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

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

Pleural and transpulmonary pressures to tailor protective ventilation in children.

This review aims to: (1) describe the rationale of pleural (PPL) and transpulmonary (PL) pressure measurements in children during mechanical ventilation (MV); (2) discuss its usefulness and limitations as a guide for protective MV; (3) propose future directions for paediatric research. We conducted a scoping review on PL in critically ill children using PubMed and Embase search engines. We included peer-reviewed studies using oesophageal (PES) and PL measurements in the paediatric intensive care unit (PICU) published until September 2021, and excluded studies in neonates and patients treated with non-invasive ventilation. PL corresponds to the difference between airway pressure and PPL Oesophageal manometry allows measurement of PES, a good surrogate of PPL, to estimate PL directly at the bedside. Lung stress is the PL, while strain corresponds to the lung deformation induced by the changing volume during insufflation. Lung stress and strain are the main determinants of MV-related injuries with PL and PPL being key components. PL-targeted therapies allow tailoring of MV: (1) Positive end-expiratory pressure (PEEP) titration based on end-expiratory PL (direct measurement) may be used to avoid lung collapse in the lung surrounding the oesophagus. The clinical benefit of such strategy has not been demonstrated yet. This approach should consider the degree of recruitable lung, and may be limited to patients in which PEEP is set to achieve an end-expiratory PL value close to zero; (2) Protective ventilation based on end-inspiratory PL (derived from the ratio of lung and respiratory system elastances), might be used to limit overdistention and volutrauma by targeting lung stress values < 20-25 cmH2O; (3) PPL may be set to target a physiological respiratory effort in order to avoid both self-induced lung injury and ventilator-induced diaphragm dysfunction; (4) PPL or PL measurements may contribute to a better understanding of cardiopulmonary interactions. The growing cardiorespiratory system makes children theoretically more susceptible to atelectrauma, myotrauma and right ventricle failure. In children with acute respiratory distress, PPL and PL measurements may help to characterise how changes in PEEP affect PPL and potentially haemodynamics. In the PICU, PPL measurement to estimate respiratory effort is useful during weaning and ventilator liberation. Finally, the use of PPL tracings may improve the detection of patient ventilator asynchronies, which are frequent in children. Despite these numerous theoritcal benefits in children, PES measurement is rarely performed in routine paediatric practice. While the lack of robust clincal data partially explains this observation, important limitations of the existing methods to estimate PPL in children, such as their invasiveness and technical limitations, associated with the lack of reference values for lung and chest wall elastances may also play a role. PPL and PL monitoring have numerous potential clinical applications in the PICU to tailor protective MV, but its usefulness is counterbalanced by technical limitations. Paediatric evidence seems currently too weak to consider oesophageal manometry as a routine respiratory monitoring. The development and validation of a noninvasive estimation of PL and multimodal respiratory monitoring may be worth to be evaluated in the future.

Peri- and neonatal factors influencing mortality and morbidity 2 years after esophageal atresia primary repair: a single center retrospective study.

