Dick Tibboel

Potent Inhibition of Estrogen Sulfotransferase by Hydroxylated Metabolites of Polyhalogenated Aromatic Hydrocarbons Reveals Alternative Mechanism for Estrogenic Activity of Endocrine Disrupters

Polyhalogenated aromatic hydrocarbons (PHAHs), such as polychlorinated dibenzo-p-dioxins and dibenzofurans, polybrominated diphenylethers, and bisphenol A derivatives are persistent environmental pollutants, which are capable of interfering with reproductive and endocrine function in birds, fish, reptiles, and mammals. PHAHs exert estrogenic effects that may be mediated in part by their hydroxylated metabolites (PHAH-OHs), the mechanisms of which remain to be identified. PHAH-OHs show low affinity for the ER. Alternatively, they may exert their estrogenic effects by inhibiting E2 metabolism. As sulfation of E2 by estrogen sulfotransferase (SULT1E1) is an important pathway for E2 inactivation, inhibition of SULT1E1 may lead to an increased bioavailability of estrogens in tissues expressing this enzyme. Therefore, we studied the possible inhibition of human SULT1E1 by hydroxylated PHAH metabolites and the sulfation of the different compounds by SULT1E1. We found marked inhibition of SULT1E1 by various PHAH-OHs, in particular by compounds with two adjacent halogen substituents around the hydroxyl group that were effective at (sub)nanomolar concentrations. Depending on the structure, the inhibition is primarily competitive or noncompetitive. Most PHAH-OHs are also sulfated by SULT1E1. We also investigated the inhibitory effects of the various PHAH-OHs on E2 sulfation by human liver cytosol and found that the effects were strongly correlated with their inhibitions of recombinant SULT1E1 (r = 0.922). Based on these results, we hypothesize that hydroxylated PHAHs exert their estrogenic effects at least in part by inhibiting SULT1E1-catalyzed E2 sulfation.

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe

Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity. To date, there are no standardized protocols for the treatment of infants with this anomaly. However, protocols based on the literature and expert opinion might improve outcome. This paper is a consensus statement from the CDH EURO Consortium prepared with the aim of achieving standardized postnatal treatment in European countries. During a consensus meeting between high-volume centers with expertise in the treatment of CDH in Europe (CDH EURO Consortium), the most recent literature on CDH was discussed. Thereafter, 5 experts graded the studies according to the Scottish Intercollegiate Guidelines Network (SIGN) Criteria. Differences in opinion were discussed until full consensus was reached. The final consensus statement, therefore, represents the opinion of all consortium members. Multicenter randomized controlled trials on CDH are lacking. Use of a standardized protocol, however, may contribute to more valid comparisons of patient data in multicenter studies and identification of areas for further research.

Interdisciplinary structural follow-up of surgical newborns: a prospective evaluation

BACKGROUND Information on physical and developmental outcomes of children with anatomical congenital anomalies (CAs) may indicate the need for early intervention and reduce impact on the childs life and parental burden. METHODS From 1999 to 2003, 101 children with CA (76.5% of initial survivors) were seen 6-monthly in a tertiary childrens hospital. Growth, neurologic outcome, mental and psychomotor development as determined with the Bayley Scales of Infant Development, and categorization of predictive sociodemographic and medical variables of the children were evaluated prospectively and longitudinally. RESULTS Congenital diaphragmatic hernia (CDH) and esophageal atresia patients showed impaired growth, that is, both height for age (-1.5 standard deviation score [SDS]) and weight for height (-1.0 SDS). Overall neurologic outcome was normal, however, suspect or abnormal for 40% of CDH patients. Overall mental development was normal, but psychomotor scores were significantly lower than the norm (95% confidence interval, 83.8-92.2 at 6 months and 87.9-98.5 at 24 months). Sex, maternal age, socioeconomic status, CA, severity-of-disease covariables, and need of medical appliances at home could predict negative outcome significantly (P < .05). CONCLUSIONS The CA survivors show impaired growth and psychomotor developmental delay up to age 2 years. This warrants specific follow-up programs and infrastructure for these patients.

A prospective comparative evaluation of persistent respiratory morbidity in esophageal atresia and congenital diaphragmatic hernia survivors

PURPOSE The aim of the study was to compare long-term respiratory morbidity in children after repair of esophageal atresia (EA) or congenital diaphragmatic hernia (CDH). PATIENTS AND METHODS Children were seen at 6, 12, and 24 months and 5 years within a prospective longitudinal follow-up program in a tertiary childrens hospital. Respiratory morbidity and physical condition were evaluated at all moments. At age 5 years, pulmonary function and maximal exercise performance were tested. RESULTS In 3 of 23 atresia patients and 10 of 20 hernia patients, bronchopulmonary dysplasia was developed. Seventeen atresia and 11 hernia patients had recurrent respiratory tract infections mainly in the first years of life. At age 5, 25% of EA and CDH patients measured showed reduced forced expiratory volume in 1 second (z-score < -2). Both atresia and hernia patients showed impaired growth, with catch-up growth at 5 years in patients with EA but not in those with hernia. Maximal exercise performance was significantly below normal for both groups. CONCLUSIONS Esophageal atresia and CDH are associated with equal risk of long-term respiratory morbidity, growth impairment, and disturbed maximal exercise performance. Prospective follow-up of EA patients aimed at identifying respiratory problems other than tracheomalacia should be an integral part of interdisciplinary follow-up programs.

TGF-β signaling is dynamically regulated during the alveolarization of rodent and human lungs

Although transforming growth factor‐beta (TGF‐β) signaling negatively regulates branching morphogenesis in early lung development, few studies to date have addressed the role of this family of growth factors during late lung development. We describe here that the expression, tissue localization, and activity of components of the TGF‐β signaling machinery are dynamically regulated during late lung development in the mouse and human. Pronounced changes in the expression and localization of the TGF‐β receptors Acvrl1, Tgfbr1, Tgfbr2, Tgfbr3, and endoglin, and the intracellular messengers Smad2, Smad3, Smad4, Smad6, and Smad7 were noted as mouse and human lungs progressed through the canalicular, saccular, and alveolar stages of development. TGF‐β signaling, assessed by phosphorylation of Smad2, was detected in the vascular and airway smooth muscle, as well as the alveolar and airway epithelium throughout late lung development. These data suggest that active TGF‐β signaling is required for normal late lung development. Developmental Dynamics 237:259–269, 2008.

Population Pharmacokinetics of Midazolam and Its Metabolites during Venoarterial Extracorporeal Membrane Oxygenation in Neonates

Background and ObjectiveMidazolam is used to sedate children during extracorporeal membrane oxygenation (ECMO). Pharmacokinetic changes are expected because of extracorporeal circulation and maturation. We present a population pharmacokinetic model for midazolam and its major metabolites in neonates during venoarterial ECMO.MethodsWe studied 20 neonates on venoarterial ECMO, with a median postnatal age of 0.79 (range 0.17–5.8) days and a bodyweight of 3.0 (range 2.7–3.9) kg at the onset of ECMO. The median ECMO duration was 124 (range 70–275) hours. Serum concentrations were measured at the initiation and discontinuation of the midazolam infusion (100–300 μg/kg/h). Analysis of concentrations of midazolam, 1-hydroxymidazolam and its glucuronide were performed using nonlinear mixed-effects modelling. A two-compartment model for midazolam and a one-compartment model for the metabolites 1-hydroxymidazolam and hydroxymidazolam glucuronide adequately described the data, with allometric scaling of all parameters.ResultsFollowing the start of ECMO, the volume of distribution of midazolam increased from 4.29 to 14.6 L/3kg, with an elimination half-life of 1.85 hours. The median midazolam and 1-hydroxymidazolam clearance values increased 3-fold within the first 5 days (up to 1.38 and 5.31 L/h/3 kg, respectively), whereas hydroxymidazolam glucuronide clearance remained constant at 0.18 L/h/3 kg. Interpatient variability estimates of midazolam, 1-hydroxymidazolam and hydroxymidazolam glucuronide clearance and midazolam and hydroxymidazolam glucuronide volumes of distribution varied between 87% and 129%. Concomitant inotropic infusion increased hydroxymidazolam glucuronide clearance by 23%.ConclusionAfter allometric scaling, clearance of midazolam and 1-hydroxymidazolam increases as a result of maturation or recovery from critical illness. In ECMO patients weighing 2.7–3.9 kg, continuously infused midazolam doses of 300 μg/kg/h for 6 hours and 150 μg/kg/h thereafter provide adequate serum concentrations for sedation. The dose must be increased substantially after 5–7 days. Hydroxymidazolam glucuronide accumulates during ECMO, providing an increased proportion of the overall effect, up to 34% after 7 days. Large unexplained interpatient variability warrants careful titration of sedation and adverse effects.

Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial).

Objectives:To determine the optimal initial ventilation mode in congenital diaphragmatic hernia. Background:Congenital diaphragmatic hernia is a life-threatening anomaly with significant mortality and morbidity. The maldeveloped lungs have a high susceptibility for oxygen and ventilation damage resulting in a high incidence of bronchopulmonary dysplasia (BPD) and chronic respiratory morbidity. Methods:An international, multicenter study (NTR 1310), the VICI-trial was performed in prenatally diagnosed congenital diaphragmatic hernia infants (n = 171) born between November 2008 and December 2013, who were randomized for initial ventilation strategy. Results:Ninety-one (53.2%) patients initially received conventional mechanical ventilation and 80 (46.8%) high-frequency oscillation. Forty-one patients (45.1%) randomized to conventional mechanical ventilation died/ had BPD compared with 43 patients (53.8%) in the high-frequency oscillation group. An odds ratio of 0.62 [95% confidence interval (95% CI) 0.25–1.55] (P = 0.31) for death/BPD for conventional mechanical ventilation vs high-frequency oscillation was demonstrated, after adjustment for center, head-lung ratio, side of the defect, and liver position. Patients initially ventilated by conventional mechanical ventilation were ventilated for fewer days (P = 0.03), less often needed extracorporeal membrane oxygenation support (P = 0.007), inhaled nitric oxide (P = 0.045), sildenafil (P = 0.004), had a shorter duration of vasoactive drugs (P = 0.02), and less often failed treatment (P = 0.01) as compared with infants initially ventilated by high-frequency oscillation. Conclusions:Our results show no statistically significant difference in the combined outcome of mortality or BPD between the 2 ventilation groups in prenatally diagnosed congenital diaphragmatic hernia infants. Other outcomes, including shorter ventilation time and lesser need of extracorporeal membrane oxygenation, favored conventional ventilation.

Remodeling of pulmonary arteries in human congenital diaphragmatic hernia with or without extracorporeal membrane oxygenation

PURPOSE The aim of this study was to describe in detail the perinatal developmental profile of the pulmonary vasculature in congenital diaphragmatic hernia (CDH) and to examine the potential beneficial effects of extracorporeal membrane oxygenation (ECMO) on the vascular morphology. Additionally the authors aimed to identify the differences in pulmonary vascular morphology among CDH cases according to the primary cause of death: either extreme lung hypoplasia (LH) or persistent pulmonary hypertension (PPH). METHODS The authors studied autopsy sections from 30 high-risk CDH cases with respect to the pulmonary arteries in relation to gestational age (GA) and ECMO treatment. They were grouped into CDH-I: 20 cases with GA greater than 34 weeks who were not subjected to ECMO and CDH-II: 10 cases with GA greater than 34 weeks, who were subjected to ECMO for an average time of 237 hours. Five age-matched neonates who died from placental insufficiency or birth asphyxia without evidence of lung hypoplasia served as controls (CON). Medial and adventitial thicknesses of pulmonary arteries were measured in lung sections stained with Elastic van Gieson by 2 investigators blinded for the clinical data. Immunohistological staining with anti-alpha-smooth muscle actin (alpha-SMA) was performed to confirm the precise location of the arterial media before morphometry. CDH cases were subgrouped and compared according to the primary cause of death. Unpaired Student t test was used for statistics, with significant P value < or =.05. RESULTS In CDH newborns, a significant increase in medial, adventitial, and total wall thickness was found in pulmonary arteries with an external diameter of less than 200 microm as compared with age-matched controls (P<.004, .0001, and .0009, respectively). ECMO-treated CDH newborns showed a significantly thinner arterial adventitia than CDH patients who did not receive this treatment (P<.0001), approaching normal values. However, the medial thickness remained increased. Morphometrically, no significant differences in CDH cases between patients dying of PPH or severe LH could be determined. CONCLUSIONS (1) In CDH, there is failure of the normal arterial remodeling processes occurring in the perinatal period. (2) Pulmonary vascular morphology in CDH does not differ between the groups with lung hypoplasia or persistent pulmonary hypertension as primary cause of death. (3) Adventitial thinning of these arteries might be one of the mechanisms by which ECMO alters PPH in CDH cases.

The COMFORT-behavior scale is useful to assess pain and distress in 0- to 3-year-old children with Down syndrome.

Summary Psychometric properties of the COMFORT‐Behavior scale were comparable between 0‐ to 3‐year‐old children with and without Down syndrome. ABSTRACT Many pediatric intensive care units use the COMFORT‐Behavior scale (COMFORT‐B) to assess pain in 0‐ to 3‐year‐old children. The objective of this study was to determine whether this scale is also valid for the assessment of pain in 0‐ to 3‐year‐old children with Down syndrome. These children often undergo cardiac or intestinal surgery early in life and therefore admission to a pediatric intensive care unit. Seventy‐six patients with Down syndrome were included and 466 without Down syndrome. Pain was regularly assessed with the COMFORT‐B scale and the pain Numeric Rating Scale (NRS). For either group, confirmatory factor analyses revealed a 1‐factor model. Internal consistency between COMFORT‐B items was good (Cronbach’s α = 0.84–0.87). Cutoff values for the COMFORT‐B set at 17 or higher discriminated between pain (NRS pain of 4 or higher) and no pain (NRS pain below 4) in both groups. We concluded that the COMFORT‐B scale is also valid for 0‐ to 3‐year‐old children with Down syndrome. This makes it even more useful in the pediatric intensive care unit setting, doing away with the need to apply another instrument for those children younger than 3.

Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube

Objective To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2–5 kg) with pulmonary hypertension (PH). Design We included 11 neonates (body weight 2–5 kg, postnatal age 2–121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics. Results A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC24 (SIL+DMS)) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC24 (SIL+DMS) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC24 (SIL+DMS) range (10th and 90th percentiles) of 1000–8000 ng/h/ml. Conclusions SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5–2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.