association [14] and the TCM dialectical classification standard of AP in the Consensus on Acute Pancreatitis Management of Chinese Medicine of Spleen and Stomach Disease Branch of China Asso- ciation of Traditional Chinese Medicine (2013) [15]; (2) patients were hospitalized within 72 h of onset; (3) no indication of surgical treat- ment; (4) did not receive relevant drug therapy recently; (5) patients and their family members agreed to cooperate with the study and signed the informed consent.

The exclusion criteria were as follows: (1) patients with acute exac- erbation of chronic pancreatitis; (2) serious heart, lung, liver, and kid- ney dysfunction; (3) complicated with gastrointestinal and abdominal tumors, mechanical ileus, and other diseases that seriously affect gastro- intestinal function; (4) patients with coagulation dysfunction, necrosis of other organs, and severe metabolic diseases; (5) pregnant and lactat- ing patients; (6) allergic to the study drug; (7) patients with mental ill- ness and immune dysfunction; (8) Patients with inflammatory bowel disease; (9) poor compliance and quit halfway of the study.

    1. Treatment

The control group received western medicine cluster therapy: Fasting immediately after admission, gastrointestinal decompression, relieve pain, spasmolysis, target-directed fluid resuscitation and anti shock, inhibits trypsin secretion, maintain electrolyte and acid-base bal- ance, dredge intestinal tract and early enteral nutrition support, inhibi- tory systemic inflammatory response syndrome, The prevention and treatment of infection, maintain the function stability of heart, lung, kid- ney and other important organs, Blood purification treatment if necessary.

Observation group was additionally treated with TCM on the basis of control group: The nasojejunal tube was placed by hand, and GQTY was dripping through the nasojejunal tube. Pieces of Chinese medicine of GQTY are provided by the Pharmacy of Jinjiang City Hospital of TCM. And by the hospital Chinese medicine decocting room in accordance with the conventional water decocting way. Finally, 400 ml of liquid was obtained for each dose, and the infusion pump was used according to the patient’s tolerance at a rate of 50-100 ml/h through the nasojejunal tube, once every 4 h, 50-100 ml each time. Treatment of two groups of patients were 1 week.

    1. Determination of the serum concentrations of DAO, ET, D-lactic acid, ITF, MFG-E8, TNF-?, IL-1?, IL-6, and IL-8

About 5 ml of peripheral venous blood was collected from each indi- vidual before the treatment and 24 h, 72 h, and 1 week after treatment. The samples were added with 35 ul of 10% EDTA for anti coagulation and then centrifuged (Ortho BioVue, Shanghai) for 10 min at 3000 rpm and 4 ?C. The supernatant (serum) was transferred to a new tube and stored at -20 ?C. The serum concentrations of DAO were quantified using a spectrophotometric method and enzyme-linked immunosorbent assay (ELISA) kit (Shanghai Ruipin Bio-tech Co. Ltd. Shanghai, China). ET was quantitatively determined by using a modified limulus experiment. D-lactic acid was detected by modified enzyme spectrophotometry. The serum concentrations of ITF and MFG-E8 were quantified by using a double-antibody sandwich ELISA kit (Shanghai Ruipin Bio-tech Co. Ltd. Shanghai, China). The serum concentrations of TNF-?, IL-1?, IL-6, and IL-8 were quantified using an ELISA kit (Shanghai Ruipin Bio-tech Co. Ltd. Shanghai, China). All of the experiments were performed in accordance with the manufacturer’s instructions. The serum concentra- tions of DAO, ET, D-lactic acid, ITF, MFG-E8, TNF-?, IL-1?, IL-6, and IL-8 were calculated on the basis of their standard curves. All experiments were repeated in triplicate.

    1. Determination of urinary lactulose and mannitol (L/M) concentrations and L/M value

Oral lactulose 10 g and mannitol 5 g before the treatment and 24 h, 72 h, and 1 week after treatment, and all urine was collected from each individual within 6 h. After mixing, 20 ml Urine sample was added with

0.2 mg thiomersal for preservative, storage at -80 ?C. The concentra- tions of urinary lactulose and mannitol were determined by high- performance liquid chromatography, and the urinary L/M values were calculated. All experiments were repeated in triplicate.

