WANG Yao (王 耀), CAO Yu (曹 语), ZHAO Shen (赵 申), LV Bo-lin (吕博琳),SHI Peng (石 鹏), FENG Wen-zhe (冯文哲)

1. Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China

2. Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, China

ABSTRACT Due to the special perianal location, anorectal diseases are prone to form chronic refractory wounds after surgery, with Qi (气) deficiency and blood stasis as the main cause. As a classical theory in TCM medicine, "simmering pus and forming flesh" attaches great importance to harmonizing Qi and blood in the wound healing period, which gradually achieves significant efficacy in clinical application after anorectal disease surgery. Literatures in recent years on "simmering pus and forming flesh" method being applied to postoperative wound healing in all kinds of anorectal diseases (such as anal fistula, perianal abscess, anal fissure, mixed hemorrhoid, etc.) were reviewed, and advantages and characteristics of its clinical efficacy in anorectal diseases were summarized, so as to provide reference for postoperative wound healing and repair treatment in anorectal diseases.

KEYWORDS Simmering pus and forming flesh; Anorectal diseases; Chronic wounds; External treatment in traditional Chinese medicine; Review

Anorectal diseases are a kind of common surgical diseases that occur in the anal canal,rectum, colon and its affiliated tissues, including anal fistula, perianal abscess, anal fissure, mixed hemorrhoids, etc.. Conservative treatment after their occurrence is often ineffective, and the later treatment is mainly through surgery. Due to its special location, the lumen is easy to detour, and most surgical wounds are open and contaminated.Long-term exposure to fecal and purulent secretions,as well as stimulation of adverse factors like pain,spasm and ischemia can lead to delayed wound healing, which is easy to form chronic wounds[1].

Traditional methods in Western medicine to promote wound healing include antibiotics,nutritionally supported medicine therapy and external wound repair therapy. They are effective,but the healing is slow, which falls far short of expectations[2-3]. Recently, external treatment in Traditional Chinese Medicine (TCM) for chronic refractory wounds gradually shows advantages in efficacy. As a unique surgical treatment for chronic wounds in TCM diagnosis and treatment, "simmering pus and forming flesh" is to apply special Chinese herbal plaster (powder) to the wound surface for assimilation, so as to promote warming and dredging of local Qi and blood, enhance its defense ability,increase the amount of pus on the wound surface,form a moist environment, and play a dominant role in the middle and late stages of wound healing[4].Analysis on relevant literatures in recent years, as well as the general situation of the "simmering pus and forming flesh" method and its application in anorectal diseases are summarized as follows.

THEORETICAL UNDERSTANDING ON"SIMMERING PUS AND FORMING FLESH" IN TCM

"Simmering pus and forming flesh" first appeared in SHEN Dou-yuan'sClarification on Plaster for Ulcers of Revealing the Mysteries of External Medicine(《外科启玄 • 明疮疡宜贴膏药论》). "When toxic sores are pacified, with less pus and fixed wounds, or less pain and itching without flesh forming, if they are not plastered, the wounds will be uncovered and vulnerable to wind and cold.Therefore, Taiyi Plaster (太乙膏) or others should be applied for simmering pus and forming flesh to keep away from invasion of pathogenic wind. The interior needs to be promoted with tonification, so as to harmonize Qi and blood and recover vitality.Thus, the body is strengthened for fighting against the sores without worsening them." This record established the theoretical basis for treating chronic wounds by expelling pus and forming flesh with plaster to speed up wound healing. In the Tang dynasty, SUN Si-miao said inEssential Recipes for Emergent Use Worth A Thousand Gold(《备急千金要方》), "If there is carrion after abscess necrosis,pig trotter soup should be used to clean it up, and Shirou Plaster/Powder (蚀肉膏散) should be applied then. After the carrion is removed, Shengji Powder(生肌散) need to be applied, and massage the area around to speed up flesh forming." A method of eliminating necrotic tissues and promoting granulation is mentioned here. During Ming and Qing dynasties, WANG Wei-de said inLife-saving Manual of Diagnosis and Treatment of External Diseases(《外科全生集》), "Suppuration is necessary for Transformation of toxin, while pus is formed due to Qi and blood." It describes that pus originates from transfromation and generation of Qi and blood.

