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BACKGROUND: The recommended dose of ephedrine in adults (0.1 mg kg-1) frequently fails to treat hypotension after induction of general anaesthesia in neonates and infants less than 6 months of age. The aim of this study was to determine the optimal dose of ephedrine in this population for the treatment of hypotension after induction of general anaesthesia with sevoflurane. METHODS: We conducted a multicentre, prospective, randomised, open-label, controlled, dose-escalation trial. Subjects were randomised if presenting a >20% change from baseline in MAP. Six cohorts of 20 subjects each were enrolled. Ten subjects in the first cohort received 0.1 mg kg-1 i. v. (reference dose). For each subsequent cohort, 10 subjects were assigned to the next higher dose (consecutively 0.6, 0.8, 1, 1.2, and 1.4 mg kg-1 i. v.), and the other subjects were assigned to one or more doses already investigated in previous cohorts. The primary outcome was the return of MAP to >80% of baseline at least once within 10 min after ephedrine administration. RESULTS: A total of 119 infants (25% females), with a mean age (standard deviation) of 2.7 (1.3) months, received their allocated dose of ephedrine. The optimal dose of ephedrine was 1.2 mg kg-1, with a percentage of success of 65.5% (95% confidence interval, 35.6-86.4). The doses of ephedrine investigated did not induce adverse events. CONCLUSIONS: Doses of ephedrine much higher (â¼10-fold) than those used in adults are necessary in neonates and infants for the treatment of hypotension after induction of general anaesthesia with sevoflurane. CLINICAL TRIAL REGISTRATION: NCT02384876.
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Anestesia Raquidea , Hipotensión , Adulto , Femenino , Recién Nacido , Lactante , Humanos , Masculino , Efedrina/uso terapéutico , Vasoconstrictores/uso terapéutico , Sevoflurano/uso terapéutico , Estudios Prospectivos , Hipotensión/inducido químicamente , Hipotensión/tratamiento farmacológico , Anestesia Raquidea/efectos adversos , Anestesia GeneralRESUMEN
BACKGROUND: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate-lipid metabolism, could be involved. METHODS: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min-max)). RESULTS: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4-99) in SOC, 47 (9-98) in burosumab, and 28 (1-94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate-lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab). CONCLUSION: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018-2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Raquitismo Hipofosfatémico Familiar , Hipertensión , Hipofosfatemia , Adolescente , Humanos , Raquitismo Hipofosfatémico Familiar/complicaciones , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Anticuerpos Monoclonales , Estudios Transversales , Estudios Prospectivos , Hipertensión/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/metabolismo , ObesidadRESUMEN
OBJECTIVE: To assess the effect of the prone position on physiological measures, including inspiratory effort, metabolic cost of breathing, and neural drive to the diaphragm as compared with the supine position in infants with severe bronchiolitis requiring noninvasive ventilation. STUDY DESIGN: Fourteen infants, median age 33 days (IQR [first and third quartiles], 25-58) were randomized to receive 7 cmH2O continuous positive airway pressure for 1 hour in the prone position or in the supine position, which was followed by cross-over to the supine position and the prone position for 1 hour, respectively. Flow, esophageal, airway, gastric, and transdiaphragmatic pressures, as well as electrical activity of the diaphragm were simultaneously recorded. The modified Wood clinical asthma score was also assessed. RESULTS: Median esophageal pressure-time product per minute was significantly lower in the prone position than in the supine position (227 cmH2O*s/minute [IQR, 156-282] cmH2O*s/minute vs 353 cmH2O*s/minute [IQR, 249-386 cmH2O*s/minute]; P = .048), as were the modified Wood clinical asthma score (P = .033) and electrical activity of the diaphragm (P = .006). The neuromechanical efficiency of the diaphragm, as assessed by transdiaphramagtic pressure to electrical activity of the diaphragm swing ratio, was significantly higher in the prone position than in the supine position (1.1 cmH2O/µV [IQR, 0.9-1.3 cmH2O/µV] vs 0.7 cmH2O/µV [IQR, 0.6-1.2 cmH2O/µV], respectively; P = .022). CONCLUSIONS: This study suggests a benefit of the prone position for infants with severe bronchiolitis requiring noninvasive ventilation by significantly decreasing the inspiratory effort and the metabolic cost of breathing. Further studies are needed to evaluate the potential impact of these physiological findings in a larger population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02602678.
