Clinical Pharmacology of Paracetamol in Neonates: A Review

Paracetamol is commonly used to control mild-to-moderate pain or to reduce opioid exposure as part of multimodal analgesia, and is the only compound recommended to treat fever in neonates. Paracetamol clearance is lower in neonates than in children and adults. After metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main metabolic conversions are conjugation with glucuronic acid and with sulphate. In the urine of neonates sulphated paracetamol concentration is higher than the glucuronidated paracetamol level, suggesting that sulfation prevails over glucuronidation in neonates. A loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours of intravenous paracetamol is suggested to achieve a compartment concentration of 11 mg/L in late preterm and term neonates. Aiming for the same target concentration, oral doses are similar with rectal administration of 25 to 30 mg/kg/d in preterm neonates of 30 weeks’ gestation, 45 mg/kg/d in preterm infants of 34 weeks’ gestation, and 60 mg/kg/d in term neonates are suggested. The above-mentioned paracetamol doses for these indications (pain, fever) are well tolerated in neonates, but do not result in a significant increase in liver enzymes, and do not affect blood pressure and have limited effects on heart rate. In contrast, the higher doses suggested in extreme preterm neonates to induce closure of the patent ductus arteriosus have not yet been sufficiently evaluated regarding efficacy or safety. Moreover, focussed pharmacovigilance to explore the potential causal association between paracetamol exposure during perinatal life and infancy and subsequent atopy is warranted

Tympanic, Infrared Skin, and Temporal Artery Scan Thermometers Compared with Rectal Measurement in Children: A Real-Life Assessment

Introduction: Body temperature measurement in children is of clinical relevance. Although rectal measurement is the gold standard, less invasive tools have become available. We aimed to describe the accuracy of tympanic, infrared skin, or temporal artery scan thermometers compared with rectal measurement to reflect core temperature. Methods: Rectal (Filac 3000; Covidien, Mechelen, Belgium), tympanic (AccuSystem Genius2 Typmanic Infrared Ear Thermometer, Covidien, Mechelen, Belgium), temporal artery scan (Exergen, Exergen Corp, Watertown, Massachusetts), and infrared (ThermoFlash Contactless Medical Electronic Thermometer, Visiomedlab, Paris, France) body temperature measurements were randomly performed and readings were collected once. Temperature readings were described as median and range, and observations were compared with rectal temperature readings (using Wilcoxon, Bland-Altman, sensitivity, and specificity tests). The child’s comfort was assessed by the child, parent, and nurse (using Likert scales) and ease of use was assessed by nurses (using visual analog scale). Results: Based on observations in 294 (median age = 3.2 years, range = 0.02–17 years) children, the mean difference was 0.49°C (tympanic scan; P < 0.0001), 0.34°C (infrared skin scan; P < 0.0001), and 0°C (temporal artery scan; P = 0.9288), respectively, when compared with rectal temperature readings. Based on visual inspection of Bland-Altman plots, all tools overestimated the temperature at lower body temperature and underestimated the temperature at higher body temperature, resulting in a sensitivity of 22% to 41% and a specificity of 98% to 100% for rectal temperatures above 38°C. The Likert scale scores and the visual analog scale scores for rectal measurement were only slightly higher when compared with the other methods. Conclusions: All noninvasive techniques underperformed compared with rectal measurement. The temporal artery scan deviations were smallest, but all noninvasive techniques overestimate lower temperatures and underestimate higher temperatures compared with rectal measurement. In our hands, temporal artery scan measurement seems to be second best, but not yet ideal

Prospective validation of neonatal vancomycin dosing regimens is urgently needed

Background: Although vancomycin is frequently used to treat neonatal late-onset sepsis, there is no consensus on the optimal dosing regimen. Because many neonates needed dosing adaptation due to suboptimal trough values, the vancomycin dosing regimen in our neonatal department was changed during 2012. Objective: We aimed to document the need for validation of neonatal vancomycin dosing by exploring serum trough levels achieved using 2 published dosing regimens (previous regimen: based on postmenstrual age and serum creatinine and new regimen: based on postmenstrual age and postnatal age) and to identify covariates associated with suboptimal vancomycin trough levels (<10 mg/L). Methods: Routine therapeutic drug monitoring serum trough levels quantified after initiation of intravenous vancomycin therapy and clinical covariates were retrospectively collected. Median vancomycin trough levels of both dosing regimens were compared using the Mann-Whitney U test. The influence of continuous and dichotomous covariates on achieving a suboptimal trough level was explored using the Van Elteren test (stratified Mann-Whitney U test) and Mantel-Haenszel test (stratified χ2 test), respectively. Covariates significant in monovariate analysis were subsequently included in a logistic regression analysis. Results: In total, 294 observations (median current weight 1870 g [range = 420–4863 g] and median postmenstrual age 35.07 weeks [range = 25.14–56.00 weeks]) were included. Using the previous and new dosing regimens, 66.3% and 76.2% of trough levels, respectively, were below 10 mg/L. Overall, suboptimal vancomycin trough values were significantly associated with lower weight (birth weight and current weight) and age (gestational age and postmenstrual age). Conclusions: The majority of vancomycin trough levels in neonates achieved using 2 published dosing regimens did not reach the target of 10 mg/L. This illustrates the urgent need for prospective validation of neonatal vancomycin dosing regimens. We anticipate that dosing regimens integrating covariates reflecting general physiological maturation and renal maturation, as well as disease characteristics, could improve vancomycin exposure in neonates