Publications by authors named "Thomas Schaible"

92 Publications

Spontaneous breathing approach in mild congenital diaphragmatic hernia: A resuscitation algorithm.

Front Pediatr 2022 18;10:945090. Epub 2022 Jul 18.

The Ritchie Centre, Hudson Institute for Medical Research, Monash University, Melbourne, VIC, Australia.

Background: Infants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not consider the individual patient's disease severity, but an individualized approach with spontaneous breathing instead of routine mechanical ventilation could be beneficial for the mildest cases. We developed a resuscitation algorithm for this individualized approach serving two purposes: improving the success rate by structuring the approach and providing a guideline for other centers.

Methods: An initial algorithm was discussed with all local stakeholders. Afterwards, the resulting algorithm was refined using input from international experts.

Results: Eligible CDH infants: left-sided defect, observed to expected lung-to-head ratio ≥50%, gestational age at birth ≥37.0 weeks, and no major associated structural or genetic abnormalities. To facilitate fetal-to-neonatal transition, we propose to start stabilization with non-invasive respiratory support and to adjust this individually.

Conclusions: Infants with mild CDH might benefit from an individualized approach for neonatal resuscitation. Herein, we present an algorithm that could serve as guidance for centers implementing this.
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http://dx.doi.org/10.3389/fped.2022.945090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339647PMC
July 2022

Impact of Time Point of Extracorporeal Membrane Oxygenation on Mortality and Morbidity in Congenital Diaphragmatic Hernia: A Single-Center Case Series.

Children (Basel) 2022 Jul 1;9(7). Epub 2022 Jul 1.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, 68167 Mannheim, Germany.

Since there are no data available on the influence of the time point of ECMO initiation on morbidity and mortality in patients with congenital diaphragmatic hernia (CDH), we investigated whether early initiation of ECMO after birth is associated with a beneficial outcome in severe forms of CDH. All neonates with CDH admitted to our institution between 2010 until 2020 and undergoing ECMO treatment were included in this study and divided into four different groups: (1) ECMO initiation < 12 h after birth ( = 143), (2) ECMO initiation between 12-24 h after birth ( = 31), (3) ECMO initiation between 24-120 h after birth ( = 48) and (4) ECMO initiation > 120 h after birth ( = 14). The mortality rate in the first (34%) and fourth group (43%) was high and in the second group (23%) and third group (12%) rather low. The morbidity, characterized by chronic lung disease (CLD), did not differ significantly in the three groups; only patients in which ECMO was initiated >120 h after birth had an increased rate of severe CLD. Our data, although not randomized and limited due to small study groups, suggest that very early need for ECMO and ECMO initiation > 120 h after birth is associated with increased mortality.
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http://dx.doi.org/10.3390/children9070986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315500PMC
July 2022

Chronic Lung Disease Following Neonatal Extracorporeal Membrane Oxygenation: A Single-Center Experience.

Front Pediatr 2022 8;10:909862. Epub 2022 Jul 8.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Objective: To assess the incidence and severity of chronic lung disease (CLD) after neonatal extracorporeal membrane oxygenation (ECMO) and to identify factors associated with its development.

Methods: A retrospective observational study in a neonatal ECMO center was conducted. All neonates who received support with ECMO in our institution between January 2019 and October 2021 were included and their pulmonary outcome was investigated.

Results: A total of 91 patients [60 with congenital diaphragmatic hernia (CDH), 26 with meconium aspiration syndrome, and 5 with other diagnoses] were included in this study. Sixty-eight (75%) neonates survived. Fifty-two (76%) ECMO survivors developed CLD. There was no statistical difference between patients with and without CLD with regard to gender or gestational age. Patients with CLD had lower birth weight, were younger at the initiation of ECMO, and required longer ECMO runs. Patients with CDH developed CLD more often than infants with other underlying diseases (94 vs. 60%). Seventeen ECMO survivors (25%) developed severe CLD.

Conclusion: The incidence of CLD after neonatal ECMO is substantial. Risk factors for its development include CDH as an underlying condition, the necessity for early initiation of ECMO, and the need for ECMO over 7 days.
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http://dx.doi.org/10.3389/fped.2022.909862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304759PMC
July 2022

Small Bowel Obstruction After Neonatal Repair of Congenital Diaphragmatic Hernia-Incidence and Risk-Factors Identified in a Large Longitudinal Cohort-Study.

