Prescriptions of anti-reflux drugs in neonatology and neonatal intensive care units: A large multicentre observational study (2014-2022).

AIMS: Gastro-oesophageal reflux is common in newborns, especially in premature infants. Treatment by medication is controversial as the drugs prescribed have not been consistently proven to be effective and are known to have adverse effects. This study sought to identify trends in the prescription of anti-reflux medication in a large group of French neonatal units. METHODS: Data on prescriptions of anti-reflux treatments-proton pump inhibitors (PPIs), antacids, histamine-2 receptor antagonists (H2RAs), and prokinetics-from 2014 to 2022 for infants with a corrected gestational age <45 weeks, were extracted from a prescription database (Logipren®) used by 63 French neonatal units, and then analysed. RESULTS: Of all infants recorded in the database during the study period (n = 152 743), 10.2% (n = 15 650) were prescribed anti-reflux medication (95% confidence interval [CI] 10.0-10.4%), mainly as monotherapy (77.5%). The rate was higher in the subgroup of preterm infants born before 28 weeks of gestation (n = 9493) (20.6%, 95% CI 19.8-21.4%; n = 1956). PPIs were the most commonly prescribed anti-reflux medications (6.9% of infants, 95% CI 6.8-7.0), followed by antacids (5.2%, 95% CI 5.1-5.3%), while H2RAs and prokinetics were rarely prescribed. Over the period, the prescription rate remained stable for PPIs, decreased for H2RAs (τ = -0.86, P = .02), and, among preterm infants born at gestational ages of 28-31 or 32-36 weeks, increased for antacids. CONCLUSIONS: Anti-reflux medications were frequently prescribed by neonatal units, especially for extremely premature infants. Most of these prescriptions were for PPIs and antacids.

Neurodevelopmental Outcomes after Premedication with Atropine/Propofol vs Atropine/Atracurium/Sufentanil for Neonatal Intubation: 2-Year Follow-Up of a Randomized Clinical Trial.

This study followed 173 newborn infants in the PREmedication Trial for Tracheal Intubation of the NEOnate multicenter, double-blind, randomized controlled trial of atropine-propofol vs atropine-atracurium-sufentanil for premedication before nonemergency intubation. At 2 years of corrected age, there was no significant difference between the groups in death or risk of neurodevelopmental delay assessed with the Ages and Stages Questionnaire. Trial registration Clinicaltrials.gov: NCT01490580.

Respiratory outcomes and survival after unplanned extubation in the NICU: a prospective cohort study from the SEPREVEN trial.

OBJECTIVE: To compare reintubation rates after planned extubation and unplanned extubation (UE) in patients in neonatal intensive care units (NICUs), to analyse risk factors for reintubation after UE and to compare outcomes in patients with and without UE. DESIGN: Prospective, observational study nested in a randomised controlled trial (SEPREVEN/Study on Epidemiology and PRevention of adverse EVEnts in Neonates). Outcomes were expected to be independent of the intervention tested. SETTING: 12 NICUs in France with a 20-month follow-up, starting November 2015. PATIENTS: n=2280 patients with a NICU stay >2 days, postmenstrual age ≤42 weeks on admission. INTERVENTIONS/EXPOSURE: Characteristics of UE (context, timing, sedative administration in the preceding 6 hours, weaning from ventilation at time of UE) and patients. MAIN OUTCOME MEASURES: Healthcare professional-reported UE rates, reintubation/timing after extubation, duration of mechanical ventilation, mortality and bronchopulmonary dysplasia (BPD). RESULTS: There were 162 episodes of UE (139 patients, median gestational age (IQR) 27.3 (25.6-31.7) weeks). Cumulative reintubation rates within 24 hours and 7 days of UE were, respectively, 50.0% and 57.5%, compared with 5.5% and 12.3% after a planned extubation. Independent risk factors for reintubation within 7 days included absence of weaning at the time of UE (HR, 95% CI) and sedatives in the preceding 6 hours (HR 1.93, 95% CI 1.04 to 3.60). Mortality at discharge did not differ between patients with planned extubation or UE. UE was associated with a higher risk of BPD. CONCLUSION: In the SEPREVEN trial, reintubation followed UE in 58% of the cases, compared with 12% after planned extubation. TRIAL REGISTRATION NUMBER: NCT02598609.

