Application of loss-increasing real-person viscera-nourishing decoction in preparation of medicine for treating critically ill antibiotic-associated diarrhea

Abstract

The invention relates to the field of traditional Chinese medicine application, and discloses application of a loss-increasing real-person viscera-nourishing decoction in preparation of a medicine for treating critically ill antibiotic-associated diarrhea, and the loss-increasing real-person viscera-nourishing decoction comprises the following active ingredient raw materials in parts by weight: 13-17 parts of ginseng, 13-17 parts of charred angelica sinensis, 18-22 parts of roasted rhizoma atractylodis macrocephalae, 13-17 parts of myristica fragrans, 5-7 parts of cinnamon and 8-12 parts of honey-fried licorice root. , 18-22 parts of parched white peony root, 8-12 parts of roasted radix aucklandiae, 8-12 parts of roasted fructus chebulae and 18-22 parts of pomegranate rind. The loss-increasing real-person viscera-nourishing decoction shows a good curative effect in the treatment process of antibiotic-related diarrhea of critical patients, also shows a good curative effect in the aspects of improving the gastrointestinal function and the overall health condition of the patients, is relatively low in recurrence rate, has good safety, and is suitable for clinical application. The compound can be effectively used for preparing the medicine for treating the critically ill antibiotic-associated diarrhea and treating the critically ill antibiotic-associated diarrhea.

Description

Technical Field

[0001] The present invention relates to the field of traditional Chinese medicine applications. Specifically, it relates to the application of Modified Zhenren Yangzang Decoction in the preparation of drugs for treating critically ill patients with antibiotic-associated diarrhea. Background Art

[0002] Antibiotic Associated Diarrhea (AAD) is a common digestive system complication that occurs during or after the use of antibiotics by patients. Its etiology mainly lies in the destruction of the normal intestinal flora by antibiotics, which then disrupts the intestinal microecological balance, weakens the intestinal barrier function, and leads to the overgrowth of pathogenic bacteria, the release of enterotoxins, and inflammatory reactions. The clinical manifestations can range from mild diarrhea to severe pseudomembranous colitis, and in extreme cases, it can even cause toxic megacolon, intestinal perforation, and even endanger life. According to foreign and domestic reports, the incidence of AAD may reach 5% - 35% and 7% - 29% respectively. In critically ill patients, due to low immune function, long-term bedridden status, and impaired basic organ functions, their diarrhea symptoms are often more severe and are prone to be accompanied by multiple organ dysfunction, significantly increasing the hospital stay and mortality rate.

[0003] Modern medical research has found that antibiotic-induced diarrhea is mainly attributed to the following aspects:

[0004] 1. Intestinal flora dysbiosis: Antibiotics not only kill pathogenic bacteria but also inhibit beneficial bacteria in the intestine, causing conditional pathogenic bacteria or drug-resistant strains to gain the upper hand, thus disrupting the original microecological balance.

[0005] 2. Intestinal mucosal barrier damage: Normal intestinal mucosa relies on short-chain fatty acids produced by the fermentation of intestinal flora to maintain energy supply. When the use of antibiotics interferes with this metabolic process, intestinal epithelial cells may be damaged due to insufficient energy, resulting in a decline in intestinal barrier function.

[0006] 3. Metabolic disorders and inflammatory reactions: Antibiotics simultaneously affect the metabolism of intestinal carbohydrates and bile acids, causing water and salt balance disorders, and directly stimulating the intestine to cause inflammation, which can all exacerbate diarrhea symptoms.

[0007] Clinically, conventional Western medicine treatment regimens mainly focus on symptomatic treatment, such as stopping or replacing antibiotics, replenishing fluids and electrolytes, or using antibacterial, anti-inflammatory, and intestinal flora-regulating drugs (such as probiotic preparations). However, these methods often have problems such as a high recurrence rate, inability to fundamentally improve intestinal function, and insufficient body immunity. Especially in critically ill patients, simple symptomatic support treatment has limited effects.

[0008] Traditional Chinese medicine (TCM) understands this disease from the perspectives of holistic view and syndrome differentiation and treatment. Although there is no specific classification of "antibiotic-associated diarrhea" in traditional TCM concepts, it already has a relatively systematic theory regarding "diarrhea" and related disorders of the spleen and stomach functions. TCM believes that the occurrence of diarrhea is mainly related to factors such as disharmony of the spleen and stomach, deficiency of spleen qi, endogenous dampness, and deficiency of kidney yang. Antibiotics themselves are mostly bitter and cold in nature. Their long-term or excessive use not only damages the vital qi of the spleen and stomach but may also exacerbate the accumulation of cold dampness, thus inducing or aggravating diarrhea symptoms. Especially for the weak and elderly patients, deficiency of spleen and kidney yang is a common pathogenesis, leading to a decline in the body's resistance to external pathogenic factors "drug toxins", disorder of gastrointestinal motility, and making the symptoms refractory to treatment and prone to recurrence.

[0009] The Zhenren Yangzang Decoction originated from the experience of ancient physicians. Its composition includes: ginseng, angelica (removed the root), and atractylodes macrocephala (baked), each six qian (each 6 grams), nutmeg (wrapped with flour and roasted), half liang (8 grams), white peony root, one liang and six qian (12 grams), terminalia chebula (seed removed), one liang and two qian (9 grams), cinnamon (removed the rough bark), and roasted licorice root, each eight qian (each 6 grams), costus root (not exposed to fire), one liang and four qian (3 grams), poppy shell (removed the pedicel and calyx, honey-roasted), three liang and six qian (9 grams). It has the effects of tonifying the five zang-organs, regulating the spleen and stomach, warming and tonifying the kidney yang, and astringing the intestine to stop diarrhea. Multiple drugs are mutually compatible in the formula. Through comprehensive effects such as supplementing qi and promoting blood circulation, warming and tonifying the spleen and kidney, and astringing and consolidating the root, it can not only improve diarrhea symptoms but also fundamentally regulate intestinal function and restore microecological balance, thereby reducing the recurrence rate of the disease. Although this decoction has been long used in the treatment of diseases such as chronic diarrhea and colitis, there is currently no public report on its application in the preparation of drugs for treating critical illness antibiotic-associated diarrhea. Therefore, its clinical effectiveness and safety still have exploration value. Summary of the Invention

[0010] In view of the deficiencies of the prior art, the present application provides the use of the modified Zhenren Yangzang Decoction in the preparation of drugs for treating critical illness antibiotic-associated diarrhea. The modified Zhenren Yangzang Decoction of the present invention can effectively treat critical illness antibiotic-associated diarrhea, relieve the clinical symptoms of patients, improve the TCM syndromes of patients, and especially shows unique advantages in reducing the frequency of stools, improving the stool characteristics, and improving the overall state of patients. At the same time, the modified Zhenren Yangzang Decoction can effectively reduce the recurrence rate, has high safety, and no obvious adverse reactions.

[0011] The active ingredient raw materials of the modified Zhenren Yangzang Decoction of the present invention include the following raw materials by weight: 13 - 17 parts of ginseng, 13 - 17 parts of carbonized angelica, 18 - 22 parts of stir-fried atractylodes macrocephala, 13 - 17 parts of nutmeg, 5 - 7 parts of cinnamon, 8 - 12 parts of roasted licorice root, 18 - 22 parts of stir-fried white peony root, 8 - 12 parts of roasted costus root, 8 - 12 parts of roasted terminalia chebula, and 18 - 22 parts of pomegranate peel.

[0012] Preferably, the active ingredient raw materials of the modified Zhenren Yangzang Decoction include the following raw materials by weight: 15 parts of ginseng, 15 parts of carbonized angelica, 20 parts of stir-fried atractylodes macrocephala, 15 parts of nutmeg, 6 parts of cinnamon, 10 parts of roasted licorice, 20 parts of stir-fried white peony root, 10 parts of roasted costus root, 10 parts of roasted terminalia chebula, and 20 parts of pomegranate peel.

[0013] Preferably, the application includes the treatment of critical illness antibiotic-associated diarrhea mainly caused by spleen-kidney yang deficiency syndrome.

[0014] Preferably, the drug further includes adding other traditional Chinese medicine extracts and / or adding other raw materials.

[0015] Preferably, the drug is a tablet, chewable tablet, powder, powder for oral use, granule, infusion, capsule, ointment, pill or liquid preparation.

[0016] Explanation of the formula of the present invention:

[0017] Based on the fact that critical illness antibiotic-associated diarrhea has spleen-kidney yang deficiency as the basis of the disease and drug toxicity triggering latent pathogens as the manifestation of the disease. Therefore, this formula uses a large dose of ginseng as the monarch drug, mainly to replenish qi and nourish the viscera. Carbonized angelica and stir-fried atractylodes macrocephala are the ministerial drugs. Carbonized angelica nourishes blood and promotes blood circulation, and stir-fried atractylodes macrocephala strengthens the spleen and harmonizes the stomach. The combination of the two replenishes qi and blood to correct the root cause of the patient's deficiency. And it is assisted by nutmeg to warm the middle-jiao and astringe the intestine, and terminalia chebula to astringe the intestine and stop diarrhea. These two drugs reflect the treatment principles of "treating the manifestation in emergency" and "astringing the slippery". At the same time, cinnamon can warm the kidney and spleen, white peony root can nourish blood and harmonize blood, and costus root is used to regulate qi and awaken the spleen. The combined use of these drugs jointly achieves the effect of regulating qi and harmonizing blood. This can not only treat the symptoms of dysentery with abdominal pain and tenesmus, but also make the whole formula not appear stagnant while astringing and tonifying. Licorice is used to replenish qi and harmonize the middle-jiao, and reconcile various drugs. Its combination with ginseng and atractylodes macrocephala can tonify the middle-jiao qi, and its combination with white peony root can relieve acute pain, playing the role of an assistant and guiding drug to make the whole formula more harmonious and effective. On this basis, the applicant added pomegranate peel, which strengthens the healthy qi and eliminates pathogenic factors, astringes the intestine and detoxifies.