Front Pediatr 2022 17;10:846630. Epub 2022 May 17.

Department of Pediatric Surgery, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Objective: In patients with a congenital diaphragmatic hernia (CDH), postoperative small bowel obstruction (SBO) is a life-threatening event. Literature reports an incidence of SBO of 20% and an association with patch repair and ECMO treatment. Adhesions develop due to peritoneal damage and underly various biochemical and cellular processes. This longitudinal cohort study is aimed at identifying the incidence of SBO and the risk factors of surgical, pre-, and postoperative treatment.

Methods: We evaluated all consecutive CDH survivors born between January 2009 and December 2017 participating in our prospective long-term follow-up program with a standardized protocol.

Results: A total of 337 patients were included, with a median follow-up of 4 years. SBO with various underlying causes was observed in 38 patients (11.3%) and significantly more often after open surgery (OS). The majority of SBOs required surgical intervention (92%). Adhesive SBO (ASBO) was detected as the leading cause in 17 of 28 patients, in whom surgical reports were available. Duration of chest tube insertion [odds ratio (OR) 1.22; 95% CI 1.01-1.46, = 0.04] was identified as an independent predictor for ASBO in multivariate analysis. Beyond the cut-off value of 16 days, the incidence of serous effusion and chylothorax was higher in patients with ASBO (ASBO/non-SBO: 2/10 vs. 3/139 serous effusion, = 0.04; 2/10 vs. 13/139 chylothorax, = 0.27). Type of diaphragmatic reconstruction, abdominal wall closure, or ECMO treatment showed no significant association with ASBO. A protective effect of one or more re-operations has been detected (RR 0.16; 95% CI 0.02-1.17; = 0.049).

Conclusion: Thoracoscopic CDH repair significantly lowers the risk of SBO; however, not every patient is suitable for this approach. GoreTex®-patches do not seem to affect the development of ASBO, while median laparotomy might be more favorable than a subcostal incision. Neonates produce more proinflammatory cytokines and have a reduced anti-inflammatory capacity, which may contribute to the higher incidence of ASBO in patients with a longer duration of chest tube insertion, serous effusion, chylothorax, and to the protective effect of re-operations. In the future, novel therapeutic strategies based on a better understanding of the biochemical and cellular processes involved in the pathophysiology of adhesion formation might contribute to a reduction of peritoneal adhesions and their associated morbidity and mortality.
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http://dx.doi.org/10.3389/fped.2022.846630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152166PMC
May 2022

Physiological-based cord clamping versus immediate cord clamping for infants born with a congenital diaphragmatic hernia (PinC): study protocol for a multicentre, randomised controlled trial.

BMJ Open 2022 03 18;12(3):e054808. Epub 2022 Mar 18.

The Ritchie Centre, Hudson Institute for Medical Research, Monash University, Melbourne, Victoria, Australia

Introduction: Pulmonary hypertension is a major determinant of postnatal survival in infants with a congenital diaphragmatic hernia (CDH). The current care during the perinatal stabilisation period in these infants might contribute to the development of pulmonary hypertension after birth-in particular umbilical cord clamping before lung aeration. An ovine model of diaphragmatic hernia demonstrated that cord clamping after lung aeration, called physiological-based cord clamping (PBCC), avoided the initial high pressures in the lung vasculature while maintaining adequate blood flow, thereby avoiding vascular remodelling and aggravation of pulmonary hypertension. We aim to investigate if the implementation of PBCC in the perinatal stabilisation period of infants born with a CDH could reduce the incidence of pulmonary hypertension in the first 24 hours after birth.

Methods And Analysis: We will perform a multicentre, randomised controlled trial in infants with an isolated left-sided CDH, born at ≥35.0 weeks. Before birth, infants will be randomised to either PBCC or immediate cord clamping, stratified by treatment centre and severity of pulmonary hypoplasia on antenatal ultrasound. PBCC will be performed using a purpose-built resuscitation trolley. Cord clamping will be performed when the infant is considered respiratory stable, defined as a heart rate >100 bpm, preductal oxygen saturation >85%, while using a fraction of inspired oxygen of <0.5. The primary outcome is pulmonary hypertension diagnosed in the first 24 hours after birth, based on clinical and echocardiographic parameters. Secondary outcomes include neonatal as well as maternal outcomes.