Pulmonary function using impulse oscillometry system and clinical outcomes at age 4 years in children born extremely preterm with or without bronchopulmonary dysplasia.

This study aimed to describe the early assessment of lung function and respiratory morbidity in children born extremely preterm with or without bronchopulmonary dysplasia (BPD). METHODS: This was a prospective study including all the children born at gestational age ≤28 weeks who received treatment in the NICU of the Centre Intercommunal de Créteil in France, from January 2006 to March 2012. Lung function, using the impulse oscillometry system, respiratory morbidity and growth were assessed at age 4 years. Lung function and clinical course of children were compared in children with and without BPD. RESULTS: We included 136 extremely premature children; 26 (19 %) had BPD. Children with and without BPD did not significantly differ in resistance measurements at 5 Hz (R5) and 20 Hz (R20) and reactance (X5) measurements at age 4 years. A total of 104 (76 %) pre-term children had respiratory resistance R5 above the 95th percentile for the reference population (z-score >1.64), regardless of BPD status. The mean (SD) R5 z-score for all children was 2.1 (±0.7), whereas the mean (SD) R20 was in the normal range (z-score = 1.1 [±0.3]). After treatment with bronchodilators, all children showed no significant change in resistance. The prevalence of asthma symptoms at age 4 years was common and estimated at 30 % regardless of BPD status. CONCLUSION: Early assessment of lung function by the impulse oscillometry system revealed that most preschool children who were born extremely preterm had abnormal total airway resistance regardless of BPD status. The system is an essential tool for the early assessment of children born prematurely.

Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach.

BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. OBJECTIVE: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation. METHODS: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. RESULTS: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. CONCLUSIONS: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04459117.

Definitions and implications of the pharmacokinetic-pharmacodynamic parameters of antibiotics in pediatric clinical practice.

Knowledge of infectious diseases and their treatments is constantly evolving. New infectious agents are regularly discovered, mainly due to improvement of identification techniques, especially the development of molecular biology and mass spectrometry. While changes in the epidemiology of infectious diseases are not always predictable or readily understood, several factors regularly enter into consideration, such as not only the natural history of diseases, the impact of vaccinations, but also the excessive and irrational use of antibiotics. Antibiotic resistance is now recognized as one of the major challenges for humanity, especially since few new molecules have been put on the market in recent years. These molecules are reserved for serious infections caused by bacteria resistant to other antibiotics and should only be prescribed by infectious diseases specialists trained in their use. Rationalization of antibiotic therapy is therefore one of the keys to reducing antibiotic resistance and the spread of resistant bacteria. In this guide, for each clinical situation, the bacterial target(s) of antibiotic treatment, the preferred antibiotic choice, and the therapeutic alternatives will be specified. Comments on the diagnosis and treatment of the infection will be added if necessary.

Neonatal bacterial infections: Diagnosis, bacterial epidemiology and antibiotic treatment.

Severe bacterial infections have a higher incidence in the neonatal period than at any other pediatric age. Incidence is even higher in premature babies than in term newborns, and severity is increased in the absence of early diagnosis and treatment. By contrast, clinical signs are nonspecific and sometimes trivial, and biomarkers perform poorly during the first 24 hours of infection. For decades, this has led to having too many children treated for extended periods with broad-spectrum antibiotics. Today, the challenge is to prescribe antibiotics in a targeted way, by identifying truly infected newborns. Over the last ten years, major paradigm shifts have occurred and should be taken into account, as a result of growing awareness of the ecological impact of early antibiotic therapy, notably antibiotic resistance, by choosing the narrowest spectrum antibiotic and stopping antibiotic therapy as soon as the diagnosis of infection has been reasonably ruled out. Among the biological tests, the most important are blood cultures. At least one blood culture, taken under aseptic conditions, of sufficient volume (1 to 2 mL), and using pediatric bottles must be taken as soon as the decision to treat has been made, before starting any antibiotic therapy. The bacteria responsible for early-onset bacterial neonatal infections (EBNI) have not changed significantly over recent years and remain dominated by Group B Streptococcus and Escherichia coli, which are the main targets of treatment. GBS is largely predominant in full-term infants, but the proportion of infections due to E. coli increases with prematurity.

Instrumental dead space: A glass ceiling for extremely low birth weight preterm infants? A dead space washout bench study.