[0018] Ginseng tastes sweet, slightly bitter, and slightly warm, and enters the spleen, lung, heart, and kidney meridians. Its main effects are to greatly replenish primordial qi, strengthen the blood vessels, stabilize collapse, invigorate the spleen and benefit the lung, promote the production of body fluid and replenish qi, and calm the mind and stabilize the will. Ginseng occupies a crucial position in traditional Chinese medicine and is widely used to condition the body and treat various diseases. In this formula, its effect of tonifying the five zang-organs and strengthening the spleen and replenishing qi is taken.

[0019] Angelica tastes sweet, pungent and warm, and enters the heart, liver, and spleen meridians. It is pungent, warm and fragrant and moist. The fragrance can enter the spleen, and the moistness can nourish blood. In this formula, its effect of nourishing blood and dispelling cold is taken.

[0020] Atractylodes macrocephala has a bitter, sweet and warm nature and enters the spleen and stomach meridians. In this formula, its effect of strengthening the spleen and harmonizing the stomach, and drying dampness is taken.

[0021] Nutmeg is pungent and warm, and enters the spleen, stomach, and large intestine meridians. In the formula, its effect of warming the middle-jiao and astringing the intestine is taken.

[0022] Terminalia chebula Retz., bitter, sour and astringent in flavor, acts on the lung and large intestine meridians. In this formula, it is used for its effect of astringing the intestine and stopping diarrhea.

[0023] Cinnamomum cassia Presl., sweet, pungent in flavor, extremely hot in property, acts on the kidney, spleen, heart and liver meridians, having the effects of tonifying fire and assisting yang, leading back floating fire, dispelling cold and relieving pain, warming and dredging the meridians. In the formula, it is used for its effects of warming the kidney and spleen, and assisting yang to stop diarrhea.

[0024] Paeonia lactiflora Pall., bitter, sour and slightly cold in flavor, acts on the liver and spleen meridians. In this formula, it is used for its effects of dispelling cold and relieving pain, nourishing blood and harmonizing blood.

[0025] Aucklandia lappa Decne., pungent, bitter and warm in flavor, acts on the spleen, stomach, large intestine, triple energizer and gallbladder meridians. It is warm in nature, promoting qi circulation with pungency and descending with bitterness, and is good at regulating the qi mechanism of the large intestine. Its aromatic flavor can also disperse the stagnant qi in the spleen and stomach. In this formula, it is used for its effects of promoting qi circulation to relieve pain, strengthening the spleen and promoting digestion.

[0026] Punica granatum L. pericarp, sour, astringent and warm in flavor, acts on the large intestine meridian. It has the effects of promoting the production of body fluid to quench thirst, astringing and consolidating, and stopping bleeding. It has significant antibacterial and astringent effects. In the formula, it is used for its astringent and antibacterial effects.

[0027] Glycyrrhiza uralensis Fisch., sweet and neutral in flavor, acts on the heart, lung, spleen and stomach meridians, having the effects of invigorating the spleen and replenishing qi, and moderating the properties of drugs. It is an important drug for regulating the middle-jiao and tonifying deficiency, and can be combined with various drugs for invigorating the spleen and replenishing qi to enhance the effect of replenishing qi in the middle-jiao. In the formula, it is used for its effect of benefiting qi and regulating the middle-jiao, so it is used after being prepared with honey.

[0028] All the drugs are combined in compatibility, taking both the root cause and symptoms into consideration, and jointly achieving the effects of promoting qi and activating blood circulation, warming the kidney and strengthening the spleen, astringing the intestine and stopping diarrhea, and also detoxifying and harmonizing the stomach. When the functions of the spleen and stomach in ascending and descending, and the kidney in storing essence are restored, the pathogenic factors can be eliminated and diarrhea can stop by itself.

[0029] Modern pharmacological effects of single herbs in the formula of the present invention:

[0030] The saponin components in ginseng can not only up-regulate IL-2, TNF-α, IFN-γ, reduce immunosuppression and play an anti-shock role. In addition, it also has the function of regulating the digestive and absorptive functions of the human body, can effectively protect the gastrointestinal tract, and helps to relieve the syndrome of spleen deficiency. In addition, ginseng polysaccharide in the chemical components of ginseng can activate and induce the proliferation of T and B lymphocytes, regulate the immune system of the body, and maintain its normal physiological functions. It not only has a promoting effect on specific immunity, but also can enhance the efficacy of non-specific immunity.

[0031] The ethanol extract from Angelica sinensis can improve the related symptoms of ulcerative colitis, significantly reduce diarrhea and occult blood, improve the symptoms of colon shortening and splenomegaly, protect the colon tissue from damage, have anti-inflammatory effects, reduce the level of serum immunoglobulin E, and regulate immunity. The compound Z-ligustilide isolated from Angelica sinensis can significantly alleviate apoptosis caused by oxidative stress in endothelial cells. In addition, the coumarin components of Angelica sinensis have significant effects. For example, osthole and its derivatives have inhibitory effects on Staphylococcus aureus, and umbelliferone significantly inhibits the growth of Pseudomonas aeruginosa, and can significantly reduce the motility of Pseudomonas aeruginosa flora, the production of virulence factors and the expression of quorum sensing-related genes.

[0032] The extract of Atractylodes macrocephala and its core chemical component atractylenolide I exhibit multiple pharmacological effects, including regulating gastrointestinal function, inhibiting inflammatory responses, and enhancing the immune system. Atractylenolide III can inhibit the expression of matrix metalloproteinases, thereby reducing the damage of the extracellular matrix and effectively preventing the formation of gastric ulcers. Atractylodes macrocephala polysaccharide can promote the migration of ICE-6 cells and the expression of E-cadherin by increasing the intracellular calcium ion concentration, thus contributing to the repair process of gastrointestinal mucosal damage. Another study shows that Atractylodes macrocephala has a regulatory effect on intestinal microorganisms, can significantly correct the imbalance of the intestinal flora, and regulate the composition and activity of the intestinal microbial community.

[0033] The volatile oils and phenylpropanoid compounds in Myristica fragrans play a protective role in the intestine by affecting the activities of neurotransmitters, inflammatory factors, and antioxidant enzymes. Among them, the aqueous extract of Myristica fragrans can block the actions of acetylcholine receptors and histamine receptors, thus helping to relieve intestinal spasm symptoms. The volatile oil of Myristica fragrans can reduce the expression of IL-8 and NF-κBp65 proteins in intestinal tissues, contribute to reducing the inflammation level, and thus promote the repair of intestinal mucosal damage. In addition, Myristica fragrans can also improve gastric damage by increasing the hormone levels related to blood vessel repair and enhancing antioxidant effects. The research results show that the crude oil suspension of Myristica fragrans can enhance the tension of the guinea pig intestine, while its petroleum ether extract can inhibit the contraction activity of the ileum, and these two effects jointly play the antidiarrheal effect of Myristica fragrans.

[0034] Research shows that the extract of Terminalia chebula can improve intestinal edema and bleeding, intestinal villus damage, protect the intestinal mucosa and relieve diarrhea symptoms.

[0035] Cinnamon contains various components with antibacterial effects, including cinnamon oil, cinnamic acid, cinnamaldehyde, etc. extracted from it. Research shows that the ethanol extract of cinnamon has a significant inhibitory effect on the growth of bacteria in meat products. In addition, the combination of cinnamon and aconite can restore the normal rhythm of intestinal motility. Research shows that when aconite and cinnamon are combined in a ratio of 2:1, the combination can up-regulate the expression levels of SCF, c-Kit genes and proteins, up-regulate 5-HT and SP in the colon, and down-regulate VIP expression, which has a positive regulatory effect on the intestinal dysfunction of yang-deficiency type STC rats. And the formula of the present invention mainly utilizes the antibacterial effect of cinnamon.

[0036] The main component of Paeonia lactiflora is paeoniflorin. Research shows that it can regulate the Ca 2+ / Na + exchange to relax smooth muscle cells, inhibit the excitement of the parasympathetic nerve, reduce the smooth muscle tension, and thus inhibit the movement of smooth muscle to achieve the purpose of antispasmodic. In addition, paeoniflorin can also relax the sphincter, promote the excretion of bile and pancreatic juice, and reduce the damage to pancreatic acini caused by the activation of pancreatic enzymes.

[0037] Aucklandia lappa has many pharmacological effects. It can promote the peristalsis of the gastrointestinal tract, effectively relieve diarrhea, protect the integrity of the gastric mucosa, resist the formation of ulcers, and contribute to the secretion and excretion of bile. The decoction and volatile oil of Aucklandia lappa can both promote gastric emptying and intestinal propulsion; the extract of Aucklandia lappa can effectively inhibit the spasm of gastrointestinal smooth muscle and relieve acute gastric mucosal injury. In addition, the combination of Aucklandia lappa and Atractylodes macrocephala can also optimize intestinal motility and sensitivity and relieve diarrhea by improving the changes in the intestinal flora structure, reducing 5-HT expression, and increasing the expression of 5-HT4R and SERT extracts.

