Evaluation of urinary acetaminophen metabolites and its association with the genetic polymorphisms of the metabolising enzymes, and serum acetaminophen concentrations in preterm neonates with patent ductus arteriosus.

Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolised by conjugation and partly by Cytochrome P450 (CYP) enzymes.We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (CYP1A2*3, CYP1A2*4, CYP1A2*1C, CYP1A2*1K, CYP1A2*6, CYP2D6*10, CYP2E1*2, CYP2E1*5B, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, and CYP3A5*11) and their effect on urinary metabolites and serum acetaminophen concentrations.Nineteen (32.8%) neonates had heterozygous CYP1A2*1C, two (3.3%) with heterozygous CYP1A2*1K, 15 (27.8%) and two (3.7%) had heterozygous and homozygous CYP2D6*10, two (3.7%) had heterozygous CYP2E1*5B, seven (12.3%) and three (5.3%) had heterozygous and homozygous CYP3A4*1B, and three (5.5%) had CYP3A5*7 amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations.A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modelling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.

Intravenous acetaminophen (at 15 mg/kg/dose every 6 hours) in critically ill preterm neonates with patent ductus arteriosus: A prospective study.

WHAT IS KNOWN AND OBJECTIVES: Acetaminophen has been increasingly used in treating patent ductus arteriosus (PDA) in preterm neonates. Variations were observed in the dosing regimen of acetaminophen across the studies. There is hardly any data available for a relatively higher dose of intravenous acetaminophen (15 mg/kg/dose every 6 hours) in the preterm population. We present here the results of a prospective study with this dose of intravenous acetaminophen for treating PDA in critically ill preterm neonates. METHODS: Preterm neonates (≤37 weeks of gestational age) with haemodynamically significant PDA were enrolled. Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was administered. Echocardiographic monitoring, liver and renal function tests were carried out. Standard definitions were adhered for defining acute kidney injury (AKI) and hepatotoxicity. RESULTS: Fifty-five neonates were recruited. Following the first dose, less than half had their serum acetaminophen concentrations in the therapeutic range. Extreme preterm neonates were less likely to have a sustained therapeutic acetaminophen concentration after the first dose. Following multiple doses and at steady state, 97.2% and 98.8% respectively were in the therapeutic range. Forty-three (78.2%) neonates had successful closure of the ductus arteriosus of which 22 were extreme preterm, 17 were very preterm and 4 were late preterm neonates; and considering their birthweights, 21 were extremely low, 16 were very low and 6 were low birthweight categories. Ten neonates had elevated alanine aminotransferase levels with three in the low-to-moderate risk of hepatotoxicity category. Eight neonates had altered renal function tests indicating AKI. WHAT IS NEW AND CONCLUSION: Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was efficacious in 78.2% of the preterm neonates with PDA. We observed a lower incidence of hepatotoxicity, and AKI in the study population. No association was observed between the serum acetaminophen concentrations and PDA closure.

Is fat-free mass-based gentamicin dosing regimen preferable than whole-body weight in neonates?

Importance: Body fluid dynamics and renal maturation status vary during the neonatal period. We hypothesized that differences in peak and trough gentamicin concentrations could be expected. Objective: To predict the peak and trough gentamicin concentrations in critically ill neonates and to predict the changes in the predicted peak plasma concentrations of gentamicin following fat-free mass dosing. Methods: Critically ill neonates that received gentamicin and have gentamicin concentration measured were recruited. Fat mass was estimated using skinfold thicknesses. Changes in the peak plasma concentrations (Cmax) using whole-body weight (estimated using the current dosing regimen) and predicted concentrations following the fat-free mass-based dosing were the outcome measures. Results: Eighty-nine critically ill neonates were recruited. Sub-therapeutic Cmax was estimated using the current dosing regimen in 32.6%, and 22.5% neonates following the first and second doses of gentamicin. Preterm neonates had significantly higher fat mass compared to term neonates. All except one had Cmax above 12 µg/ml after the first dose and all had after the second gentamicin dose following the predicted fat-free mass-based gentamicin dosing. The recommended doses are as follows: extreme preterm: 7.95 mg/kg every 48 h; very preterm: 7.30 mg/kg every 36-48 h; late preterm: 5.90 mg/kg every 36-48 h; and term neonates at 5.10 mg/kg every 24 h. Interpretation: Fat-free mass dosing may be considered for obtaining optimal therapeutic effects in the neonatal population.