Long-term digestive, respiratory, and neurological morbidity is significant in children who have undergone surgery for esophageal atresia (EA), especially after staged repair for long-gap EA. Risk factors for morbidity after primary repair (non-long-gap populations) have been less documented. We investigated peri- and neonatal factors associated with unfavorable outcomes in children 2 years after primary esophageal anastomosis. This was a single-center retrospective study, based on neonatal, surgical, and pediatric records of children born between December 1, 2002, and December 31, 2018, and followed up to age 2 years. The primary endpoint was unfavorable outcome at 2 years of age, defined by death or survival with severe respiratory, digestive, or neurologic morbidity. Univariate analyses followed by logistic regression analyses were performed to identify the peri- and neonatal risk factors of unfavorable outcomes among survivors at discharge. A total of 150 neonates were included (mean birth weight 2520 ± 718 g, associated malformations 61%); at age 2, 45 (30%) had one or more severe morbidities and 11 had died during the neonatal stay and 2 after discharge (8.7% deaths). In multivariate analyses of the 139 survivors at discharge, duration of ventilatory support (invasive and non-invasive) for more than 8 days (OR 3.74; CI95% [1.68-8.60]; p = 0.001) and achievement of full oral feeding before hospital discharge (OR 0.20; CI95% [0.06-0.56]; p = 0.003) were independently associated with adverse outcome after adjustment for sex, preterm birth, associated heart defect, any surgical complication, and the occurrence of more than one nosocomial infections during the neonatal stay. CONCLUSIONS: Post-operative ventilation and feeding management strategies may represent an opportunity for quality-of-care improvement to positively impact long-term outcomes after primary esophageal atresia repair. WHAT IS KNOWN: • Children operated on for esophageal atresia experience long-term digestive, respiratory, and neurologic morbidity, especially after multiple-stage esophageal repair. • Exclusive oral feeding at discharge is associated with a decreased risk of medical complications in the first years of life, in studies including all types of esophageal atresia repair. Outcomes of children after primary repair (non-long gap populations) have been less documented. WHAT IS NEW: • In our retrospective cohort of children with one-stage esophageal atresia repair, ventilatory support for more than 8 days and inability to achieve full oral feeding before hospital discharge in the neonatal period were independently associated with adverse digestive, respiratory, and neurologic outcomes at 2 years in survivors. • Both these factors are potentially modifiable, representing an opportunity for quality-of-care improvement to positively impact long-term outcomes. These results might also help identify children at risk of unfavorable evolution, to customize a multi-disciplinary follow-up program.

Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children Receiving Continuous Renal Replacement Therapy.

We aimed to develop a piperacillin population pharmacokinetic (PK) model in critically ill children receiving continuous renal replacement therapy (CRRT) and to optimize dosing regimens. The piperacillin plasma concentration was quantified by high-performance liquid chromatography. Piperacillin PK was investigated using a nonlinear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration according to the target of 100% interdose interval time in which concentration is one to four times above the MIC (100% fT > 1 to 4× MIC). A total of 32 children with a median (interquartile range [IQR]) postnatal age of 2 years (0 to 11), body weight (BW) of 15 kg (6 to 38), and receiving CRRT were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. BW and residual diuresis (Qu) explained some between-subject variabilities on volume of distribution (V), where [Formula: see text], and clearance (CL), where [Formula: see text], where CLpop and Vpop are 6.78 L/h and 55.0 L, respectively, normalized to a 70-kg subject and median residual diuresis of 0.06 mL/kg/h. Simulations with intermittent and continuous administrations for 4 typical patients with different rates of residual diuresis (0, 0.1, 0.25, and 0.5 mL/kg/h) showed that continuous infusions were appropriate to attain the PK target for patients with residual diuresis higher than 0.1 mL/kg/h according to BW and MIC, while for anuric patients, less frequent intermittent doses were mandatory to avoid accumulation. Optimal exposure to piperacillin in critically ill children on CRRT should be achieved by using continuous infusions with escalating doses for high-MIC bacteria, except for anuric patients who require less frequent intermittent doses.

Meropenem Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children Receiving Continuous Renal Replacement Therapy.

BACKGROUND AND OBJECTIVE: We aimed to develop a meropenem population pharmacokinetic model in critically ill children receiving continuous renal replacement therapy and simulate dosing regimens to optimize patient exposure. METHODS: Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem pharmacokinetics was investigated using a non-linear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration, according to the target of a 100% inter-dose interval time in which concentration is one to four times above the minimum inhibitory concentration (100% fT>1-4×MIC). RESULTS: A total of 27 patients with a median age of 4 [interquartile range 0-11] years, a median body weight of 16 [range 7-35] kg receiving continuous renal replacement therapy were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. Body weight (BW) produced significant effects on volume of distribution (V) and BW and continuous renal replacement therapy effluent flow rate (Qeff) produced significant effects on clearance (CL): [Formula: see text] and [Formula: see text], where Vpop and CLpop estimates were 32.5 L and 5.88 L/h, respectively, normalized to a 70-kg BW and median Qeff at 1200 mL/h. Using this final model and Monte Carlo simulations, for patients with Qeff over 1200 mL/h, meropenem continuous infusion was adequate in most cases to attain 100% fT>1-4xMIC. For bacterial infections with a low minimum inhibitory concentration (≤2 mg/L), meropenem intermitent administration was appropriate for patients weighing more than 20 kg with Qeff <500 mL/h and for patients weighing more than 10 kg with Qeff <100 mL/h. CONCLUSIONS: Meropenem exposure in critically ill children receiving continuous renal replacement therapy needs dosing adjustments to the minimum inhibitory concentration that take into account body weight and the continuous renal replacement therapy effluent flow rate.

