Anti-infective prescribing practices in critically ill children on continuous renal replacement therapy: a multicenter survey of French-speaking countries.

BACKGROUND: Use of continuous renal replacement therapy in children receiving anti-infective drugs may lead to inappropriate concentrations with risks related to treatment failure, toxicity and emergence of multidrug-resistant bacteria. We aimed to describe anti-infective prescribing practices in critically ill children undergoing continuous renal replacement therapy. METHODS: An online survey to assess continuous renal replacement therapy, anti-infective prescribing and therapeutic drug monitoring practices was sent by e-mail to physicians working in pediatric intensive care units through the French-speaking Group of Pediatric Intensive Care and Emergency medicine (GFRUP). RESULTS: From April 1st, 2021 to May 1st, 2021, 26/40 pediatric intensive care units participated in the survey, corresponding to a response rate of 65%. Twenty-one were located in France and five abroad. All pediatric intensive care units administered continuous renal replacement therapy, primarily with Prismaflex™ System. Anti-infective prescriptions were adjusted to the presence of continuous renal replacement therapy in 23 (88%) pediatric intensive care units mainly according to molecular weight in 6 (23%), molecule protein binding in 6 (23%) and elimination routes in 15 (58%) including residual diuresis in 9 (35%), to the continuous renal replacement therapy flow in 6 (23%) and to the modality of continuous renal replacement therapy used in 15 (58%), pediatric intensive care units. There was broad variability among pediatric intensive care units and among physicians within the same unit. Barriers to therapeutic drug monitoring were mainly an excessive delay in obtaining results in 11 (42%) and the lack of an on-site laboratory in 8 (31%) pediatric intensive care units. CONCLUSIONS: Our survey reported wide variability in anti-infective prescribing practices in children undergoing continuous renal replacement therapy, thus highlighting a gap in knowledge and the need for education and recommendations.

Low Dosing Norepinephrine Effects on Cerebral Oxygenation and Perfusion During Pediatric Shock.

Background: Cerebral hypoperfusion and impaired oxygen delivery during pediatric critical illness may result in acute neurologic injury with subsequent long-term effects on neurodevelopmental outcome. Yet, the impact of norepinephrine on cerebral hemodynamics is unknown in children with shock. We aimed to describe the norepinephrine effects on cerebral perfusion and oxygenation during pediatric shock. Patients and Methods: We conducted an observational multicentre prospective study in 3 French pediatric intensive care units. Children <18 years of age excluding traumatic brain injury were included in the study if they need norepinephrine for shock. Systemic and cerebral hemodynamics were compared between the time of initiation of norepinephrine (T0), and the steady-state (Tss). Cardiac output (CO) was measured using ultrasound. Cerebral perfusion was assessed on middle cerebral arteries (MCA) using transcranial doppler ultrasound. Cerebral tissue oxygen saturation (rScO2) was recorded using near infrared spectroscopy, and we calculated cerebral fractional tissue oxygen extraction (cFTOE = SpO2-rScO2/SpO2). Main Results: Fourteen children (median [IQR] age of 3.5[1; 13.5] years) were included. Norepinephrine at 0.2[0.1; 0.32] µg/kg/min significantly increased mean arterial blood pressure (61[56; 73] mmHg at Tss vs. 49[42;54] mmHg at T0, p=10-3) without change of CO. MCA velocities, pulsatility index, rScO2, and cFTOE did not significantly change between T0 and Tss. Some individuals observed variations in estimated CBF, which slightly improved in 7 patients, remained unchanged in 5, and was impaired in 2. No patient experienced significant variations of rScO2. Conclusions: Low-dosing norepinephrine, despite a homogeneous and significant increase in arterial blood pressure, had little effects on cerebral perfusion and oxygenation during pediatric shock. This reinforces the need for personalized tailored therapies in this population. Trial Registration: Clinicaltrials.gov, NCT03731104. Registered 6 November, 2018. https://clinicaltrials.gov/ct2/show/NCT03731104.