Ethics And Dissemination: Central ethical approval was obtained from the Medical Ethical Committee of the Erasmus MC, Rotterdam, The Netherlands (METC 2019-0414). Local ethical approval will be obtained by submitting the protocol to the regulatory bodies and local institutional review boards.

Trial Registration Number: NCT04373902.
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http://dx.doi.org/10.1136/bmjopen-2021-054808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935184PMC
March 2022

The Chest Radiographic Thoracic Area Can Serve as a Prediction Marker for Morbidity and Mortality in Infants With Congenital Diaphragmatic Hernia.

Front Pediatr 2021 23;9:740941. Epub 2021 Dec 23.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Valid postnatal prediction parameters for neonates with congenital diaphragmatic hernia (CDH) are lacking, but recently, the chest radiographic thoracic area (CRTA) was proposed to predict survival with high sensitivity. Here, we evaluated whether the CRTA correlated with morbidity and mortality in neonates with CDH and was able to predict these with higher sensitivity and specificity than prenatal observed-to-expected (O/E) lung-to-head ratio (LHR). In this retrospective cohort study, all neonates with CDH admitted to our institution between 2013 and 2019 were included. The CRTA was measured using the software Horos (V. 3.3.5) and compared with O/E LHR diagnosed by fetal ultrasonography in relation to outcome parameters including survival, extracorporeal membrane oxygenation (ECMO) support, and chronic lung disease (CLD). In this study 255 neonates were included with a survival to discharge of 84%, ECMO support in 46%, and 56% developing a CLD. Multiple regression analysis demonstrated that the CRTA correlates significantly with survival ( = 0.001), ECMO support ( < 0.0001), and development of CLD ( = 0.0193). The CRTA displayed a higher prognostic validity for survival [area under the curve (AUC) = 0.822], ECMO support (AUC = 0.802), and developing a CLD (AUC = 0.855) compared with the O/E LHR. Our data suggest that the postnatal CRTA might be a better prognostic parameter for morbidity and mortality than the prenatal O/E LHR.
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http://dx.doi.org/10.3389/fped.2021.740941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733701PMC
December 2021

Longitudinal Follow-Up With Radiologic Screening for Recurrence and Secondary Hiatal Hernia in Neonates With Open Repair of Congenital Diaphragmatic Hernia-A Large Prospective, Observational Cohort Study at One Referral Center.

Front Pediatr 2021 17;9:796478. Epub 2021 Dec 17.

Department of Pediatric Surgery, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

After neonatal repair of congenital diaphragmatic hernia (CDH) recurrence is the most severe surgical complication and reported in up to 50% after patch implantation. Previous studies are difficult to compare due to differences in surgical techniques and retrospective study design and lack of standardized follow-up or radiologic imaging. The aim was to reliably detect complication rates by radiologic screening during longitudinal follow-up after neonatal open repair of CDH and to determine possible risk factors. At our referral center with standardized treatment algorithm and follow-up program, consecutive neonates were screened for recurrence by radiologic imaging at defined intervals during a 12-year period. 326 neonates with open CDH repair completed follow-up of a minimum of 2 years. 68 patients (21%) received a primary repair, 251 (77%) a broad cone-shaped patch, and 7 a flat patch (2%). Recurrence occurred in 3 patients (0.7%) until discharge and diaphragmatic complications in 28 (8.6%) thereafter. Overall, 38 recurrences and/or secondary hiatal hernias were diagnosed (9% after primary repair, 12.7% after cone-shaped patch; = 0.53). Diaphragmatic complications were significantly associated with initial defect size ( = 0.26). In multivariate analysis left-sided CDH, an abdominal wall patch and age below 4 years were identified as independent risk factors. Accordingly, relative risks (RRs) were significantly increased [left-sided CDH: 8.5 ( = 0.03); abdominal wall patch: 3.2 ( < 0.001); age ≤4 years: 6.5 ( < 0.002)]. 97% of patients with diaphragmatic complications showed no or nonspecific symptoms and 45% occurred beyond 1 year of age. The long-term complication rate after CDH repair highly depends on surgical technique: a comparatively low recurrence rate seems to be achievable in large defects by implantation of a broad cone-shaped, non-absorbable patch. Longitudinal follow-up with regular radiologic imaging until adolescence is essential to reliably detecting recurrence to prevent acute incarceration and chronic gastrointestinal morbidity with their impact on prognosis. Based on our findings and literature review, a risk-stratified approach to diaphragmatic complications is proposed.
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http://dx.doi.org/10.3389/fped.2021.796478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719630PMC
December 2021

Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure -A clinical practice Guideline Level 3.

