Clinical observation of Yinchen Jianpi Tuihuang Granule in treatment of 52 cases of neonatal pathological jaundice

Xiaoxia Zhang, Xiaoping Liu, Xiuchun Xie, Aimin Feng

Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China

Abstract

Key words: Yinchen Jianpi Tuihuang Granule; Yinzhihuang oral liquid; traditional Chinese medicine;damp-heat stagnation and steaming; neonatal pathological jaundice; clinical observation

Introduction

Neonatal jaundice is the most common disease among the newborns, it belongs to the category of “fetal jaundice”and “jaundice” in the theory of traditional Chinese medicine (TCM).The incidence of neonatal jaundice in China is up to 50%-80%[1-2].The majority of affected newborns had good prognosis, and severe jaundice may trigger bilirubin encephalopathy, even cause permanent neurodevelopmental disorders[3].In clinical treatment,western medicine provides drug intervention to children whose daily jaundice value reaches or exceeds the boundary of low-risk zone and the low- and medium-risk zone (the 40thpercentile line).As for children at mediumand high-risk zone and the high-risk zone, phototherapy or blood exchange therapy are recommended[4].In western medicine treatment of neonatal pathological jaundice at the low-risk zone and the low- and mediumrisk zone, the drugs applied are not effective except oral phenobarbital, while TCM treatment formulated based on clinical signs and symptoms of children has achieved good outcome[5].We have previously reported clinical efficacy of Ying’an mixture on preventing and treating neonatal jaundice in 2002[6].Through the modifications on the above mixture, we produced a novel formula for treatment of neonatal pathological jaundice with syndrome of dampheat stagnation and steaming, which has achieved obvious outcome, as reported below.

Materials and Methods

General information

One hundred and twenty children were included in this study.They were born in the Obstetrics Department of our hospital from November 2018 to July 2019, diagnosed with pathological jaundice, and stayed with their mothers in the same ward after birth.The included children were randomly divided into two groups, with 60 cases in each group, receiving Yinzhihuang oral liquid and Yinchen Jianpi Tuihuang Granule, respectively.Inclusion criteria:All children should meet the diagnostic criteria for neonatal pathological jaundice (Practical Neonatology;the Fourth Edition); meet the criteria for syndrome of damp-heat stagnation and steaming in Pediatrics of Chinese Medicine (Author: Wang Shou-chuan; the Ninth Edition); manifestations include yellow skin and appearance, bright tangerine color, crying loudly, rejecting to suckle, thirst and dry lips, constipation, deep yellow urine, red tongue, yellow greasy fur.Exclusion criteria:premature infants; low birth weight infants; children who have been clinically diagnosed with biliary atresia,bilirubin encephalopathy, and neonatal hemolytic disease;children with complications; children with infectious factors; children who parents do not cooperate; children of fetal jaundice with stirring wind syndrome or collapse syndrome.Elimination criteria: (1) those who take other medicines in addition to the designated medicine; (2)those who replaced the medicines during treatment.There were 60 cases in the control group, 12 cases were excluded,and 48 cases were finally included; there were 60 cases in the treatment group, 8 cases were excluded, and 52 cases were finally included.Control group (48 cases): 27 males and 21 females; gestational age 37.5-41 weeks (39.1±0.8);body weight 2.7-4.2 Kg (3.1±0.4).Treatment group (52 cases): 27 males and 25 females; gestational age 37.2-41.1 weeks (39.2±1.0); body weight 2.6-4.4 Kg (3.4±0.5).The gender, gestational age, and body weight of children in the two groups were comparable (P＞0.05).All children’s guardians in this study have signed informed consent.

Treatment method

In the control group, children were given Yinzhihuang oral liquid 3.3 ml, 3 times per day; while children in the treatment group were given oral Yinchen Jianpi Tuihuang Granules (Herba Artemisiae Scopariae 5 g, Poria 6 g,Herba Lysimachiae 6 g, Fried Rhizoma Atractylodis Macrocephalae 6 g, prepared Radix Glycyrrhizae 3 g),which were self-made in our hospital,firstly dissolved in 5-10 ml hot water at 80-90℃ and stirred well, twice per day.

Outcome measures

At the same period everyday (08:30-10:00 am), the bilirubin level was measured with NJ33A infant transdermal jaundice tester (produced by Shanghai Hao Shun Technology Co., Ltd.) at 2-5 days, and the jaundice level from the forehead (between the median point of the two eyebrow arches) and the chest (the position of manubrium) was measured, and the average value of the two indicators was calculated.The urine and stools, the incidence of vomiting and diaper dermatitis, as well as the rate of transferring to hospitalization for phototherapy in two groups were observed and compared.