[0038] The extract of pomegranate peel has significant anti-inflammatory effects. It can reduce the production of inflammatory promoting factors such as IL-1β, IL-6, TNF-α, IFN-γ, and increase the expression of anti-inflammatory factors. In addition, the extract can also reduce the degree of oxidative stress and the level of the inflammatory marker MPO, which helps to repair the damage of the colon epithelial structure caused by the inflammatory reaction and has a protective effect on the intestinal mucosa. Research shows that ellagic acid in pomegranate peel has a better gastrointestinal protective effect than punicalin and punicalagin, and it has excellent abilities to repair intestinal damage and resist diarrhea. Moreover, pomegranate peel also shows strong resistance to drug-resistant bacteria and can significantly inhibit the growth and reproduction of Helicobacter pylori, metronidazole-resistant strains and their sensitive strains.

[0039] Licorice has the effects of analgesia, anti-inflammatory, enhancing immune ability and antioxidant. The glycyrrhizin component contained in licorice has the ability to regulate the level of prostaglandin E2 (PGE2), thereby achieving its significant anti-inflammatory effect. Another study reveals that when Paeonia lactiflora and licorice are used in combination, they can significantly exert a synergistic analgesic effect and effectively relieve pain.

[0040] The present invention adjusts the compatibility of monarch, minister, assistant, and courier drugs in the modified Zhenren Yangzang Decoction, uses ginseng as the monarch drug, highlights the core role of regulating and tonifying the five zang-organs, provides the application of the modified Zhenren Yangzang Decoction for preparing drugs for treating critically ill patients with antibiotic-associated diarrhea, and follows the treatment principles of "tonifying qi and activating blood circulation, warming the kidney and strengthening the spleen, astringing the intestine to stop diarrhea, and harmonizing the stomach and detoxifying".

[0041] The modified Zhenren Yangzang Decoction of the present invention has shown good curative effects in the treatment of critically ill patients with antibiotic-associated diarrhea. It can not only effectively relieve the diarrhea symptoms of patients, improve the related traditional Chinese medicine syndromes, but also relieve other accompanying clinical manifestations, such as abdominal pain, hyperactive bowel sounds, etc., and reduce the clinical nursing burden.

[0042] The modified Zhenren Yangzang Decoction has also shown good curative effects in improving the gastrointestinal function and overall health status of patients. Critically ill patients have severe conditions and poor gastrointestinal functions. The modified Zhenren Yangzang Decoction conducts comprehensive nursing care for patients on the basis of the overall concept of traditional Chinese medicine and syndrome differentiation and treatment, and the clinical effects are relatively obvious.

[0043] The recurrence rate of the modified Zhenren Yangzang Decoction in the treatment of critically ill patients with antibiotic-associated diarrhea is relatively low, and no obvious adverse reactions have been found, showing good safety. Description of the Drawings

[0044] Figure 1 For the completion status of two groups of patients (n).

[0045] Figure 2 For the gender comparison of two groups of patients (n).

[0046] Figure 3 For the age comparison of two groups of patients (years).

[0047] Figure 4 For the comparison of antibiotic use in two groups of patients (n).

[0048] Figure 5 For the comparison of feeding methods in two groups of patients (n).

[0049] Figure 6 For the comparison of the composition of underlying diseases in two groups of patients (n).

[0050] Figure 7 For the comparison of C-reactive protein in two groups of patients (mg / L).

[0051] Figure 8 For the comparison of lactic acid in two groups of patients (mmol / L).

[0052] Figure 9 For the comparison of white blood cell count in two groups of patients (×10 9 / L).

[0053] Figure 10 For comparison in other general situations.

[0054] Figure 11 For comparison of the overall efficacy of AAD in two groups of patients (n).

[0055] Figure 12 For comparison of the total symptom scores of AAD in two groups of patients before and after treatment.

[0056] Figure 13 For comparison of the AAD symptom scores in two groups of patients before and after treatment.

[0057] Figure 14A For comparison of the scores of each AAD symptom in two groups before treatment.

[0058] Figure 14B For comparison of the scores of each AAD symptom in two groups after treatment.

[0059] Figure 14C For comparison of the scores of each AAD symptom in the experimental group before and after treatment.

[0060] Figure 14D For comparison of the scores of each AAD symptom in the control group before and after treatment.

[0061] Figure 15 For comparison of the gastrointestinal dysfunction scores in two groups of patients before and after treatment.

[0062] Figure 16 For comparison of the gastrointestinal dysfunction scores in two groups of patients before and after treatment.

[0063] Figure 17 For comparison of the APACHE II scores in two groups of patients before and after treatment.

[0064] Figure 18 For comparison of the APACHE II scores in two groups of patients before and after treatment.

[0065] Figure 19 For comparison of the overall efficacy of traditional Chinese medicine syndromes in two groups of patients (n).

[0066] Figure 20 For comparison of the total scores of traditional Chinese medicine syndromes in two groups of patients before and after treatment.

[0067] Figure 21 For comparison of the total scores of traditional Chinese medicine syndromes in two groups of patients before and after treatment.

[0068] Figure 22A For comparison of the scores of each traditional Chinese medicine syndrome in two groups before treatment.

[0069] Figure 22B For comparison of the scores of each traditional Chinese medicine syndrome in two groups after treatment.

[0070] Figure 22CComparison of TCM syndrome scores before and after treatment in the experimental group.

[0071] Figure 22D Comparison of TCM syndrome scores before and after treatment in the control group.

[0072] Figure 23 Comparison of recurrence rates between the two groups (n). Specific implementation manner

[0073] Combined with the embodiments of the present invention below, the technical solutions in the embodiments will be described clearly and completely. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

[0074] Embodiment 1

[0075] Modified Zhenren Yangzang Decoction: Ginseng 15g, Carbonized Angelica 15g, Stir-fried Atractylodes Macrocephala 20g, Nutmeg 15g, Cinnamon 6g, Prepared Licorice 10g, Stir-fried White Peony Root 20g, Tendered Aucklandia Root 10g, Tendered Terminalia Chebula 10g, Pomegranate Peel 20g.

[0076] After the medicine is decocted, it is divided into two bags, each bag with a volume of 100 ml. Before taking the medicine, soak it in warm water and heat it to make the liquid reach an appropriate temperature, preferably about 40°C, and extract it with a 50-ml sterile syringe. Take it orally or by nasal feeding 1 hour after normal nasal feeding in the morning and evening, and treat continuously for 1 week.

[0077] Research on the beneficial effects of the present invention:

[0078] I. Research materials and methods

[0079] (1) Research materials

[0080] 1. Research subjects

[0081] The clinical observation subjects of this study were all from the emergency intensive care unit ward of Zhejiang Provincial Tongde Hospital. The case collection time was from August 2022 to February 2024, and all the patients who visited met the diagnostic criteria for critically ill antibiotic-associated diarrhea.

[0082] 2. Diagnostic criteria and syndrome differentiation criteria

[0083] 2.1 Western medicine diagnostic criteria

[0084] Refer to the "Diagnostic Criteria for Nosocomial Infections (Trial) in 2003".

[0085] For patients who experience diarrhea symptoms after recent use or current use of antibiotics, changes in the nature of the stool may be observed, such as watery stools, bloody stools, stools containing mucus or purulent blood, and even pseudomembranes in the form of plaque-like strips may appear. And it may be accompanied by one of the following conditions: ① Fever symptoms with a body temperature reaching or exceeding 38°C; ② Signs such as abdominal pain, abdominal tenderness, or rebound tenderness; ③ Elevated peripheral white blood cell count. In addition, for etiological diagnosis, it must be based on the premise of conforming to clinical diagnosis. If any of the following three conditions are met, the diagnosis can be confirmed: ① The fecal smear shows dysbiosis, or the culture results find a significantly dominant flora; ② If conditions permit, during fiber colonoscopy, symptoms such as intestinal wall congestion, edema, and bleeding are observed, or grayish-yellow (white) plaque-like pseudomembranes with a diameter of 2 - 20 mm are found; ③ The bacterial toxin assay results show positive. It should be noted that: ① The definition of acute diarrhea is that the number of diarrhea episodes reaches or exceeds 3 times within 24 hours; ② Diarrhea caused by acute exacerbation of chronic enteritis, acute gastrointestinal infection, and non-infectious factors needs to be excluded.

[0086] 2.2 Diagnostic Criteria for TCM Diarrhea

[0087] Based on the "Guiding Principles for Clinical Research of New Chinese Medicines (Trial Version)" in 2002 and the "Consensus Opinions of Chinese Medicine Diagnosis and Treatment Experts on Diarrhea (2017)", combined with clinical practice:

[0088] ① The number of stools > 3 times / day, and the stools are thin, and in severe cases, they are watery or contain undigested food;

[0089] ② Abdominal distension with gurgling sounds, and may be accompanied by vomiting;

[0090] ③ Fever, fatigue, dry skin, etc.;

[0091] ④ The symptoms persist > 24 hours.

[0092] The above are the essential items, and the rest are concurrent symptoms.