    1. Outcome measurements

According to the diagnostic criteria of SAP [14], (1) symptoms such as abdominal pain, abdominal distension, nausea and vomiting with sig- nificant effect disappeared, and all the indicators recovered normally by laboratory examination; (2) all clinical symptoms and manifestations were alleviated, and all indicators of laboratory examination were sig- nificantly improved; (3) the ineffective symptoms were still serious, and the total effective rate = (the number of effective cases + the num- ber of effective cases)/the total number of casesx100%.

Table 1

Analyze of demographic details for Observation and control groups.

Control group (n = 70)

Observation group (n = 68)

?2/t/z

P

Age(mean +- sd)

35.4 +- 5.103

35.29 +- 5.854

-0.113

0.04

Gender

0.087

0.768

Male(n/%)

54(77.14%)

51(75%)

Female(n/%)

16(22.86%)

17(25%)

Course of disease

19.33 +- 8.36

18.16 +- 7.50

-0.862

0.268

Hospitalization days (median (range))

10(8,14)

8(8,10)

-4.315

<0.000

BMI(kg/m2, mean +- sd)

22.49 +- 2.20

22.70 +- 2.33

0.549

0.558

Etiology

1.577

0.667

Hypertriglycerdemia

30(42.86%)

28(41.18%)

0.04

0.842

Hypertriglycerdemia + Alcohol

24(34.29%)

20(29.41%)

0.378

0.539

Gallstone

9(12.86%)

14(20.56%)

1.493

0.223

Other

7(10%)

6(8.82%)

0.056

0.813

BMI: Body Mass Index,*p < 0.05, ***p < 0.001.

    1. Statistical methods

All statistical analyses were conducted using SPSS 20.0 statistical software. The measured data are expressed as mean +- standard devia- tion.The measurement data accord with Normal distribution measure- ment data to mean +- the standard deviation (SD). The independent sample t-test and paired sample t-test were used to analyze the differ- ences between groups or in the groups, respectively. The median and quartiles were used for groups with non-parametric (non-normal) dis- tribution. The Mann-Whitney U test and Wilcoxon-test were used to analyze the differences between groups or in the groups, respectively. Enumeration data were described by percentage. The rank sum test was used for grade data, and the ?2 test was used for inter-group com- parison. Statistical significance was considered at P < 0.05.

  1. Results
    1. Patient characteristics

Table 1 summarizes the demographic data for patients and controls who were matched for age, gender, course of disease, hospitalization days, BMI, and etiology. Compared with the control group, the age of the observation group was statistically different (P < 0.05). The hospi- talization days in the observation group was shorter compared with those in the control group, and the difference was statistically signifi- cant (P < 0.000). No significant differences were observed in other indi- cators between the observation and control groups (P > 0.05).

    1. Observation of clinical effect

As shown in Table 2, the observation group had a higher complete response (CR) rate (94.12%) compared with the control group (82.86%), and the difference was statistically different (P < 0.05); how- ever, the control group had a higher improvement rate (15.71%, P < 0.05). No significant differences were observed in the remission and overall response rate (ORR) between the observation and control groups (ORR = 100%, P > 0.05).

Table 2

Comparison of clinical efficacy between two Groups (n/%).

    1. Analyses of APACHE II score

As shown in Table 3, no significant differences were observed in the APACHE II score between the two groups before treatment (P > 0.05). One week after treatment, the APACHE II scores in both groups were lower than those before the treatment. The observation group had a lower score (7.84 +- 2.00) than the control group (10.86 +- 2.77)

(P < 0.0001).

    1. Evaluation of indicators related to intestinal mucosal barrier function

As shown in Table 4, no significant differences were observed in DAO, ET, D-lactate, ITF, MFG-8, and L/M levels between the two groups before treatment (P > 0.05). However, the DAO, ET, D-lactate, and L/M levels in both groups were lower 24 h, 72 h, and 1 week after treatment than those before treatment. Moreover, the observation group had lower levels than the control group. Of note, only the DAO and L/M levels had significant differences 1 week after treatment (P < 0.0001). The ITF and MFG-8 levels in both groups were higher after treatment than before treatment. Moreover, the observation group had higher levels than the control group. Of note, only the MFG-8 levels had signif- icant differences 1 week after treatment (P < 0.0001).

    1. Evaluation of the expression levels of inflammatory factors

As shown in Table 5, no significant differences were observed in the TNF-?, IL-1?, IL-6, and IL-8 levels between the two groups before treat- ment (P > 0.05). One week after treatment, the expression levels of in- flammatory factors in both groups were lower than those before treatment. Moreover, the observation group had lower expression levels than the control group. Of note, only the TNF-?, IL-6, and IL-8 levels had significant differences (P < 0.001); the IL-1? levels showed no significant differences (P > 0.05).