Prehospital capillary lactate in children differentiates epileptic seizure from febrile seizure, syncope, and psychogenic nonepileptic seizure.

PURPOSE: The aim of the study was to examine prehospital capillary lactate in children as a diagnostic biomarker to differentiate epileptic seizures from febrile seizures, syncope, and psychogenic nonepileptic seizures (PNES). METHODS: Capillary lactate concentrations taken in a pediatric prehospital setting within 2 h of the paroxysmal event were compared retrospectively between patients with epileptic seizure, febrile seizure, syncope, and PNES, based on the final diagnosis from the hospitalization report. RESULTS: One hundred and two patients were included, 53 (52%) with epileptic seizures, 41 (40%) with febrile seizures, and 8 (8%) with syncope or PNES. Capillary lactate in patients with a final diagnosis of epileptic seizure was significantly increased in comparison to the concentrations in patients with febrile seizure (p < 0.0007) and in comparison to the concentrations in patients with syncope or PNES (p < 0.0204). The area under the ROC-curve was 0.71 (95% CI 0.61-0.80). For a cutoff concentration of prehospital capillary lactate >3.9 mmol/l (Youden index), the sensitivity was 49% and the specificity 92%. CONCLUSION: Prehospital capillary lactate concentrations are a useful tool for differentiating the nature of a paroxysmal event in children.

Assessment of the Effects of a High Amikacin Dose on Plasma Peak Concentration in Critically Ill Children.

OBJECTIVES: This study aimed to assess the incidence of amikacin plasma peak concentration (Cmax) below 60 mg·L-1 in critically ill children receiving an amikacin dosing regimen of 30 mg kg-1·day-1. Secondary objectives were to identify factors associated with low Cmax and to assess the incidence of acute kidney injury (AKI). METHODS: A retrospective observational study was performed in two French pediatric intensive care units. All admitted children who received 30 mg·kg-1 amikacin and had a Cmax measurement were eligible. Clinical and biological data, amikacin dose, and concentrations were collected. RESULTS: In total, 30 patients were included, aged from 3 weeks to 7 years. They received a median amikacin dosage of 30 mg kg-1·day-1 (range 29-33) based on admission body weight (BW), corresponding to 27 mg kg-1·day-1 (range 24-30) based on actual BW. Cmax was < 60 mg·L-1 in 21 (70%) children and none had a Cmax ≥ 80 mg·L-1. Among the 15 patients with a measured minimum inhibitory concentration (MIC), 13 (87%) had a Cmax/MIC ratio > 8. Univariate analysis showed that factors associated with Cmax < 60 mg·L-1 were high estimated glomerular filtration rate (p = 0.015) and low blood urea concentration (p = 0.001). AKI progression or occurrence was observed after amikacin administration in two (7%) and six (21%) patients, respectively. CONCLUSIONS: Despite the administration of the maximal recommended amikacin dose, Cmax was below the pharmacokinetic target in 70% of our pediatric population. Further studies are needed to develop a pharmacokinetic model in a population of critically ill children to optimize target attainment.

A twelve-year neonatal and pediatric high-frequency oscillatory ventilation transport experience.

OBJECTIVE: To describe the evolution over a 12-year period of a pediatric intensive care unit transport team's (PICU-TT) experience of pediatric and neonatal interhospital transportation on high-frequency oscillation ventilation (HFOV). METHODS: This was a monocentric retrospective observational study from January 2006 to December 2017. All patients aged under 18 years old who were transported on HFOV by the Robert Debré Hospital PICU-TT were included. RESULTS: Over a 12-year period, 125 patients were transported on HFOV, including 107 newborns and 18 children. Median (range) age and weight were 9 days (1 h-9 years) and 3.3 (0.6-39) kg, respectively. Initial median oxygenation index, SpO2 /FiO2 ratio and mean airway pressure were 32, 91, and 18 cmH2 O, respectively, without significant difference between values before and after transport. Adverse events occurred during 28 transportations (22%) including three recovered cardiac arrests and one death. Overall survival rate at discharge was 74%, 78% in neonates and 56% in pediatrics, respectively. HFOV transportation rate increased over the last four years of the study for neonates and remained stable for older children. Extra-corporeal membrane oxygenation (ECMO) initiation rate on arrival decreased and survival rate increased significantly during the last four years of the study (p < .05). CONCLUSION: This study showed the feasibility of HFOV transportation by a PICU-TT, despite some challenges. A trend towards using ECMO more than HFOV for the most severe respiratory and/or circulatory failures was seen over the 12-year period. The HFOV transportation rate has increased for less severe neonatal patients.

