Population Pharmacokinetics of Intravenous Ganciclovir and Oral Valganciclovir in a Pediatric Population To Optimize Dosing Regimens.

Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, to optimize dosing schemes. All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using nonlinear mixed-effect modeling. Monte Carlo simulations were used to optimize the dosing regimen to maintain the area under the concentration-time curve (AUC) in the preventive or therapeutic target. Among the 105 children (374 concentration-time observations) included, 78 received intravenous (i.v.) ganciclovir, 19 received oral valganciclovir, and 6 received both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe the bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and medical status of critically ill children were significantly associated with ganciclovir elimination. Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg of body weight/day oral or 15 to 20 mg/kg/day i.v. in children with normal eGFR and to 56 mg/kg/day oral or 20 to 25 mg/kg/day i.v. in children with augmented eGFR. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.).

Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

Population Pharmacokinetics of Intravenous and Oral Acyclovir and Oral Valacyclovir in Pediatric Population To Optimize Dosing Regimens.

Acyclovir is an antiviral currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. This study aimed to characterize the pharmacokinetics (PK) of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Children receiving acyclovir or valacyclovir were included in this study. PK were described using nonlinear mixed-effect modeling. Dosing simulations were used to obtain trough concentrations above a 50% inhibitory concentration for HSV or VZV (0.56 mg/liter and 1.125 mg/liter, respectively) and maximal peak concentrations below 25 mg/liter. A total of 79 children (212 concentration-time observations) were included: 50 were taking intravenous (i.v.) acyclovir, 22 were taking oral acyclovir, and 7 were taking both i.v. and oral acyclovir, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect, and the estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination. To obtain target maximal and trough concentrations, the more suitable initial acyclovir i.v. dose was 10 mg/kg of body weight/6 h for children with normal renal function (eGFR ≤ 250 ml/min/1.73 m2) and 15 to 20 mg/kg/6 h for children with augmented renal clearance (ARC) (eGFR > 250 ml/min/1.73 m2). The 20-mg/kg/8 h dose for oral acyclovir and valacyclovir produced effective concentrations in more than 75% of children; however, a 15-mg/kg/6 h dose, if possible, is preferred. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.).

Severe atypical Lemierre syndrome caused by methicillin-sensitive Staphylococcus aureus: Two pediatric case reports.

BACKGROUND: Lemierre syndrome is typically associated with ear, nose, and throat (ENT) infections caused by Fusobacterium necrophorum. Since 2002, cases of atypical Lemierre-like syndrome secondary to Staphylococcus aureus have been reported. CASES: We report two pediatric cases of atypical Lemierre syndrome with a similar presentation: exophthalmia, absence of pharyngitis, metastatic lung infection, and intracranial venous sinus thrombosis. Both patients had a favorable outcome following treatment with antibiotics, anticoagulation, and corticosteroids. CONCLUSION: Regular therapeutic monitoring of antibiotic levels helped to optimize antimicrobial treatment in both cases.

False-Positive Ethanol Level in Urine and Plasma Samples of a Resuscitated Infant.

We report the case of an 11-month-old male infant with a complex congenital heart disease who was admitted in the intensive care unit following cardiorespiratory arrest at home. Toxicological urine screening reported an ethanol concentration of 0.65 g/L using an enzymatic assay, without suspicion of alcohol intake; a significant amount of ethanol concentration was found in two plasma samples using the same enzymatic assay. Plasma and urine ethanol concentrations were below the limit of quantification (LOQ) when tested using a gas chromatography method. Urine ethanol level was also below the LOQ when tested by enzymatic assay after an initial urine ultrafiltration. These results confirmed our suspicion of matrix interference due to elevated lactate and lactate dehydrogenase levels interfering in the enzymatic assay. This analytical interference, well-known in postmortem samples, extensively studied in vitro, has been rarely reported in vivo, especially in children. To the best of our knowledge, this case is only the sixth one reported in an infant's plasma and the first initially discovered from urine. Indeed, as for ethanol, this last matrix has not been studied in the context of this artifact that may induce false-positive ethanol results while seeking a diagnosis in life-threatening or fatal situations that are potentially subject to forensic scrutiny. In parallel to a synthetic literature review, we propose a simple, informative decision tree, in order to help health professionals suspecting a false-positive result when performing an ethanol assay.