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.

Estimation of piperacillin clearance with different glomerular filtration rate formulas in critically ill children.

AIMS: Glomerular filtration rate (GFR) is difficult to assess in critically ill children using gold standard method and alternatives are needed. This study aimed to determine the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children, using a published piperacillin pharmacokinetics (PK) population model. METHODS: All children hospitalized in the paediatric intensive care unit of a single institution who were receiving piperacillin were included. PK were described using the nonlinear mixed effect modelling software MONOLIX. In the initial PK model, GFR was estimated according to the Schwartz 1976 formula. We evaluated a set of 12 additional validated formulas, developed using plasma creatinine and/or cystatin C concentrations, in the building model to assess the lowest between-subject variability for piperacillin clearance. RESULTS: We included 20 children with a median (range) postnatal age of 1.9 (0.1-19) years, body weight of 12.5 (3.5-69) kg. Estimated GFR according to the Schwartz 1976 formula was 160.5 (38-315) mL min-1 1.73 m-2 . Piperacillin clearance was best predicted by the Bouvet combined formula. CONCLUSION: The combined Bouvet formula was the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children.

Neonatal factors related to survival and intellectual and developmental outcome of patients with early-onset urea cycle disorders.

PURPOSE: We aimed to identify prognostic factors for survival and long-term intellectual and developmental outcome in neonatal patients with early-onset urea cycle disorders (UCD) experiencing hyperammonaemic coma. METHODS: We retrospectively analysed ammonia (NH3) and glutamine levels, electroencephalogram and brain images obtained during neonatal coma of UCD patients born between 1995 and 2011 and managed at a single centre and correlated them to survival and intellectual and developmental outcome. RESULTS: We included 38 neonates suffering from deficiencies of argininosuccinate synthetase (ASSD, N = 12), ornithine transcarbamylase (OTCD, N = 10), carbamoylphosphate synthetase 1 (CPSD, N = 7), argininosuccinate lyase (ASLD, N = 7), N-acetylglutamate synthase (NAGS, N = 1) or arginase (ARGD, N = 1). Symptoms occurred earlier in mitochondrial than in cytosolic UCD. Sixty-eight percent of patients survived, with a mean (standard deviation-SD) follow-up of 10.4 (5.3) years. Mortality was mostly observed in OTCD (N = 7/10) and CPSD (N = 4/7) patients. Plasma NH3 level during the neonatal period, expressed as area under the curve, but not glutamine level was associated with mortality (p = .044 and p = .610). 62.1% of the patients had normal intellectual and developmental outcome. Intellectual and developmental outcome tended to correlate with UCD subtype (p = .052). No difference in plasma NH3 or glutamine level during the neonatal period among developmental outcomes was identified. EEG severity was linked to UCD subtypes (p = .004), ammonia levels (p = .037), duration of coma (p = .043), and mortality during the neonatal period (p = .020). Status epilepticus was recorded in 6 patients, 3 of whom died neonatally, 1 developed a severe intellectual disability while the 2 last patients had a normal development. CONCLUSION: UCD subtypes differed by survival rate, intellectual and developmental outcome and EEG features in the neonatal period. Hyperammonaemia expressed as area under the curve was associated with survival but not with intellectual and developmental outcome whereas glutamine was not associated with one of these outcomes. Prognostic value of video-EEG monitoring and the association between status epilepticus and mortality should be assessed in neonatal hyperammonaemic coma in further studies.

Administration of gamma-hydroxybutyrate instead of beta-hydroxybutyrate to a liver transplant recipient suffering from propionic acidemia and cardiomyopathy: A case report on a medication prescribing error.