BACKGROUND: When ventilating extremely low birth weight infants, clinicians face the problem of instrumental dead space, which is often larger than tidal volume. Hence, aggressive ventilation is necessary to achieve CO2 removal. Continuous tracheal gas insufflation can wash out CO2 from dead space and might also have an impact on O2 and water vapor transport. The objective of this bench study is to test the impact of instrumental dead space on the transport of CO2 , O2 , and water vapor and the ability of continuous tracheal gas insufflation to remedy this problem during small tidal volume ventilation. METHODS: A test-lung located in an incubator at 37°C was ventilated with pressure levels needed to reach different tidal volumes from 1.5 to 5 mL. End-tidal CO2 at the test-lung exit, O2 concentration, and relative humidity in the test-lung were measured for each tidal volume with and without a 0.2 L/min continuous tracheal gas insufflation flow. RESULTS: CO2 clearance was improved by continuous tracheal gas insufflation allowing a 28%-44% of tidal volume reduction. With continuous tracheal gas insufflation, time to reach desired O2 concentration was reduced from 20% to 80% and relative humidity was restored. These results are inversely related to tidal volume and are particularly critical below 3 mL. CONCLUSION: For the smallest tidal volumes, reduction of instrumental dead space seems mandatory for CO2 , O2 , and water vapor transfer. Continuous tracheal gas insufflation improved CO2 clearance, time to reach desired O2 concentration and humidification of airways and, thus, may be an option to protect lung development.

Humidity during high-frequency oscillatory ventilation compared to intermittent positive pressure ventilation in extremely preterm neonates: An in vitro and in vivo observational study.

BACKGROUND: Inappropriate humidification of inspired gas during mechanical ventilation can impair lung development in extremely low birthweight (ELBW) infants. Humidification depends on multiple factors, such as the heater-humidifier device used, type of ventilation, and environmental factors. Few studies have examined inspired gas humidification in these infants, especially during high-frequency oscillatory ventilation (HFOV). Our objective was to compare humidity during HFOV and intermittent positive pressure ventilation (IPPV), in vitro and in vivo. METHODS: In vitro and in vivo studies used the same ventilator during both HFOV and IPPV. The bench study used a neonatal test lung and two heater-humidifiers with their specific circuits; the in vivo study prospectively included preterm infants born before 28 weeks of gestation. RESULTS: On bench testing, mean absolute (AH) and relative (RH) humidity values were significantly lower during HFOV than IPPV (RH = 79.4 ± 8.1% vs. 89.0 ± 6.2%, p < 0.001). Regardless of the ventilatory mode, mean RH significantly differed between the two heater-humidifiers (89.6 ± 6.7% vs 78.7 ± 6.8%, p = 0.003). The in vivo study included 10 neonates (mean ± SD gestational age: 25.7 ± 0.9 weeks and birthweight: 624.4 ± 96.1 g). Mean RH during HFOV was significantly lower than during IPPV (74.6 ± 5.7% vs. 83.0 ± 6.7%, p = 0.004). CONCLUSION: RH was significantly lower during HFOV than IPPV, both in vitro and in vivo. The type of heater-humidifier also influenced humidification. More systematic measurements of humidity of inspired gas, especially during HFOV, should be considered to optimize humidification and consequently lung protection in ELBW infants.

Determinants of morbidity and mortality related to health care-associated primary bloodstream infections in neonatal intensive care units: a prospective cohort study from the SEPREVEN trial.