ESC Heart Fail 2022 02 22;9(1):506-518. Epub 2021 Nov 22.

Department of Cardiothoracic Surgery, University Hospital Bergmannsheil, Ruhr-University, Bochum, Germany.

Aims Worldwide applications of extracorporeal circulation for mechanical support in cardiac and circulatory failure, which are referred to as extracorporeal life support (ECLS) or veno-arterial extracorporeal membrane oxygenation (va-ECMO), have dramatically increased over the past decade. In spite of the expanding use and the immense medical as well as socio-economic impact of this therapeutic approach, there has been a lack of interdisciplinary recommendations considering the best available evidence for ECLS treatment. Methods and Results In a multiprofessional, interdisciplinary scientific effort of all scientific societies involved in the treatment of patients with acute cardiac and circulatory failure, the first evidence- and expert consensus-based guideline (level S3) on ECLS/ECMO therapy was developed in a structured approach under regulations of the AWMF (Association of the Scientific Medical Societies in Germany) and under use of GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. This article presents all recommendations created by the expert panel, addressing a multitude of aspects for ECLS initiation, continuation, weaning and aftercare as well as structural and personnel requirements. Conclusions This first evidence- and expert consensus-based guideline (level S3) on ECLS/ECMO therapy should be used to apply the best available care nationwide. Beyond clinical practice advice, remaining important research aspects for future scientific efforts are formulated.
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http://dx.doi.org/10.1002/ehf2.13718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788014PMC
February 2022

MR lung perfusion measurements in adolescents after congenital diaphragmatic hernia: correlation with spirometric lung function tests.

Eur Radiol 2022 Apr 6;32(4):2572-2580. Epub 2021 Nov 6.

Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Objectives: To evaluate whether lung perfusion continues to be reduced in 10-year-old children after congenital diaphragmatic hernia (CDH) and whether lung perfusion values correlate with spirometric lung function measurements.

Methods: Fifty-four patients after CDH repair received dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI)-based lung perfusion measurements at the age of 10 years (10.2 ± 1.0 years). Additionally, a control group of 10 children has been examined according to the same protocol. Lung spirometry was additionally available in 43 patients of the CDH group. A comparison of ipsilateral and contralateral parameters was performed.

Results: Pulmonary blood flow (PBF) was reduced on the ipsilateral side in CDH patients (60.4 ± 23.8 vs. 93.3 ± 16.09 mL/100 mL/min; p < 0.0001). In comparison to the control group, especially the ratio of ipsilateral to contralateral, PBF was reduced in CDH patients (0.669 ± 0.152 vs. 0.975 ± 0.091; p < 0.0001). There is a positive correlation between ipsilateral pulmonary blood flow, and spirometric forced 1-s volume (r = 0.45; p = 0.0024).

Conclusions: Pulmonary blood flow impairment persists during childhood and correlates with spirometric measurements. Without the need for ionizing radiation, MRI measurements seem promising as follow-up parameters after CDH.

Key Points: • Ten-year-old children after congenital diaphragmatic hernia continue to show reduced perfusion of ipsilateral lung. • Lung perfusion values correlate with lung function tests after congenital diaphragmatic hernia.
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http://dx.doi.org/10.1007/s00330-021-08315-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921025PMC
April 2022

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline].

Med Klin Intensivmed Notfmed 2021 Nov;116(8):678-686

Department of Pediatric Surgery, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Deutschland.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.
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http://dx.doi.org/10.1007/s00063-021-00868-3DOI Listing
November 2021

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline].

Anaesthesist 2021 11;70(11):942-950

Department of Pediatric Surgery, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Deutschland.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.
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http://dx.doi.org/10.1007/s00101-021-01058-8DOI Listing
November 2021

Genetics of diaphragmatic hernia.