Mobile Extracorporeal Membrane Oxygenation: 5-Year Experience of a French Pediatric and Neonatal Center.

OBJECTIVES: Extracorporeal membrane oxygenation is an established therapy for refractory cardiac and/or pulmonary failure that is not available in all centers. When infants and children require extracorporeal membrane oxygenation, they are sometimes placed on extracorporeal membrane oxygenation support in peripheral centers where extracorporeal membrane oxygenation is not available and then transferred on extracorporeal membrane oxygenation to specialized centers. The objective of this study is to first describe one of the largest cohorts of infants and children transported by a mobile unit while on extracorporeal membrane oxygenation. DESIGN: We undertook a single-center retrospective study that included patients transported while on extracorporeal membrane oxygenation between November 1, 2014, and May 31, 2019. PATIENTS: All patients transported by our mobile extracorporeal membrane oxygenation unit during the study period were included. Computerized data collection was approved by the French Data Protection Authority (Commission nationale de l'informatique et des libertés n° 2121127V0). MAIN RESULTS: Over the study period, our extracorporeal membrane oxygenation mobile team transported 80 patients on extracorporeal membrane oxygenation among which 20 were newborns (25%) and 60 were children of 1 month to 17 years old (75%); 57 patients were on venoarterial-extracorporeal membrane oxygenation (71%) and 23 on venovenous-extracorporeal membrane oxygenation (29%). The average duration of transport was 8.4 hours with a median of 8 hours; the average distance travelled was 189 ± 140 km. Transport was by air and then ground for 50% of the patients and by ground for 42%. We observed a significant decrease in the Vasoactive-Inotropic Score (125 vs 99; p = 0.005) and PaCO2 levels (67 vs 49 mm Hg; p = 0.0005) after arrival in our unit. Survival rate 6 months after PICU discharge was 46% (37). There was a statistically significant relationship between initial lactate level and mortality (p = 0.02). We observed minor adverse events in 39% of the transports and had no mortality during transport. CONCLUSIONS: We describe one of the largest cohorts of infants and children transported by a mobile unit while on extracorporeal membrane oxygenation. Our findings confirm that it is safe to start extracorporeal membrane oxygenation in a referring center and to transport patients using an extracorporeal membrane oxygenation mobile team. The only risk factor associated with higher mortality was an initially elevated lactate level.

ShiF acts as an auxiliary factor of aerobactin secretion in meningitis Escherichia coli strain S88.

BACKGROUND: The neonatal meningitis E. coli (NMEC) strain S88 carries a ColV plasmid named pS88 which is involved in meningeal virulence. Transcriptional analysis of pS88 in human serum revealed a strong upregulation of an ORF of unknown function: shiF, which is adjacent to the operon encoding the siderophore aerobactin. The aim of this work is to investigate the role of shiF in aerobactin production in strain S88. RESULTS: Study of the prevalence of shiF and aerobactin operon in a collection of 100 extra-intestinal pathogenic E. coli strains (ExPEC) and 50 whole genome-sequenced E. coli strains revealed the colocalization of these two genes for 98% of the aerobactin positive strains. We used Datsenko and Wanner's method to delete shiF in two S88 mutants. A cross-feeding assay showed that these mutants were able to excrete aerobactin meaning that shiF is dispensable for aerobactin excretion. Our growth assays revealed that the shiF-deleted mutants grew significantly slower than the wild-type strain S88 in iron-depleted medium with a decrease of maximum growth rates of 23 and 28% (p < 0.05). Using Liquid Chromatography-Mass Spectrometry, we identified and quantified siderophores in the supernatants of S88 and its shiF deleted mutants after growth in iron-depleted medium and found that these mutants secreted significantly less aerobactin than S88 (- 52% and - 49%, p < 0.001). CONCLUSIONS: ShiF is physically and functionally linked to aerobactin. It provides an advantage to E. coli S88 under iron-limiting conditions by increasing aerobactin secretion and may thus act as an auxiliary virulence factor.

