Pharmacokinetic profile of acyclovir in a child receiving continuous kidney replacement therapy for acute liver failure.

BACKGROUND: Continuous venovenous hemodiafiltration (CVVHDF) is one of the treatments of critically ill children presenting severe acute liver failure. This affliction might be induced by HSV infection requiring a treatment by acyclovir. Continuous kidney replacement therapy (CKRT) can alter its pharmacokinetics, according to its physicochemical properties and CVVHDF settings. CASE-DIAGNOSIS/TREATMENT: The patient was a 21-month-old female presenting liver failure with hyperammonemia treated by acyclovir with presumed HSV infection. CKRT was initiated on day 1 with substantial replacement and dialysate flow rates (respectively 75 and 220 mL/kg/h). Acyclovir was intravenously administered every 8 h with a 1-h infusion of 500 mg/m2. Plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry assay to estimate the area under a curve (AUC) and CKRT clearance by 2 methods (one based on pre- and post-filter concentrations and the other one on dialysate flow rates). Clearance was estimated between 19.2 and 26.3 mL/min with the first method and between 27.6 and 44.3 mL/min with the second one. Concentrations were highly above the therapeutic index (peak concentration was measured at 28 mg/L), but AUC was appropriate. CONCLUSIONS: This case describes acyclovir pharmacokinetics during CKRT in a pediatric patient treated by acyclovir. The patient was treated with adapted exposure with the usual dosing, but lower dosing should be investigated with complementary studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02539407.

What are the clues for an inherited metabolic disorder in Reye syndrome? A single Centre study of 58 children.

OBJECTIVES: Reye Syndrome is an acute encephalopathy with increased liver enzymes and blood ammonia, without jaundice. The prevalence of an underlying inherited metabolic disorder (IMD) is unclear, nor the clinical or biological factors directing toward this diagnosis. Our aims were to define these clues in a large series of patients. PATIENTS AND METHODS: We retrospectively studied all patients with Reye admitted in our institution from 1995. We defined 3 groups: Group 1 with a confirmed IMD, Group 2 considered as free of IMD, Group 3 unclassified. Statistical analysis compared patients in Groups 1 and 2, to find criteria for a diagnosis of IMD. RESULTS: Fifty-eight children were included; 41 (71%) had a confirmed IMD, 12 (20%) were free of IMD, and 5 remained unclassified. IMDs included Urea Cycle Disorders (51%), Fatty-Acid Oxidation Disorders (24%), ketogenesis defects (5%), other mitochondrial energy metabolism defects (10%), NBAS mutation (7%), Glycosylation Disorders (2%). In Group 2, the trigger was a viral infection, or a drug, deferasirox in three children. Univariate analysis showed that onset before 2 years-old, recurrent Reye and the association with rhabdomyolysis were significantly associated with IMD. Blood ammonia was a poor discriminating marker. All children were admitted into the intensive care unit, 23% needed continuous venovenous hemodialysis and one died from brain oedema. CONCLUSION: Metabolic tests should be performed early in all cases of Reye, regardless of triggers. As they can be inconclusive, we suggest to systematically go to Next-Generation Sequencing study. These children should be transferred early to a specialized unit.

Hepatobiliary Complications in Children with Sickle Cell Disease: A Retrospective Review of Medical Records from 616 Patients.

Hepatobiliary complications in children with sickle cell disease (SCD) are rarely reported but can be life-threatening. We retrospectively assessed their prevalence in a cohort of 616 children followed in a French university-hospital SCD reference center. Eligibility criteria were the following: age <18 years, seen at least twice with an interval of more than 6 months from January 2008 to December 2017, with all genotypes of SCD. Patients with hepatobiliary complications were identified via the local data warehouse and medical files were thoroughly reviewed. At least one hepatobiliary complication was reported in 37% of the children. The most frequent was cholelithiasis, in 25% of cases, which led to systematic screening and elective cholecystectomy in the case of gallstones. Overall, 6% of the children experienced acute sickle cell hepatic crisis, sickle cell intra-hepatic cholestasis, or acute hepatic sequestration, with severity ranging from mild liver pain and increased jaundice to multiple organ failure and death. Emergency treatment was exchange transfusion, which led to normalization of liver tests in most cases. Five children had chronic cholangiopathy, associated with auto-immune hepatitis in two cases. One needed liver transplantation, having a good outcome but with many complications. Transfusion iron load and infectious hepatitis cases were mild. Hepatotoxicity of an iron chelator was suspected to contribute to abnormal liver test results in five patients. We propose recommendations to prevent, explore, and treat hepatobiliary complications in SCD children. We underline the need for emergency exchange transfusion when acute liver failure develops and warn against liver biopsy and transplantation in this condition.