Eur J Hum Genet 2021 12 8;29(12):1729-1733. Epub 2021 Oct 8.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Congenital diaphragmatic hernia (CDH) is a life-threatening malformation characterised by failure of diaphragmatic development with lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). The incidence is 1:2000 corresponding to 8% of all major congenital malformations. Morbidity and mortality in affected newborns are very high and at present, there is no precise prenatal or early postnatal prognostication parameter to predict clinical outcome in CDH patients. Most cases occur sporadically, however, genetic causes have long been discussed to explain a proportion of cases. These range from aneuploidy to complex chromosomal aberrations and specific mutations often causing a complex phenotype exhibiting multiple malformations along with CDH. This review summarises the genetic variations which have been observed in syndromic and isolated cases of congenital diaphragmatic hernia.
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http://dx.doi.org/10.1038/s41431-021-00972-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632982PMC
December 2021

Assessing Anticoagulation in Neonates With Congenital Diaphragmatic Hernia During Extracorporeal Membrane Oxygenation: Does Anti-Factor Xa or Thromboelastometry Provide Additional Benefit?

Front Pediatr 2021 17;9:685906. Epub 2021 Sep 17.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

The optimal management of anticoagulation in neonatal/pediatric patients during extracorporeal membrane oxygenation (ECMO) has not been established yet and varies greatly among ECMO centers worldwide. Therefore, we aimed to assess whether the use of anti-factor Xa assay and/or thromboelastometry correlate better than activated clotting time with heparin dose in newborns with congenital diaphragmatic hernia during ECMO. We also examined whether these coagulation assays correlate with thrombotic and/or hemorrhagic complications, when the management of anticoagulation is based only on activated clotting time values. A prospective observational study in a neonatal ECMO center was conducted. We included all neonates with congenital diaphragmatic hernia born in our institution between March 2018 and January 2019 and requiring support with venoarterial ECMO. A total of 26 ECMO runs were analyzed. During the study, the heparin dose was still adjusted according to activated clotting time values. Measurements of anti-factor Xa assay, activated partial thromboplastin time, and a thromboelastometry from the same blood specimen were performed twice a day. Anti-factor Xa levels showed a moderate correlation with heparin dose, whereas the other tests showed a weak correlation. Four patients (17.4%) had thrombotic complications, 2 patients (8.7%) experienced life-threatening bleeding, and in 11 patients (47.8%) disseminated intravascular coagulation (DIC) occurred. Anti-factor Xa levels were lower in the group with thrombotic complications (0.23 vs. 0.27 IU/ml; = 0.002), while activated partial thromboplastin time was higher in the group with hemorrhagic complications (69.4 s vs. 59.8 s; = 0.01). In patients experiencing DIC, heparin dose and anti-factor Xa levels were lower, while no difference in activated clotting time and clotting time in INTEM and INTEM-HEPTEM were shown. Anti-factor Xa levels correlate better to heparin dose than activated clotting time. The use of anti-factor Xa assay instead of activated clotting time for dosing of unfractionated heparin could reduce thrombotic complications in neonates with congenital diaphragmatic hernia on ECMO support. The thromboelastometry showed no additional benefit for this purpose.
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http://dx.doi.org/10.3389/fped.2021.685906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485026PMC
September 2021

Severe Pneumonia in Neonates Associated with : Case Report and Review of the Literature.

Pathogens 2021 Aug 15;10(8). Epub 2021 Aug 15.

Department of Hygiene, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

The causative agent of legionellosis is the Gram-negative intracellular bacteria spp. Its clinical presentation varies from a mild febrile illness called Pontiac fever to the severe and possible fatal pneumonia, Legionnaires' disease. Immunocompromised patients, in particular, are affected. Only a small number of infected neonates are described in the literature. Most of them have been associated with water birth or the use of air humidifiers. In the last five years, a growing number of cases have been reported in Germany by the national institute of disease surveillance and prevention (Robert-Koch Institute). Here, we describe a fatal case report of pulmonary legionellosis with acute respiratory distress syndrome (ARDS), sepsis, associated cutaneous manifestation, and extracorporeal membrane oxygenation in a full-term neonate. Moreover, we present a review of the literature discussing the epidemiology, risk factors, clinical features, diagnostics, treatment options, and prevention for this rare condition in neonates.
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http://dx.doi.org/10.3390/pathogens10081031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400773PMC
August 2021

Parental risk factors for congenital diaphragmatic hernia - a large German case-control study.

