Local anesthetics systemic toxicity in children: analysis of the French pharmacovigilance database.

PURPOSE: To characterize clinical profile of pediatric local anesthetic (LA) systemic toxicity (LAST) and to identify determinants of life-threatening outcomes. METHODS: Spontaneous reports notified to the French Pharmacovigilance Network were retrieved and followed by a case-by-case review, according to the following criteria: LA as suspected drug, age < 18 years, adverse drug reactions related to nervous system, cardiac, respiratory, psychiatric or general disorders. Multivariate logistic regression analysis was performed to identify factors leading to life-threatening reaction (i.e. continuous seizures or cardiorespiratory arrest). RESULTS: Among 512 cases retrieved, 64 LAST cases were included (neonates 11%, infants 30%, children 36%, adolescents 23%) mainly involving lidocaine (47%), lidocaine + prilocaine (22%) and ropivacaine (14%). Toxicity profiles were neurological (58%), cardiac (11%) or mixed (20%) and 7 patients (11%) developed methemoglobinemia. LAST was life-threatening for 23 patients (36%) and 2 patients died. Doses were above recommendations in 26 patients (41%) and were not different between life-threatening and non-life-threatening cases. The context of use (general and orthopedic surgery, p = 0.006) and the type of LA agent (lidocaine, p = 0.016) were independently associated with a life-threatening outcome. CONCLUSION: In this national retrospective analysis, LAST in children appear to be a rare event. Neurological and cardiac signs were the most frequently reported reactions. LAST in children can be life-threatening, even at therapeutic doses. Although a fatal outcome may anecdotally occur, the vast majority of patients recovered after appropriate medical care.

Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study.

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% fT> 4 × MIC and a trough concentration below the toxic concentration (50 mg.L-1 for cefotaxime, 150 mg.L-1 for piperacillin, and 44 mg.L-1 for meropenem). Between May 2019 and January 2020, 80 patients were included and received 106 antibiotic courses: 74 (70%) were administered in intermittent infusion (II) and 32 (30%) in continuous infusion (CI). Compared to II, CI provided more optimal PK exposure (n = 22/32, 69% for CI versus n = 35/74, 47% for II, OR 1.2, 95%CI 1.01-1.5, p = 0.04), less underexposure (n = 4/32, 13% for CI versus n = 36/74, 49% for II, OR 0.7, 95%CI 0.6-0.84, p < 0.001), and more overexposure (n = 6/32, 19% for CI versus n = 3/74, 4% for II, OR 1.2, 95%CI 1.03-1.3, p = 0.01). Five adverse events have been reported during the study period, although none has been attributed to beta-lactam treatment. CONCLUSION: CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion. WHAT IS KNOWN: • Since beta-lactams are time-dependent antibiotics, the probability to attain the pharmacokinetic target is higher with continuous infusion compared to that with intermittent infusion. • In daily practice, continuous or extended infusions are rarely used despite recent guidelines, and toxicity is hardly reported. WHAT IS NEW: • Continuous infusion provided a higher probability to attain an optimal pharmacokinetic target compared to intermittent infusion, but also a higher risk of overexposure. • Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.

Cefepime population pharmacokinetics and dosing regimen optimization in critically ill children with different renal function.

OBJECTIVE: Cefepime is commonly used in pediatric intensive care units, where unpredictable variations in the patients' pharmacokinetic (PK) variables may require drug dose adjustments. The objectives of the present study were to build a population PK model for cefepime in critically ill children and to optimize individual initial dosing regimens. METHODS: Children (aged from 1 month to 18 years; body weight >3 kg) receiving cefepime were included. Cefepime total plasma concentrations were measured using high performance liquid chromatography. Data were modelled using nonlinear, mixed-effect modeling software, and Monte Carlo simulations were performed with a PK target of 100% fT > MIC. RESULTS: Fifty-nine patients (median (range) age: 13.5 months (1.1 months to 17.6 years)) and 129 cefepime concentration measurements were included. The cefepime concentration data were best fitted by a one-compartment model. The selected covariates were body weight with allometric scaling and estimated glomerular filtration rate on clearance. Mean population values for clearance and volume were 1.21 L/h and 4.8 L, respectively. According to the simulations, a regimen of 100 mg/kg/d q12 h over 30 min or 100 mg/kg/d as a continuous infusion was more likely to achieve the PK target in patients with renal failure and in patients with normal or augmented renal clearance, respectively. DISCUSSION: Appropriate cefepime dosing regimens should take renal function into account. Continuous infusions are required in critically ill children with normal or augmented renal clearance, while intermittent infusions are adequate for children with acute renal failure. Close therapeutic drug monitoring is mandatory, given cefepime's narrow therapeutic window.