N-acetylcysteine as an antidote for paracetamol poisoning: a multicenter study. / Estudio multicéntrico sobre el tratamiento con N-acetilcisteína como antídoto en la intoxicación por paracetamol.

OBJECTIVES: To identify the most common problems related to use of N-acetylcysteine to reverse the toxic effects of paracetamol poisoning. MATERIAL AND METHODS: Retrospective descriptive observational study of clinical records for patients treated for paracetamol poisoning in 4 emergency departments during 3 years (2017-2019). We analyzed epidemiologic, clinical, and care variables, especially those related to the suitability and safety of using N-acetylcysteine as an antidote. RESULTS: We included 332 cases of poisoning of 260 patients (78%) were over the age of 16 years, and 242 (73%) were female. Two hundred sixty-eight poisonings (81%) were the result of voluntary intake. The elimination half-life was determined in 20 cases (6%). Gastrointestinal decontamination was incorrectly prescribed on 39 occasions (28%). Treatment with the antidote was begun in 195 cases (58.7%). No serious clinical signs or symptoms were present in 282 cases (85%). The correlation of paracetamol levels in urine was stronger with the amount of drug ingested voluntarily (R2 = 0.23) than with accidental intake (R2 = 0.007). Predefined severity criteria were significantly related to reported dose ingested per body weight (P = .001) and the interval between intake and first medical assistance (P = .008). CONCLUSION: Even though clear protocols are available to guide the use of antidote treatment in cases of paracetamol poisoning, variability in fundamental aspects of management is excessive.

OBJETIVO: Conocer los aspectos clínicos relacionados con el tratamiento del antídoto N-acetilcisteína (NAC) en las intoxicaciones por paracetamol. METODO: Estudio observacional y retrospectivo de los pacientes atendidos por intoxicación por paracetamol en cuatro servicios de urgencias durante 3 años (2017-2019). Se analizan variables epidemiológicas, clínicas y asistenciales, así como la idoneidad y seguridad en el empleo del tratamiento antidótico. RESULTADOS: Se incluyeron 332 intoxicaciones: 260 casos (78%) tenían más de 16 años y 242 (73%) fueron mujeres. Doscientos sesenta y ocho intoxicaciones (81%) fueron de causa voluntaria y la semivida de eliminación se determinó en 20 ocasiones (6%). La descontaminación digestiva se indicó de forma incorrecta en 39 ocasiones (28%). Se inició tratamiento con antídoto en 195 casos (58,7%). En 282 casos (85%) no hubo ninguna clínica de gravedad. La correlación entre la dosis referida ingerida y la paracetamolemia en los casos de ingesta voluntaria (R2 = 0,23) fue más fuerte que en los casos de ingesta accidental (R2 = 0,007). Existieron diferencias estadísticamente significativas al relacionar los criterios de gravedad con la dosis referida ajustada al peso (p = 0,001) y el intervalo desde la ingesta y la primera asistencia médica (p = 0,008). CONCLUSIONES: Existe variabilidad en aspectos fundamentales del tratamiento antidótico en las intoxicaciones por paracetamol, a pesar de estar claramente protocolizado su manejo.

Experience of a Strategy Including CYP2C19 Preemptive Genotyping Followed by Therapeutic Drug Monitoring of Voriconazole in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation.

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1-5.5 µg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).