Two pediatric cases of multisystem inflammatory-like syndrome following COVID-19 vaccination.

Multisystem inflammatory syndrome in children (MIS-C) is a novel post-infectious disease occurring in the context of SARS-CoV2 infection. COVID-19 vaccines have been authorized since December 2020, and adverse events including myocarditis have been reported following vaccination. We describe the cases of two pediatric patients presenting with clinical and laboratory features suggestive of MIS-C a few days after receiving their first dose of the Pfizer BNT162b2 vaccine. The outcome was favorable for both patients (after corticosteroid and immunoglobulin administration for one patient). These cases suggest an association between the COVID-19 vaccine and the occurrence of MIS-C.

Therapeutic approach to pediatric patients with acute chest syndrome: national multicenter survey of non invasive ventilation (NIV) and transfusion.

BACKGROUND: Intensive care units (ICUs) have seen a spike in the use of noninvasive ventilation (NIV) for many medical conditions. We sought to investigate the attitudes and clinical practice regarding the management of acute chest syndrome (ACS) with a focus on NIV in pediatric ICUs. METHOD: Members of the French Group for Pediatric Intensive Care Emergencies (GFRUP) were asked to complete an online survey on physicians' attitudes toward children with ACS admitted to the PICU during 2015. RESULTS: The survey was answered by teams from 17 PICUs (240 beds). In total, 15 centers (88%) had a local transfusion unit and 14 (82%) worked in connection with a sickle cell disease (SCD) reference center. During 2015, 360 patients with SCD were managed (median: 7 per center; 21) of whom 137 (38%) for an ACS (median: 4 ACS per center; 8). The median length of PICU stay for ACS was 5 days (3.1). Among the 137 patients who presented with ACS, 73 (53%) received simple blood transfusion and 16 (12%) received exchange transfusion. For patients who required noninvasive ventilatory support, NIV with bilevel pressure (BiPAP) was the most frequent method (n = 68, 50%), followed by continuous positive airway pressure (CPAP) (n = 23, 17%) and high-flow oxygen (n = 21, 15%). The proportion of patients on BiPAP was up to 71% in the centers most frequently managing ACS patients. CONCLUSION: BiPAP is commonly used in PICUs for SCD patients with ACS, especially in trained centers. Future physiological studies and randomized controlled trials might help to choose the best ventilatory support for ACS.

Population pharmacokinetics of cefazolin in critically ill children infected with methicillin-sensitive Staphylococcus aureus.

OBJECTIVES: Cefazolin is one of curative treatments for infections due to methicillin-sensitive Staphylococcus aureus (MSSA). Both growth and critical illness may impact the pharmacokinetic (PK) parameters. We aimed to build a population PK model for cefazolin in critically ill children in order to optimize individual dosing regimens. METHODS: We included all children (age < 18 years, body weight (BW) > 2.5 kg) receiving cefazolin for MSSA infection. Cefazolin total plasma concentrations were quantified by high-performance liquid chromatography. A data modelling process was performed with the software MONOLIX. Monte Carlo simulations were used in order to attain the PK target of 100% fT > 4 ×MIC. RESULTS: Thirty-nine patients with a median (range) age of 7 (0.1-17) years and a BW of 21 (2.8-79) kg were included. The PK was ascribed to a one-compartment model, where typical clearance and volume of distribution estimations were 1.4 L/h and 3.3 L respectively. BW, according to the allometric rules, and estimated glomerular filtration rate (eGFR) on clearance were the two influential covariates. Continuous infusion with a dosing of 100 mg/kg/day to increase to 150 mg/kg/day for children with a BW < 10 kg or eGFR >200 mL/min/1.73m2 were the best schemes to reach the PK target of 100% fT> 4 ×MIC. CONCLUSIONS: In critically ill children infected with MSSA, continuous infusion seems to be the most appropriate scheme to reach the PK target of 100 % fT > 4 ×MIC in children with normal and augmented renal function.