Background: Health care-associated primary bloodstream infections (BSIs), defined as not secondary to an infection at another body site, including central line-associated BSI, are a leading cause of morbidity and mortality in patients in neonatal intensive care units (NICUs). Our objective was to identify factors associated with severe morbidity and mortality after these infections in neonates in NICUs. Methods: This ancillary study of the SEPREVEN trial included neonates hospitalized ≥2 days in one of 12 French NICUs and with ≥ 1 BSI during the 20-month study period. BSIs (all primary and health care-associated) were diagnosed in infants with symptoms suggestive of infection and classified prospectively as possible (one coagulase-negative staphylococci (CoNS)-growing blood culture) or proven (two same CoNS, or ≥1 recognized pathogen-growing blood culture). BSI consequences were collected prospectively as moderate morbidity (antibiotic treatment alone) or severe morbidity/mortality (life-saving procedure, permanent damage, prolonged hospitalization, and/or death). Results: Of 557 BSIs identified in 494 patients, CoNS accounted for 378/557 (67.8%) and recognized bacterial or fungal pathogens for 179/557 (32.1%). Severe morbidity/mortality was reported in 148/557 (26.6%) BSIs. Independent factors associated with severe morbidity/mortality were corrected gestational age <28 weeks (CGA) at infection (P < .01), fetal growth restriction (FGR) (P = .04), and proven pathogen-related BSI vs. CoNS-related BSI (P < .01). There were no differences in severe morbidity and mortality between proven and possible CoNS BSIs. In possible BSI, S. epidermidis was associated with a lower risk of severe morbidity than other CoNS (P < .01), notably S. capitis and S. haemolyticus. Conclusions: In BSIs in the NICU, severe morbidity/mortality was associated with low CGA at infection, FGR, and proven pathogen-related BSIs. When only one blood culture was positive, severe morbidity/mortality were less frequent if it grew with S. epidermidis compared to other CoNS. Further studies to help distinguish real CoNS BSIs from contaminations are needed. Study registration: ClinicalTrials.gov (NCT02598609).

Frequencies, Modalities, Doses and Duration of Computerized Prescriptions for Sedative, Analgesic, Anesthetic and Paralytic Drugs in Neonates Requiring Intensive Care: A Prospective Pharmacoepidemiologic Cohort Study in 30 French NICUs From 2014 to 2020.

Objectives: No consensus exists about the doses of analgesics, sedatives, anesthetics, and paralytics used in critically ill neonates. Large-scale, detailed pharmacoepidemiologic studies of prescription practices are a prerequisite to future research. This study aimed to describe the detailed prescriptions of these drug classes in neonates hospitalized in neonatal intensive care units (NICU) from computerized prescription records and to compare prescriptions by gestational age. Materials and Methods: We included all neonates requiring intensive care in 30 French level III units from 2014 through 2020 with a computerized prescription for an analgesic, sedative, anesthetic, or paralytic agent. We described frequencies of prescription, methods of administration, concomitant drug prescriptions, and dosing regimen, and compared them across gestational ages. Results: Among 65,555 neonates, 29,340 (44.8%) were prescribed at least one analgesic (acetaminophen in 37.2% and opioids in 17.8%), sedative (9.8%), anesthetic (8.5%), and/or paralytic agent (1%). Among preterm infants born before 28 weeks, 3,771/4,283 (88.0%) were prescribed at least one of these agents: 69.7% opioids, 41.2% sedatives, 32.5% anesthetics, and 5.8% paralytics. The most frequently prescribed agents were sufentanil (in 10.3% of neonates) and morphine (in 8.0% of neonates) for opioids, midazolam (9.3%) for sedatives, ketamine (5.7%) and propofol (3.3%) for anesthetics. In most neonates, opioids and sedatives were prescribed as continuous infusion, whereas anesthetics were prescribed as single doses. Opioids, sedatives and paralytics were mostly prescribed in association with another agent. Doses varied significantly by gestational age but within a limited range. Gestational age was inversely related to the frequency, cumulative dose and duration of prescriptions. For example, morphine prescriptions showed median (IQR) cumulative doses of 2601 (848-6750) vs. 934 (434-2679) µg/kg and median (IQR) durations of 7 (3-15) vs. 3 (2-5) days in infants born <28 vs. ≥ 37 weeks of gestation, respectively (p-value<0.001). Conclusion: The prescriptions of analgesic, sedative, anesthetic, or paralytic agent were frequent and often combined in the NICU. Lower gestational age was associated with higher frequencies, longer durations and higher cumulative doses of these prescriptions. Dose-finding studies to determine individualized dosing regimens and studies on long-term neurodevelopmental outcome according to received cumulative doses are required.

Patient-Ventilator Synchrony in Extremely Premature Neonates during Non-Invasive Neurally Adjusted Ventilatory Assist or Synchronized Intermittent Positive Airway Pressure: A Randomized Crossover Pilot Trial.