[0093] 2.3 Syndrome Differentiation Criteria for Spleen and Kidney Yang Deficiency Type:

[0094] Main symptoms: The stools are not formed, thin, and even clear and watery, or the grains are not digested.

[0095] Sub-symptoms: ① Loss of appetite; ② Lassitude and weakness; ③ Listlessness and reluctance to talk; ④ Cold pain in the umbilical and abdominal regions; ⑤ Fear of cold and cold limbs; ⑥ Soreness and coldness in the waist and knees.

[0096] Tongue and pulse: ① The tongue is pale, and the coating is thin and white; ② The pulse is deep and thready or thready and weak.

[0097] Syndrome type diagnosis: The main symptoms are essential symptoms. If 1 - 2 sub-symptoms are met, the diagnosis can be made, and the tongue and pulse can be used as a reference.

[0098] 3. Inclusion Criteria

[0099] ① Age ≥ 18 years old, gender is not limited;

[0100] ② Meet the diagnostic criteria for antibiotic-related diarrhea;

[0101] ③ Combine with unstable, decreased or failed function of two or more organ systems, and the Acute Physiology and Chronic Health Evaluation (APACHE Ⅱ score) > 15 points;

[0102] ④ Meet the syndrome differentiation criteria for spleen-kidney yang deficiency syndrome;

[0103] ⑤ Have no obvious contraindications to the study drugs;

[0104] ⑥ Agree to participate in this study and sign the informed consent form, and can take drugs according to doctor's advice.

[0105] 4. Exclusion criteria

[0106] ① Diarrhea patients caused by other reasons;

[0107] ② Pregnant or lactating women;

[0108] ③ Patients allergic to the drugs used in the protocol;

[0109] ④ Combine with severe liver and kidney diseases, hematopoietic system diseases, endocrine system diseases, etc. that may cause diarrhea, and patients with mental diseases;

[0110] ⑤ When the patient was admitted to the hospital, he / she had already developed severe complications such as coma, shock, and gastrointestinal bleeding. After the doctor evaluated the patient's condition, it was judged that the patient might face life-threatening within the next 24 hours;

[0111] ⑥ Currently, patients who have participated in other clinical trials.

[0112] If any of the above conditions is met, the relevant cases will be excluded.

[0113] 5. Exclusion and dropout criteria

[0114] ① Cases that are misincluded because they do not meet the inclusion criteria, cannot cooperate to complete the trial, violate the drug use regulations and clinical trial protocols, and receive other drug experiments during the trial will all be excluded.

[0115] ② Cases where statistical analysis cannot be performed due to incomplete data, or cases where the patients are no longer suitable to continue participating in the trial due to severe adverse reactions, special physiological changes, or cases where the patients are lost to follow-up or withdraw voluntarily. All these situations are regarded as dropout cases.

[0116] 6. Termination criteria

[0117] ① Severe adverse events related to the study drugs occur;

[0118] ②After evaluation by the researchers, it was considered that if the trial continued, it might cause potential harm to the subjects;

[0119] ③The subjects requested to end the treatment trial prematurely due to various factors.

[0120] 7. Ethical requirements

[0121] This study has passed the ethical review and approval of the relevant department (Ethical Review No.

[2022] 178 of Zhejiang Tongde Hospital), and all subjects have been informed of the relevant risks and signed the informed consent form.

[0122] (2) Research methods

[0123] 1. Sample size estimation

[0124] This study is a clinical research, and the protocol design strictly follows the principle of randomized controlled trial. The outcome index of this study is the final treatment effective rate of the experimental group and the control group, and the sample size is calculated based on the following formula:

[0125]

[0126] According to the previous literature on the comparison of traditional Chinese and Western medicine diagnosis and treatment programs for critically ill patients with antibiotic-associated diarrhea, P1 is the traditional Chinese medicine treatment group with an effective rate of about 90%, and P2 is the Western medicine control group with an effective rate of about 50%. According to the statistical sample size principle, taking α = 0.05 and β = 0.1, then Z α = 1.96, Z β = 1.28, represents the mean of P1 and P2, represents the mean of 1 - P1 and 1 - P2. According to the sample size estimation formula, according to the requirements of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines" and the previous situation of subjects visiting the emergency medicine department ward of our hospital, plus the expected maximum dropout rate of 10%, it can be calculated that n1 = n2 ≈ 30 cases, so at least 60 subjects need to be included.

[0127] 2. Grouping method

[0128] The 60 subjects collected in this study were randomly grouped by generating a random number table using the statistical software SPSS 27.0, and finally 30 subjects were generated in each of the control group and the experimental group.

[0129] 3. Treatment plan

[0130] 3.1 Basic treatment:

[0131] Routine nursing, reasonable selection of enteral nutrition preparations. Actively control infection, maintain respiratory and circulatory, internal environment stability, actively optimize the microcirculation state, and maintain water, electrolyte, and acid-base balance, maintain normal vital signs, and routine treatment of other underlying diseases, etc.

[0132] 3.2 Experimental group (Traditional Chinese medicine treatment group)

[0133] The patients were treated with the modified Zhenren Yangzang Decoction (ginseng 15 g, carbonized angelica 15 g, stir-fried atractylodes macrocephala 20 g, nutmeg 15 g, cinnamon 6 g, roasted licorice 10 g, stir-fried white peony root 20 g, roasted costus root 10 g, roasted terminalia chebula 10 g, pomegranate peel 20 g). It was decocted by the preparation room of Zhejiang Provincial Tongde Hospital (Zhejiang drug preparation number Z20200025000) in a unified manner. After each dose of the medicine was decocted, it was divided into two bags, with each bag having a volume of 100 ml. Before taking the medicine, it was soaked and heated with warm water to make the liquid medicine reach an appropriate temperature, about 40 °C being the best. Then, it was extracted with a 50-ml sterile syringe and taken orally or by nasogastric feeding 1 hour after normal nasogastric feeding in the morning and evening for 1 week continuously.

[0134] 3.3 Control group

[0135] The patients were given montmorillonite powder (3 grams per bag, produced by Zhejiang Hailisheng Pharmaceutical Co., Ltd.). The initial dose was doubled, that is, 2 bags were taken for the first time, and then 1 bag was taken each time. After dissolving the montmorillonite powder with cold water, it was given to the patients by nasogastric feeding 3 times a day. At the same time, Bifidobacterium triple viable bacteria capsules (210 mg per capsule, produced by Shanghai Xinyi Pharmaceutical Factory Co., Ltd., national drug approval number S10950032) were taken 3 capsules each time. After dissolving with warm water, it was given by nasogastric feeding 3 times a day. The above treatment plan was carried out continuously for 1 week.

[0136] 4. Observation indicators

[0137] 4.1 General conditions

[0138] At the time of enrollment, the baseline conditions of the subjects such as gender, age, antibiotic use, feeding method, composition of underlying diseases, CRP, lactic acid, white blood cell count, mean arterial pressure, oxygenation index, body temperature, respiration, heart rate, etc. were recorded, and statistical analysis was carried out to judge whether it affected the test results.

[0139] 4.2 AAD efficacy indicators

[0140] Antibiotic-associated diarrhea symptom score: Referring to the standards of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines (Trial)" promulgated in 2002, the degree of symptoms before and after treatment in the two groups was observed, and the symptom score = ∑(symptom severity) was calculated.

[0141] 4.3 Critical illness-related indicators

[0142] ① Gastrointestinal dysfunction score: It was formulated according to the GIF scoring system proposed by Reintam in 2008, and an evaluation was carried out once before treatment and on the 7th day after treatment. The higher the score, the worse the gastrointestinal function.

[0143] ②APACHE II score: It covers the following three aspects of assessment: First is the assessment of acute physiological parameters, second is the consideration of chronic health status, and finally is the age score. The scores of these three parts will be accumulated to obtain the final score. Such a comprehensive assessment is carried out respectively before treatment and on the 7th day after treatment. The higher the score, the worse the patient's basic condition.

[0144] 4.4 Efficacy indicators of traditional Chinese medicine syndromes

[0145] Refer to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines (Trial)" in 2002 edition to formulate the traditional Chinese medicine syndrome scale. Based on the severity of symptoms, this scale uses a four-level grading standard to score each symptom (level 0 means the patient has no relevant symptoms; level I indicates that the symptoms are relatively mild and have little impact on daily life; level II means the symptoms become more obvious and have a certain impact on daily life; level III means the symptoms are severe and have a significant adverse impact on the patient's work and life). They are recorded as 0, 1, 2, and 3 points respectively. The traditional Chinese medicine syndrome score is the sum obtained by adding up the scores of each symptom.

[0146] 4.5 Assessment of recurrence

[0147] One week after the completion of the treatment course for the subjects with effective treatment, follow-up for the assessment of recurrence is carried out. During the follow-up, the symptom score of antibiotic-associated diarrhea of the subjects is compared with the data at the end of the treatment to judge the recurrence rate.

[0148] 4.6 Safety observation

[0149] Record the vital signs of the subjects in both groups, specifically including blood pressure, respiration, heart rate, and body temperature. At the same time, record the relevant test results of the subjects in both groups, mainly covering the three major routine items, liver and kidney function indicators, inflammation-related indicators, and electrolyte examinations. In addition, the routine electrocardiogram examination results of the subjects in both groups will also be recorded. During the research process, once any adverse reactions occur in the subjects, they will be immediately recorded and corresponding measures will be taken, and the correlation between these adverse reactions and the test drugs will be analyzed.