BMC Pediatr 2021 06 14;21(1):278. Epub 2021 Jun 14.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Evidence for periconceptional or prenatal environmental risk factors for the development of congenital diaphragmatic hernia (CDH) is still scarce. Here, in a case-control study we investigated potential environmental risk factors in 199 CDH patients compared to 597 healthy control newborns.

Methods: The following data was collected: time of conception and birth, maternal BMI, parental risk factors such as smoking, alcohol or drug intake, use of hairspray, contact to animals and parental chronic diseases. CDH patients were born between 2001 and 2019, all healthy control newborns were born in 2011. Patients and control newborns were matched in the ratio of three to one.

Results: Presence of CDH was significantly associated with maternal periconceptional alcohol intake (odds ratio = 1.639, 95% confidence interval 1.101-2.440, p = 0.015) and maternal periconceptional use of hairspray (odds ratio = 2.072, 95% confidence interval 1.330-3.229, p = 0.001).

Conclusion: Our study suggests an association between CDH and periconceptional maternal alcohol intake and periconceptional maternal use of hairspray. Besides the identification of novel and confirmation of previously described parental risk factors, our study underlines the multifactorial background of isolated CDH.
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http://dx.doi.org/10.1186/s12887-021-02748-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201820PMC
June 2021

Computed tomography based measurements to evaluate lung density and lung growth after congenital diaphragmatic hernia.

Sci Rep 2021 03 3;11(1):5035. Epub 2021 Mar 3.

Department of Radiology and Nuclear Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Emphysema-like-change of lung is one aspect of lung morbidity in children after congenital diaphragmatic hernia (CDH). This study aims to evaluate if the extent of reduced lung density can be quantified through pediatric chest CT examinations, if side differences are present and if emphysema-like tissue is more prominent after CDH than in controls. Thirty-seven chest CT scans of CDH patients (mean age 4.5 ± 4.0 years) were analyzed semi-automatically and compared to an age-matched control group. Emphysema-like-change was defined as areas of lung density lower than - 950 HU in percentage (low attenuating volume, LAV). A p-value lower than 0.05 was regarded as statistically significant. Hypoattenuating lung tissue was more frequently present in the ipsilateral lung than the contralateral side (LAV 12.6% vs. 5.7%; p < 0.0001). While neither ipsilateral nor contralateral lung volume differed between CDH and control (p > 0.05), LAV in ipsilateral (p = 0.0002), but not in contralateral lung (p = 0.54), was higher in CDH than control. It is feasible to quantify emphysema-like-change in pediatric patients after CDH. In the ipsilateral lung, low-density areas are much more frequently present both in comparison to contralateral and to controls. Especially the ratio of LAV ipsilateral/contralateral seems promising as a quantitative parameter in the follow-up after CDH.
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http://dx.doi.org/10.1038/s41598-021-84623-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930262PMC
March 2021

Vancomycin-induced ototoxicity in very-low-birthweight infants.

J Antimicrob Chemother 2020 08;75(8):2291-2298

Department of Paediatrics, University of Luebeck, University Hospital of Schleswig-Holstein, Luebeck, Germany.

Background: Vancomycin is an extensively used anti-infective drug in neonatal ICUs. However, exposure-toxicity relationships have not been clearly defined.

Objectives: To evaluate the risk profile for hearing deficits in vancomycin-exposed very-low-birthweight infants (VLBWI).

Methods: In a large cohort study of the German Neonatal Network (GNN; n = 16 967 VLBWI) we assessed the association of vancomycin treatment and pathological hearing tests at discharge and at 5 year follow-up. We performed audits on vancomycin exposure, drug levels, dose adjustments and exposure to other ototoxic drugs in a subgroup of 1042 vancomycin-treated VLBWI.