In TCM theory, pus is formed during Qi and blood fighting against pathogenic toxin, and"simmering pus and forming flesh" focuses on"simmering pus". "Simmering" means "warming",and "pus" is transformed and generated by Qi and blood. Warming and dredging of Qi and blood can carry the pathogen out to eliminate necrotic tissues and promote granulation, as well as smooth the muscular layer and form the skin, so as to promote wound healing. Changes of pus are emphasized in"simmering pus" and are described by the shape,color, quality and odour. Disease prognoses and efficacy are determined according to them. Wound healing characteristics are different. "Pus" occurs in the early stage of wound healing, mainly caused by decayed flesh due to heat exuberance and pathogenic toxin inundation between skin and flesh.If the pus is thin in quality, dark in color and smelly in odour, it is advisable to "expel pus and remove putrefaction", so as to drain them out easily. In the middle and late stages of wound healing, the "pus"turns into a clear and thick secretion with a lightly stink odour. At this time, it is a normal metabolite of exuberant Qi and blood, so it is appropriate to"simmer pus".

ETIOLOGY, PATHOGENESIS AND TREATMENT OF CHRONIC PERIANAL WOUNDS

In TCM, chronic perianal wounds are classified as "ulcers", and their pathogenic factors are mostly related to "deficiency" and "stasis".Mastery of External Medicine(《外科心法》) records, "If a wound does not heal, and its pus is clear and thin, it is because of Qi-blood deficiency." It discusses that factors causing a refractory wound are Qi deficiency and blood stasis. Its etiology is ascribed to deficiency of vital Qi, disorder of zang-fu viscera, stasis and stagnation of Qi-blood and meridians, malnutrition of flesh and skin, as well as invasion of six climatic exopathogens and pathogenic toxin, which lead to long-term non-healing of the wound surface[5]. It is believed that the main pathogenesis is that when the body's vital Qi is damaged, the exogenous pathogen can be excessive after its invasion, causing it failing to be dispersed and remaining in the wound surface.Meanwhile, Qi-blood deficiency leads to blood stasis, and the blood stasis transforms into heat to burn muscles, bones, skin and flesh to necrotic tissues and pus. Therefore, it is difficult to promote tissue regeneration and it becomes refractory. In clinical diagnosis and treatment, it is found that it is more common in elderly patients and those with body weakness after surgery. Their manifestations of Qi-blood deficiency are wound subsidence, nonhealing for a long time, sparse pus, greyish white granulation tissue, etc.[6]. Finally, the course of disease is prolonged, and the wound surface is difficult to recover.

Orthodox Manual of External Diseases(《外科正宗》) records, "After the rupture stage, fivezang viscera are damaged, and Qi and blood are badly consumed, in which tonifying method should be used exclusively." "Pus" is formed by steaming and brewing of exuberant heat between skin and flesh, which is the main symptom during the stage that sores and ulcers cannot dissipate, and also the manifestation of pathogenic factors being carried out by vital Qi. It is actually formed by transformation and generation of Qi and blood. Sufficient Qi and blood promotes generation and transformation of local fluid to form a moist environment, which is particularly important for wound healing[7-8].Therefore, TCM treatment for sores and ulcers takes supplementing Qi and blood, as well as eliminating necrotic tissues and promoting tissue regeneration[3]as its principle. Through external application, TCM medicine acts locally to discharge pus out of sores and ulcers, warm and dredge Qi and blood, and make vital Qi sufficient to carry out the toxin, so as to promote wound healing. At the same time,modern studies have found that external use of TCM medicine can promote local capillary permeability of wounds[9], activate intracellular enzyme activity[10], activate oxidative metabolic function of immunologically competent cells[11], increase the content of fibronectin[12], and then increase the repair ability of local wounds, in which multiple factors are combined to promote wound healing. Moreover,from the aspect of maintaining and mobilizing body regeneration, "simmering pus and forming flesh"makes Qi and blood sufficient. It plays an important role in the middle and late stages of surgical wound healing, which is the stage of eliminating necrotic tissues and promoting granulation, as well as smoothing the muscular layer and forming skin.