Beta-hydroxybutyrate (BHB) is a synthetic ketone body used as an adjuvant energy substrate in the treatment of patients with metabolic cardiomyopathy. A medication prescribing error led to the administration of the general anesthetic sodium gamma-hydroxybutyrate (GHB) instead of sodium BHB in a liver transplant recipient with propionic acidemia and cardiomyopathy, causing acute coma. A 15-year-old boy suffering from neonatal propionic acidemia underwent liver transplantation (LT) for metabolic decompensation and cardiomyopathy (treated with cardiotropic drugs and BHB) diagnosed a year previously. The patient had been rapidly extubated after LT, and was recovering well. Eight days after LT, the patient suddenly became comatose. No metabolic, immunological, hypertensive, or infectious complications were apparent. The brain magnetic resonance imaging and electroencephalography results were normal. The coma was soon attributed to a medication prescribing error: administration of GHB instead of BHB on day 8 post-LT. The patient recovered fully within a few hours of GHB withdrawal. The computerized prescription system had automatically suggested the referenced anesthetic GHB (administered intravenously) instead of the non-referenced ketone body BHB, triggering coma in our patient. A computerized prescription system generated a medication prescribing error for a rare disease, in which the general anesthetic GHB was mistaken for the nonreferenced energy substrate BHB.

Population pharmacokinetics of meropenem in critically ill children with different renal functions.

PURPOSE: We aimed to develop a meropenem population pharmacokinetic (PK) model in critically ill children and simulate dosing regimens in order to optimize patient exposure. METHODS: Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem PK was investigated using a non-linear mixed-effect modeling approach. RESULTS: Forty patients with an age of 16.8 (1.4-187.2) months, weight of 9.1 (3.8-59) kg, and estimated glomerular filtration rate (eGFR) of 151 (19-440) mL/min/1.73 m2 were included. Eleven patients received continuous replacement renal therapy (CRRT). Concentration-time courses were best described by a two-compartment model with first-order elimination. Body weight (BW), eGFR, and CRRT were covariates explaining the between-subject variabilities on central/peripheral volume of distribution (V1/V2), inter-compartment clearance (Q), and clearance (CL): V1i = V1pop × (BW/70)1, Qi = Qpop × (BW/70)0.75, V2i = V2pop × (BW/70)1, CLi = (CLpop × (BW/70)0.75) × (eGFR/100)0.378) for patients without CRRT and CLi = (CLpop × (BW/70)0.75) × 0.9 for patients with CRRT, where CLpop, V1pop, Qpop, and V2pop are 6.82 L/h, 40.6 L, 1 L/h, and 9.2 L respectively normalized to a 70-kg subject. Continuous infusion, 60 and 120 mg/kg per day, is the most adequate dosing regimen to attain the target of 50% fT > MIC and 100% fT > MIC for patients infected by bacteria with high minimum inhibitory concentration (MIC) value (> 4 mg/L) without risk of accumulation except in children with severe renal failure. CONCLUSION: Continuous infusion allows reaching the fT > MIC targets safely in children with normal or increased renal clearance.

Pulmonary hypertension after bone marrow transplantation in children.

INTRODUCTION: Pulmonary hypertension is a rare but important cause of mortality after haematopoietic stem cell transplantation (HSCT) in children. This complication is poorly characterised in the literature. We report here a series of children who developed pulmonary hypertension after HSCT. METHODS: Between January 2008 and December 2015, we retrospectively analysed 366 children who underwent HSCT (age range 0.5-252 months; median 20.3 months). During the post-HSCT course, echocardiography scans motivated by respiratory symptoms identified 31 patients with elevated tricuspid regurgitation velocity (>2.8 m·s-1), confirmed when possible by right heart catheterisation (RHC). RESULTS: 22 patients had confirmed pulmonary hypertension with mean±sd pulmonary arterial pressure 40.1±10 mmHg (range 28-62 mmHg) and pulmonary vascular resistance 17.3±9.2 Wood Units (range 8-42 Wood Units). Among the 13 responders at reactivity test, only one patient responded to calcium channel blockers. Seven patients (32%) died. 15 pulmonary hypertension patients were alive after a mean±sd follow-up of 6.5±2.3 years (range 2-10 years). All survivors could be weaned off pulmonary hypertension treatment after a median follow-up of 5 months (range 3-16). The delay between clinical symptoms and initiation of pulmonary hypertension therapy was significantly longer in patients who subsequently died (mean±sd 33.5±23 days; median 30 days) than in survivors (mean±sd 7±3 days) (p<0.001). CONCLUSION: Pulmonary hypertension is a severe complication of HSCT with an underestimated incidence and high mortality. Aggressive and timely up-front combination therapy allowed normalisation of pulmonary pressure and improved survival.