  1. Discussion

AP can be classified as stomachache, abdominal pain, and chest knots in TCM. According to TCM, the main cause of the disease is the loss of emotion, food, insects, gallstones, and other causes of Qi and pathogenic resistance; liver and gall bladder dampness-heat

Table 3

Comparison of ApacheII score between two Groups(x+- SD).

Group n CR SD PR DCR

CR: Complete Response; SD: Stable Disease; PR: Partial Response; DCR: Disease Control Rate. *p < 0.05.

P 0.142 <0.000

ApacheII: Acute physiological alteration and chronic health evaluation II. ***p < 0.001.

Control group

70

58(82.86)

11(15.71)

1(1.43)

70(100)

Group

n

Before treatment

1 weeks t p

Observation group

68

64(94.12)

3(4.41)

1(1.43)

68(100)

Control group

70

18.60 +- 4.312

10.86 +- 2.77 30.82 <0.000

?2

4.45

5.12

0

5.126

Observation group

68

18.88 +- 3.87

7.84 +- 2.00 29.04 <0.000

p

0.039

0.028

0.984

0.089

t/z

0.405

6.148

Table 4

Comparison of the expression level of intestinal mucosal barrier function related indicators between two groups(x+- SD).

Group

Treatment time

DAO(U/L)

ET(U/L)

Lactate (mg/L)

ITF (ng/ml)

MFG-8 (ng/ml)

L/M

Control group(n = 70)

Before treatment

38.55 +- 6.61

20.67 +- 2.88

39.56 +- 1.79

18.84 +- 1.67

10.21 +- 0.79

0.68 +- 0.04

24 h

33.76 +- 6.88a

19.14 +- 3.16a

34.45 +- 3.28a

20.07 +- 1.67a

11.27 +- 1.00a

0.65 +- 0.05a

72 h

25.91 +- 6.22a

16.20 +- 2.81a

30.09 +- 2.82a

21.59 +- 1.55a

13.06 +- 1.12a

0.58 +- 0.06a

1 week

13.65 +- 3.79a

12.77 +- 1.93a

25.45 +- 1.96a

23.93 +- 1.61a

15.26 +- 0.82a

0.50 +- 0.03a

Observation group (n = 68)

Before treatment

39.41 +- 6.852

20.77 +- 2.97

39.56 +- 1.78

18.74 +- 1.73

10.20 +- 0.83a

0.68 +- 0.04

24 h

33.78 +- 6.87a

18.14 +- 3.93a**

33.01 +- 4.80a**

22.51 +- 2.69a***

13.36 +- 2.72a***

0.70 +- 0.08a**

72 h

24.52 +- 6.58a

11.92 +- 3.81a**

25.89 +- 5.42a***

27.18 +- 3.46a***

19.29 +- 3.90a***

0.48 +- 0.10a***

1 week

7.29 +- 1.51a***

5.79 +- 1.51a

14.77 +- 1.61a

37.88 +- 1.85a

27.93 +- 1.79a***

0.24 +- 0.02a***

DAO: Diamine oxidase; ET: Endotoxin; D-lactate: D – lactic acid; ITF: Intestinal trefoil factor; MFG-8: Fat bulb epidermal growth factor 8; L/M: Ratio of urinary lactulose to mannitol. Before treatment vs 24 h, 72 h, 1 week, respectively, ap < 0.05. *Control group vs Observation group, **p < 0.01, ***p < 0.001.

Table 5

Comparison of the expression level of inflammatory factors between two groups(x+- SD).

Group

Treatment time

TNF-?(ng/L)

IL-1?(ng/L)

IL-6(ng/L)

IL-8(ng/L)

Control group(n = 70)

Before treatment 24 h

72 h

1 week

407.88 +- 55.00

372.20 +- 51.07a

333.99 +- 52.98a

271.83 +- 41.40a

45.65 +- 4.18

42.72 +- 5.51a

38.56 +- 4.58a

32.26 +- 3.40a

400.43 +- 14.05

390.90 +- 18.44a

363.16 +- 19.69a

314.62 +- 15.19a

330.35 +- 17.22

302.32 +- 25.33a

272.64 +- 25.81a

211.24 +- 10.56a

Observation group (n = 68)

Before treatment 24 h

72 h

1 week

408.24 +- 55.86

356.61 +- 52.08a

273.85 +- 40.16a??