Early Bayesian Dose Adjustment of Vancomycin Continuous Infusion in Children: a Randomized Controlled Trial.

Methicillin-resistant staphylococcal infections are a global burden. Area under the serum concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio is the pharmacokinetic (PK) parameter that best predicts vancomycin efficacy. Its therapeutic range is narrow, difficult to achieve because of a wide intersubject variability, especially in children, and is not routinely targeted since the AUC is rarely available. We investigated if an early Bayesian dose adjustment would increase the rate of vancomycin target attainment, in the first 24 hours of treatment (H24), in children.We conducted a single-centre randomized controlled trial in 4 pediatric departments of Necker-Enfants Malades hospital (Paris, France). Patients aged 3 months to 17 years for whom intravenous vancomycin was started were eligible and randomized in a 1:1 ratio: routine care were compared with an early vancomycin therapeutic drug monitoring (3h after treatment initiation) followed by an early Bayesian dose adjustment using a previously published population-based PK model that included age, bodyweight and serum creatinine as covariates. The primary outcome was the proportion of patients of each group achieving vancomycin therapeutic range at H24, defined by AUC0-24/MIC≥400 and AUC0-24 ≤800mg-h/L.Ninety-nine patients were enrolled: 49 were randomized to the Bayesian group and 50 to the control group. Modified intention-to-treat analysis included 82 patients: 85% of Bayesian group patients achieved H24 vancomycin target versus 57% of control group patients (p=0.007) with no difference regarding iatrogenic events. Early Bayesian dose adjustment increased the proportion of children achieving vancomycin target at H24, which may improve clinical outcomes of methicillin-resistant staphylococcal infections.

Successful extracorporeal membrane oxygenation transport of a 4-month-old brain-dead infant for organ donation: A case report.

A 4-month-old infant was declared brain-dead 2 days after being initiated on venoarterial ECMO for a refractory septic shock. All brain death diagnostic criteria were fulfilled according to French law, and parental consent was given for organ donation. The hospital where ECMO was initiated had no authorization for organ procurement, and the donor was then transferred to the local referral center for child organ recovery with our mobile ECMO team to maintain organ perfusion. The kidneys were recovered and successfully transplanted to a child who is now well and alive. Although the transport elements of this case report are of limited relevance to an international audience as no other country, to our knowledge, has this particular organization, it does show excellent collaboration between teams to realize the goal of organ donation for this family. This is the first case describing a successful inter-hospital transport for organ procurement of a brain-dead infant on ECMO. Brain-dead pediatric patients undergoing ECMO can be considered as potential organ donors to expand the donor pool.

Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance.

