A Single-center Cross-sectional Study Of Drug-induced Liver Injury In Children

Objective:1.Investigating the clinical diagnosis and treatment of drug-induced liver injury(DILI)status in children,and analyzing the characteristics of suspected drugs and the clinical features of pediatric cases,which in order to provide reference for clinical diagnosis and treatment and to enhance the health care workers’ awareness of DILI in children.2.Exploring the cognitive errors in the course of using acetaminophen,typical hepatotoxic drugs,and analyzing the errors influence factors,so as to provide data supporting for reducing the risk of DILI caused by APAP,and provide the theoretical basis of publicity and education for rational drug use.Methods:1.By hospital information system(HIS)of a Third-level Grade-A Hospital in Shanxi Province,gathered pediatric cases whose diagnosis were drug-induced liver injury from January 1,2017 to 2019 July 31,and screened the cases further through RUCAM scale.The medical records about those pediatric cases were collected and classified according the following five aspects: general data,clinical manifestations,medication records,liver function biochemistry index value,DILI intervention and prognosis.Referring to the clinical classification judgment standards of 2015 edition of Guidelines for The Diagnosis and Treatment of Drug-Induced Liver Injury,the DILI cases were classified according to the R value calculation results.And the R value calculation formula(R=(ALT value/ ALT ULN)/(ALP value/ ALP ULN))was improved to adapt to the characteristics of children cases: alkaline phosphatase(ALP)was replaced with gamma-glutamyl transpeptidase(GGT).The cases were grouped according to DILI’s clinical classification,severity of injury,suspected drug category,and those clinical characteristics were analyzed comprehensively.2.Through the collection of domestic and foreign APAP cognitive survey of the relevant literature,multinational child fever management guidelines and APAP drug instructions,a questionnaire was designed for the possible risk links in the course of APAP administration,and the contents of items were reviewed and checked by the experts and members of the research group to form the final questionnaire,included 25 items.The sample size of the questionnaire was determined according to 5~10 times of the number of items in the questionnaire,and the sample size was finally determined to be 138~275 after considering the 10% lose-follow-up rate,and the survey was conducted for a period of 1 month.The questionnaires were divided into two types.The paper types was collected in outpatient hall of a Third-level Grade-A Children’s Hospital in Taiyuan,moreover the electronic types was edited on “questionnaire star”,a electronic questionnaire platform,and was forwarded on the basis of WeChat links.Combining above two types,the parents in Shanxi Province were investigated strictly according to the inclusion and exclusion criteria,so as to understand the cognitive status of APAP children in Shanxi Province.Results:1.Analysis results of 62 children with drug-induced liver injury1.1 A total of 986 cases of abnormal liver function in children were collected by HIS,of which 70 cases were diagnosed as DILI.And 62 cases of DILI were further screened by RUCAM.1.2 The male to female ratio of cases was about 1.7:1,with an average age of(4.178±1.407)years and an average weight of(19.056±14.410)kg.1.3 Grouping with the clinical classification,the number of cases in hepatocyte injury type,mixed type and cholestasis type was 29,4,and 5,respectively.And grouping with the different severity of injury,the number of cases in mild,moderate and severe liver injury was 51,3,5,and 3 cases of acute liver failure,respectively.The gender,age and weight of each group were compared according to different clinical classification and severity of injury,and the difference was not statistically significant(P >0.05).1.4 To observe modified R value formula of classification differentiation,biochemical indexes of liver function for comparison between groups,the results show that the level of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in “hepatocyte injury type” and “mixed type” higher than the “abnormal liver function and biochemical examination” group;the level of GGT in “mixed type” and “cholestasis type” higher than “hepatocyte injury type” and “mixed type”;the level of direct bilirubin(DBIL)and ALP in “mixed type” higher than the “abnormal liver function and biochemical examination” group.The difference of above results were statistically significant(P<0.05).1.5 Among the clinical manifestations,the five with high frequency were poor