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).

Population pharmacokinetics of enoxaparin in early stage of paediatric liver transplantation.

AIMS: Preventing post-liver transplantation (LT) hepatic artery and portal vein thrombosis includes enoxaparin administration. Enoxaparin pharmacokinetics (PK) has not been investigated in children following LT. We described an enoxaparin PK model in 22 children the first week following LT. METHODS: Anti-Xa activity time-courses were analysed using a nonlinear mixed effects approach with Monolix version 2016R. RESULTS: Anti-Xa activity time-courses were well described by a one-compartment model with first order absorption and elimination. Bodyweight prior to surgery (BWPREOP ) and the related postoperative variation (BW(t)) were the main covariates explaining CL and V between subject variabilities. Parameter estimates were CLi  = CLTYP * (BWPREOP /70)3/4 ; Vi  = VTYP * (BW(t)/70)1 ; where typical clearance (CLTYP ) and typical volume of distribution (VTYP ) were 1.23 l h-1 and 14.6 l, respectively. Standard dosing regimens of 50 IU kg-1  12 h-1 were insufficient to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 . Specifically, seven children (32%) never attained the target range during the whole period of treatment and all children were at least once underdosed. According to the final results, we simulated individualized dosing regimens within 4 h following the first administration. More than 100 IU kg-1  12 h-1 are suggested to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 from the first day. CONCLUSION: Thanks to this model, the initial and maintenance doses could be assessed to rapidly achieve the target range. Higher doses per kg, especially in the youngest children, are suggested.

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.

Early Noninvasive Ventilation and Nonroutine Transfusion for Acute Chest Syndrome in Sickle Cell Disease in Children: A Descriptive Study.

OBJECTIVES: To describe the need for transfusion and short- and long-term evolutions of pediatric sickle cell disease patients with acute chest syndrome for whom early continuous noninvasive ventilation represented first-line treatment. DESIGN: Single-center retrospective chart study in PICU. SETTING: A tertiary and quaternary referral PICU. PATIENTS: All sickle cell disease patients 5-20 years old admitted with confirmed acute chest syndrome and not transfused in the previous month were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic data, laboratory and radiologic findings, transfusions, invasive ventilation, oxygen and noninvasive ventilation settings, duration of opioid treatment, length of hospital stay, and severe sickle cell disease complications in the ensuing 2 years were extracted from medical charts. Sixty-six acute chest syndrome in 48 patients were included. Continuous early noninvasive ventilation was well tolerated in 65 episodes, with positive expiratory pressure 4 cm H2O and pressure support 10 cm H2O (median) administered continuously, then discontinued during 7 days (median). No patient necessitated invasive ventilation or died. Twenty-three acute chest syndrome (35%) received transfusions; none received blood exchange. Transfused patients had more frequent upper lobe radiologic involvement, more severe anemia, higher reticulocyte counts, and higher C-reactive protein than nontransfused patients. Their evolution was more severe in terms of length of opioid requirement, length of noninvasive ventilation treatment, overall time on noninvasive ventilation, and length of stay. At 2-year follow-up after the acute chest syndrome episode, no difference was observed between the two groups. CONCLUSIONS: Early noninvasive ventilation combined with nonroutine transfusion is well tolerated in acute chest syndrome in children and may spare transfusion in some patients. Early recognition of patients still requiring transfusion is essential and warrants further studies.

Long-term metabolic follow-up and clinical outcome of 35 patients with maple syrup urine disease.

