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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.

SUBMITTER: Ye L

PROVIDER: S-EPMC8721278 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesIn the emergency department (ED), health care providers miss delirium approximately 75% of the time, because they do not routinely screen for this syndrome. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is a brief (<1 minute) delirium assessment that may be feasible for use in the ED. The study objective was to determine its validity and reliability in older ED patients.MethodsIn this prospective observational cohort study, patients aged 65 years or older were enrolled at an academic, tertiary care ED from July 2009 to February 2012. An emergency physician (EP) and research assistants (RAs) performed the CAM-ICU. The reference standard for delirium was a comprehensive (~30 minutes) psychiatrist assessment using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. All assessments were blinded to each other and were conducted within 3 hours. Sensitivities, specificities, and likelihood ratios were calculated for both the EP and the RAs using the psychiatrist's assessment as the reference standard. Kappa values between the EP and RAs were also calculated to measure reliability.ResultsOf 406 patients enrolled, 50 (12.3%) had delirium. The median age was 73.5 years old (interquartile range [IQR] = 69 to 80 years), 202 (49.8%) were female, and 57 (14.0%) were nonwhite. The CAM-ICU's sensitivities were 72.0% (95% confidence interval [CI] = 58.3% to 82.5%) and 68.0% (95% CI = 54.2% to 79.2%) in the EP and RAs, respectively. The CAM-ICU's specificity was 98.6% (95% CI = 96.8% to 99.4%) for both raters. The negative likelihood ratios (LR-) were 0.28 (95% CI = 0.18 to 0.44) and 0.32 (95% CI = 0.22 to 0.49) in the EP and RAs, respectively. The positive likelihood ratios (LR+) were 51.3 (95% CI = 21.1 to 124.5) and 48.4 (95% CI = 19.9 to 118.0), respectively. The kappa between the EP and RAs was 0.92 (95% CI = 0.85 to 0.98), indicating excellent interobserver reliability.ConclusionsIn older ED patients, the CAM-ICU is highly specific, and a positive test is nearly diagnostic for delirium when used by both the EP and RAs. However, the CAM-ICU's sensitivity was modest, and a negative test decreased the likelihood of delirium by a small amount. The consequences of a false-negative CAM-ICU are unknown and deserve further study.

Project description:BACKGROUND:Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI. METHODS:We examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes. RESULTS:The cases examined for the determination of DILI avoidability had probability likelihood of "probable" or "highly probable" by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as "avoidable" ("probable" or "definite") by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf's kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively. CONCLUSION:We found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.

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

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