Results: In the GNN cohort, 28% (n = 4739) were exposed to IV vancomycin therapy. In multivariable logistic regression analysis, vancomycin exposure proved to be independently associated with pathological hearing test at discharge (OR 1.18, 95% CI 1.03-1.34, P = 0.016). Among vancomycin-treated infants, a cumulative vancomycin dose above the upper quartile (>314 mg/kg bodyweight) was associated with pathological hearing test at discharge (OR 2.1, 95% CI 1.21-3.64, P = 0.009), whereas a vancomycin cumulative dose below the upper quartile was associated with a reduced risk of pathological tone audiometry results at 5 years of age (OR 0.29, 95% CI 0.1-0.8, P = 0.02, n = 147).

Conclusions: Vancomycin exposure in VLBWI is associated with an increased, dose-dependent risk of pathological hearing test results at discharge and at 5 years of age. Prospective studies on long-term hearing impairment are needed.
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http://dx.doi.org/10.1093/jac/dkaa156DOI Listing
August 2020

Perinatal stabilisation of infants born with congenital diaphragmatic hernia: a review of current concepts.

Arch Dis Child Fetal Neonatal Ed 2020 Jul 13;105(4):449-454. Epub 2020 Mar 13.

The Ritchie Centre, Hudson Institute for Medical Research, Monash University, Melbourne, Victoria, Australia

Congenital diaphragmatic hernia (CDH) is associated with high mortality rates and significant pulmonary morbidity, mainly due to disrupted lung development related to herniation of abdominal organs into the chest. Pulmonary hypertension is a major contributor to both mortality and morbidity, however, treatment modalities are limited. Novel prenatal and postnatal interventions, such as fetal surgery and medical treatments, are currently under investigation. Until now, the perinatal stabilisation period immediately after birth has been relatively overlooked, although optimising support in these early stages may be vital in improving outcomes. Moreover, physiological parameters obtained from the perinatal stabilisation period could serve as early predictors of adverse outcomes, thereby facilitating both prevention and early treatment of these conditions. In this review, we focus on the perinatal stabilisation period by discussing the current delivery room guidelines in infants born with CDH, the physiological changes occurring during the fetal-to-neonatal transition in CDH, novel delivery room strategies and early predictors of adverse outcomes. The combination of improvements in the perinatal stabilisation period and early prediction of adverse outcomes may mitigate the need for specific postnatal management strategies.
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http://dx.doi.org/10.1136/archdischild-2019-318606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363792PMC
July 2020

Corrigendum: Endothelial Progenitor and Mesenchymal Stromal Cells in Newborns With Congenital Diaphragmatic Hernia Undergoing Extracorporeal Membrane Oxygenation.

Front Pediatr 2020;8:41. Epub 2020 Feb 19.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

[This corrects the article DOI: 10.3389/fped.2019.00490.].
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http://dx.doi.org/10.3389/fped.2020.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042973PMC
February 2020

Validation of a Prediction Rule for Mortality in Congenital Diaphragmatic Hernia.

Pediatrics 2020 04 5;145(4). Epub 2020 Mar 5.

Intensive Care and Departments of Pediatric Surgery.

Background: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly with a mortality of ∼27%. The Congenital Diaphragmatic Hernia Study Group (CDHSG) developed a simple postnatal clinical prediction rule to predict mortality in newborns with CDH. Our aim for this study is to externally validate the CDHSG rule in the European population and to improve its prediction of mortality by adding prenatal variables.

Methods: We performed a European multicenter retrospective cohort study and included all newborns diagnosed with unilateral CDH who were born between 2008 and 2015. Newborns born from November 2011 onward were included for the external validation of the rule ( = 343). To improve the prediction rule, we included all patients born between 2008 and 2015 ( = 620) with prenatally diagnosed CDH and collected pre- and postnatal variables. We build a logistic regression model and performed bootstrap resampling and computed calibration plots.

Results: With our validation data set, the CDHSG rule had an area under the curve of 79.0%, revealing a fair predictive performance. For the new prediction rule, prenatal herniation of the liver was added, and absent 5-minute Apgar score was taken out. The new prediction rule revealed good calibration, and with an area under the curve of 84.6%, it had good discriminative abilities.

Conclusions: In this study, we externally validated the CDHSG rule for the European population, which revealed fair predictive performance. The modified rule, with prenatal liver herniation as an additional variable, appears to further improve the model's ability to predict mortality in a population of patients with prenatally diagnosed CDH.
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http://dx.doi.org/10.1542/peds.2019-2379DOI Listing
April 2020

Increased mobilization of mesenchymal stem cells in patients with acute respiratory distress syndrome undergoing extracorporeal membrane oxygenation.