BACKGROUND: Critically ill children frequently display observed alterations of pharmacokinetic (PK) parameters, leading to a reduction in ß-lactam concentrations. This study aimed to develop a PK population model for piperacillin in order to optimize individual dosing regimens. METHODS: All children aged ≤ 18 years, weighing more than 2.5 kg, and receiving piperacillin infusions were included in this study. Piperacillin was quantified by high-performance liquid chromatography, and PK were described using the non-linear mixed-effect modeling software MONOLIX. Monte Carlo simulations were used to optimize dosing regimens in order to attain two PK targets: 50% fT>MIC and 100% fT>MIC. RESULTS: We included 50 children with a median (range) postnatal age of 2.3 years (0.1-18), body weight (BW) of 11.9 kg (2.7-50), Pediatric Logistic Organ Dysfunction-2 (PELOD-2) severity score of 4 (0-16), and estimated glomerular filtration rate (eGFR) of 142 mL.min-1.1.73 m-2 (29-675). A one-compartment model with first-order elimination adequately described the data. Median (range) values for piperacillin clearance (CL) and volume of distribution were 3 L.h-1 (0.71-10) and 0.33 L.kg-1 (0.21-0.86), respectively. BW was integrated with the allometric relationship. eGFR and PELOD-2 severity score were the covariates explaining between-subject variability in CL and volume, respectively. According to the simulations, extended and continuous infusion provided the highest probability of reaching the target of 50% fT>MIC and 100% fT>MIC for normal and augmented renal clearance, respectively. CONCLUSIONS: Unlike standard intermittent piperacillin dosing regimens, extended and continuous infusion allows the PK targets to be reached, for children with normal or augmented renal clearance. TRIAL REGISTRATION NUMBER: Registered at http://www.clinicaltrials.gov (NCT02539407).

A multicenter randomized controlled trial of a 3-L/kg/min versus 2-L/kg/min high-flow nasal cannula flow rate in young infants with severe viral bronchiolitis (TRAMONTANE 2).

PURPOSE: High-flow nasal cannula (HFNC) therapy is increasingly proposed as first-line respiratory support for infants with acute viral bronchiolitis (AVB). Most teams use 2 L/kg/min, but no study compared different flow rates in this setting. We hypothesized that 3 L/kg/min would be more efficient for the initial management of these patients. METHODS: A randomized controlled trial was performed in 16 pediatric intensive care units (PICUs) to compare these two flow rates in infants up to 6 months old with moderate to severe AVB and treated with HFNC. The primary endpoint was the percentage of failure within 48 h of randomization, using prespecified criteria of worsening respiratory distress and discomfort. RESULTS: From November 2016 to March 2017, 142 infants were allocated to the 2-L/kg/min (2L) flow rate and 144 to the 3-L/kg/min (3L) flow rate. Failure rate was comparable between groups: 38.7% (2L) vs. 38.9% (3L; p = 0.98). Worsening respiratory distress was the most common cause of failure in both groups: 49% (2L) vs. 39% (3L; p = 0.45). In the 3L group, discomfort was more frequent (43% vs. 16%, p = 0.002) and PICU stays were longer (6.4 vs. 5.3 days, p = 0.048). The intubation rates [2.8% (2L) vs. 6.9% (3L), p = 0.17] and durations of invasive [0.2 (2L) vs. 0.5 (3L) days, p = 0.10] and noninvasive [1.4 (2L) vs. 1.6 (3L) days, p = 0.97] ventilation were comparable. No patient had air leak syndrome or died. CONCLUSION: In young infants with AVB supported with HFNC, 3 L/kg/min did not reduce the risk of failure compared with 2 L/kg/min. This clinical trial was recorded on the National Library of Medicine registry (NCT02824744).

Achievement of Therapeutic Vancomycin Exposure With Continuous Infusion in Critically Ill Children.