CLINICAL APPLICATION OF "SIMMERING PUS AND FORMING FLESH" THEORY IN ANORECTAL DISEASES

Anal Fistula

Anal fistula refers to abnormal passages where the anal canal or anorectum communicates with skin around the anus, which is induced by pathological causes. It is also called anal fistula in TCM. After anal fistula surgery, a chronic wound surface can be formed due to various factors.Clinically, TCM intervention can directly promote healing, with prominent efficacy, bidirectional regulation, less drug dependence, mild side effects and other advantages[15]. At present, the "simmering pus and forming flesh" method is mostly used in the treatment of chronic anal fistula after surgery,and has outstanding efficacy in aspects of wound recovery time, healing rate, amount of secretions,postoperative pain, etc[16]. YANG Jian-hua[15]et al.selected Zihuang Shengji Plaster (紫黄生肌膏),which containedRadix Lithospermi,Radix et Rhizoma Rhei,Sanguis Draconis,Radix Angelicae Sinensis,Margarita, etc., for external application on postoperative wounds of low anal fistula. Compared with vaseline gauze for external application, results showed that Zihuang Shengji Plaster had advantages in wound healing rates and granulation growth in the middle and late stages after the external application, with certain safety. XU Zhi-wei[17]et al.studied treatments for postoperative wounds of anal fistula respectively by external application of gauze with Compound Shengji Yuhong Plaster (复方生肌玉红膏), which containedRadix Angelicae Sinensis,Rhizoma Coptidis,Caulis Spatholobi,Rhizoma Bletillae,Cera Chinensis,Radix Angelicae Dahuricae,Radix Lithospermi,Radix Glycyrrhizae,Margarita,Olibanum, Myrrha,Calomelas,Sanguis Draconisand sesame oil, and vaseline gauze. At the same time, Zhilou Prescription Ⅰ (痔瘘1号方)was also applied for washing. Results showed that the external application of gauze with Compound Shengji Yuhong Plaster could speed up the healing,keep the wounds clean, reduce inflammatory secretions, and alleviate pain of the wounds. FANG Yuan-yuan[18]et al. used Badu Shengji Powder (拔毒生肌散), including 10 gBorneolum Syntheticum,10 gOs Draconis Praeparatum, 10 gCalamina,10 gCera Chinensis, 15 gGypsum Fibrosum Praeparatum, 6 gHydrargyri Oxydum Rubrum, 6 gCalomelasand 6 gMinium, combined with gauze with Huanglian Plaster (黄连膏), containing 30 gRadix Rehmanniae Recens, 15 gRadix Angelicae Sinensis,9 gRhizoma Coptidis, 9 gCortex Phellodendri, 9 gRhizoma Curcumae Longae, 360 g sesame oil and 120 g Cera Flava. It was compared with traditional external application of vaseline gauze, and they were all applied to postoperative wounds of low and complex anal fistula. In the end, the former could significantly shorten the hospitalization period,reduce the VAS score and improve the secretion,without obvious side effects. HOU Yan-mei[19]et al. studied external application of Jiedu Shengji Decoction (解毒生肌汤), which included 15 gRadix Lithospermi, 15 gOlibanum, 15 gMyrrha, 15 gSanguis Draconis, 5 gBorneolum Syntheticum,20 gRadix Angelicae Dahuricae, 20 gCatechuand 20 gRadix Angelicae Sinensis, combined with gauze with Zicao Oil (紫草油) for dressing change,on postoperative wounds in complex anal fistula of floating line drainage with multiple incisions. It was compared with external application of warm water and gauze with Zicao Oil. It was found that the external application of Jiedu Shengji Decoction with Zicao Oil gauze promoted benign effusion in the early stage, which relieved edema and pain,and promoted healing. CAO Bo[20]and others' study found that in Qiyu Plaster (芪榆油膏), containing 120 g rawRadix Astragali seu Hedysari, 60 g rawRadix Sanguisorbae, 60 g tails of Radix Angelicae Sinensis, 30 gRadix Salviae Miltiorrhizae, 30 gRadix Lithospermi, 30 gRhizoma Bletillae, 30 gOlibanum, 30 gMyrrhaand 30 gSanguis Draconis,compatibility ofRadix Astragali seu HedysariandRadix Angelicae Sinensismight induce gene expression of endogenous VEGF mRNA, stimulate epithelial cell proliferation and migration to form new blood vessels, and promote wound repair. Its application on postoperative wounds in low anal fistula was found to shorten the healing period.MIAO Mi[21]et al. conducted animal experiments and found that Wugu Qilin Plaster (五谷麒麟膏), including 30 g maggots, 30 gSanguis Draconis, 15 gRadix Lithospermi, egg yolk oil, sesame oil, etc., might mainly change the ratio of Bcl-xl/Bak, affect growth and apoptosis of granulation tissue cells on the wound surface, and accelerate wound repair. They also concluded that efficacy in the high dose group was the best.