BACKGROUND: Maple syrup urine disease (MSUD) is a rare disease that requires a protein-restricted diet for successful management. Little is known, however, about the psychosocial outcome of MSUD patients. This study investigates the relationship between metabolic and clinical parameters and psychosocial outcomes in a cohort of patients with neonatal-onset MSUD. METHODS: Data on academic achievement, psychological care, family involvement, and biochemical parameters were collected from the medical records of neonatal MSUD patients treated at Necker Hospital (Paris) between 1964 and 2013. RESULTS: Thirty-five MSUD patients with a mean age of 16.3 (2.1-49.0) years participated. Metabolic decompensations (plasma leucine >380 µmol/L) were more frequent during the first year of life and after 15 years, mainly due to infection and dietary noncompliance, respectively. Leucine levels increased significantly in adulthood: 61.5% of adults were independent and achieved adequate social and professional integration; 56% needed occasional or sustained psychological or psychiatric care (8/19, with externalizing, mood, emotional, and anxiety disorders being the most common). Patients needing psychiatric care were significantly older [mean and standard deviation (SD) 22.6 (7.7) years] than patients needing only psychological follow-up [mean (SD) 14.3 (8.9) years]. Patients with psychological follow-up experienced the highest lifetime number of decompensations; 45% of families had difficulty coping with the chronic disease. Parental involvement was negatively associated with the number of lifetime decompensations. CONCLUSION: Adults had increased levels of plasma leucine, consistent with greater chronic toxicity. Psychological care was associated with age and number of decompensations. In addition, parental involvement appeared to be crucial in the management of MSUD patients.

Regional Pediatric Acute Stroke Protocol: Initial Experience During 3 Years and 13 Recanalization Treatments in Children.

BACKGROUND AND PURPOSE: To evaluate hyperacute management of pediatric arterial ischemic stroke, setting up dedicated management pathways is the first recommended step to prove the feasibility and safety of such treatments. A regional pediatric stroke alert protocol including 2 centers in the Paris-Ile-de-France area, France, was established. METHODS: Consecutive pediatric patients (28 days-18 years) with confirmed arterial ischemic stroke who had acute recanalization treatment (intravenous r-tPA [recombinant tissue-type plasminogen activator], endovascular procedure, or both) according to the regional pediatric stroke alert were retrospectively reviewed during a 40-month period. RESULTS: Thirteen children, aged 3.7 to 16.6 years, had recanalization treatment. Median time from onset to magnetic resonance imaging was 165 minutes (150-300); 9 out of 13 had large-vessel occlusion. Intravenous r-tPA was used in 11 out of 13 patients, with median time from onset to treatment of 240 minutes (178-270). Endovascular procedure was performed in patients time-out for intravenous r-tPA (n=2) or after intravenous r-tPA inefficiency (n=2). No intracranial or peripheral bleeding was reported. One patient died of malignant stroke; outcome was favorable in 11 out of 12 survivors (modified Rankin Scale score 0-2). CONCLUSIONS: Hyperacute recanalization treatment in pediatric stroke, relying on common protocols and adult/pediatric ward collaboration, is feasible. Larger systematic case collection is encouraged.

Twenty-eight years of intestinal transplantation in Paris: experience of the oldest European center.

Our aim was to describe our achievements in pediatric intestinal transplantation (ITx) and define areas for improvement. After a period (1987-1990) of nine isolated small bowel transplants (SBTx) where only one patient survived with her graft, 110 ITx were performed on 101 children from 1994 to 2014: 60 SBTx, 45 liver-small bowel, four multivisceral (three with kidneys), and one modified multivisceral. Indications were short bowel syndrome (36), motility disorders (30), congenital enteropathies (34), and others (1). Induction treatment was introduced in 2000. Patient/graft survival with a liver-containing graft or SBTx was, respectively, 60/41% and 46/11% at 18 years. Recently, graft survival at 5/10 years was 44% and 31% for liver-containing graft and 57% and 44% for SBTx. Late graft loss occurred in 13 patients, and 7 of 10 retransplanted patients died. The main causes of death and graft loss were sepsis and rejection. Among the 55 currently living patients, 21 had a liver-containing graft, 19 a SBTx (17 after induction), and 15 were on parenteral nutrition. ITx remains a difficult procedure, and retransplantation even more so. Over the long term, graft loss was due to rejection, over-immunosuppression was not a significant problem. Multicenter studies on immunosuppression and microbiota are urgently needed.