Statistical analysis

SPSS 19.0 software was used to process and analyze the data.The measurement data were expressed as mean±standard deviation (±s) using t test.The count data were expressed as percentages and tested byx2test.AP＜0.05 level indicated a statistically significant difference between the two groups.

Results

Comparison of the average transdermal bilirubin level in the two groups at 2-5 days (Table 1)

Table 1 Comparison of the average transdermal bilirubin level between two groups at 2-5 days

Comparison of adverse reactions in the two groups(Table 2)

Table 2 Comparison of adverse reactions between two groups

Comparison of the rate of transferring to hospitalization for phototherapy in the two groups during treatment

Thirteen children in the control group were transferred to phototherapy treatment, accounting for 26%; while only four children in the treatment group needed phototherapy treatment, accounting for 8%.There were significant differences between two groups (P＜0.05).

Discussion

Neonatal jaundice is a prevalent disease among newborns.According to the difference of disease cause, neonatal jaundice can be divided into physiological jaundice and pathological jaundice.Neonatal pathological jaundice means the abnormality of bilirubin during metabolism within 28 days after neonatal birth, resulting in the increase of bilirubin level in the blood.The clinical manifestations include yellow staining of the skin, mucous membranes and sclera[7-8].The bilirubin metabolism of newborns is different from that of adults.The number of red blood cells is relatively higher, the survival time is shorter, and the production of bilirubin is higher in newborns; the development of hepatocytes is immature,leading to the dysfunctions of bilirubin uptake, binding and excretion[9]; or prolonged meconium excretion time after birth and breastfeeding may cause an increase in enterohepatic circulation of bilirubin[10].These factors can cause neonatal jaundice.Clinical studies have suggested that approximately 60% of newborns may have jaundice to varying degrees within a week, and this disease will have a certain impact on newborns.Most of neonatal jaundice are physiological jaundice, with moderate clinical symptoms, and can be relieved without treatment.However,pathological jaundice still remains.Once the newborn has already developed pathological jaundice and is not promptly intervened, it may easily cause hyperbilirubinemia, severe hyperbilirubinemia or hyperbilirubinemia that is partially lower than the current physiological jaundice standard is at high risk to induce bilirubin encephalopathy or nuclear jaundice[11].More unbound hemobilirubin penetrates the blood-brain barrier and will affect the neurodevelopment of newborns, even cause death in newborns.Therefore,early detection, early intervention and timely treatment are very necessary to promote the recession of jaundice and prevent the progression of neonatal jaundice from lowand middle-risk zones to high-risk zone.All the parents of children with neonatal jaundice are expecting to shorten the curing time, reduce the adverse reactions, improve parent’s compliance, and lower treatment costs, which are also important issues concerned by clinicians.The existing clinical treatment of western medicine includes drug intervention, phototherapy and blood exchange treatment.The drug applied, Phenobarbital, is a liver enzyme inducer,which can enhance the ability of hepatocytes to uptake unbound bilirubin, and promote the metabolism and excretion of bilirubin.However, this drug takes 2-3 days to take effect, so early administration is recommended[12].In addition, the adjuvant therapy is usually phototherapy, and intermittent phototherapy is frequently used in clinical practice.Intermittent irradiation of blue light that is not absorbed by bilirubin molecules can change fat-soluble indirect bilirubin to water-soluble one, and then discharge bilirubin through urine and bile, thereby effectively reducing the serum level of bilirubin[13].However, both continuous phototherapy and intermittent phototherapy may results in the changes of feeding patterns and environmental changes.Separation of mothers and infants can cause infant discomfort and symptoms such as vomiting, crying, dysphoria, which not only affects the curative, but also causes aspiration pneumonia and even suffocation if not handled properly[14].As for children transferring to hospitalization for phototherapy or those who have to undergo blood transfusion treatment, the mother-baby separation and the increasing cost are commenced.