[0150] 5. Evaluation criteria

[0151] 5.1 Western medicine efficacy judgment criteria for AAD

[0152] Effective rate = (number of cases with clinical cure + marked effect + effective cases) ÷ total number of cases × 100%.

[0153] ① Clinical cure: Diarrhea disappears within 1 week after treatment, and the stool characteristics return to normal;

[0154] ② Marked effect: The diarrhea degree score decreases by 6 points within 1 week after treatment, and the stool shape returns to normal;

[0155] ③Effective: The reduction in the diarrhea severity score within 1 week after treatment is 3 points ≤ reduction < 6 points;

[0156] ④Ineffective: The reduction in the diarrhea severity score within 1 week after treatment is < 3 points, or there is no obvious change in the stool shape.

[0157] 5.2 Evaluation criteria for the curative effect of TCM syndromes in AAD

[0158] Calculated using the Nimodipine method. Specifically, the curative effect index is obtained through the following formula:

[0159] Curative effect index = (score before treatment - score after treatment) ÷ score before treatment × 100%. According to this index, the curative effect can be divided into the following four grades:

[0160] ①Clinical cure: When the main symptoms and signs completely disappear or almost disappear, and the curative effect index ≥ 95%;

[0161] ②Marked effect: If the main symptoms and signs are significantly improved, and 70% ≤ curative effect index < 95%;

[0162] ③Effective: When the main symptoms and signs show improvement, and 30% ≤ curative effect index < 70%;

[0163] ④Ineffective: If the main symptoms and signs are not significantly improved or even deteriorated, and the curative effect index < 30%.

[0164] Total effective rate = (number of cured cases + number of markedly effective cases + number of effective cases) ÷ total number of cases × 100%.

[0165] 5.3 Evaluation criteria for recurrence rate

[0166] (Total AAD score before treatment - Total AAD score at follow-up) ÷ Total AAD score before treatment × 100% ≤ 30% is considered recurrence;

[0167] If the total AAD score at follow-up ≥ the total AAD score before treatment, it is also considered recurrence.

[0168] Recurrence index = (Total AAD score at follow-up - Total AAD score after treatment) ÷ Total AAD score at follow-up × 100%,

[0169] Recurrence rate = number of recurrence cases ÷ number of follow-up cases × 100%.

[0170] 5.4 Safety evaluation criteria

[0171] Formulated with reference to the "Guiding Principles for Clinical Research of New Chinese Medicines (Trial)" in 2002 Edition:

[0172] ①Grade I: Safe, no adverse reactions were observed during treatment;

[0173] ② Level II: Relatively safe. Even if adverse reactions occur, no special treatment is required, and subsequent drug administration can continue.

[0174] ③ Level III: There are safety issues. Some adverse reactions may occur during the trial, but after appropriate treatment, the trial can still continue.

[0175] ④ Level IV: Severe adverse reactions occur, and the clinical trial must be terminated immediately.

[0176] (III) Statistical methods

[0177] In this study, SPSS 27.0 software was used to analyze and process the data. For measurement data that conform to a normal distribution, a t-test was used; for count data, Fisher's exact test was selected. For measurement data and ranked data that do not conform to a normal distribution, the Mann-Whitney U nonparametric rank sum test was used for analysis. Analysis results: Measurement data were expressed in the form of mean (χ) ± standard deviation (s) or quartiles, while ranked data were presented in the form of the number of cases and percentages (%) to more intuitively show the distribution and characteristics of the data. In terms of statistical significance, α = 0.05 was set. If P < 0.05, the test results had significant differences; if P > 0.05, the test results had no statistical differences.

[0178] II. Results

[0179] (I) Case completion

[0180] From August 2022 to February 2024, a total of 62 patients were included in this study. Through random grouping, the patients were divided into an experimental group and a control group, with 31 patients in each group. Among them, one patient in both the control group and the experimental group was excluded from the study due to inability to cooperate in completing the scale filling. After strict screening, 30 patients in each of the experimental group and the control group finally completed the entire research process. Generally speaking, the dropout rate of this study was 3.30%. See Table 1 Figure 1 :

[0181] Table 1 Completion of two groups of patients (n)

[0182]

[0183] (II) Comparison of general information

[0184] 1. Gender comparison

[0185] A total of 60 subjects were successfully recruited in this study, including 28 males and 32 females. Further breakdown shows that there were 13 males and 17 females in the experimental group, with a male-to-female ratio of approximately 1:1.31; while in the control group, there were 15 males and 15 females, with a male-to-female ratio of 1:1. Statistical analysis of the gender distribution between the experimental group and the control group showed no significant difference (P > 0.05). Therefore, the two groups were comparable in terms of gender composition. See Table 2 for details. Figure 2 。

[0186] Table 2 Comparison of gender between two groups of patients (n)

[0187]

[0188]

[0189] Note: For the comparison of gender between two groups of patients, Fisher's exact test was used.

[0190] 2. Comparison of age

[0191] Among the 60 subjects with complete data collection, the oldest was 85 years old and the youngest was 40 years old. The age distribution in the experimental group was between 41 and 85 years old, with a median age of 78 years; the age distribution in the control group was between 40 and 85 years old, with a median age of 76.5 years. The ages of the patients in the experimental group and the control group were non-normally distributed, and the non-parametric rank sum test could be used to analyze the ages of the two groups of subjects. The results showed that there was no statistical difference in the comparison of ages between the two groups (P > 0.05), and they were comparable. See Table 3 for details. Figure 3 :

[0192] Table 3 Comparison of age between two groups of patients (years)

[0193]

[0194] 3. Comparison of the use of antibiotics

[0195] Among the 60 subjects finally included, the main way of using antibiotics was triple-drug therapy. Specifically, there were 11 cases of single-drug therapy, 14 cases of dual-drug therapy, and 35 cases of triple-drug therapy. In the experimental group, there were 6 subjects with single-drug therapy, 7 subjects with dual-drug therapy, and 17 subjects with triple-drug therapy. In the control group, there were 5 cases of single-drug therapy, 7 cases of dual-drug therapy, and 18 cases of triple-drug therapy. There was no statistical difference in the use of antibiotics between the experimental group and the control group (P > 0.05), and they were comparable. See Table 4 for details. Figure 4 。

[0196] Table 4 Comparison of the use of antibiotics between two groups of patients (n)

[0197]

[0198] Note: For the comparison of the genders of the two groups of patients, Fisher's exact test was used.

[0199] 4. Comparison of feeding methods

[0200] A total of 60 subjects were finally included, and their feeding methods were mainly divided into two types: enteral nutrition and parenteral nutrition. Among them, 21 cases in the experimental group used enteral nutrition and 9 cases used parenteral nutrition. In the control group, 24 cases used enteral nutrition and 6 cases used parenteral nutrition. There was no statistical difference in the feeding methods between the experimental group and the control group (P>0.05), and they were comparable. See Table 5 for details. Figure 5 。

[0201] Table 5 Comparison of feeding methods of two groups of patients (n)

[0202]

[0203] Note: For the comparison of the genders of the two groups of patients, Fisher's exact test was used.

[0204] 5. Comparison of the composition of underlying diseases

[0205] A comparison of the composition of underlying diseases of the 60 subjects finally included found that among the experimental group, 24 cases had essential hypertension, 16 cases had type 2 diabetes, 17 cases had coronary atherosclerotic heart disease, 15 cases had cerebrovascular diseases, and 22 cases had sepsis. Among the control group, 20 cases had essential hypertension, 21 cases had type 2 diabetes, 14 cases had coronary atherosclerotic heart disease, 10 cases had cerebrovascular diseases, and 20 cases had sepsis. There was no statistical difference in the composition of underlying diseases between the experimental group and the control group (P>0.05), and they were comparable. See Table 6 for details. Figure 6 。

[0206] Table 6 Comparison of the composition of underlying diseases of two groups of patients (n)

[0207]

[0208] Note: For the comparison of the genders of the two groups of patients, Fisher's exact test was used.

[0209] 6. Comparison of C-reactive protein

[0210] The C-reactive protein levels of the 60 subjects finally included were statistically analyzed, and it was found that the C-reactive protein values of the patients in the experimental group and the control group were both non-normally distributed, and non-parametric rank sum test could be used for analysis. The results showed that there was no statistical difference in age between the two groups (P>0.05), and they were comparable. See Table 7 for details. Figure 7 :

[0211] Table 7 Comparison of C-reactive protein of two groups of patients (mg / L)

[0212]

[0213] 7. Comparison of Lactate

[0214] Statistics were performed on the lactate levels of the finally included 60 subjects. It was found that the lactate values of the patients in the experimental group and the control group were both non-normally distributed, and non-parametric rank sum test could be used for analysis. The results showed that there was no significant difference in age between the two groups (P > 0.05), and they were comparable. See Table 8, Figure 8 :

[0215] Table 8 Comparison of Lactate in Two Groups of Patients (mmol / L)

[0216]

[0217] 8. Comparison of White Blood Cell Count

[0218] Statistics were performed on the white blood cell counts of the finally included 60 subjects. It was found that the white blood cell counts of the patients in the experimental group and the control group were both non-normally distributed, and non-parametric rank sum test could be used for analysis. The results showed that there was no significant difference in age between the two groups (P > 0.05), and they were comparable. See Table 9, Figure 9 :

[0219] Table 9 Comparison of White Blood Cell Count in Two Groups of Patients (×10 9 / L)

[0220]

[0221] 9. Comparison of Other General Conditions

[0222] Statistics were performed on the other general conditions of the finally included 60 subjects. It was found that the heart rate, body temperature, respiration, oxygenation index, and mean arterial pressure of the patients in the experimental group and the control group were all non-normally distributed, and non-parametric rank sum test could be used for analysis. The results showed that there was no significant difference in other general conditions between the two groups (P > 0.05), and they were comparable. See Table 10, Figure 10 :

[0223] Table 10 Comparison of Other General Conditions

[0224]

[0225] (III) Comparison of Therapeutic Effects

[0226] 1. Comparison of Overall Therapeutic Effects

[0227] The overall efficacy of Western medicine for AAD in the finally included 60 subjects was statistically analyzed. It was found that after 1 week of treatment, the total effective rate of the overall efficacy of AAD in the experimental group was 83.30%, and that in the control group was 60.00%. When comparing the total effective rates of the two groups, the difference was statistically significant (P < 0.05). See Table 11 for details. Figure 11 :

[0228] Table 11 Comparison of the efficacy of AAD between the two groups of patients (n)

[0229]

[0230] Note: For the comparison of the overall efficacy of AAD between the two groups of patients, Fisher's exact test was used.