Diagnostic evaluation and management of seizures and status epilepticus in children with known epilepsy or new-onset seizures: A retrospective and comparative analysis.

OBJECTIVES: The purpose of this study was to describe and compare the initial management, including clinical/biological investigation and treatment, of new-onset seizures and status epilepticus (SE) in children versus seizures and SE in those with known epilepsy. METHODS: This was a retrospective, single-center, observational study conducted in an urban pediatric hospital in Paris. All patients, aged from 1 month to 18 years, admitted to the pediatric intensive care unit, the high-dependency care unit, and those who required hospitalization in the short-term unit of the emergency department between January 1 and December 31, 2014 for seizures and/or SE were included. RESULTS: We analyzed the data of 190 children: new-onset seizures (N=118; group A) versus those with known epilepsy (N=72; group B). At least one diagnostic test was performed on 156 patients (82.1%) (group A, N=104, 88.1%; group B, N=52, 72.2%; P=0.05). In group B, blood levels of antiepileptic drugs were measured in 14 of the 38 patients with SE, of whom six were under dosed. Treatments were: first line, diazepam (group A, 80%; group B, 46%; P<0.001); second line, diazepam (group A, 56%; group B, 34%; P=0.02) or clonazepam (group A, 24%; group B, 46%; P=0.001); third line, phenytoin (group A, 54%; group B, 22%; P<0.001) or clonazepam (group A, 18%; group B, 61%; P<0.001). CONCLUSION: Diagnostic evaluation and treatment should be individualized for children with known epilepsy.

Management of 35 critically ill hyperammonemic neonates: Role of early administration of metabolite scavengers and continuous hemodialysis.

Neurological involvement is frequent in inherited metabolic disease of the intoxication type. Hyperammonemic coma related to these diseases may cause severe neurological sequelae. Early optimal treatment is mandatory combining metabolite scavengers (MS) and sometimes continuous veno-venous hemodialysis (CVVHD). We aimed to describe the therapeutic management of hyperammonemia in neonates upon diagnosis of their metabolic disease and to compare neonates managed with MS alone or with both MS and CVVHD. We conducted a retrospective study including all neonates admitted for initial hyperammonemia to the pediatric intensive care unit of a Reference Center of Inherited Metabolic Diseases, between 2001 and 2012. The study included 35 neonates. Before admission, MS were initiated for 11 neonates. At admission, the median ammonia levels were 391 µmol/L and were significantly lower in neonates who received MS before admission. At admission, ammonia levels were 644 µmol/L in dialyzed and 283 µmol/L in non-dialyzed neonates. The median time to reach a 50% decrease of the initial ammonia levels was significantly shorter in dialyzed neonates; however, the normalization of ammonia levels was similar between dialyzed and non-dialyzed neonates. Hemodynamic disorders were more frequent in dialyzed neonates. CONCLUSION: MS represent an effective treatment for hyperammonemia and should be available in all pediatric units to avoid the need for CVVHD. Although CVVHD enhances the kinetics of toxic metabolite decrease, it is associated with adverse hemodynamic effects.

Severe and fatal forms of COVID-19 in children.