OBJECTIVE: Describe and assess a continuous infusion dosing scheme of vancomycin therapy in critically ill children. DESIGN: Retrospective single-center study, January to June 2015. SETTING: PICU located within a French tertiary academic pediatric hospital. PATIENTS: All children admitted in the PICU from January 2015 to June 2015, receiving continuous infusion of vancomycin therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and biological data, vancomycin dosing information, and plasma concentrations were recorded. Using a previously published population pharmacokinetics model, pharmacokinetic parameters were derived for each patient and vancomycin concentrations described after the loading dose. Areas under the curve were estimated for each patient, and an initial covariate-adjusted dose was calculated for every patient. A total of 87 vancomycin concentrations were analyzed from 28 patients between 1 month and 17 years old. The median (range) loading dose was 14.8 (12-16) mg/kg followed by a continuous infusion of vancomycin of 44 (35-61) mg/kg/d. On their first sample, 12 patients (43%) had a concentration between 15 and 30 mg/L. On day 1, the median (range) estimated area under the curve was 349 (201-1,001) mg/L × hr, and seven patients (25%) had an area under the curve greater than 400 mg/L × hr. Using the pharmacokinetics model, the median (range) calculated initial daily dose, taking into account age, bodyweight, and serum creatinine concentration, was 53 (36-69) mg/kg/d resulting in a simulated day 1 area under the curve of 409 (341-593) mg/L × h with a theoretical pharmacokinetic target attainment of 57%. CONCLUSIONS: The current continuous infusion of vancomycin dosing scheme used in our population was inappropriate and led to underexposure. Using pharmacokinetic approaches such as covariate-adjusted initial dosing and Bayesian estimation of exposure should prove useful for achieving the pharmacokinetic target.

Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children.

BACKGROUND: During sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels. OBJECTIVE: The aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children. METHODS: All children aged < 18 years, weighing more than 2.5 kg, and receiving intermittent cefotaxime infusions were included in this study. Cefotaxime and desacetylcefotaxime were quantified by high-performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed-effect modeling software MONOLIX, and Monte Carlo simulations were used to optimize dosing regimen in order to maintain serum concentrations above the target concentration (defined at 2 mg·L-1) throughout the dosing interval. RESULTS: We included 49 children with a median (range) postnatal age of 23.7 (0.2-229) months, and median body weight (range) of 10.9 (2.5-68) kg. A one-compartment model with first-order elimination adequately described the data. Median (range) values for cefotaxime clearance, desacetylcefotaxime clearance, and volume of distribution were 0.97 (0.3-7.1) L·h-1, 3.2 (0.6-16.3) L·h-1, and 0.3 (0.2-0.41) L·kg-1, respectively. Body weight and postnatal age were statistically significant covariates. Cefotaxime-calculated residual concentrations were low, and no patient succeeded in attaining the target. Unlike intermittent administration, a dosing regimen of 100 mg·kg-1·day-1 administered by continuous infusion provided a probability of target attainment of 100%, regardless of age and weight. CONCLUSIONS: Standard intermittent cefotaxime dosing regimens in critically ill children are not adequate to reach the target. We showed that, for the same daily dose, continuous infusion was the only administration that enabled the target to be attained, for children over 1 month of age. As continuous administration is achievable in the pediatric intensive care unit, it should be considered for clinical practice. TRIAL REGISTRATION NUMBER: Registered at http://www.clinicaltrials.gov , NCT02539407.

Fluoroquinolones in pediatrics: review of hospital prescription use over 2 years.

OBJECTIVE: Numerous studies have shown that the tolerance of children to fluoroquinolones (FQs) is satisfactory, and some indications have been recently agreed upon. However, vigilance is required when prescribing FQ to children. The aim of our study was to describe the prescription of FQs to children hospitalized in our hospital. MATERIALS AND METHODS: This is a chart retrospective observational study at the Robert-Debré teaching Hospital between January 2009 and December 2010. Data was collected about patients (name, sex, weight, age) and prescribed treatments (indication, international nonproprietary names, dose, number of doses per day, administration route). Quality of collected data was assessed by analyzing the clinical files of 32 randomly selected patients. RESULTS: We analyzed data for 397 patients (3 days - 18 years old and 640 g - 115 kg). Ciprofloxacin was prescribed for 382 patients (96%), ofloxacin for 10 patients (3%), and levofloxacin for 5 patients (1%). Febrile neutropenia was the most common indication (108 patients, i.e., 27%), followed by inflammatory bowel disease (50 patients, 13%). Doses conformed to recommendations for 88% of the patients. Analysis of the 32 cases indicated an overall compliance percentage of 94.4%. CONCLUSION: This is the first study to collect so much data on FQ prescriptions for hospitalized children. Use in practice went beyond the licensed indication. Doses were consistent with those for recommended indications.