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Carbajal R.,University of Monastir | Carbajal R.,French Institute of Health and Medical Research | Carbajal R.,University Pierre and Marie Curie | Eriksson M.,Örebro University | And 21 more authors.
The Lancet Respiratory Medicine | Year: 2015

Background: Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries. Methods: EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with ClinicalTrials.gov, number NCT01694745. Findings: From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35·0 weeks (SD 4·6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0·0001). In the participating NICUs, the median use of sedation or analgesia was 89·3% (70·0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0·0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136·2 h [SD 173·1] vs 39·8 h [94·7] h; p<0·0001). Multivariable and propensity score analyses confirmed this association (p<0·0001). Interpretation: Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia. Funding: European Community's Seventh Framework Programme. © 2015 Elsevier Ltd.


Draaken M.,University of Bonn | Prins W.,University of Bonn | Zeidler C.,University of Bonn | Hilger A.,University of Bonn | And 12 more authors.
International Journal of Molecular Medicine | Year: 2012

Anorectal malformations (ARMs) comprise a broad spectrum of anomalies, including anal atresia, congenital anal fistula and persistence of the cloaca. Research suggests that genetic factors play an important role in ARM development. However, few genetic variants have been identified. Embryogenesis is orchestrated by crosstalk of the wingless-type MMTV integration site family (WNT) and fibroblast growth factor (FGF) signaling pathways in a process that involves several intracellular cascades. Studies in mice have implicated several genes from these pathways in the etiology of ARMs. We performed sequencing analysis of seven of these previously reported genes in 78 patients with ARMs occurring within the context of at least one additional congenital anomaly. No associations were identified with variants in WNT3A, WNT5A, WNT11, DACT1, FGF10 or the T gene. In the FGFR2 gene, three novel heterozygous nucleotide substitutions were identified. Further investigations, including the study of family members, revealed that these variants were not causally related to the phenotype in the present ARM cohort. Mutations in the seven investigated genes may nonetheless be a cause of ARMs in rare cases. However, further studies should consider genes encoding other proteins in the WNT/FGF signaling pathways as possible candidates.


Breuer G.,Anasthesiologische Klinik Universitatsklinikum Erlangen | Morhart P.,Kinder und Jugendklinik Erlangen | Topf H.-G.,Kinder und Jugendklinik Erlangen | Pierre M.St.,Anasthesiologische Klinik Universitatsklinikum Erlangen | Schroth M.,Cnopfsche Kinderklinik
Anasthesiologie und Intensivmedizin | Year: 2013

Since the mid-nineties Simulation Based Training (SBT) has rapidly gained more and more acceptance in the areas of anaesthesiology and emergency medicine. Meanwhile, a multitude of clinical projects have been initiated which have implemented SBT-programmes into a classical student education system. This article describes an exemplary student teaching project of an anaesthesiology and paediatric department at a university hospital. A five-year-period was evaluated and the course concept was analysed with respect to evidence-based teaching. Students underwent a clinically orientated assessment at the end of every course in a semi-standardised oral examination. Applying Wilcoxon-Mann-Whitney tests for non-parametric unpaired samples, statistical significance was found in a pre-post-analysis. After implementing SBT, a significant improvement of the GPA (p<0.001) and the subjective learning benefit for postgraduate clinical competence was observed (p<0.005). Furthermore, evidence-based criteria for effective learning with "high-fidelity simulation" were identified in the literature and compared with the course-curriculum. All ten criteria were applicable to the curriculum. SBT represents an important and longlasting tool to close the gap between theoretical studies and the patient care of daily routine. Therefore, SBT should be an important component of education and, in addition, could build a "bridge" to interdisciplinary cooperation. Consequently, according to this teaching project, a close cooperation was established in the field of new teaching conceptions in paediatric anaesthesia and neonatal emergency medicine. This contribution would like to encourage the transfer of existing expertise with simulation in anaesthesiology to other clinical specialties, as a symbiotic effect and to overcome barriers/cross over boundaries. © 2013 Anästh Intensivmed.