Evaluation of Genetic Polymorphisms of the Antioxidant Enzymes and Biomarkers of Oxidative Stress in Preterm Neonates With Respiratory Distress Syndrome Receiving External Surfactant.

Background: Preterm neonates, particularly extremely preterm, are susceptible to respiratory distress syndrome (RDS) due to surfactant deficiency. Single nucleotide polymorphisms (SNPs) in the antioxidant enzymes influence the balance between antioxidant and oxidative stress molecules. Objectives: To ascertain the role of SNPs of antioxidant enzymes and oxidative stress biomarkers in preterm neonates with RDS. Design: Observational, cross-sectional study. Methods: Preterm neonates diagnosed with RDS receiving external surfactant within 24 hours were considered as the cases and those without RDS were the control group. Umbilical cord blood and peripheral blood samples before administering surfactant (day 1), and on days 2 and 3 were collected. Plasma malondialdehyde, 8-hydroxy-2-deoxy guanosine (8-OH-dG), advanced oxidation protein products (AOPP), total antioxidant capacity (TAC), visfatin, reduced glutathione, and chaperonin 60 were evaluated using enzyme-linked immunosorbent assay. SNPs in manganese superoxide dismutase (MnSOD), copper/zinc superoxide dismutase (Cu/Zn SOD), glutathione peroxidase (GPX1 and GPX3), catalase (CAT), glutathione S-transferase (GSTP1) were evaluated using real-time polymerase-chain-reaction. The receiver-operating characteristics curve was used for predicting the accuracy of biomarkers using the area under the curve (AUC) and 95% confidence intervals (95% CI). Results: GSTP1, MnSOD, and eNOS (rs1799983) SNPs were observed to significantly influence the oxidative biomarker concentrations in the entire study population. SNPs in GSTP1, MnSOD, and eNOS (rs1799983) were significantly associated with differences in oxidative stress biomarkers. MnSOD (rs4880) significantly increased the risk of pulmonary complications in neonates with RDS. DNA damage product (8-OH-dG) concentrations before surfactant administration has the best predictive accuracy (AUC: 0.8; 95% CI: 0.7-1; P = .001) for pulmonary complications with a cut-off value of 5008.8 pg/mL. TAC concentrations are significantly greater on day 2 and day 3 amongst neonates receiving surfactant compared to the control group. AOPP in the umbilical cord blood was observed to significantly predict the severity of RDS (AUC: 0.8; 95% CI: 0.6-1; P = .01) with an optimal cut-off value of 88.78 µmol/L. Conclusion: We observed that SNPs in eNOS and MnSOD significantly influence the production of oxidative stress biomarkers in preterm neonates. Baseline 8-OH-dG concentrations best predict the risk of pulmonary complications and AOPP concentrations in the umbilical cord blood predict the risk of RDS severity.

Off-label drug use and the risk of medication errors in critically ill neonates: A conceptual pilot study.