INTRODUCTION: Synchronization of non-invasive ventilation is challenging in extremely premature infants. We compared patient-ventilator synchrony between non-invasive neurally adjusted ventilatory assist (NIV-NAVA) using transdiaphragmatic (Edi) catheter and synchronized intermittent positive airway pressure (SiPAP) using an abdominal trigger. METHODS: This study was a monocentric, randomized, crossover trial in premature infants born before 28 weeks of gestation, aged 3 days or more, and below 32 weeks postmenstrual age. NIV-NAVA and SiPAP were applied in a random order for 2 h with analysis of data from the second hour. The primary outcome was the asynchrony index. RESULTS: Fourteen patients were included (median [IQR] gestational age at birth 25.6 (25.3-26.4) weeks, median [IQR] birth weight 755 [680-824] g, median [IQR] postnatal age 26.5 [19.8-33.8] days). The median (IQR) asynchrony index was significantly lower in NIV-NAVA versus SiPAP (49.9% [44.1-52.6] vs. 85.8% [74.2-90.9], p < 0.001). Ineffective efforts and auto-triggering were significantly less frequent in NIV-NAVA versus SiPAP (3.0% vs. 32.0% p < 0.001 and 10.0% vs. 26.6%, p = 0.004, respectively). Double triggering was significantly less frequent in SiPAP versus NIV-NAVA (0.0% vs. 9.0%, p < 0.001). No significant difference was observed for premature cycling and late cycling. Peak Edi and swing Edi were significantly lower in NIV-NAVA as compared to SiPAP (7.7 [6.1-9.9] vs. 11.0 [6.7-14.5] µV, p = 0.006; 5.4 [4.2-7.6] vs. 7.6 [4.3-10.8] µV, p = 0.007, respectively). No significant difference was observed between NIV-NAVA and SiPAP for heart rate, respiratory rate, COMFORTneo scores, apnoea, desaturations, or bradycardias. DISCUSSION/CONCLUSION: NIV-NAVA markedly improves patient-ventilator synchrony as compared to SiPAP in extremely premature infants.

Premedication before laryngoscopy in neonates: Evidence-based statement from the French society of neonatology (SFN).

Context: Laryngoscopy is frequently required in neonatal intensive care. Awake laryngoscopy has deleterious effects but practice remains heterogeneous regarding premedication use. The goal of this statement was to provide evidence-based good practice guidance for clinicians regarding premedication before tracheal intubation, less invasive surfactant administration (LISA) and laryngeal mask insertion in neonates. Methods: A group of experts brought together by the French Society of Neonatology (SFN) addressed 4 fields related to premedication before upper airway access in neonates: (1) tracheal intubation; (2) less invasive surfactant administration; (3) laryngeal mask insertion; (4) use of atropine for the 3 previous procedures. Evidence was gathered and assessed on predefined questions related to these fields. Consensual statements were issued using the GRADE methodology. Results: Among the 15 formalized good practice statements, 2 were strong recommendations to do (Grade 1+) or not to do (Grade 1-), and 4 were discretionary recommendations to do (Grade 2+). For 9 good practice statements, the GRADE method could not be applied, resulting in an expert opinion. For tracheal intubation premedication was considered mandatory except for life-threatening situations (Grade 1+). Recommended premedications were a combination of opioid + muscle blocker (Grade 2+) or propofol in the absence of hemodynamic compromise or hypotension (Grade 2+) while the use of a sole opioid was discouraged (Grade 1-). Statements regarding other molecules before tracheal intubation were expert opinions. For LISA premedication was recommended (Grade 2+) with the use of propofol (Grade 2+). Statements regarding other molecules before LISA were expert opinions. For laryngeal mask insertion and atropine use, no specific data was found and expert opinions were provided. Conclusion: This statement should help clinical decision regarding premedication before neonatal upper airway access and favor standardization of practices.

Predictive Performance of Population Pharmacokinetic Models of Levetiracetam in Children and Evaluation of Dosing Regimen.