appetite,fever,rash,pruritus and yellow staining of the skin.1.6 Among the suspicious drugs leading to DILI,there are three common types of drugs,including 29 cases of anti-infective drugs(46.77%),14 cases of antineoplastic drugs(22.58%),and 4 cases of nervous system drugs(6.45%).The severity of liver injury caused by the first two kinds of drugs is mild,while the liver injury caused by the latter is severe.There were 2 cases of liver injury caused by antipyretic analgesia and antirheumatic drugs(3.23%),and the severity of liver injury were severe or more.And APAP,as a typical hepatotoxic drug in analgesic-antipyretics,was associated with 4 cases(including the cases of overdose of Compound Paracetamol and Chlorphenamine),related to the administration of APAP,among which 3 were cases of acute liver failure.1.7 The prognosis of 62 cases of DILI in children was great,with 21 cases cured,40 cases improved,1 case unhealed and no death cases.The effective cure rate of liver protecting treatment was 98.31%.2.Results of a survey on drug use behavior and risk cognition in children with APAP2.1 A total of 143 paper questionnaires and 113 electronic questionnaires were collected,and 7 invalid questionnaires were eliminated.A total of 249 copies of effective questionnaires were recovered,with the effective recovery rate of 97.27%.Most of the respondents were urban residents(78.71%),and most were in higher education(78.72% are college degree or above).2.2 In terms of the APAP administration behavior,Among the 7 common cold drugs and antipyretic drugs,the three most frequently used drugs were ibuprofen suspension,157 cases(63.05%),children’s paracetamol and Huang Namin granules,134 cases(53.82%),acetaminophen mixed drops,85 cases(34.14%).However,the results of the attention to the contents of the drug instruction manual show that,249 parents mainly focused on "single dose"(83.13%)and "maximum daily dose"(59.84%),while "drug ingredients"(34.94%)and "main components of drugs"(22.09%)were relatively few.By one-way analysis of variance,it was further found that education level and occupation were the influencing factors of the attention of instruction.2.3 In terms of APAP medication knowledge,the average awareness rate of 249 parents was 75.34%,and the score of urban residents was higher than that of rural residents(P<0.05).The identification results of APAP compound preparations showed that 29(11.65%)could accurately identify one APAP compound preparation,29(11.65%)could accurately identify 2 kinds,24(9.64%)could accurately identify 3 kinds,and only 14 parents(5.62%)could identify 4 or more compound preparations containing APAP.Among 249 parents,111parents(44.58%)mistakenly believed that ibuprofen suspension contained APAP.Further analysis showed that education level and occupation were the influence factors of identification ability.Among them,the scores of “college degree or above”,“medical workers” and “teachers and professional technical workers” were relatively high in each group,and the differences were statistically significant(P<0.05).Conclusion:1.The clinical classification of DILI cases in children was dominated by hepatocellular injury,and the main clinical symptoms were poor appetite,fever,rash,itching and jaundice.The design of RUCAM is not suitable for children.RUCAM,as an assessment tool,can provide reference for the diagnosis of DILI in children,but the definite diagnosis of cases still depends on the clinician’s experience.As the common drugs causing DILI in children,antibacterial agents and antineoplastic agents have relatively light degree of liver damage and short latency of hepatotoxicity.However,APAP,as a representative drug which induce acute liver failure in children,health care workers and parents still need to be vigilant of its risks.2.Parents are generally aware of the importance of drug instructions,but there is still a gap between the basic knowledge of drug use in urban areas and rural areas,and education level and occupation are also major factors.Most parents can keep a watchful eye on the directions,but few are concerned about the effective ingredients of drugs.In the identification of acetaminophen compound preparation,parents mostly make judgments based on the daily medication experience,and few parents can accurately understand the ingredients.In order to ensure the drug safety for children,medical staff should give full play to their professional advantages,provide medication guidance to parents,and go to the grassroots to conduct drug education for more parents,so as to enhance their awareness of rational drug use,to reduce the occurrence of unreasonable drug use behavior and reduce the risk of drug use.