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Bronquiolitis/terapia , Capacidad Inspiratoria , Posición Prona/fisiología , Frecuencia Respiratoria/fisiología , Presión de las Vías Aéreas Positiva Contínua/métodos , Estudios Cruzados , Esófago/fisiopatología , Humanos , Lactante , Recién Nacido , Posicionamiento del Paciente/métodosRESUMEN
OBJECTIVES: Micronutrient supplementation in critically ill adults remains controversial. In the pediatric setting, the impact of oxidative stress on the overall micronutrient status has been poorly explored, due to the limited number of studies and to confounding factors (i.e., malnutrition or extra losses). In order to better understand this phenomenon, we aim to describe micronutrient status, focusing on seven micronutrients, in well-nourished critically ill children presenting with severe oxidative stress. DESIGN: Prospective, transversal, observational, single-center study. SETTING: PICU, and anesthesiology department, Lyon, France. PATIENTS: Three groups of patients were clinically defined: severe oxidative stress PICU group (at least two organ dysfunctions), moderate oxidative stress PICU group (single organ dysfunction), and healthy control group (prior to elective surgery); oxidative stress intensity was controlled by measuring plasma levels of glutathione peroxidase and glutathione. Children presenting any former condition leading to micronutrient deficiency were excluded (malnutrition, external losses). INTERVENTIONS: Plasma levels of selenium, zinc, copper, vitamin A, vitamin E, vitamin C, and ß-carotene were measured in PICU oxidative stress conditions and compared with those of healthy children. MEASUREMENTS AND MAIN RESULTS: Two hundred one patients were enrolled (51, 48, and 102 in severe, moderate, and healthy control groups, respectively). Median age was 7.1 years (interquartile range, 2.1-13.8 yr). There was a significant trend (p < 0.02) toward plasma level decrease of six micronutrients (selenium, zinc, copper, vitamin E, vitamin C, and ß-carotene) while oxidative stress intensity increased. Biological markers of oxidative stress (glutathione peroxidase and glutathione) were in accordance with the clinical definition of the three groups. CONCLUSIONS: A multiple micronutrient deficiency or redistribution occurs in critically ill children presenting with severe oxidative stress. These findings will help to better identify children who might benefit from micronutrient supplementation and to design adapted supplementation trials in this particular setting.
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Enfermedad Crítica , Micronutrientes/sangre , Micronutrientes/deficiencia , Estrés Oxidativo/fisiología , Adolescente , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: Significant muscle wasting develops in critically ill adults, with subsequent worse outcomes. In the pediatric setting, occurrence and effects of muscle wasting are undescribed; this is in part due to a lack of validated, objective methods for assessing muscle wasting. A single measurement of quadriceps femoris thickness has failed to show consistent reproducibility. We hypothesized that averaging repeated measurements could afford good reproducibility to allow for quadriceps femoris thickness decline detection and monitoring. DESIGN: A prospective bedside observational study. SETTING: Two PICUs. PATIENTS: Mechanically ventilated critically ill children were 15 years and younger. INTERVENTIONS: Transverse and longitudinal axis measurements of quadriceps femoris anterior thickness were undertaken using bedside ultrasound. The average of four measurement values was recorded. The location of measurement was marked for consistency within subsequent measurements by the same or another trained operator, to assess intra- and interoperator repeatability and reproducibility of the technique. Where feasible, serial measurements were undertaken until the time of extubation in a group of children with prolonged PICU stay (> 5 d). MEASUREMENTS AND MAIN RESULTS: Seventy-three children were enrolled to assess intra- and interoperator ultrasound reliability. Their median (25-75 interquartile range) age and weight were 30 months (4.5-96) and 10 kg (5-23.5). In the intraoperator repeatability study, mean relative difference in quadriceps femoris muscle thickness was 0.36% ± 2.5% (lower and upper limits of agreement: -4.5/+5.2%). In the interoperator reproducibility study, intraclass correlation coefficient was 0.998. In the 17 children monitored over their PICU stay, quadriceps femoris thickness significantly decreased at day 5 by 9.8% (p = 0.006) and by 13.3% (< 0.001) at the last performed measurement. CONCLUSIONS: Quadriceps femoris thickness decrease, proposed as a surrogate for muscle mass, is an early, frequent, and intense phenomenon in PICU. Quadriceps femoris ultrasonography is a reliable technique to monitor this process and in future could help to guide rehabilitation and nutrition interventions.