[0231] 2. Comparison of AAD symptom scores

[0232] 2.1 Comparison of the total AAD symptom scores of the two groups of patients before and after treatment

[0233] The total scores of Western medicine symptoms of the finally included 60 subjects were statistically analyzed. It was found that before treatment and the difference between before and after treatment, the total AAD symptom scores of the two groups of patients were non-normally distributed, and non-parametric rank sum test could be used for analysis. The results showed that there was no statistical difference in the total AAD symptom scores between the two groups of patients before treatment (P > 0.05). After 1 week of treatment with different regimens, there was a difference in the difference of the total AAD symptom scores between the two groups of patients before and after treatment (P < 0.01). See Table 12 for details. Figure 12 :

[0234] Table 12 Comparison of the total AAD symptom scores of the two groups of patients before and after treatment

[0235]

[0236]

[0237] 2.2 Comparison of the total AAD symptom scores of the two groups of patients before and after treatment

[0238] The total scores of Western medicine symptoms of the finally included 60 subjects were statistically analyzed. The results showed that before and after treatment, the total AAD symptom scores of the two groups of patients showed the characteristics of non-normal distribution, and non-parametric rank sum test could be used for analysis. The results showed that compared with before treatment, the total AAD symptom scores after treatment in both the experimental group and the control group were significantly different (P < 0.01).

[0239] See Table 13 for details. Figure 13 :

[0240] Table 13 Comparison of AAD symptom scores of the two groups of patients before and after treatment

[0241]

[0242] 2.3 Comparison of the symptom scores of AAD

[0243] After 1 week of treatment with different regimens, there were statistically significant differences in the symptom scores of AAD between the experimental group and the control group compared with those before treatment (P < 0.05): among them, there were significant statistical differences in the symptom scores in the experimental group (P < 0.01), there was a statistical difference in the dehydrated appearance in the control group compared with that before treatment (P < 0.05), and there were significant statistical differences in the other symptom scores compared with those before treatment (P < 0.01). Before treatment, we performed a statistical analysis on the syndrome scores of the two groups and found no statistical difference (P > 0.05), so they were comparable. After treatment, by comparing the syndrome scores of the two groups, we found that there were significant statistical differences in aspects such as the number of diarrhea, stool characteristics, abdominal pain, and bowel sounds (P < 0.05), while there was no statistical difference in the dehydrated appearance (P > 0.05). See Table 14 and Figure 14 for details. (The comparison of the symptom scores of AAD all used the nonparametric rank sum test)

[0244] Table 14 Comparison of the symptom scores of AAD in two groups of patients before and after treatment

[0245]

[0246]

[0247] 3. Comparison of the gastrointestinal dysfunction scores

[0248] 3.1 Comparison of the gastrointestinal dysfunction scores of two groups of patients before and after treatment

[0249] For the finally included 60 subjects, a statistical analysis was performed on the gastrointestinal dysfunction scores before and after treatment, and the results showed that these scores did not conform to the normal distribution. Therefore, we used the nonparametric rank sum test for data analysis. The analysis results showed that: before treatment, there was no statistical difference in the gastrointestinal dysfunction scores of the two groups of patients (P > 0.05), so they were comparable. After one week of different treatment regimens, there was a statistical difference in the gastrointestinal dysfunction scores of the two groups of patients (P < 0.05). See Table 15 for details Figure 15 .

[0250] Table 15 Comparison of the gastrointestinal dysfunction scores of two groups of patients before and after treatment

[0251]

[0252] 3.2 Comparison of the gastrointestinal dysfunction scores of two groups of patients before and after treatment

[0253] The gastrointestinal dysfunction scores of the two groups of patients before and after treatment were not normally distributed, and non-parametric rank sum test could be used for analysis. The results showed that: compared with before treatment, the gastrointestinal dysfunction score of the experimental group after treatment had a significant difference (P < 0.01), while there was no statistical difference in the gastrointestinal dysfunction score of the control group after treatment compared with before treatment (P > 0.05). See Table 16 for details. Figure 16 。

[0254] Table 16 Comparison of gastrointestinal dysfunction scores of two groups of patients before and after treatment

[0255]

[0256] 4. Comparison of APACHE II scores

[0257] 4.1 Comparison of APACHE II scores of two groups of patients before and after treatment

[0258] The APACHE II scores of the 60 finally included subjects were statistically analyzed. It was found that the APACHE II scores of the two groups of patients before and after treatment were normally distributed, and t-test could be used for analysis. The results showed that: before treatment, the mean score of the experimental group was 23.93 ± 2.50, and the mean score of the control group was 24.20 ± 2.19, showing no statistical difference (P > 0.05) and being comparable. After 1 week of treatment with different regimens, the mean score of the experimental group was 20.83 ± 3.49, and the mean score of the control group was 22.77 ± 2.27, showing a statistically significant difference in score comparison (P < 0.05). See Table 17 for details. Figure 17 。

[0259] Table 17 Comparison of APACHE II scores of two groups of patients before and after treatment

[0260]

[0261]

[0262] 4.2 Comparison of APACHE II scores of two groups of patients before and after treatment

[0263] The APACHE II scores of the two groups of patients before and after treatment were normally distributed, and t-test could be used for analysis. The results showed that: after 1 week of treatment with different regimens, compared with before treatment, the APACHE II scores of both groups of patients had a significant difference (P < 0.01). See Table 18 for details. Figure 18 。

[0264] Table 18 Comparison of APACHE II scores of two groups of patients before and after treatment

[0265]

[0266] 5. Comparison of Therapeutic Effects of Traditional Chinese Medicine Syndromes

[0267] 5.1 Comparison of Overall Therapeutic Effects of Traditional Chinese Medicine Syndromes

[0268] After 1 week of treatment with the combined modified Zhenren Yangzang Decoction or simple Western medicine therapy, the total effective rate of the overall therapeutic effect of traditional Chinese medicine syndromes in the experimental group was 86.70%, and that in the control group was 50.00%. The comparison of the total effective rates between the two groups was statistically significant (P < 0.05). See Table 19 for details. Figure 19 。

[0269] Table 19 Comparison of Overall Therapeutic Effects of Traditional Chinese Medicine Syndromes in Two Groups of Patients (n)

[0270]

[0271] Note: For the comparison of the total effective rates of traditional Chinese medicine syndromes in two groups of patients, Fisher's exact test was used.

[0272] 5.2 Comparison of Total Scores of Traditional Chinese Medicine Syndromes in Two Groups of Patients before and after Treatment

[0273] Statistical analysis was performed on the total scores of traditional Chinese medicine syndromes of the 60 finally included subjects. The results showed that the scores before treatment and the differences before and after treatment were both normally distributed. Therefore, t-test could be used for analysis. The results showed that: before treatment, the mean score of the experimental group was 12.97 ± 2.30, and the mean score of the control group was 12.67 ± 2.55. The results showed that there was no statistical difference in the total scores of traditional Chinese medicine syndromes between the two groups of patients (P > 0.05), and they were comparable. However, after one week of treatment with different regimens, the mean score of the difference before and after treatment in the experimental group was 6.10 ± 2.28, and the mean score of the control group was 3.67 ± 2.17, showing a significant statistical difference (P < 0.01). See Table 20 for specific statistical results. Figure 20 。

[0274] Table 20 Comparison of Total Scores of Traditional Chinese Medicine Syndromes in Two Groups of Patients before and after Treatment

[0275]

[0276] 5.3 Comparison of Total Scores of Traditional Chinese Medicine Syndromes in Two Groups of Patients before and after Treatment

[0277] The total scores of traditional Chinese medicine syndromes in two groups of patients before and after treatment were normally distributed, and t-test could be used for analysis. The results showed that: after 1 week of treatment with different regimens, compared with before treatment, the total scores of traditional Chinese medicine syndromes in both groups of patients had significant differences (P < 0.01). See Table 21 for details. Figure 21 。

[0278] Table 21 Comparison of Total Scores of Traditional Chinese Medicine Syndromes in Two Groups of Patients before and after Treatment

[0279]

[0280]