OBJECTIVES: The aim of this study was to describe severe forms of novel coronavirus disease 2019 in children, including patient characteristics, clinical, laboratory, and imaging findings, as well as the disease management and outcomes. METHODS: This was a retrospective, single-center, observational study conducted in a pediatric intensive and high-dependency care unit (PICU, HDU) in an urban hospital in Paris. All patients, aged from 1 month to 18 years, admitted for confirmed or highly suspected SARS-CoV-2 were included. RESULTS: We analyzed the data of 27 children. Comorbidities (n=19, 70%) were mainly neurological (n=7), respiratory, (n=4), or sickle cell disease (n=4). SARS-CoV-2 PCR results were positive in 24 children (nasopharyngeal swabs). The three remaining children had a chest CT scan consistent with COVID-19. Respiratory involvement was observed in 24 patients (89%). Supportive treatments were invasive mechanical ventilation (n=9), catecholamine (n=4), erythropheresis (n=4), renal replacement therapy (n=1), and extracorporeal membrane oxygenation (n=1). Five children died, of whom three were without past medical history. CONCLUSION: This study highlighted the large spectrum of clinical presentation and time course of disease progression as well as the non-negligible occurrence of pediatric life-threatening and fatal cases of COVID-19 mostly in patients with comorbidities. Additional laboratory investigations are needed to further analyze the mechanism underlying the variability of SARS-Cov-2 pathogenicity in children.

Report of severe accidental baclofen intoxication in a healthy 4-year-old boy and review of the literature.

The number of reports on baclofen intoxication has increased in recent years. Here we report the case of a 4-year-old boy in deep coma who was referred to the pediatric intensive care unit. The patient was intubated and mechanically ventilated. A computerized tomography scan without contrast showed a collapsed appearance of the ventricular system suggesting diffuse cerebral edema. A multichannel electroencephalogram registered 6 h after admission showed a very slow and ample continuous pattern, without structure, nonreactive to stimulations, expressing diffuse and severe nonspecific cerebral pain. A targeted analysis to determine the baclofen plasma levels was performed. Test results of plasma samples were highly positive for baclofen (2009 ng/mL). Following 36 h of mechanical ventilation, the patient rapidly regained consciousness and recovered normal neurological behavior. The present case demonstrates the importance of considering baclofen overdosage in cases of deep coma with areflexia, and emphasizes the importance of warning parents about the potential toxicity of baclofen when prescribing the drug to a family member. A review of the literature on pediatric baclofen overdose is included.

Postdiarrheal hemolytic and uremic syndrome with severe multiorgan involvement and associated early risk factors.

AIM: Identifying early clinical and biological factors associated with severe forms of postdiarrheal hemolytic uremic syndrome (D+HUS) that may help practitioners determine appropriate treatment. METHODS: This retrospective study was conducted in 49 children with D+HUS between 2001 and 2011. Severe forms were defined as occurrence of one of the following conditions: death, major neurological involvement, cardiovascular involvement, and/or the presence of sequelae (neurological, cardiovascular, pancreatic, or renal). RESULTS: During the acute phase, 35 children exhibited at least one type of extrarenal involvement including 13 severe forms with a median delayed occurrence after admission of 4.5 days (range: 1-8) for comatose children and 5 days (range: 2-6) for cardiovascular involvement; 32 children required dialysis and three died. In multivariate analysis, (i) major neurological involvement (n=13), (ii) dialysis (n=32), and (iii) sequelae (n=12) were associated with (i) fever during the prodromal phase requiring dialysis at admission, (ii) C-reactive protein level (CRP) >22mg/L at admission, and (iii) major neurological involvement and a white blood cell count (WBC)>20×103/mm3 during the acute stage, respectively. CONCLUSIONS: D+HUS is a multiorgan disease with a delayed occurrence of life-threatening extrarenal organ involvement. Severe forms appear to be associated with early biological and clinical inflammatory parameters.

[Respiratory failure in cystic fibrosis: management in pediatric intensive care unit, lung transplantation recommendation]. / Les défaillances respiratoires dans la mucoviscidose: prise en charge en réanimation; indications de la transplantation.

Admission to the ICU for respiratory failure of a child with cystic fibrosis is a telltale sign of the severity of the disease. Bronchopulmonary exacerbation, pneumothorax and hemoptysis are the primary causes, for which respiratory assistance is indispensable in these life-threatening situations. Non-invasive ventilation (NIV) has enabled significant progress in improving patient survival. The modalities of NIV must be tailored to both the patient and the cause of respiratory failure. Invasive ventilation, on the other hand, should be a treatment of last resort, because often associated with high mortality. It must be adapted to the therapeutic strategy involving an impending transplantation, including in critical situations where placement on a high emergency list is a possibility. Since admission to ICU is at times the reflection of the terminal evolution of the disease, ongoing treatment must hence be adapted to the comfort of the child.