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Atrofia Muscular/diagnóstico por imagen , Músculo Cuádriceps/diagnóstico por imagen , Adolescente , Niño , Preescolar , Enfermedad Crítica , Femenino , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Pediátrico , Masculino , Atrofia Muscular/patología , Variaciones Dependientes del Observador , Pruebas en el Punto de Atención , Estudios Prospectivos , Músculo Cuádriceps/patología , Reproducibilidad de los Resultados , Respiración Artificial , Muslo , UltrasonografíaRESUMEN
Endocrine disruptors (ED) are ubiquitous pollutants, possibly implicated in chronic disease. Exposure of vulnerable populations; including neonates, infants and children; must therefore be limited. Informing parents is now a public health challenge. We conducted a quantitative cross-sectional study at the Lyon Mother and child Hospital. We used questionnaires to assess the beliefs and knowledge about ED of parents and pediatric healthcare professionals in the pediatric ward in Lyon, France. A total of 746 questionnaires were completed: 444 for professionals and 302 for parents. The majority of both populations had already heard of ED but only 10% of parents and 5% of professionals felt sufficiently informed. Professionals answered better than parents (73% vs. 60%). The main source of information was similar: media. Only 20% of professionals had read a scientific article about ED and 4% have followed a training. Environmental exposure and EDs is an increasing concern for parents but specific knowledge remains scare for parents and professionals. Specific training is needed.
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Disruptores Endocrinos , Conocimientos, Actitudes y Práctica en Salud , Padres , Humanos , Estudios Transversales , Femenino , Encuestas y Cuestionarios , Masculino , Padres/psicología , Francia , Adulto , Exposición a Riesgos Ambientales , Niño , Pediatría , LactanteRESUMEN
PURPOSE: Toxic shock syndrome (TSS) is a rare disease responsible for significant morbidity and mortality. Intravenous immunoglobulin (IG) therapy in paediatric TSS could improve shock and organ failure, but more consistent efficacy and safety data are needed. Our objective was to determine whether a randomised clinical trial (RCT) assessing intravenous IG in TSS in children is feasible. METHODS: We performed a multicentre, feasibility, double-blind RCT assessing efficacy of high-dose intravenous IG versus albumin 4% (control group) within the first 12 hours of shock onset. Included patients were aged above 1 month and below 18 years with suspected TSS and septic shock. Feasibility was assessed by measuring inclusion rate, protocol compliance and missing data regarding death and the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) Score. Other secondary clinical outcomes were evaluated during hospital stay, at 60 day and 1 year. RESULTS: 28 patients, admitted in 6 paediatric intensive care units during 36 consecutive months and followed for 1 year, received the allocated treatment: 13 in intravenous IG group, 15 in control group. The median age was 10.6 years and the sex ratio was 1. Inclusion rate was above 50%, protocol deviations were below 30% and missing data regarding death and PELOD-2 Score below 10%. No difference concerning secondary clinical outcomes between groups was observed, and more adverse events were reported in the control group. CONCLUSION: It seems to be feasible to conduct an RCT assessing intravenous IG efficacy and safety in paediatric TSS but must be realised internationally, with choice of a clinically relevant endpoint and a specific design in order to be realistic. TRIAL REGISTRATION NUMBER: NCT02219165.