In the TCM theory, neonatal jaundice is called “newborn jaundice” or “fetal jaundice”.In the Zhu Bing Yuan Hou Lun (General Treatise on Causes and Manifestations of All Diseases), it’s stated that, since the fetus is affected by and fumigated in the heat in mother’s visceral qi, they are prone to have yellow skin all over the body after birth,which is newborn jaundice.The other condition is that, as the neonatal viscera is immature and insufficient, and the spleen is often inadequate to resist exogenous evil that may invade and affect the spleen, the spleen loses the function of transportation and accordingly the evil invades the liver and gallbladder, the liver has no free activity and the gallbladder fails to control conveyance and dispersion,ultimately the bile over flows to the skin and turns yellow.As mentioned in the Youke Zhunsheng (TCM Standards for Diagnosis and Treatment of Pediatrics), fetal jaundice is the result of mother’s dampness and heat, which is transmitted to the fetus.In the Youke Shimi (Comments on Treatment of Pediatrics), fetal jaundice refers to yellow skin and appearance all over the body upon the birth,high fever, lack of neonatal meconium, loquat juice-like urination, rejection to feeding, continuous crying, which is caused by the transmission of the heat and dampness from the mother.Once the dampness-heat or cold-dampness invades the viscera, the evil enters the pericardium, then jaundice may rapidly aggravate, thus disturbing the spirits and causing convulsions, coma, fetal jaundice with stirring wind syndrome or collapse syndrome.From these ancient books, we can found that TCM research on neonatal jaundice has a long history and clarifies the etiology and pathogenesis of jaundice, the formation of “newborn jaundice” has external and internal causes: external factors are mainly related to dampness and heat.Zhu Danxi proposed that among the six climate factors, damp-heat is dominant factor for the majority of diseases.Ye Tianshi believed that, dampness pathogen is the most harmful threat for human health.According to the findings of Xue Shengzi, the heat and dampness govern the sky and the earth, respectively, they aggravate each other.If the two factors are separated, the disease is moderate and slow; if they are combined, the disease is severe and fast.Wang Mengying believed that, with the dampness, the heat is depressed and congested, thus becoming hotter; with the heat, the dampness is rising and steaming upwards,thus becoming aggravated.The combination of heat and dampness is the most common cause of various diseases.Neonatal viscera is usually immature and insufficient to resist exogenous evil, so newborns are prone to the disease.The internal cause is mainly the deficiency of congenital endowment in infants, or the transmission of dampness from the mother; the disease is located in the liver and gallbladder, and it is closely related to the spleen.In the practice of modern medicine, clinical syndromes of neonatal jaundice are divided into four types: dampheat stagnation and steaming type, cold-dampness blocking type, stagnation of qi and blood stasis type, and pathogenic toxin type.They have corresponding formula with some modifications based on the syndromes, and achieved good effects.In terms of TCM treatment, some doctors have used TCM retention enema or acupuncture therapy to treat neonatal jaundice[15].The curative effect is satisfactory, but the operations are difficult and may aggravate the pain, which is not accepted by parents.TCM medicated bath takes advantage of newborn’s characteristics such as thin skin and large body surface area, it combines Chinese medicine with bathing and touching, allows the medicine to penetrate into the capillaries through the skin, promotes blood circulation, gastrointestinal motility and defecation, and reduces enterohepatic circulation of bilirubin, thus effectively prevents and treats early mild neonatal jaundice[16].As neonatal skin is so delicate and susceptible to allergies, it requires the operations of trained professional nurses, rather than parents, and the therapeutic effect of medicated bath on pathological jaundice at low- and middle-high-risk zones needs further study.Therefore, Chinese medicine granules administered after dissolved are dialectical treatment in clinic, due to convenient operations, low cost, small amount and tolerance by newborns, it is increasingly favored by the majority of doctors and families.In this study, neonatal jaundice cases with damp-heat stagnation and steaming syndrome were treated with drugs to clear heat, promote diuresis, and eliminate jaundice, as well as tonifying the spleen.

