Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method

Abstract

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China.Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI.Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%).Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

Incidence, clinical features and risk factors of tacrolimus induced idiosyncratic liver injury in renal transplant recipients: A nested case-control study

“…Additionally, the present study is the first to report that tac-DILI tends to occur at a younger age. Drug use is recognized as a cause of pediatric liver disease, but little is known about DILI in children and adolescents ( Ferrajolo et al, 2010 ; Ye et al, 2021 ). Age distribution analysis showed that 15.2% and 53.3% of non-tac-DILI and patients with tac-DILI, respectively, were ≤18 years of age.…”

Treatment of Drug-Induced Liver Injury

“…The top drugs causing RUCAM-based DILI worldwide have been assessed as to whether they were metabolized through CYP isoforms [62]. Literature provided highquality data on clinical features of DILI [1][2][3][4][5][6][7][8][9][10][16][17][18][19][20][21][22][23][24][25][26][27][28]39,64]. However, although most of the clinical features are well established, a variety of mechanistic steps remain unresolved in this complex disease.…”

“…Cessation of all non-essential drugs is mandatory as soon as the idiosyncratic DILI is suspected [13,28,29,90,91]. This alone has a positive effect on LTs as shown in many reports on DILI with verified diagnosis based on the RUCAM [1][2][3][4][5][6][7][8][9]. In most cases, a complete resolution of the liver injury is achieved, while in a few others, a protracted course of LTs is observed.…”

“…Drug-induced liver injury (DILI) remains an important concern among scientists, physicians, regulators, and experts in the field, with a focus on general aspects [1][2][3][4][5][6] or more specifically on drugs such as multiple antidepressants [7], teriflunomide [8], tigecyc-line [9], or potassium para-aminobenzoate [10]. The last three decades have witnessed substantial efforts on the question of how best to ensure the diagnosis of DILI in patients with abnormal liver tests (LTs) under treatment with drugs.…”

Drug-induced Liver Injury in Pediatrics

“…The updated Roussel Uclaf Causality Assessment Method (RUCAM) is an algorithmic diagnostic method for DILI (Table 1) (9,10). The RUCAM was created for adults, but it has been used successfully in children in the DILIN prospective study, the Latin American DILI Registry, the Spanish DILI registry and in 2 pediatric retrospective studies (16)(17)(18)(19). It is based on liver test thresholds, liver injury pattern, timing of events, risk factors, comedications, known hepatotoxicity of the drug, response to re-exposure, and most importantly, exclusion of alternative causes (ruling out infections, ischemia, gallbladder disease and autoimmune hepatitis, among others).…”