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Albúminas , Estudios de Factibilidad , Inmunoglobulinas Intravenosas , Choque Séptico , Humanos , Niño , Masculino , Femenino , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/efectos adversos , Inmunoglobulinas Intravenosas/uso terapéutico , Método Doble Ciego , Choque Séptico/tratamiento farmacológico , Choque Séptico/mortalidad , Preescolar , Adolescente , Resultado del Tratamiento , Lactante , Albúminas/administración & dosificación , Albúminas/uso terapéutico , Albúminas/efectos adversosRESUMEN
PURPOSE: MRI is the main imaging modality for pediatric brain tumors, but amino acid PET can provide additional information. Simultaneous PET-MRI acquisition allows to fully assess the tumor and lower the radiation exposure. Although symptomatic posterior fossa tumors are typically resected, the patient management is evolving and will benefit from an improved preoperative tumor characterization. We aimed to explore, in children with newly diagnosed posterior fossa tumor, the complementarity of the information provided by amino acid PET and MRI parameters and the correlation to histopathological results. PATIENTS AND METHODS: Children with a newly diagnosed posterior fossa tumor prospectively underwent a preoperative 11 C-methionine (MET) PET-MRI. Images were assessed visually and semiquantitatively. Using correlation, minimum apparent diffusion coefficient (ADC min ) and contrast enhancement were compared with MET SUV max . The diameter of the enhancing lesions was compared with metabolic tumoral volume. Lesions were classified according to the 2021 World Health Organization (WHO) classification. RESULTS: Ten children were included 4 pilocytic astrocytomas, 2 medulloblastomas, 1 ganglioglioma, 1 central nervous system embryonal tumor, and 1 schwannoma. All lesions showed visually increased MET uptake. A negative moderate correlation was found between ADC min and SUV max values ( r = -0.39). Mean SUV max was 3.8 (range, 3.3-4.2) in WHO grade 4 versus 2.5 (range, 1.7-3.0) in WHO grade 1 lesions. A positive moderate correlation was found between metabolic tumoral volume and diameter values ( r = 0.34). There was no correlation between SUV max and contrast enhancement intensity ( r = -0.15). CONCLUSIONS: Preoperative 11 C-MET PET and MRI could provide complementary information to characterize pediatric infratentorial tumors.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Neoplasias Infratentoriales , Meduloblastoma , Niño , Humanos , Metionina , Fluorodesoxiglucosa F18 , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Racemetionina , Neoplasias Encefálicas/diagnóstico por imagen , AminoácidosRESUMEN
BACKGROUND: This study aimed to compare the humoral responses to mRNA COVID-19 vaccination in people living with HIV (PWH) and HIV-negative individuals. METHODS: We included PWH with an undetectable viral load under ART and HIV-negative participants from the French nationwide ANRS COV-POPART cohort who had received two doses of vaccine as a primary vaccination. We compared humoral response between controls and PWH, stratified by CD4 cell count (<200/mm3 and ≥200/mm3 CD4 cell counts) at 1, 6, and 12 months after primary vaccination. RESULTS: A total of 1776 participants were included in this analysis, 684 PWH (99% were on ART, median CD4 counts 673 cells/mm3) and 1092 controls. At 1 month, after adjustment on age, sex, and BMI, PWH had lower seroneutralization titers than controls, and PWH with <200 CD4 cell/mm3 had lower anti-Spike SARS-CoV-2 IgG antibodies. Same results were found at 6 months. However, in participants who received a booster dose between 6 and 12 months postprimary vaccination, we did not observe differences between PWH and controls at 12 months. CONCLUSION: PWH had high responses to primary mRNA COVID-19 vaccination. In those who received a booster dose after 6 months, the humoral response at 12 months increased to similar levels to controls, even in those with low CD4 counts at baseline.