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.

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

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

Breastfeeding disruption during hospitalisation for bronchiolitis in children: a telephone survey.

BACKGROUND: Hospitalisation for an acute bronchiolitis might lead to unwanted weaning off breast feeding for several reasons (respiratory distress, use of enteral or parenteral feeding, mothers tiredness, among others), yet it has never been really evaluated or quantified. METHODS: We conducted this telephone survey to evaluate breastfeeding disruption during hospitalisation for bronchiolitis and try to identify its determining factors for future interventions. This cross-sectional study extends over one epidemic season of bronchiolitis in a tertiary care hospital. All patients aged 6 months or younger hospitalised with acute bronchiolitis and receiving at least partial breast feeding were eligible for the study (n=144). Patients discharged home whose parents accepted to be contacted for a phone survey were included. Parents were contacted 3 months (range 0.5-6) after discharge. RESULTS: Eighty-four patients were included in the study. Median length of hospital stay was 3 days (1; 34), and 27 patients spent some time in paediatric intensive care unit. Forty-three mothers stated that hospitalisation modified their breast feeding (17 stopped, 12 switched to partial breast feeding and 14 reduced without stopping). Mothers stated that the causes of breastfeeding disturbance were lack of support and advices (n=27) followed by child's respiratory disease (n=14), logistic hospital difficulties (n=13) and personal organisation issues (n=4). CONCLUSION: Admission to hospital with bronchiolitis may adversely affect breast feeding. Correct advices and support could be a determining factor, and further studies should focus on preventive interventions.

Delayed hemolytic transfusion reaction in children with sickle cell disease.

BACKGROUND: Transfusion is a cornerstone of the management of sickle cell disease but carries a high risk of hemolytic transfusion reaction, probably because of differences in erythrocyte antigens between blood donors of European descent and patients of African descent. Patients may experience hemolytic transfusion reactions that are delayed by from a few days to two weeks and manifest as acute hemolysis (hemoglobinuria, jaundice, and pallor), symptoms suggesting severe vaso-occlusive crisis (pain, fever, and acute chest syndrome), and profound anemia, often with reticulocytopenia. This case-series study aims to describe the main characteristics of this syndrome, to discuss its pathophysiology, and to propose a management strategy. DESIGN AND METHODS: We identified 8 pediatric cases of delayed hemolytic transfusion reactions between 2006 and 2009 in the database of the Necker Hospital, France. All patients had received cross-matched red cell units compatible in the ABO, RH, and KEL systems. We reviewed the medical charts in the computerized blood transfusion databases. All patients were admitted to the intensive care unit. We progressively adopted the following strategy: intravenous immunoglobulins, and darbopoietin alpha when the reticulocyte count was below 150×10(9)/L, without further blood transfusion during the acute episode unless absolutely necessary. RESULTS: The median time between the transfusion and the diagnosis of delayed hemolytic transfusion reaction was six days. All patients had severe bone pain; all but one had a high-grade fever. Five patients had hemoglobin levels less than than 4 g/dL and 3 had reticulocytopenia. In 5 patients, no new antibody was found; one patient had weakly reactive antibodies. Only 2 patients had new allo-antibodies possibly responsible for the delayed hemolytic reaction. CONCLUSIONS: The initial symptoms of delayed hemolytic transfusion reaction were complex and mimicked other complications of sickle cell disease. In most of our cases, no new antibody was identified, which underlines the complexity of the pathophysiology of this syndrome.

Newborns' cord blood plasma cotinine concentrations are similar to that of their delivering smoking mothers.