Perianal Abscess

Perianal abscess is called "anorectal abscess" in TCM. Its onset is urgent and its clinical symptoms are obvious. It is an acute suppurative disease caused by intestinal bacterial infection.Clinically, one-time radical surgery is mostly used for treatment. Postoperative wounds are like those in the repair stage after rupture according to TCM"sore and ulcer" theory. The "simmering pus and forming flesh" method should be used to guide medication, which has good efficacy[22]. CHEN Zhi[23]studied treatment for perianal abscess after surgery by changing external use plaster of Chinese materia medica, including Shuitiao Plaster (水调膏), Youtiao Plaster (油调膏) and Yixiao Plaster (一效膏), based on stages. Compared with external application of vaseline and Ethacridine Lactate, it was found that the application of Chinese materia medica plaster on the wounds by stages could promote growth of granulation tissues, shorten the healing period,increase the amount of secretions on the 7th day after the surgery, and accelerate healing. GU Huanxin[24]and others applied Qufu Shengxue Powder (祛腐生血散), containing 20 gHydrargyrum Oxydatum Crudum, 12 gCalomelas, 12 g Sanguis Draconis,12 gBorneolum Syntheticum, 12 gOlibanum Praeparataand 12 gCrinis Carbonisatus, combined with Shengji Xiangpi Plaster (生肌橡皮膏), containing 16.2 gCrinis Carbonisatus, 16.2 gRadix Angelicae Sinensis, 32.4 g Carapax et Plastrum Testudinis,40.5 g rawGypsum Fibrosum, 40.5 gCalamina,24.3 g elephant skin powder, 676 g sesame oil and 122 gCera Flava, in the study on healing postoperative wounds in 15 cases of leukemia after chemotherapy with perianal abscess. According to different stages of wounds, TCM treatment based on syndrome differentiation was performed. It was found that according to the stages of wounds,customized plaster, powder and oil gauze could obviously shorten the healing period and promote healing, which yielded twice the result with half the effort. ZHU Song[25]treated postoperative wounds of perianal abscess by stages from the perspective of TCM syndrome differentiation. In the initial stage (eliminating necrotic tissues stage of ulcers),gauze with Hongyou Plaster (红油膏) was used for treatment. In the middle stage (forming flesh stage,3-4 days), Shengji Yuhong Plaster (生肌玉红膏) was used for treatment. In the late stage (sore astringing stage, 7-20 days), Shengji Powder (生肌散) was used for treatment. As a result, the wounds healed quickly in clinicl, with a healing rate of 97.06%,and no adverse reactions and recurrences were found during follow-ups. CHEN Hong-xia[26]used an ancient method on postoperative wounds of perianal abscess with routine vaseline gauze for drainage.Based on this, white sugar was used for filling in the treatment group. Results showed that the filling sugar increased pus, providing a good moist environment for healing the wounds. Combined with adequate drainage in the treatment, "simmering pus and forming flesh" and "expelling pus" were well coordinated, which was conducive to wound repair.WANG Qing-ren'sCorrection on Errors in Medical Classics(《医林改错》) in the Qing dynasty records,"Mu'er Powder (木耳散) is used to treat sores and ulcers. It is too effective to be underestimated. Bake 1 Liang (两) woodear and grind it into powder. Mix it with 1 Liang (两) white sugar evenly and soak them in warm water to make paste. Apply it on the sores and ulcers to wrap it up."