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Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Infecciones por VIH , Inmunidad Humoral , Inmunización Secundaria , SARS-CoV-2 , Humanos , Masculino , Femenino , COVID-19/inmunología , COVID-19/prevención & control , Persona de Mediana Edad , Infecciones por VIH/inmunología , Francia , Anticuerpos Antivirales/sangre , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Vacunación , Carga Viral , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Inmunoglobulina G/sangreAsunto(s)
Antígenos HLA-DR/análisis , Linfohistiocitosis Hemofagocítica/sangre , Choque Séptico/sangre , Choque/clasificación , Biomarcadores/análisis , Biomarcadores/sangre , Antígenos HLA-DR/sangre , Humanos , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/fisiopatología , Monocitos , Choque/sangre , Choque Séptico/fisiopatologíaRESUMEN
Autotaxin (ATX) is a secreted enzyme with a lysophospholipase D activity, mainly secreted by adipocytes and widely expressed. Its major function is to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), an essential bioactive lipid involved in multiple cell processes. The ATX-LPA axis is increasingly studied because of its involvement in numerous pathological conditions, more specifically in inflammatory or neoplastic diseases, and in obesity. Circulating ATX levels gradually increase with the stage of some pathologies, such as liver fibrosis, thus making them a potentially interesting non-invasive marker for fibrosis estimation. Normal circulating levels of ATX have been established in healthy adults, but no data exist at the pediatric age. The aim of our study is to describe the physiological concentrations of circulating ATX levels in healthy teenagers through a secondary analysis of the VITADOS cohort. Our study included 38 teenagers of Caucasian origin (12 males, 26 females). Their median age was 13 years for males and 14 years for females, ranging from Tanner 1 to 5. BMI was at the 25th percentile for males and 54th percentile for females, and median blood pressure was normal. ATX median levels were 1,049 (450-2201) ng/ml. There was no difference in ATX levels between sexes in teenagers, which was in contrast to the male and female differences described in the adult population. ATX levels significantly decreased with age and pubertal status, reaching adult levels at the end of puberty. Our study also suggested positive correlations between ATX levels and blood pressure (BP), lipid metabolism, and bone biomarkers. However, except for LDL cholesterol, these factors were also significantly correlated with age, which might be a confounding factor. Still, a correlation between ATX and diastolic BP was described in obese adult patients. No correlation was found between ATX levels and inflammatory marker C-reactive protein (CRP), Body Mass Index (BMI), and biomarkers of phosphate/calcium metabolism. In conclusion, our study is the first to describe the decline in ATX levels with puberty and the physiological concentrations of ATX levels in healthy teenagers. It will be of utmost importance when performing clinical studies in children with chronic diseases to keep these kinetics in mind, as circulating ATX might become a non-invasive prognostic biomarker in pediatric chronic diseases.
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BACKGROUND: This study aimed to collect obstetric anesthesia practice and patient-reported outcomes as an update to the last French Obstetric Anesthesia survey from 1996. METHODS: Maternity units were randomly selected across France and surveyed for 7 consecutive days from February, 2016, to January, 2017. Data was gathered prospectively by questionnaires filled out by patients and anesthesia providers. RESULTS: There were 1885 questionnaires received from 56 units, with 379 cesarean delivery (CD) and 1506 vaginal delivery (VD) cases analyzed. The overall neuraxial labor analgesia (NLA) rate was 82.5% (95% CI [82.4-82.6]), with 70.3% (95% CI [71.4-71.6]) receiving automated administration (PCEA/PIEB). NLA was effective throughout labor in 68.2% of cases, however, severe pain was reported by 29.4% of patients. The overall rate of alternative approaches for labor analgesia was 19.5% (95%CI [19.2-19.7]). Obesity (OR 2.8; 95% CI [1.0-7.5], p < 0.04) and delivery in level I units (OR 0.6; 95% CI [0.5-0.9], p < 0.01) were associated with severe pain during VD. Satisfaction was found to be similar in patients delivering with or without NLA. The incidence of pain during CD was similar in scheduled versus non-scheduled CD. Failure of NLA during CD was associated with severe pain (OR 10.0; 95% CI [3.1-31.9], p < 0.01) and dissatisfaction (OR 26.2; 95% CI [3.0-225.1], p < 0.01). CONCLUSION: Despite the high NLA rate in France, a significant proportion of women experience severe pain during labor and delivery. This study emphasizes the need for further practice guidelines in obstetric anesthesia to ensure optimal pain management and improve patients' experience during childbirth. CLINICALTRIALS: govNCT02853890.