[0281] 5.4 Comparison of TCM Syndrome Scores

[0282] The TCM syndrome scores of the 60 subjects finally included were statistically analyzed. It was found that after 1 week of treatment with different regimens, there were significant statistical differences in the TCM symptom scores of the experimental group compared with those before treatment (P < 0.01). Among the control group, there were significant statistical differences in loose stools, cold pain in the umbilical and abdominal regions, fullness and stuffiness in the epigastric and abdominal regions, soreness and weakness in the waist and knees, and listlessness with weak speech compared with those before treatment (P < 0.01), there was a statistical difference in lassitude and fatigue compared with those before treatment (P < 0.05), and there was no statistical difference in cold intolerance of the body and limbs compared with those before treatment (P > 0.05). After comparing the syndrome scores of the two groups after treatment, there were statistical differences in loose stools, cold pain in the umbilical and abdominal regions, fullness and stuffiness in the epigastric and abdominal regions, lassitude and fatigue, cold intolerance of the body and limbs, and soreness and weakness in the waist and knees (P < 0.05), while there was no statistical difference in listlessness with weak speech (P > 0.05). See Table 22 and Figure 22 for details. (The nonparametric rank sum test was used for the comparison of TCM syndrome scores)

[0283] Table 22 Comparison of AAD Symptom Scores of Two Groups of Patients before and after Treatment

[0284]

[0285]

[0286] (IV) Comparison of Recurrence Rate and Safety

[0287] 1. Comparison of Recurrence Rate

[0288] After 1 week of treatment, the patients with effective treatment in the two groups were followed up. Among them, a total of 22 effective treatment cases were successfully followed up in the experimental group, including 4 relapses and 18 non-relapses, with an overall recurrence rate of 18.18%. A total of 15 effective treatment cases were successfully followed up in the control group, including 8 relapses and 7 non-relapses, with an overall recurrence rate of 53.33%. Comparing the recurrence rates of the two groups, the difference was statistically significant (P < 0.05), indicating that there were differences between the traditional Chinese medicine treatment group and the western medicine control group in the short-term efficacy (about 1 week) of AAD treatment. See Table 23 for details Figure 23 .

[0289] Table 23 Comparison of Recurrence Rates of Two Groups (n)

[0290]

[0291] Note: Fisher's exact test was used for the comparison of recurrence rates between the two groups

[0292] 2. Comparison of Safety

[0293] During the 1-week trial period, the vital signs of all subjects fluctuated within the normal range, and no obvious abnormalities were found in the test results of the three routine examinations, liver and kidney functions, and routine electrocardiogram, either before or after treatment. Meanwhile, no adverse reaction events occurred during the entire trial process.

[0294] III. Analysis of Research Results

[0295] 1. Comparison of Basic Patient Conditions

[0296] A total of 62 critically ill patients with antibiotic-associated diarrhea were included in this study, and finally 60 patients completed the study. Among them, the median age of the experimental group was 78 years old, and the median age of the control group was 76.5 years old. It can be seen that whether in the control group or the experimental group, the age of the patients with the disease is generally relatively high, which may be related to the decline of various organ functions in the elderly, poor overall health conditions, and often accompanied by multiple chronic diseases. These factors, combined with the generally existing problems of weakened gastrointestinal motility and insufficient blood supply to the gastrointestinal tract, make them more likely to encounter intestinal microbiota imbalance when using broad-spectrum antibiotics, thus increasing the risk of gastrointestinal dysfunction. Traditional Chinese medicine believes that the spleen and stomach of the elderly are weak and unable to normally receive and transform the essence of water and grains. The kidney yang is insufficient, with weak warming function, and the two yin cannot open and close normally. When combined, the ascending and descending functions are disordered, the clear and turbid are not separated, and they are mixed and discharged downward, resulting in diarrhea. Generally speaking, the samples of this study were all from the emergency intensive care unit of Zhejiang Provincial Tongde Hospital. The sample size is not large. Although it cannot represent the overall demographic characteristics of critically ill patients with antibiotic-associated diarrhea, it still has certain reference value.

[0297] 2. Comparative Analysis of Overall Therapeutic Effects

[0298] 2.1 Comparative Analysis of Total AAD Symptom Scores

[0299] After 1 week of different treatment regimens, the AAD symptom scores of both groups of patients were significantly improved, and this improvement was statistically significant (P < 0.05). Comparing the treatment effects of the two groups, the overall effective rate of the experimental group reached 83.30%, while that of the control group was 60.00%. Further analysis showed that the effective rate of the experimental group was significantly better than that of the control group (P < 0.05). This fully shows that montmorillonite powder combined with probiotics and the modified Zhenren Yangzang Decoction can all effectively relieve diarrhea symptoms, but the modified Zhenren Yangzang Decoction performs better in terms of overall therapeutic effects.

[0300] Montmorillonite powder, a commonly used antidiarrheal drug in clinical practice, has a fixing and inhibitory effect on viruses, bacteria and their toxins in the digestive tract. In addition, it can strengthen the defensive ability of the mucosal barrier and resist the invasion of external attacking factors. Bifidobacterium triple viable capsules, on the other hand, can regulate the intestinal flora, improve the condition of flora imbalance, optimize gastrointestinal function and promote gastrointestinal peristalsis. From the perspective of traditional Chinese medicine, both have the effect of strengthening the healthy qi and stopping diarrhea, similar to drugs such as ginseng. Zengsun Zhenren Yangzang Decoction, on the basis of strengthening the healthy qi and stopping diarrhea, adds drugs for warming the kidney and strengthening the spleen, regulating the stomach and detoxifying, so the antidiarrheal effect is better. From the perspective of modern pharmacology, drugs such as ginseng, angelica, and white peony can regulate the human immune function. Nutmeg, chebula fruit, and costus root can reduce the expression of inflammatory factors and protect the gastrointestinal mucosa. Cinnamon and pomegranate peel have good antibacterial effects. The whole formula can exert anti-inflammatory and antibacterial effects, regulate immunity, and thus promote the recovery of intestinal function. Therefore, the curative effect is better than that of the western medicine control group.

[0301] 2.2 Comparative analysis of scores of various symptoms

[0302] After 1 week of treatment with different regimens, there were significant statistical differences in the scores of various symptoms in the experimental group compared with those before treatment (P < 0.01), indicating that Zengsun Zhenren Yangzang Decoction has good curative effects in improving symptoms such as diarrhea frequency, stool character, abdominal pain, borborygmus, and dehydration appearance. There were significant statistical differences in diarrhea frequency, stool character, abdominal pain, and borborygmus in the control group compared with those before treatment (P < 0.01), and there was a statistical difference in dehydration appearance compared with that before treatment (P < 0.05), indicating that montmorillonite powder combined with probiotics can also improve symptoms such as diarrhea frequency, stool character, abdominal pain, borborygmus, and dehydration appearance. Further comparing the scores of various symptoms after treatment in the two groups, the results showed that there were statistical differences in diarrhea frequency, stool character, abdominal pain, and borborygmus (P < 0.05), while there was no statistical difference in dehydration appearance (P > 0.05). This indicates that Zengsun Zhenren Yangzang Decoction is superior to montmorillonite powder combined with probiotics in relieving pain and diarrhea.

[0303] 3. Comparative analysis of gastrointestinal dysfunction scores

[0304] After 1 week of treatment with different regimens, the gastrointestinal dysfunction score of the experimental group after treatment showed a significant difference compared with that before treatment (P < 0.01), while there was no statistically significant difference in the scores of the control group before and after treatment (P > 0.05). In addition, there was also an obvious statistical difference in the gastrointestinal dysfunction scores between the experimental group and the control group after treatment (P < 0.05). This indicates that in terms of the improvement of the overall gastrointestinal function in the short term, the experimental group is superior to the control group. Currently, pharmacology has shown that drugs such as ginseng, angelica, and atractylodes can regulate the body's immune system, repair gastrointestinal mucosal damage, and protect the gastrointestinal tract. In addition, atractylodes, white peony, and licorice can improve the intestinal flora, and cinnamon and pomegranate peel have antibacterial and anti-inflammatory effects. As a compound prescription, the Modified Zhenren Yangzang Decoction can both support the "healthy qi" and dispel the "pathogenic factors", so it is more obvious in the overall improvement of gastrointestinal function compared with the western medicine control group.

[0305] 4. Comparative analysis of APACHE II scores

[0306] After 1 week of treatment with different regimens, the APACHE II scores of both groups improved compared with before (P < 0.05), the APACHE II scores of both groups decreased significantly (P < 0.01), and there was a statistically significant difference between the experimental group and the control group after treatment (P < 0.05). This indicates that both treatment methods can improve the overall condition of patients to a certain extent, and in terms of the improvement of the overall state of patients, the experimental group is superior to the control group. It can be seen that the clinical efficacy of the Modified Zhenren Yangzang Decoction in improving the overall state of patients is superior to that of montmorillonite powder combined with probiotics, which reflects the advantages of the holistic concept of traditional Chinese medicine. While helping to regulate the spleen and kidney, astringe diarrhea, it also nourishes the five zang-organs, making the functions of the zang-fu organs harmonious and the pathogenic factors removed and the healthy qi restored.