Anal Fissure

Anal fissure is an ulcer that occurs after a longitudinal tear in the skin layer of the anal canal[27-28]. It is believed in TCM that anal fissure is mostly caused as the follows. Blood heat and intestine dryness as well as depletion of Yin (阴)fluid induce constipation and exertion during defecation, which damages skin of the anus. Longterm blockage of Qi and blood circulation leads to stasis and stagnation of the local part of the anus.Without nourishing by Qi, blood and fluid, the broken skin fails to heal for a long time and this disease occurs. AsGolden Mirror of Medicine(《医宗金鉴》) records, "A person's Qi and blood circulate without stopping. Even slightly stagnation can lead to swelling." The postoperative wound surface is locally opened, which is easy to become a chronic one if it is treated improperly. GUO Ya-ping[29]et al.applied the functional dressing of alginate extracted from shells in TCM medicine shell to postoperative wounds in anal fissure. Compared with vaseline gauze treatment, it was found that applying the functional dressing of alginate could significantly shorten healing time, alleviate postoperative dressing change pain, and significantly improve the healing rate. LI Ming[30]et al. externally applied Baijie Powder (白竭散), includingRhizoma BletillaeandSanguis Draconis, to postoperative wounds in anal fissure, comparing with external application of vaseline gauze. Advantages of the two methods were compared. Results showed that the external application of Baijie Powder could obviously shorten healing time and speed up growth of granulation tissues, promote expressions of the vascular endothelial growth factor (VEGF) and VEGFR-2 of the wounds 7 days after the surgery, stimulate formation of new blood vessels, make ischemic tissues repair, and accelerate wound healing.CHEN Sheng[31]conducted a comparative study on treatments for postoperative wounds in anal fissure with Shenzhu Shengji Decoction (参术生肌汤), including 12 gRhizoma Bletillae, 9 gCortex Phellodendri, 9 gRadix Salviae Miltiorrhizaeand 9 gRhizoma Atractylodis Macrocephalae, and potassium permanganate fumigation. Both of them were combined with vaseline gauze at the same time. It was found that on the 3rd, 7th, 11th and 14th days after the surgery, there was benign effusion in the early stage in the treatment group treated with Shenzhu Shengji Decoction. And proliferation of granulation tissues was quickened. LI Yan[32]and others performed comparative treatments for postoperative wounds in anal fissure through external application of Shengji Xiangpi Plaster,which contained rawCrinis Carbonisatus,Radix Rehmanniae Recens, wholeRadix Angelicae Sinensis, rawCarapax et Plastrum Testudinis,elephant skin powder,Gypsum Fibrosum,Calamina,

Cera Chinensis,Cera Flavaand sesame oil, and external application of vaseline. Results showed that after the external appication of gauze with Shengji Xiangpi Plaster and on the 7th and 11th days after the surgery, transverse and longitudinal diameters of the wounds were reduced, fibroblasts and capillaries were promoted to form, and growth of granulation tissues was accelerated. Meanwhile, on the 3rd and 7th days, there was much pus secreted from the wounds, with a thick quality. Granulation and epithelial tissues grew rapidly, in line with the TCM external treatment theory of "simmering pus and forming flesh".