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Anestesia Obstétrica , Dolor de Parto , Femenino , Humanos , Embarazo , Analgésicos , Cesárea , Estudios Transversales , Parto Obstétrico , Dolor de Parto/tratamiento farmacológicoRESUMEN
Despite the high prevalence of late-onset sepsis (LOS) in neonatal intensive care units, a reliable diagnosis remains difficult. This prospective, multicenter cohort study aimed to identify biomarkers early to rule out the diagnosis of LOS in 230 neonates ≥7 days of life with signs of suspected LOS. Blood levels of eleven protein biomarkers (PCT, IL-10, IL-6, NGAL, IP-10, PTX3, CD14, LBP, IL-27, gelsolin, and calprotectin) were measured. Patients received standard of care blinded to biomarker results, and an independent adjudication committee blinded to biomarker results assigned each patient to either infected, not infected, or unclassified groups. Performances of biomarkers were assessed considering a sensitivity of at least 0.898. The adjudication committee classified 22% of patients as infected and all of these received antibiotics. A total of 27% of the not infected group also received antibiotics. The best biomarkers alone were IL-6, IL-10, and NGAL with an area under the curve (95% confidence interval) of 0.864 (0.798-0.929), 0.845 (0.777-0.914), and 0.829 (0.760-0.898), respectively. The best combinations of up to four biomarkers were PCT/IL-10, PTX3/NGAL, and PTX3/NGAL/gelsolin. The best models of biomarkers could have identified not infected patients early on and avoided up to 64% of unjustified antibiotics. At the onset of clinical suspicion of LOS, additional biomarkers could help the clinician in identifying non-infected patients.
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Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials.
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Desarrollo de Medicamentos , Adolescente , Adulto , Niño , Humanos , Francia , PredicciónRESUMEN
AIMS: To identify all available trigger tools applicable to the pediatric population in hospital settings to detect adverse drug events (ADEs) and to describe their performances by positive predictive value (PPV). METHODS: PubMed® was searched until December 2021. The reference sections were also consulted for new articles. Studies were selected when they used one or more triggers to identify AEs and used data on pediatric inpatient settings. Studies mentioning triggers related to AEs that were only caused by care procedures were excluded. Only triggers related to ADEs were included. PPVs of triggers were reported. Mean PPVs were calculated for multi-study triggers. The interest of each trigger in a real-time detection system was assessed. RESULTS: Thirty studies were included. A total of 271 unique triggers were identified, 179 of which were related to drug-induced harms. Among them, 68 could be used for prevention of ADEs, 80 for verification and 31 for reporting. Nineteen triggers (11%) had a mean PPV between 50% and 100%, including 5 that had a 100% PPV. CONCLUSION: The performances of individual triggers need to be more adequately studied. The detection of ADEs through computerized triggers and/or real-time detection systems remains an emerging field, very much needed in children especially, due to frequent off-label use.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Niño , Niño Hospitalizado , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Hospitales , HumanosRESUMEN
The diagnosis of serious bacterial infection (SBI) in young febrile children remains challenging. This prospective, multicentre, observational study aimed to identify new protein marker combinations that can differentiate a bacterial infection from a viral infection in 983 children, aged 7 days-36 months, presenting with a suspected SBI at three French paediatric emergency departments. The blood levels of seven protein markers (CRP, PCT, IL-6, NGAL, MxA, TRAIL, IP-10) were measured at enrolment. The patients received the standard of care, blinded to the biomarker results. An independent adjudication committee assigned a bacterial vs. viral infection diagnosis based on clinical data, blinded to the biomarker results. Computational modelling was applied to the blood levels of the biomarkers using independent training and validation cohorts. Model performances (area under the curve (AUC), positive and negative likelihood ratios (LR+ and LR-)) were calculated and compared to those of the routine biomarkers CRP and PCT. The targeted performance for added value over CRP or PCT was LR+ ≥ 5.67 and LR- ≤ 0.5. Out of 652 analysed patients, several marker combinations outperformed CRP and PCT, although none achieved the targeted performance criteria in the 7 days-36 months population. The models seemed to perform better in younger (7-91 day-old) patients, with the CRP/MxA/TRAIL combination performing best (AUC 0.895, LR+ 10.46, LR- 0.16). Although computational modelling using combinations of bacterial- and viral-induced host-protein markers is promising, further optimisation is necessary to improve SBI diagnosis in young febrile children.