BACKGROUND: In utero exposure to constituents of tobacco smoke has perinatal and postnatal health consequences. Umbilical cord plasma cotinine levels have been shown to correlate with self-reported daily number of cigarettes at the end of pregnancy, but the exact relationship between maternal and newborn plasma cotinine (and nicotine) is unknown. METHODS: Concentrations of cotinine, nicotine's main metabolite, were determined in venous blood of delivering mothers and in arterial umbilical cord blood of their newborns at birth. Data from eighteen mother-newborn dyads were analyzed. RESULTS: The mothers smoked 95.1 (SD=96, range 10-420) cigarettes the week preceding delivery. Their mean plasma cotinine concentration at delivery was 106 ng/mL (SD=53, range 17-245) and the newborns' mean umbilical cord plasma cotinine was 88.2 ng/mL (SD=53, range 10-198, p<0.001). The difference can be explained by the elimination time of around 6h which occurred between sampling in mothers and in umbilical cord blood. Arterial umbilical cord blood plasma cotinine was highly associated with that of the smoking mothers: y=0.79x+0.97, Rsq=0.95, p<0.001. CONCLUSIONS: Maternal and newborn plasma cotinine concentrations are strongly associated. There is probably no placental barrier for plasma cotinine between pregnant mothers and their newborns. Lack of a placental barrier for cotinine (and probably nicotine) can partially explain smoking related perinatal disorders.

Reduced monoamine oxidase A activity in pregnant smokers and in their newborns.

BACKGROUND: Tobacco smoking is associated with reduced monoamine oxidase A (MAOA) activity. Smoking-associated low MAOA activities in pregnancy and in newborns may have negative perinatal and postnatal consequences. We aimed to compare, in everyday clinical conditions, biomarkers of MAOA activity in smoking (SPW) and lifetime nonsmoking pregnant women (NSPW) and in cord blood and to assess the newborns' behavior during the first 48 hours of life. METHODS: Thirty SPW and 29 NSPW in their second trimester of pregnancy were included. Plasma MAOA dependent metabolites of norepinephrine: dihydroxyphenylglycol; dopamine: homovanillic and dihydroxyphenylacetic acid; and serotonin: 5-hydroxy-indol acetic acid were measured at the end of the second trimester, at delivery, and in arterial cord blood along with plasma cotinine. The newborns' discomfort was evaluated every 8 hours by a standardized questionnaire. RESULTS: The SPW smoked, on average, 73 cigarettes per week at the end of second trimester and 80 cigarettes per week at delivery. Mean plasma cotinine was 84 ng/mL, 105 ng/mL, and 95 ng/mL at the end of second trimester, at delivery, and in cord blood, respectively (NSPW < 10 ng/mL). Plasma markers of MAOA activity, in particular those reflecting dopamine's catabolism, were significantly lower in SPW and in the arterial cord blood of their newborns than in NSPW and their newborns. Newborns of SPW showed significantly more facial discomfort than those of NSPW. CONCLUSIONS: Smoking is associated with MAOA inhibition in pregnant women and in their newborns at birth. Further studies are needed to estimate the behavioral significance of these findings.

Mycoplasma pneumoniae and asthma in children.

The aim of this prospective study of a population of children (age, 2-15 years) hospitalized for severe asthma was to test them for acute infection due to Mycoplasma pneumoniae and acute infection due to Chlamydia pneumoniae. Of 119 patients with previously diagnosed asthma, acute M. pneumoniae infection was found in 24 (20%) and C. pneumoniae infection was found in 4 (3.4%) of the patients during the current exacerbation. Of 51 patients experiencing their first asthma attack, acute M. pneumoniae infection was proven in 26 (50%) of the patients (P<.01) and C. pneumoniae in 4 (8.3%). In the control group of 152 children with stable asthma or rhinitis, 8 (5.2%) had M. pneumoniae infection (P<.005). Of the 29 patients experiencing their first asthma attack and infected with M. pneumoniae or C. pneumoniae, 18 (62%) had asthma recurrences but only 6 (27%) of the 22 patients who did not have such infections had asthma recurrences (P<.05). M. pneumoniae may play a role in the onset of asthma in predisposed children and could be a trigger for recurrent wheezing.