Levetiracetam is a broad-spectrum antiepileptic drug that exhibits high interindividual variability in serum concentrations in children. A population pharmacokinetic approach can be used to explain this variability and optimize dosing schemes. The objectives are to identify the best predictive population pharmacokinetic model for children and to evaluate recommended doses using simulations and Bayesian forecasting. A validation cohort included children treated with levetiracetam who had a serum drug concentration assayed during therapeutic drug monitoring. We assessed the predictive performance of all the population pharmacokinetic models published in the literature using mean prediction errors, root mean squared errors, and visual predictive checks. A population model was finally constructed on the data, and dose simulations were performed to evaluate doses. We included 267 levetiracetam concentrations ranging from 2 to 69 mg/L from 194 children in the validation cohort. Six published models were externally evaluated. Most of the models underestimated the variability of our population. A 1-compartment model with first-order absorption and elimination with allometric scaling was finally fitted on our data. In our cohort, 57% of patients had a trough concentration <12 mg/L and 12% <5 mg/L. To reach a trough concentration >5 mg/L, doses ≥30 mg/kg/d for patients ≤50 kg and ≥2000 mg/d for patients >50 kg are required. In our population, a high percentage of children had low trough concentrations. Our population pharmacokinetic model could be used for therapeutic drug monitoring of levetiracetam in children.

Dosing Recommendations for Lamotrigine in Children: Evaluation Based on Previous and New Population Pharmacokinetic Models.

Lamotrigine is a broad-spectrum antiepileptic drug with high interindividual variability in serum concentrations in children. The aims of this study were to evaluate the predictive performance of pediatric population pharmacokinetic (PPK) models published on lamotrigine, to build a new model with our monitoring data and to evaluate the current recommended doses. A validation cohort included patients treated with lamotrigine who had a serum level assayed during therapeutic drug monitoring (TDM). PPK models published in the literature were first applied to the validation cohort. We assessed their predictive performance using mean prediction errors, root mean squared errors, and visual predictive checks. A new model was then built using the data. Dose simulations were performed to evaluate the doses recommended. We included 270 lamotrigine concentrations ranging from 0.5 to 17.9 mg/L from 175 patients. The median (range) age and weight were 11.8 years (0.8-18 years) and 32.7 kg (8-110 kg). We tested 6 PPK models; most had acceptable bias and precision but underestimated the variability of the cohort. We built a 1-compartment model with first-order absorption and elimination, allometric scaling, and effects of inhibitor and inducer comedications. In our cohort, 22.6% of trough concentrations were below 2.5 mg/L. In conclusion, we proposed a PPK model that can be used for TDM of lamotrigine in children. In our population, a high percentage of children had low trough concentrations of lamotrigine. As the intervals of recommended doses are large, we suggest aiming at the higher range of doses to reach the target concentration.

Managing neonatal pain in the era of non-invasive respiratory support.

Non-invasive ventilation is currently the preferred respiratory support for premature infants with respiratory distress. The lung-protective effects of non-invasive ventilation should however not prompt disregard for the possible pain and discomfort it can generate. Non-pharmacological interventions should be used in all premature infants, regardless of their respiratory support, and are not detailed in this review. This review includes currently available evidence and gaps in knowledge regarding three aspects of pain management in premature infants receiving non-invasive ventilation: optimisation of non-invasive ventilation especially through the choice of positive pressure source, appropriate interface and synchronisation; sedative or analgesic drug use for strategies aiming at administering surfactant with reduction or avoidance of tracheal ventilation; risks and benefits of some analgesic and/or sedative drugs used to treat or prevent prolonged pain and discomfort during non-invasive ventilation. In spite of limited robust evidence, this overview should trigger caregivers' reflections on their daily practice.

Pharmacokinetic and pharmacodynamic considerations of cephalosporin use in children.

Introduction: Cephalosporins are a major class of antibiotics, frequently used in children because of their remarkable antibacterial activity and excellent safety profile. Time above the minimal inhibitory concentration of the non-protein-bound fraction (fT>MIC) is the pharmacokinetic/pharmacodynamic parameter that correlates with the therapeutic efficacy. In the pediatric population, the inter-individual variability in cephalosporin pharmacokinetics is large because of maturational changes. However, the prescription of cephalosporins promotes emergence of Enterobacteriaceae producing broad-spectrum ß-lactamases.Areas covered: Here we describe in vitro activities and the main pharmacokinetic characteristics of cephalosporins in children. On the basis of these characteristics, we propose an estimation of the fT>MIC for each molecule as a tool to help optimize the use of cephalosporins. We also provide an inventory of the clinical use of cephalosporins and present prospects for the development of new molecules or associations to address the emergence of resistant strains.Expert opinion: Cephalosporins represent a heterogeneous group of antibiotics with various pharmacokinetics and in vitro antimicrobial activity that the clinician needs to master to optimize their use. However, their broad use plays a role in the emergence of broad-spectrum ß-lactamase-producing strains and must thus be restricted to probabilistic broad-spectrum therapy and situations without therapeutic alternatives.