Grunewald T.G.P.,TU Munich | Greulich N.,TU Munich | Kontny U.,University Hospital Freiburg | Fruhwald M.,University of Munster | And 10 more authors.
Klinische Padiatrie | Year: 2012

Background: Although prognosis of children with solid tumors is steadily improving, long-term survival is not achievable in all patients, especially in patients with recurrent or refractory disease. Despite the increasing number of targeted therapeutics (TT), only very few TT have been introduced into clinical protocols. Accordingly, clinical experience concerning the efficacy and safety of these drugs is limited. This may possibly discourage oncologists from administering TT to children. Methods: We performed a comprehensive review of the literature to identify TT that may be considered for treatment of children and young adults with solid tumors. Moreover, we interviewed an expert panel of the Society for Pediatric Oncology and Hematology (GPOH) using questionnaires in a modified Delphi process in order to describe the experts' experiences in the use of these TT. Results: Among 30 TT identified to be possibly useful in children and young adults, imatinib, bevacizumab and rapamycin were most widely used. These drugs were reported as having mostly little to no severe adverse events and seem to induce at least partial responses in a subset of patients. In addition, our study confirms and expands the present knowledge about adverse events and the potential efficacy of 5 other commonly used TT in this population. Conclusions: This information may be useful for oncologists when administering these TT to children and young adults with solid tumors. Controlled clinical trials are urgently needed to test their safety and efficacy. © Georg Thieme Verlag KG · Stuttgart · New York.


Schaefer M.,CnopfSche Kinderklinik | Kaiser A.,Klinikum Nurnberg | Stehr M.,CnopfSche Kinderklinik | Beyer H.J.,CnopfSche Kinderklinik
Journal of Pediatric Urology | Year: 2013

Purpose: To evaluate the use of small intestinal submucosa (SIS) for bladder augmentation in a series of select patients. Material and methods: Six patients (age 6.5-15.4, mean 9.8 years) underwent bladder augmentation with SIS: one after a cloacal exstrophy repair, one after multiple surgery of the bladder because of vesicoureteral reflux, two with spina bifida, two after bladder exstrophy repair. All suffered from a microbladder with a mean volume of 61.5 ml (range 15-120, 7-36% of expected bladder capacity for age). Preoperative bladder compliance ranged from 1.0 to 3.3 (mean 1.3) ml/cmH2O. Results: Follow-up time ranged from 4.6 to 33.5 (mean 24.4) months. An increase of bladder volume was achieved in four patients (53-370 ml, 16-95% of expected bladder capacity for age). Bladder compliance postoperatively ranged from 0.9 to 5.6 (mean 3.0) ml/cmH2O. Histological examinations showed a complete conversion of SIS, leaving irregular urothelial lining and bladder wall containing muscular, vascular and relatively thick connective tissue in four patients and regular urothelium in two patients. Major complications were bladder stones in two patients and a bladder rupture in one patient. Conclusion: Bladder augmentation with SIS in humans failed to fulfill the hopes raised by animal studies. Due to the insufficient increase in bladder compliance and therefore failure to accomplish sufficient protection of the upper urinary tract, bladder augmentation with SIS cannot be recommended as a substitute for enterocystoplasty. © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.


Schmid I.,Ludwig Maximilians University of Munich | Haberle B.,Ludwig Maximilians University of Munich | Albert M.H.,Ludwig Maximilians University of Munich | Corbacioglu S.,University of Regensburg | And 10 more authors.
Pediatric Blood and Cancer | Year: 2012

Purpose: Overall survival is poor in children with primary unresectable hepatocellular carcinoma. Sorafenib has been shown to significantly improve progression-free survival in adult hepatocellular carcinoma (HCC) patients. We evaluated the experience of PLADO (cisplatin 80mg/m 2/day, doxorubicin 2×30mg/m 2/day) in combination with sorafenib in pediatric HCC patients. Patients and Methods: Clinical data of 12 patients (7-16 years), 7 with unresectable tumor, were retrospectively assessed. Results: In total 6/12 (50%) patients are in complete remission after a median follow-up of 20 months (4 with PLADO/sorafenib/resection, 2 with liver transplantation after local relapse). Of the seven patients with unresectable tumor, PLADO/sorafenib resulted in partial response (PR) in four, stable disease (SD) in two, and progression in one. Three are alive in CR after complete resection after 12 (alternative therapy after two cycles PLADO/sorafenib), 12 and 18 months (six cycles PLADO/sorafenib), respectively. All four patients with elevated alpha-fetoprotein levels had a marked drop after two cycles. Of the five patients with primary complete tumor resection one is alive disease-free at 27 months. Four had local or metastatic relapses (13, 7, 12, and 13 months), two of whom were rescued by liver transplantation (CR after 25 and 32 months). The main toxicity attributable to sorafenib was a hand-foot skin reaction (HFSR) in seven patients. Conclusion: Sorafenib in combination with PLADO may be a promising approach in pediatric HCC; HFSR was the most important toxicity. Data based on prospective studies are needed to evaluate pharmacokinetics, resectability rates, and survival in pediatric HCC treated with sorafenib. © 2011 Wiley Periodicals, Inc.