174.36 +- 25.83a???

45.38 +- 4.48

39.78 +- 7.71a?

31.57 +- 6.36a

17.36 +- 3.21a

401.01 +- 14.06

376.26 +- 29.83a?

332.30 +- 41.08a???

215.01 +- 12.05a??

330.65 +- 17.75

292.95 +- 27.82a

246.36 +- 27.08a

134.55 +- 7.70a??

TNF-?: Tumor necrosis factor ?; IL-1?: Interleukin 1 beta; IL-6: Interleukin-6; IL-8: Interleukin-8. Before treatment vs 24 h, 72 h,1 week, respectively, ap < 0.05. *Control group vs Obser- vation group, *p < 0.05, **p < 0.01, ***p < 0.001.

stagnation; and accumulation in the upper abdomen. The rapid devel- opment of the disease, wet and hot gas agglomeration does not dis- perse, and produce heat toxin; blood stasis caused by blood feve; The heat poison blood stasis interconnects, cause blood septic meat rot into pus [16,17]. Therefore, the basic treatment of this disease should be to clear the dampness and heat, promote qi and blood circulation, re- move silt and detoxify. GQYT is composed of 13 TCMs, including raw Rhubarb, Sodium sulfate, Senna leaf, Magnolia officinalis, Bupleurum, Corydal is tangerine peel, wood incense, dandelion, white, and liquorice prepared with Sal via miltiorrhiza [13]. It has the effect of clearing away heat, detoxifying, purging, purifying, and cleansing dampness. Pharma- cological studies have shown that rhubarb enema has a significant effect on AP as it can improve the total effective rate, speed up the recovery of intestinal function, shorten the length of hospital stay, and control the inflammatory factors in patients [18-20]. Bupleurum has anti- inflammatory and anti-epidemic functions [21]. These findings provide a theoretical basis for the application of GQYT in the treatment of AP. The results of this study showed that inflammatory cytokines TNF-?, IL-6, and IL-8 in AP patients were reduced by GQYT combined with clus- ter therapy for 1 week. The expression levels of inflammatory cytokines were statistically significant in the observation group compared with the control group (P < 0.05). This finding suggests that GQYT combined with cluster therapy can effectively reduce the inflammatory response and improve the immune function of the body.

SAP due to infection is mainly caused by intestinal bacterial translo-

cation. The intestinal barrier prevents intestinal pathogenic bacteria and toxins from reaching the parenteral tissues through the intestinal wall. Therefore, maintaining intestinal barrier function may be the key to preventing damage from AP [22,23]. A previous study showed that 59% of AP patients had associated intestinal barrier injury, with in- creased intestinal mucosal permeability, leading to intestinal bacterial translocation, pancreatic tissue necrosis and infection, and Multiple organ dysfunction syndrome [24,25]. The results of the present study showed that the indicators related to intestinal mucosal barrier function (DAO, MFG-8, L/M) in AP patients were reduced by GQYT combined with cluster therapy for 1 week. The levels of these indicators were sta- tistically significant in the observation group compared with the control

group (P < 0.05). This finding suggests that GQYT combined with clus- ter therapy can effectively promote the recovery of intestinal mucosal barrier function.

In addition, this study found that compared with the control group, the observation group had shorter hospital stay, faster recovery, signif- icantly lower APACHE II score, and higher CR rate (94.12%) after 1 week of treatment (P < 0.05). This finding suggests that GQYT can reduce the severity of the disease and promote the recovery of patients with AP.

  1. Conclusion

GQYT combined with cluster therapy for the treatment of AP has definite curative effect and rapid onset, reduces the level of inflamma- tory factors, and improves intestinal mucosal barrier function and APACHE II score. Thus, it has obvious clinical therapeutic advantages and can be used as a new therapeutic regimen for AP.

Declaration of Competing Interest

The authors declare that they have no conflict of interest.

Acknowledgement

The study was supported by Fujian Traditional Chinese Medicine Sci- ence and Technology Project in 2016-2019 (Document No: Fujian-Wei TCM Letter [2017] 237, Project No: 2017FJZYLC105); Research Subsidy Project of Jinjiang Hospital of Traditional Chinese Medicine Affiliated to Fujian University of Traditional Chinese Medicine in 2017 (Project No: YN201703); Guo Senren National Grass-roots veteran traditional Chinese Medicine expert inheritance Studio Construction Project (Document No: National Traditional Chinese Medicine Education [2016] No. 41).

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