Continuous-Infusion Vancomycin in Neonates: Assessment of a Dosing Regimen and Therapeutic Proposal.

Introduction: Vancomycin remains the reference antibiotic in neonates for care-related infections caused by ß-lactam-resistant Gram-positive bacteria. Achieving the optimal serum vancomycin level is challenging because of high inter-individual variability and the drug's narrow therapeutic window. Continuous infusion might offer pharmacokinetic and practical advantages, but we lack consensus on the dosing regimen. The aim was to determine the proportion of neonates achieving an optimal therapeutic vancomycin level at the first vancomycin concentration assay and which dosing regimen is the most suitable for neonates. Methods: All neonates receiving continuous-infusion vancomycin (loading dose 15 mg/kg and maintenance dose 30 mg/kg/d) in a neonatal intensive care unit were retrospectively analyzed. The proportion of neonates reaching the target serum vancomycin level was calculated. After reviewing the literature to identify all published articles proposing a dosing regimen for continuous-infusion vancomycin for neonates, regimens were theoretically applied to our population by using maintenance doses according to covariate(s) proposed in the original publication. Results: Between January 2013 and December 2014, 75 neonates received 91 vancomycin courses by continuous infusion. Median gestational age, birth weight, and postnatal age were 27 weeks (interquartile range 26-30.5), 815 g (685-1,240), and 15 days (9-33). At the first assay, only 28/91 (30.8%) courses resulted in vancomycin levels between 20 and 30 mg/L (target level), 23/91 (25.3%) >30 mg/L and 40/91 (43.9%) <20 mg/L. We applied six published dosing regimens to our patients. One of these dosing regimens based on corrected gestational age (CGA) and serum creatinine level (SCR) would have allowed us to prescribe lower doses to neonates with high vancomycin levels and higher doses to neonates with low levels. Conclusions: A simplified dosing regimen of continuous-infusion vancomycin did not achieve therapeutic ranges in neonates; a patient-tailored dosing regimen taking into account CGA and SCR level or an individualized pharmacokinetic model can help to anticipate the inter-individual variability in neonates and would have been more suitable.

Continuous intravenous to oral morphine switch in very premature ventilated infants: A retrospective study on efficacy, efficiency, and tolerability.

Background: Continuous intravenous (IV) morphine is commonly used in ventilated neonates. Oral route is theoretically feasible but data on oral morphine in ventilated premature infants are lacking. Objective: To assess the efficacy, efficiency, and tolerability of a continuous intravenous to oral morphine switch protocol. Design: Retrospective study. Setting: Single level III center's neonatal intensive care unit. Patients: Ventilated premature infants hospitalized in the NICU in 2016 and 2017, receiving continuous IV morphine with an expected ventilation course of at least 72 more hours. We excluded patients treated for withdrawal syndrome or palliative care. Interventions: Continuous IV to oral morphine switch with the same initial cumulated daily dose. Main outcome measures: Pain scores (ComfortNeo scale) and morphine doses were analyzed over time using Friedman's test in the 24 hours preceding and the 48 hours following the oral switch. Adverse effects attributable to opioids were collected. Results: Seventeen infants were included with a median [IQR] gestational age at birth of 25.9 [24.6-26.9] weeks and a median postnatal age at oral switch of 30 [22-36] days. One patient's intravenous treatment had to be resumed because of a high ComfortNeo score. All others remained on oral morphine. No significant change over time was observed for ComfortNeo scores (P = .15). Median [IQR] doses were 13.5 [10-20] µg/kg/h in the IV period and significantly increased to 15 [10-25] µg/kg/h in the oral period (P = .009). No short-term respiratory, digestive, or urinary adverse event was observed. After a median [IQR] duration of 13 [4-20] days of oral morphine treatment, 11 (65%) patients showed signs of withdrawal. Upon hospital discharge, 16 infants (94%) had bronchopulmonary dysplasia and none had severe cerebral abnormality on brain imaging. Conclusion: Oral morphine might be useful in ventilated neonates in the NICU but deserves further studies and additional safety assessment.

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models.

Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128 mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6 mg/L and a root mean squared error of 25.1 mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50 mg/L. Simulations suggested increasing doses, especially for children ≤40 kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight.