Anne Debeer

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.

Pharmacokinetics of single dose intravenous propacetamol in neonates: effect of gestational age

Aim: To investigate the pharmacokinetics and pharmacodynamics of single dose propacetamol in preterm and term infants on the first day of life. Methods: Neonates were stratified by gestational age. Preterm (< 37 weeks) and term (37–41 weeks) infants received a single dose of propacetamol in the first 24 hours of life when they had minor, painful procedures or as additional treatment in infants receiving opioids. Blood samples were taken from an arterial line, and pain was evaluated by a multidimensional pain scale. Results were reported as mean (SD). Student’s t and Wilcoxon tests were used to compare the groups. Results: Thirty neonates were included, 10 of which were term infants. Serum half life was 277 (143) minutes in the preterm infants and 172 (59) minutes in the term infants (p < 0.05). Clearance was 0.116 (0.08) litre/kg/h in the preterm infants and 0.170 (0.06) litre/kg/h in the term infants (p < 0.05). Gestational age correlated with serum half life (r = −0.46). No effect of sex or administration of prenatal steroids was found on the pharmacokinetics of paracetamol. In neonates who only received propacetamol (n = 15), the level of analgesia seemed to be associated with the therapeutic (> 5 mg/l) level. Conclusions: A correlation was found between gestational age and the serum half life of propacetamol. The maturational trend of clearance and half life in preterm and term neonates is in line with data on the pharmacokinetics of propacetamol beyond the newborn period.

Prenatal diagnosis, prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) can be associated with genetic or structural anomalies with poor prognosis. In isolated cases, survival is dependent on the degree of lung hypoplasia and liver position. Cases should be referred in utero to tertiary care centers familiar with this condition both for prediction of outcome as well as timed delivery. The best validated prognostic indicator is the lung area to head circumference ratio. Ultrasound is used to measure the lung area of the index case, which is then expressed as a proportion of what is expected normally (observed/expected LHR). When O/E LHR is < 25% survival chances are < 15%. Prenatal intervention, aiming to stimulate lung growth, can be achieved by temporary fetal endoscopic tracheal occlusion (FETO). A balloon is percutaneously inserted into the trachea at 26–28 weeks, and reversal of occlusion is planned at 34 weeks. Growing experience has demonstrated the feasibility and safety of the technique with a survival rate of about 50%. The lung response to, and outcome after FETO, is dependent on pre‐existing lung size as well gestational age at birth. Early data show that FETO does not increase morbidity in survivors, when compared to historical controls. Several trials are currently under design. Copyright

Perinatal growth characteristics and associated risk of developing threshold retinopathy of prematurity.

PURPOSE To document perinatal growth characteristics in infants who developed threshold retinopathy of prematurity (ROP) in an attempt to describe prenatal and postnatal growth-related risk factors for threshold ROP. METHODS To document birth weight as well as absolute and relative weight gain (g/d and g/kg/d) in the first 6 weeks of life in infants who developed threshold ROP and who were admitted to a single tertiary neonatal intensive care unit between 1996 and 2000. These data were compared (case-control approach) with infants of the same gestational age (GA) who did not developed threshold ROP. RESULTS Small for gestational age (SGA; ie, weight <10th percentile for a given GA) and growth restriction (<25th percentile for a given GA) are risk factors for threshold ROP (relative risk = 3.7 and 4.5, respectively). Absolute weight gain (g/d) is also associated with an increased risk of developing threshold ROP (P<.05). In contrast, relative weight gain (g/kg/d) is not significantly different between threshold ROP infants and GA-matched controls. CONCLUSIONS SGA and a birth weight below the 25(th) percentile are risk factors for threshold ROP. Postnatal weight and absolute weight gain (g and g/d, respectively) in the first 6 weeks of life are statistically significant but of less clinical relevance because smaller infants at birth stay relatively smaller during the first 6 weeks of life. Even with normal (ie, same weight as control infants) postnatal relative weight gain (g/kg/d), growth retarded or restricted infants at birth still have an increased risk of developing threshold ROP.

DEVELOPMENTAL PHARMACOLOGY: NEONATES ARE NOT JUST SMALL ADULTS…

Abstract Neonatal drug dosing needs to be based on the physiological characteristics of the newborn and the pharmacokinetic parameters of the drug. Size-related changes can in part be modelled based on allometry and relates to the observation that metabolic rate relates to weight by a kg0.75 trend. Until adult metabolic activity has been reached, ontogeny, i.e. isoenzyme-specific maturation and maturation of renal clearance also contributes to drug metabolism, making isoenzyme-specific documentation of maturation necessary. Changes in body composition and ontogeny are most prominent in neonates. The body fat content (/kg) is markedly lower and the body water content (/kg) is markedly higher in neonates. These findings have an impact on the distribution volume of both lipophilic and hydrophilic drugs. Drugs are cleared either by metabolism or elimination. While the first is mainly hepatic, the second route is mainly renal. Both hepatic metabolism and renal clearance display maturation in early life although other covariables (e.g. polymorphisms, co-administration of drugs, first pass metabolism, disease characteristics) further contribute to the interindividual variability in drug disposition. Documentation of these maturational processes based on in vivo ‘case’ studies is of value since these drug-specific observations can subsequently be extrapolated to other drugs which are either already being prescribed or even considered for use in neonates by the introduction of these observations in ‘generic physiologically-based pharmacokinetic’ models.

Changing Perspectives on the Perinatal Management of Isolated Congenital Diaphragmatic Hernia in Europe

Congenital diaphragmatic hernia (CDH) should be diagnosed in the prenatal period and prompt referral to a tertiary referral center for imaging, genetic testing, and multidisciplinary counseling. Individual prediction of prognosis is based on the absence of additional anomalies, lung size, and liver herniation. In severe cases, a prenatal endotracheal balloon procedure is currently being offered at specialized centers. Fetal intervention is now also offered to milder cases within a trial, hypothesizing that this may reduce the occurrence of bronchopulmonary dysplasia in survivors. Postnatal management has been standardized by European high-volume centers for the purpose of this and other trials.

Prenatal intervention for isolated congenital diaphragmatic hernia.

Purpose of review We aim to review the recent literature regarding early prenatal prediction of outcome in babies diagnosed with isolated congenital diaphragmatic hernia, as well as results of fetal therapy for this condition. Recent findings Current survival rates in population-based studies are around 55–70%. Highly specialized centers report 80% and more, but discount the hidden mortality, mainly in the antenatal period. Fetuses presenting with liver herniation and a lung-to-head ratio of less than 1.0 measured in midgestation have a poor prognosis. Other volumetric techniques are being evaluated for use in midtrimester. Recently, a randomized trial failed to show benefit from prenatal therapy, but lacked power to document the potential advantage of prenatal therapy in severe cases. We proposed percutaneous fetal endoluminal tracheal occlusion with a balloon at 26–28 weeks through a 3.3 mm incision. In severe cases, fetal endoluminal tracheal occlusion increased lung size as well as survival, with an early (7 day) survival, late neonatal (28 day) survival and survival at discharge of 75, 58 and 50%, respectively, comparing favorably with 9% in contemporary controls. Airways can be restored prior to birth improving neonatal survival (83.3% compared with 33.3%). The procedure carries a risk for preterm prelabour rupture of the fetal membranes, although that may decrease with experience. Summary Fetuses with severe congenital diaphragmatic hernia can be identified in the second trimester. Fetal endoluminal tracheal occlusion can be considered as a minimally invasive fetal therapy, improving outcome in such highly selected cases.

Premature foetal closure of the arterial duct: clinical presentations and outcome

AIMS The prevalence of intra-uterine ductal dysfunction is unknown and the clinical consequences are poorly understood. The aim of this study was to investigate the echocardiographic (ECHO) abnormalities and outcomes of this rare phenomenon. METHODS AND RESULTS Retrospective analysis of foetal (n = 602) and neonatal ECHO databases (n = 1477) between 1998 and 2007. Clinical and imaging studies were reviewed for pathology due to or associated with premature closure of the duct. Twelve cases were identified. Eight (1.3%) were diagnosed pre-natally at a median gestational age of 29.0 weeks (range: 20.0-37.5 weeks). Four neonates (0.3%) with significant cyanosis and absence of the arterial duct were also included. The most common ECHO features were: excessive right ventricular (RV) hypertrophy (100%), more than expected tricuspid and pulmonary regurgitation (100% and 92%, respectively), and right atrial dilation (75%). Premature induction of delivery was advised for five patients. Neonatal therapy consisted of observation and oxygen administration (n = 7), ventilation with pulmonary vasodilators (n = 5), and one required extracorporeal membrane oxygenation. There were three deaths due to respiratory failure with severe pulmonary hypertension. During follow-up, two children required additional right heart procedures and one developed a non-compaction cardiomyopathy. CONCLUSION Foetal premature closure of the arterial duct causes stress at different foetal ages and many different levels of the right heart and pulmonary circulation, resulting in a wide range of secondary pathology. Disproportionate RV hypertrophy is the most common finding. Clinical outcomes range from mild symptomatology to lethal respiratory insufficiency.

Covariates of tramadol disposition in the first months of life

BACKGROUND Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited. METHODS A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score. RESULTS In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h(-1) (70 kg)(-1) (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h(-1) (70 kg)(-1) (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability. CONCLUSIONS Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited micro-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.

Fetal cerebral hemorrhage caused by vitamin K deficiency after complicated bariatric surgery.

BACKGROUND: Restrictive bariatric surgery decreases obesity-related morbidity and mortality. With the widespread use of these interventions, an increasing number of women who have undergone bariatric surgery become pregnant. CASE: A women, pregnant 2 years after laparoscopic gastric banding, presented with prolonged vomiting due to slippage of the gastic band resulting in gastric outlet obstruction. Parenteral feeding was initiated for 3 weeks until the patient was delivered because of a nonreassuring fetal heart rate pattern. A postnatal diagnosis of an extensive intracranial fetal hemorrhage due to maternal vitamin K deficiency was made. CONCLUSION: Although restrictive bariatric surgery is generally considered safe, we want to warn of possible severely adverse outcomes related to the intervention. In case of food intolerance, early vitamin substitution is indicated.