PubMed | Asklepios Childrens Hospital St Augustin, Hannover Medical School, University of Bonn, University of Würzburg and 9 more.
Type: Journal Article | Journal: Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus | Year: 2015

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and anorectal malformations (ARM) represent the severe ends of the fore- and hindgut malformation spectra. Previous research suggests that environmental factors are implicated in their etiology. These risk factors might indicate the influence of specific etiological mechanisms on distinct developmental processes (e.g. fore- vs. hindgut malformation). The present study compared environmental factors in patients with isolated EA/TEF, isolated ARM, and the combined phenotype during the periconceptional period and the first trimester of pregnancy in order to investigate the hypothesis that fore- and hindgut malformations involve differing environmental factors. Patients with isolated EA/TEF (n = 98), isolated ARM (n = 123), and the combined phenotype (n = 42) were included. Families were recruited within the context of two German multicenter studies of the genetic and environmental causes of EA/TEF (great consortium) and ARM (CURE-Net). Exposures of interest were ascertained using an epidemiological questionnaire. Chi-square, Fishers exact, and Mann-Whitney U-tests were used to assess differences between the three phenotypes. Newborns with isolated EA/TEF and the combined phenotype had significantly lower birth weights than newborns with isolated ARM (P = 0.001 and P < 0.0001, respectively). Mothers of isolated EA/TEF consumed more alcohol periconceptional (80%) than mothers of isolated ARM or the combined phenotype (each 67%). Parental smoking (P = 0.003) and artificial reproductive techniques (P = 0.03) were associated with isolated ARM. Unexpectedly, maternal periconceptional multivitamin supplementation was most frequent among patients with the most severe form of disorder, i.e. the combined phenotype (19%). Significant differences in birth weight were apparent between the three phenotype groups. This might be attributable to the limited ability of EA/TEF fetuses to swallow amniotic fluid, thus depriving them of its nutritive properties. Furthermore, the present data suggest that fore- and hindgut malformations involve differing environmental factors. Maternal periconceptional multivitamin supplementation was highest among patients with the combined phenotype. This latter finding is contrary to expectation, and warrants further analysis in large prospective epidemiological studies.


PubMed | Cnopfsche Kinderklinik, Carl von Ossietzky University, Section Pediatric Oncology and Universitatsklinikum Heidelberg
Type: Journal Article | Journal: European journal of pediatric surgery reports | Year: 2016

Gardner fibromas (GFs) have only recently been described as poorly circumscribed tumor-like lesions, which are exceedingly rare in children. GFs are associated with


PubMed | University of Padua, Complexo Hospitalario Universitario Of runa, University of Memphis, Karolinska Institutet and 17 more.
Type: Journal Article | Journal: The Lancet. Respiratory medicine | Year: 2015

Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries.EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with ClinicalTrials.gov, number NCT01694745.From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35.0 weeks (SD 4.6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0.0001). In the participating NICUs, the median use of sedation or analgesia was 89.3% (70.0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0.0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136.2 h [SD 173.1] vs 39.8 h [94.7] h; p<0.0001). Multivariable and propensity score analyses confirmed this association (p<0.0001).Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia.European Communitys Seventh Framework Programme.


PubMed | Asklepios Childrens Hospital St Augustin, Hannover Medical School, University of Bonn, University of Cologne and 9 more.
Type: Journal Article | Journal: European journal of pediatrics | Year: 2016

The purpose of our study was to investigate the importance of amniotic fluid (AF) for fetal growth during late gestation using esophageal atresia (EA) patients as a model. In this retrospective cohort study, we compared the z-scores adapted for birth weights (BW z-scores) for each of 517 European newborns with congenital pre-gastric intestinal atresia, i.e., EA, to a European reference population. To account for the influence of the intestinal atresia on fetal growth per se, we compared adapted birth weights for each of 504 European newborns with post colonic intestinal atresia (anorectal malformation (ARM) with atresia of the anus) to the same European reference population. Analysis of the complete cohort showed (i) a significantly higher rate of small for gestational age newborns among EA compared to ARM newborns (p<0.001) and (ii) significantly lower BW z-scores among EA compared to ARM newborns (p<0.001). BW z-scores of EA newborns were significantly lower in term compared to preterm newborns with an inverse correlation with gestational age (GA) (Spearman correlation coefficient, r=-0.185, p<0.001).Enteral uptake of AF seems to play a pivotal role in fetal growth during late gestation. Peak velocity of fetal weight gain occurs at 33weeks of gestation and continues until birth. During this period, fetal growth is mainly characterized by cellular hypertrophy. Amniotic fluid (AF) comprises large amounts of hormones and growth regulators. What is New: A significantly higher rate of small for gestational age and lower birth weights and z-scores are observed among newborn infants with congenital pre-gastric intestinal atresia. These findings suggest that enteral uptake of AF is a major predictor for fetal growth during late gestation.

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