Neonatal physiological jaundice usually occurs at 2-3 days and peaks at 4-5 days, while pathological jaundice occurs earlier.Therefore, in this study, we selected pathological jaundice cases diagnosed after birth for observations at 2-5 days after treatment.In this study, the average daily bilirubin level at 2-5 days was comparable between the treatment group and the control group (P＞0.05), but the incidence of adverse reactions such as diarrhea,vomiting, diaper dermatitis, and the rate of transferring to hospitalization for phototherapy in the treatment group was significantly decreased (P＜0.05), indicating that Yinchen Jianpi Tuihuang Granules could effectively promote the reduction of bilirubin in newborns at lowmiddle risk and middle-high risk, reduce the incidence of high-risk jaundice, and decrease the possibility of phototherapy; results showed that Yinchen Jianpi Granules induced fewer reactions such as neonatal diarrhea,vomiting, and diaper dermatitis, and fewer cases were transferred to hospital for phototherapy.Yinchen Jianpi Tuihuang Granule is a self-made prescription in our hospital.It is formulated according to unique physiological and pathological characteristics of newborns, and modified based on Ying’an mixture with additions and subtractions, it highlights the advantages of TCM treatment.This formula has the functions of clearing heat and eliminating jaundice, removing dampness and strengthening spleen.Herba Artemisiae Scopariae is a monarch drug, which acts to clear heat, remove dampness,eliminate jaundice, and exert choleretic effect.It is a traditional multipurpose drug for eliminating jaundice and choleretic effect.Modern pharmacological study has demonstrated that, Herba Artemisiae Scopariae can enhance gallbladder contraction, strengthen hepatocyte function, promote bile secretion, increase bilirubin and bile acid excretion, and play a choleretic role[17].It also protects the integrity and good permeability of liver cell membranes, prevents liver cell degeneration and necrosis, promotes liver cell regeneration, improves liver microcirculation, and enhances liver detoxification function[18].Therefore, Herba Artemisiae Scopariae contributes to excrete bilirubin and bile acid, effectively repair damaged liver cells, and enhance blood circulation of the liver and bile wall.Herba Lysimachiae is a ministerial drug, which has the effects of clearing heat and dampness, promoting diuresis and treating strangurtia.In the Jingui Yaolue (Synopsis of Golden Chamber), jaundice results from the dampness and all jaundice-related diseases are characterized by the diuresis.Modern pharmacological research shows that, Herba Lysimachiae can reduce bilirubin[19]; the combination of Herba Lysimachiae and Herba Artemisiae Scopariae can reduce bilirubin levels and enhance the effect of eliminating yellowing.Poria and Rhizoma Atractylodis Macrocephalae are supplemented:Poria clears dampness and promotes diuresis, strengthens spleen and harmonizes stomach, tranquilizes the mind and has mild medicinal properties, it is beneficial to the diuresis without hurting any energy and regarded as essential drug for diuresis, in addition, it has liverprotective effect as shown in modern pharmacological research[20]; as mentioned in Bencao Qiuzhen (Science of Materia Medica), Rhizoma Atractylodis Macrocephalae is the first essential drug for replenishing spleen qi, and fried Rhizoma Atractylodis Macrocephalae is used to invigorate spleen and supplement qi for children whose spleen is often insufficient; modern pharmacological research conforms the effect of Rhizoma Atractylodis Macrocephalae on regulating the gastrointestinal tract and protecting liver[21].The combination of these two drugs contributes to invigorate spleen and supplement qi, offsets the foundation of acquired constitution, protects the liver, relieves the cold nature of other drugs, and reduces the intestinal burden of children; in addition, as conductant drug, prepared Radix Glycyrrhizae replenishes the spleen and supplements qi, and reconciles all drugs.It plays a comprehensive role, not only clears heat, eliminates dampness, treats stranguria, but also strengthens the spleen, nourishes qi,regulates gastrointestinal tract, and reduces liver-intestinal circulation.In this study, all cases with neonatal jaundice included in the treatment group and the control group had damp-heat stagnation and steaming syndrome.In addition, the other three types including cold-dampness blocking type, stagnation of qi and blood stasis type, and pathogenic toxin type are occasionally found in clinical practice, but the latter two are rare.Except for the dampheat stagnation and steaming type, the most common type is the cold-dampness blocking type.The clinical manifestations of children are mostly dark yellow skin;abdominal distension, loose stools; yellow and less urine;tiredness; pale tongue, white greasy fur.This type can be treated with some drugs added to previous formula.For children with diarrhea who have frequent stools,Codonopsis pilosula (5 g) is supplemented, it is sweet and moderate, and belongs to the spleen and lung meridians.It acts to tonify spleen-stomach, replenish qi and promote the production of body liquid.Modern pharmacological studies have shown that Codonopsis pilosula may regulate gastrointestinal contraction and protect gastrointestinal mucosa[22].Combined with other drugs, it can strengthen the spleen, protect the gastrointestinal mucosa, and reduce the incidence of diarrhea.

In summary, Yinchen Jianpi Tuihuang Granule is an effective option for the treatment of neonatal pathological jaundice with damp-heat stagnation and steaming syndrome, and it lowers the incidence of vomiting, diarrhea and diaper dermatitis, as well as the rate of transferring to hospitalization for phototherapy.Therefore, Yinchen Jianpi Tuihuang Granules has a definite effect, easy administration method, and good compliance from parents.It is a better choice recommended for children with neonatal jaundice at low-risk zone and mediumhigh-risk zones.However, this study has some limitations due to less cases included and lack of experimental basis.Therefore, further research on mechanism of action is needed to provide more scientific data for clinical application.