BACKGROUND: Off-label drug (OLD) use is common in neonates. OBJECTIVE: There is a dearth of information associating the OLD use and the risk of medication errors in critically ill neonates. Hence, the present study was carried out. METHODS: Drug prescriptions in neonates admitted to the intensive care unit of a tertiary care hospital between September 2018 and June 2019 were evaluated. Details on their demographics, reason for admission in intensive care unit, drug-related information and serum creatinine were extracted. United States Food and Drug Administration approved drug labels were compared. World Health Organization (WHO) anatomy, therapeutic and chemical (ATC) classification was used for drug categorization. We assessed the risk of medication errors in the adult population using a validated tool: medication risk score (MERIS). RESULTS: One hundred and seventy-one neonates with 2394 prescriptions were included in this study. Seventy one percent of the neonates in the present study received at least one OLD/unlicensed prescription item. A trend in increased numbers of OLD/unlicensed drug use in more premature and lower birth weight neonates were observed. Medication risk score was significantly higher in neonates receiving OLD/unlicensed drugs compared to those with only labelled drugs. Very and extreme pre-term (along with very low and extremely low birth weight) neonates were at higher risk of medication errors compared to others. Presence of OLD/unlicensed prescribed items is associated with a potentially increased risk of medication errors by an odds ratio of 20.4 compared to labelled drugs. CONCLUSION: Significant proportions of critically ill neonates received at least one OLD/unlicensed drug and such use was associated with potentially increased risk of medication errors.

Drug utilisation in adult, paediatric and neonatal intensive care units, with an emphasis on systemic antimicrobials.

INTRODUCTION: Critically ill adults, children and neonates receive drugs that are often administered parenterally and in infusions. Considering patient illness severity, empirical broad-spectrum antimicrobials are commonly used. We conducted the present study to evaluate the drug use in this population, with a special focus on antimicrobials. MATERIAL AND METHODS: A prospective cross-sectional study was implemented in adult, paediatric and neonatal intensive care units. Various prescribing and supplemental indicators were used for drug comparisons. The World Health Organisation's list of essential drugs, the national drug formulary and critically important antimicrobial drugs were assessed. Proportions and median (range) were used to represent categorical and numerical values. RESULTS: Four hundred and ninety-six critically ill patients were enrolled in the study, with 5,636 prescribed drugs used for 31,993 patient-days. Critically ill adults received significantly more drugs compared to children and the neonatal population (11 [8-16], 9 [6-17] and 5 [3-12] respectively). Critically ill neonates received significantly fewer of the drugs listed in the national formulary compared to older children and adults (94.1% [10.1], 92.4% [32.4] and 80.1% [20.4]). Critically ill neonates received fewer antimicrobials (82% compared to 91.3% in adults and 98% in children). Furthermore, critically ill adults received more broad-spectrum antimicrobials compared to neonates. Prolonged empirical antimicrobial use was observed more in critically ill children (52%) compared to adults (29.8%). A large majority of the antimicrobials were critically important for 87.7%, 83.9% and 86.5% of patients in the adult, paediatric and neonatal intensive care units. CONCLUSIONS: We observed significant differences in terms of drug classes predominantly used in various age groups of critically ill patients, particularly regarding the nature and type of antimicrobial drugs and the duration of antimicrobial therapy.

Possible effects of excipients used in the parenteral drugs administered in critically ill adults, children, and neonates.

BACKGROUND: Critically ill patients receiving parenteral drugs are at an increased risk of exposure to various excipients administered simultaneously and at increased amounts. Hence, we carried out the present study. RESEARCH DESIGN AND METHODS: Patients admitted in the adult, pediatric, and neonatal intensive care units were recruited following their consent. Details on their demographics, diagnoses, and drugs administered and the excipients were collected. RESULTS: Almost all the critically ill patients received drugs containing at least one excipient. Significant numbers of critically ill neonates received at least one of either known to be harmful or potentially harmful excipients. Critically ill neonates had significantly greater daily exposure of macrogol than children and adults; and benzyl alcohol (v/v) and propyl paraben compared to adults. Critically ill neonates and children had greater exposure to benzyl alcohol (w/v), methyl paraben, sodium metabisulfite than adults did. Benzyl alcohol exposure was likely to be several-fold high in critically ill patients. Exposures to benzyl alcohol and propylene glycol were possibly linked to increased risk of mortality particularly in neonates. CONCLUSION: Critically ill neonates and children are likely to receive a significantly greater quantity of harmful excipients than critically ill adults. Benzyl alcohol and propylene glycol exposure are likely to be associated with increased risk of mortality in critically ill.