[Local salicylate transcutaneous absorption: an unrecognized risk of severe intoxication: a case report]. / Application cutanée localisée d'acide salicylique : un risque méconnu d'intoxication : à propos d'un cas.

INTRODUCTION: Although rare, salicylate intoxication through the skin should not be ignored as it can be severely life-threatening. We describe an original case of accidental poisoning with salicylates topically applied to the scalp of a 6-week-old infant. CLINICAL REPORT: A 6-week-old infant, with no prior history, was admitted to the pediatric intensive care unit for treatment of severe disorders of consciousness associated with significant tachypnea. Laboratory results revealed metabolic acidosis with elevated anion gap, ketonuria, and normal glycemia. Initial assessment ruled out the hypothesis of accidental ingestion of salicylates. However, the presence of salicylic acid derivatives in organic acid chromatography, confirmed by plasma salicylate levels at 580 mg/L, ultimately re-established the diagnosis. Further inquiry retrospectively highlighted the prolonged topical application in occlusion (3 days) of an extemporaneous preparation containing 23% salicylic acid on the scalp. The course after urine alkalinization was rapidly favorable without sequelae. COMMENT AND CONCLUSIONS: Salicylate intoxication is potentially lethal, particularly in infants under 12 months of age. The vast majority of these intoxications result from accidental ingestion. The present observation underscores the original and undescribed risk of intoxication due to a localized application to the scalp. In the presence of warning symptoms, salicylate poisoning should be investigated, including topical application of salicylic acid, even if localized. Careful attention should be paid to following the indications of use of this product in terms of concentration, characteristics of the infant, and exposed skin. The use of extended topical application of salicylic acid in concentrations greater than 3% should be avoided.

[Stop of antibiotic prophylaxis in mild/moderate grade vesico-ureteral reflux]. / Arrêt de l'antibioprophylaxie urinaire dans les reflux vésico-urétéraux de grade I, II ou III.

UNLABELLED: Vesicoureteric reflux (VUR) is found in about 30 % of children with pyelonephritis (PN). It has been identified as a risk factor for the development of urinary tract infections, renal scars, hypertension and chronic renal failure but this risk is considerably smaller than previously assumed. Currently the therapeutic option was to use an antibiotic prophylaxis in order to keep the urinary tract sterile in order to prevent pyelonephritis and new renal scars. The review of the available data has shown that the antibiotic prophylaxis therapy is subject to discussion. The aim of this study was to evaluate the follow up of children with low-grade reflux before and after stopping the urinary antibiotic prophylaxis as soon as they became toilet-trained. METHODS: Fifty-eight children with low-grade reflux (grade I, II, III) were enrolled in this study. The follow up ranged from October 2002 till February 2007. The children who have not attained bladder control received antibiotic prophylaxis. This treatment was stopped as soon as they became toilet-trained. The presence of urinary tract infection (UTI) was considered in case of unexplained fever and urinalysis and urine culture were performed. RESULTS: VUR, mainly grade II, was discovered at a median age of 16 months. The prophylaxis was stopped at a median age of 40 months. The follow up after stopping the antibacterial prophylaxis was 27 months. Under treatment 2 pyelonephritis occurred, without treatment 2 pyelonephritis and 3 cystitis were diagnosed. At the end of the follow up, the grade of reflux decreased in half of the cases and disappeared in 3 cases. CONCLUSION: By stopping the urinary antibiotic prophylaxis in children with mild/moderate grade VUR when they became toilet-trained, there is no increase of the incidence of UTI, pyelonephritis. This study does not support the role for urinary antibiotic prophylaxis in preventing the recurrence of pyelonephritis.