Mixed Hemorrhoid

After surgery of mixed hemorrhoid, the perianal incision is often exposed to a fecal contaminated environment. The internal anal sphincter is easy to be stimulated and cause local muscle spasm,leading to obstruction in local incision drainage,delaying wound healing, and forming a chronic wound[33]. WU Ben-sheng[34]et al. studied application of Zihuang Shengji Plaster, which included 15 gRadix Lithospermi, 10 gRadix et Rhizoma Rhei, 15 gRadix Angelicae Dahuricae,30 g body ofRadix Angelicae Sinensis, 6 gBorneolum Syntheticum, 12 gSanguis Draconis,6 gMargarita, 30 gRadix Glycyrrhizae, 60 gCera Chinensisand 500 g sesame oil, combined with Waike Zuoyu Prescription (外科坐浴方) in treatment for postoperative wounds in mixed hemorrhoid.It is compared with treatment by Waike Zuoyu Prescription alone, which consisted of 20 gRhizoma Smilacis Glabrae, 20 gHerba Houttuyniae, 20 gFructus Cnidii, 20 gHerba Portulacae, 20 g saltCortex Phellodendri, 20 gRadix Sophorae Flavescentis, 10 gNatrii Sulfasand 10 g rawRadix et Rhizoma Rhei. Wound healing situations during different stages were observed. Pathological examinations on granulation tissues in the wounds on the 7th and 14th days after the surgery were performed. Results showed that wound pain was significantly relieved and elimination of edema in wound edges was accelerated in the treatment group. The pathological examinations showed that numbers of new capillaries and fibroblasts of wound tissues in the treatment group on the 7th d after the surgery were significantly more, which promoted wound healing together. YE Yu-fei[35]et al.used fumigation by TCM medicine for treating mixed hemorrhoid patients after surgery according to stages. Based on their different stages, they were given modified Sihuang Qudu Decoction (四黄祛毒汤) due to syndrome differentiation, which was compared with fumigation of Kangfuxin liquid.Results showed that the treatment by Chinese materia medica based on syndrome differentiation due to stages had prominent advantages of shortening the healing period, relieving pain, and causing moderate effusion, which was more conducive to the patients'wound healing. XU Zhi-wei[36]et al. compared treatments for postoperative wounds in mixed hemorrhoid by changing dressings with Compound Shengji Yuhong Plaster, which containedRadix Angelicae Sinensis,Rhizoma Coptidis, Caulis Spatholobi,Rhizoma Bletillae,Cera Chinensis,Radix Angelicae Dahuricae,Radix Lithospermi,Radix Glycyrrhizae,Margarita, Olibanum,Myrrha,Calomelas,Sanguis Draconisand sesame oil, and vaseline. At the same time, Zhilou Prescription Ⅰ,includingRadix Sophorae Flavescentis,CortexPhellodendri, Radix Angelicae Dahuricae,Natrii Sulfas,Galla Chinensis,Herba Taraxaci,Radix Angelicae SinensisandRadix Paeoniae Rubra,with a dosage of 15 g for each, was also applied for washing in the two groups. Results showed that the treatment with Compound Shengji Yuhong Plaster could effectively speed up healing time, alleviate pain, let granulation tissues grew faster, and protect the wounds in the early stage without damage.

SUMMARY AND PROSPECT

To sum up, in the TCM external treatment for chronic perianal wounds, "eliminating pus and necrotic tissues" should be applied for cleaning the wounds in the early stage, during the middle and late stages, "simmering pus and forming flesh"by medication is needed. Attach importance to harmonizing Qi and blood. Make local blood flow smoothly to provide a moist environment for wound repair, so as to promote wound healing in a short term. Moreover, it can avoid tissue reinjury caused by routine dressing change. It makes the TCM external treatment of "simmering pus and forming flesh" occupy an advantage in treating anorectal diseases. This method is economical, simple and practical for treating sores and ulcers in TCM surgery. It has prominent efficacy in shortening wound healing time, promoting granulation proliferation, increasing the amount of secretions,and alleviating postoperative pain after the surgery of anorectal diseases. It has high feasibility in clinical application. However, there are still some clinical shortages. A study[37]has found that the therapy of "simmering pus and forming flesh" is not suitable for some diseases with hyperinflammatory reaction and neutrophil infiltration as the main pathological manifestation (including ulcers caused by gangrenous pyoderma or vasculitis). In addition, there is a lack of standard TCM treatment based on syndrome differentiation and systematic mechanism research. The composition, preparation method, dosage form and dosage of various commonly used plaster (powder) also lack unified standard, and there are differences in clinical application. Therefore, standardized treatment based on syndrome differentiation, standardization of medication and related mechanism research need to be strengthened for the TCM methods of"simmering pus and forming flesh" for wound healing in anorectal diseases, so as to provide guidance for clinical application.