[0307] 5. Comparative analysis of the curative effects of traditional Chinese medicine syndromes

[0308] 5.1 Comparative analysis of the total scores of traditional Chinese medicine syndromes

[0309] After one week of treatment with different regimens, the total score of TCM syndrome in both groups was improved compared with that before (P < 0.05), and there was a significant difference between the two groups (P < 0.01). The overall effective rate of TCM syndrome in the experimental group was 86.70%, and that in the control group was 50.00%, with a significant difference between the two groups (P < 0.01), indicating that both treatments had an improvement effect on TCM syndrome, but the overall efficacy of Zengsun Zhenren Yangzang Decoction was better than that of Western medicine. Comparing the efficacy of TCM syndrome scores in the experimental group and the control group, it can be found that the overall effective rate of TCM syndrome in the experimental group was higher than that in the control group. While affirming the clinical efficacy of Zengsun Zhenren Yangzang Decoction, it is also related to the inclusion of indicators related to spleen and kidney deficiency and cold in TCM syndrome, such as "fear of cold and cold limbs" and "fatigue and fatigue", which is the development of the TCM theory that the spleen governs transportation and transformation and the kidney governs excretion, and it is also the embodiment of the therapeutic effect of Zengsun Zhenren Yangzang Decoction that emphasizes the invigoration of qi and nourishment of zang organs. This also suggests that most of our critically ill patients with antibiotic-associated diarrhea have the commonality of spleen and kidney deficiency and cold.

[0310] 5.2 Comparative analysis of various syndrome scores in traditional Chinese medicine

[0311] After one week of treatment with different treatment schemes, the TCM symptom scores of the experimental group showed significant statistical differences compared with those before treatment (P < 0.01), indicating that Zengsun Zhenren Yangzang Decoction has a good therapeutic effect in improving symptoms such as loose stools, cold pain in the navel and abdomen, fullness in the epigastric and abdominal distension, fatigue, cold body and limbs, soreness of the waist and knees, and fatigue and laziness. In the control group, there were significant statistical differences in loose stools, cold pain in the navel and abdomen, fullness in the epigastrium and abdomen, soreness of the waist and knees, and fatigue and laziness compared with before treatment (P < 0.01), and there was a statistical difference in fatigue compared with before treatment (P < 0.05). There was no statistical difference in cold body and cold limbs compared with before treatment (P > 0.05). This shows that montmorillonite powder combined with probiotics has a good therapeutic effect on improving the symptoms of loose stools, cold pain in the navel and abdomen, fullness in the epigastrium and abdomen, soreness of the waist and knees, and fatigue and laziness, and has a certain effect on improving the symptom of fatigue, but is almost ineffective for cold body and cold limbs. This suggests that in critically ill patients, the improvement of diarrhea symptoms is related to spleen and kidney yang deficiency, and the improvement of diarrhea will bring about the improvement of related symptoms. After treatment, the two groups showed statistically significant differences in the scores of various symptoms, including loose stools, cold pain in the navel and abdomen, fullness in the epigastric region, fatigue, cold body and limbs, and soreness of the waist and knees (P < 0.05), while there was no statistical difference in fatigue and laziness (P > 0.05). This further shows that patients with critically ill antibiotic-associated diarrhea have a common pathogenesis - spleen and kidney deficiency and coldness, and Zengsun Zhenren Yangzang Decoction can greatly improve the patients' TCM symptoms.

[0312] It can be seen that: under the guidance of traditional Chinese medicine theory, the syndrome differentiation and treatment of traditional Chinese medicine has a good curative effect on improving the traditional Chinese medicine syndromes of spleen-kidney yang deficiency syndrome in critically ill patients with antibiotic-associated diarrhea. The Modified Zhenren Yangzang Decoction is a clinical practice prescription established by Professor Chen Mingxian, the inventor of this application, based on the characteristics of treating both the symptoms and root causes and the compatibility of astringency with dredging. Since the diarrhea in this study was accompanied by the use of antibiotics, Professor Chen Mingxian, the inventor of this application, believes that the root cause of this disease is closely related to the cold and bitter nature of antibiotics themselves. This study shows that antibiotic-associated diarrhea is particularly common in elderly critically ill patients. Most of these patients have yang deficiency due to long-term illness. After long-term combined use of antibiotics, they often experience persistent diarrhea symptoms.

[0313] When deeply analyzing the pathological mechanisms of critically ill patients, Professor Chen Mingxian, the inventor of this application, particularly emphasized their physical characteristics of being weak and having disharmony between yin and yang. Due to long-term invasion by diseases, the body functions of these patients have been severely damaged. Coupled with long-term use of antibiotics, it directly weakens yang qi, making the already weak body even more overwhelmed. In this state, the functions of the three zang-organs of the kidney, spleen, and stomach are prone to disorder. The kidney yang deficiency fails to secure and astringe, and the fire of the gate of vitality fails to warm the middle jiao, further exacerbating the body's deficiency-cold symptoms. The impairment of spleen yang and the disharmony of the stomach's descending function are the key links in this pathological process. The spleen is responsible for transportation and transformation, and the stomach is responsible for receiving and digesting. The two coordinate with each other to jointly maintain the body's digestion and absorption functions. However, in critically ill patients, due to the impairment of spleen yang, the function of transporting and transforming water and grains is disordered, resulting in the failure to transform water and grains and the failure to distinguish the clear from the turbid. At the same time, the disharmony of the stomach's descending function also causes the upward reversal of stomach qi, further disturbing the normal body functions. In this case, the application of the Modified Zhenren Yangzang Decoction is particularly important. This prescription is based on regulating and tonifying the functions of the three zang-organs of the spleen, stomach, and kidney, combining attacking and tonifying, and guided by the treatment methods of "tonifying the deficiency", "warming the cold", and "astringing the slippery". Its purpose is to supplement qi and activate blood circulation, warm the kidney and strengthen the spleen, astringe the intestine and stop diarrhea, and harmonize the stomach and detoxify. Through this series of treatment principles, the Modified Zhenren Yangzang Decoction can restore the normal operation of qi, blood, yin, and yang throughout the body, thereby achieving the effects of strengthening the spleen and stomach, warming the kidney yang, and stopping diarrhea and dysentery. During the treatment process, we should not only closely monitor the remission of patients' symptoms, but also pay more attention to adjusting their body functions and improving their own immunity to promote the return of their physiological state to normal. Only by taking all aspects into consideration can we truly achieve the treatment of both the symptoms and root causes and thus achieve a profound and lasting therapeutic effect.

[0314] 6. Comparative analysis of recurrence rates

[0315] The recurrence rate of the experimental group was 18.18%, and that of the control group was 53.33%. The difference between the two was statistically significant (P < 0.05), indicating that the modified Zhenren Yangzang Decoction had better short-term efficacy in the treatment of critically ill patients with antibiotic-associated diarrhea. It also showed that the modified Zhenren Yangzang Decoction grasped the key pathogenesis of spleen-kidney yang deficiency in critically ill patients, solved the problem fundamentally, regulated the body function, enhanced the body's anti-infection ability, thus reducing the recurrence rate of the disease, improving the prognosis of this disease and enhancing the quality of life of patients.

[0316] 7. Comparative analysis of safety

[0317] During the 1-week research process, no adverse reaction events occurred. The vital signs of all subjects fluctuated within the normal range, and there were no obvious abnormalities in the results of the three routine examinations, liver and kidney functions, and electrocardiogram before and after treatment. It shows that the modified Zhenren Yangzang Decoction, montmorillonite powder, and Bifidobacterium triple viable capsules are all relatively safe and reliable. Considering that the number of cases included in this study is not large, it does not mean that the modified Zhenren Yangzang Decoction is absolutely safe and has no side effects. Further pharmacological research or expanded clinical trials can be carried out to clarify the relevant adverse reactions and provide reference for subsequent popularization and application.

[0318] The above is the description of the embodiments of the present invention. Through the above description of the disclosed embodiments, those skilled in the art can implement or use the present invention. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments shown herein, but will conform to the widest scope consistent with the principles and novel points disclosed herein.

Claims

1. The application of Zengsun Zhenren Yangzang Decoction in the preparation of a drug for treating critical antibiotic-associated diarrhea. The active ingredient raw materials of the Zengsun Zhenren Yangzang Decoction include the following raw materials by weight: 13-17 parts of ginseng, 13-17 parts of angelica charcoal, 18-22 parts of stir-fried Atractylodes macrocephala, 13-17 parts of nutmeg, 5-7 parts of cinnamon, 8-12 parts of roasted licorice, 18-22 parts of stir-fried white peony root, 8-12 parts of stewed costusroot, 8-12 parts of stewed Terminalia chebula, and 18-22 parts of pomegranate peel.

2. The use according to claim 1, characterized in that: The active ingredients of the Zengsun Zhenren Yangzang Decoction include the following ingredients by weight: 15 parts of ginseng, 15 parts of angelica charcoal, 20 parts of stir-fried Atractylodes macrocephala, 15 parts of nutmeg, 6 parts of cinnamon, 10 parts of roasted licorice, 20 parts of stir-fried white peony root, 10 parts of stewed costusroot, 10 parts of stewed Terminalia chebula, and 20 parts of pomegranate peel.

3. The use according to claim 1 or 2, characterized in that: The application includes the treatment of critical antibiotic-associated diarrhea characterized by spleen and kidney deficiency and cold syndrome.

4. The use according to claim 1 or 2, characterized in that: The medicine also includes adding other Chinese herbal medicine extracts and / or adding other raw materials.

5. The use according to claim 1 or 2, characterized in that: The medicine is in the form of tablets, chewable tablets, powders, granules, granules, capsules, ointments, pills or liquid preparations.

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