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Background and Aims: Intracranial Hypertension (ICH) is a life-threatening complication of brain injury. The invasive measurement of intracranial pressure (ICP) remains the gold standard to diagnose ICH. Measurement of Optic Nerve Sheath Diameter (ONSD) using ultrasonography is a non-invasive method for detecting ICH. However, data on paediatric brain injury are scarce. The aim of the study was to determine the performance of the initial ONSD measurement to predict ICH occurring in children with severe brain injury and to describe the ONSD values in a control group. Methods: In this cross-sectional study, ONSD was measured in children aged 2 months-17 years old with invasive ICP monitoring: before placement of ICP probe and within the 60 min after, and then daily during 3 days. ONSD was also measured in a control group. Results: Ninety-nine patients were included, of whom 97 were analysed, with a median (IQR) age of 8.7 [2.3-13.6] years. The median (IQR) PIM 2 score was 6.6 [4.4-9.7] and the median (IQR) PELOD score was 21 [12-22]. Aetiologies of brain injury were trauma (n = 72), infection (n = 17) and stroke (n = 8). ICH occurred in 65 children. The median (IQR) ONSD was 5.58 mm [5.05-5.85]. ONSD performed poorly when it came to predicting ICH occurrence within the first 24 h (area under the curve, 0.58). There was no significant difference between the ONSD of children who presented with ICH within the first 24 h and the other children, with a median (IQR) of 5.6 mm [5.1-5.9] and 5.4 mm [4.9-5.8], respectively. Infants aged less than 2 years had a median (IQR) ONSD of 4.9 mm [4.5-5.2], significantly different from children aged more than 2 years, whose median ONSD was 5.6 mm [5.2-5.9]. Age, aetiology or ICP levels did not change the results. Thirty-one controls were included, with a median age of 3.7 (1.2-8.8) years. The median (IQR) of their ONSD measurement was 4.5 mm [4.1-4.8], significantly lower than the patient group. Conclusion: In a paediatric severe brain injury population, ONSD measurement could not predict the 24 h occurrence of ICH. Severity of patients, timing and conditions of measurements may possibly explain these results.
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BACKGROUND: Hypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels. METHODS: The FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double-blind trial. A total of 60 patients (10-60 years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/day), increased 1,25(OH)2D levels (> 150 pmol/L), and 25-OH-D levels >20 nmol/L will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-h calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-h calciuria in patients who still display at W16 a 24-h hypercalciuria. DISCUSSION: The current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the "off-label" use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04495608 . Registered on July 23, 2020.
Asunto(s)
Nefrocalcinosis , Nefrolitiasis , Insuficiencia Renal Crónica , Adulto , Fluconazol/efectos adversos , Humanos , Hipercalciuria/diagnóstico , Hipercalciuria/tratamiento farmacológico , Hipercalciuria/etiología , Fosfatos , Estudios Prospectivos , Insuficiencia Renal Crónica/complicaciones , Vitamina D/metabolismoRESUMEN
BACKGROUND AND PURPOSE: The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs. EXPERIMENTAL APPROACH: The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k). KEY RESULTS: Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05). CONCLUSION AND IMPLICATIONS: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.