PLoS One 2020 27;15(1):e0227460. Epub 2020 Jan 27.

Department of Pediatrics I, University Children's Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany.

Background: The acute respiratory distress syndrome (ARDS) is characterized by pulmonary epithelial and endothelial barrier dysfunction and injury. In severe forms of ARDS, extracorporeal membrane oxygenation (ECMO) is often the last option for life support. Endothelial progenitor (EPC) and mesenchymal stem cells (MSC) can regenerate damaged endothelium and thereby improve pulmonary endothelial dysfunction. However, we still lack sufficient knowledge about how ECMO might affect EPC- and MSC-mediated regenerative pathways in ARDS. Therefore, we investigated if ECMO impacts EPC and MSC numbers in ARDS patients.

Methods: Peripheral blood mononuclear cells from ARDS patients undergoing ECMO (n = 16) and without ECMO support (n = 12) and from healthy volunteers (n = 16) were isolated. The number and presence of circulating EPC and MSC was detected by flow cytometry. Serum concentrations of vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) were determined.

Results: In the ECMO group, MSC subpopulations were higher by 71% compared to the non-ECMO group. Numbers of circulating EPC were not significantly altered. During ECMO, VEGF and Ang2 serum levels remained unchanged compared to the non-ECMO group (p = 0.16), but Ang2 serum levels in non-survivors of ARDS were significantly increased by 100% (p = 0.02) compared to survivors.

Conclusions: ECMO support in ARDS is specifically associated with an increased number of circulating MSC, most likely due to enhanced mobilization, but not with a higher numbers of EPC or serum concentrations of VEGF and Ang2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984734PMC
April 2020

Endothelial Progenitor and Mesenchymal Stromal Cells in Newborns With Congenital Diaphragmatic Hernia Undergoing Extracorporeal Membrane Oxygenation.

Front Pediatr 2019 22;7:490. Epub 2019 Nov 22.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Endothelial progenitor (EPC) and mesenchymal stromal cells (MSC) can regenerate damaged endothelium and thereby improve pulmonary endothelial dysfunction. We do not know, how extracorporeal membrane oxygenation (ECMO) might affect EPC- and MSC-mediated regenerative pathways in patients with congenital diaphragmatic hernia (CDH). Therefore, we investigated, if ECMO support impacts EPC and MSC numbers in CDH patients. Peripheral blood mononuclear cells from newborns with ECMO-dependent ( = 18) and ECMO-independent CDH ( = 12) and from healthy controls ( = 12) were isolated. The numbers of EPC and MSC were identified by flowcytometry. Serum levels of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 were determined. EPC and MSC were elevated in newborns with CDH. ECMO-dependent infants had higher EPC subpopulation counts (2,1-7,6-fold) before treatment compared to ECMO-independent infants. In the disease course, EPC and MSC subpopulation counts in ECMO-dependent infants were lower than before ECMO initiation. During ECMO, VEGF serum levels were significantly reduced (by 90.5%) and Ang2 levels significantly increased (by 74.8%). Our data suggest that ECMO might be associated with a rather impaired mobilization of EPC and MSC and with a depression of VEGF serum levels in newborns with CDH.
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http://dx.doi.org/10.3389/fped.2019.00490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882772PMC
November 2019

The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia.

BMJ Open 2019 11 5;9(11):e032122. Epub 2019 Nov 5.

Department of Intensive care and Pediatric Surgery, Erasmus University Rotterdam, Rotterdam, The Netherlands.

Introduction: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking.

Methods And Analysis: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses.

Ethics And Dissemination: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained.

Trial Registration Number: NTR6982; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-032122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858099PMC
November 2019

iNO Therapy in Patients with Congenital Diaphragmatic Hernia - Discrepancy between Widespread Use and Therapeutic Effects.

Klin Padiatr 2019 Nov 29;231(6):320-325. Epub 2019 Aug 29.

Department of Pediatric Surgery, Universitätsklinikum Mannheim, Mannheim, Germany.

Background: Despite recent studies failing to prove beneficial effects of iNO therapy in patients with CDH, its use is still widespread. The aim of this work was to analyze iNO use in a retrospective cohort focusing on outcome parameters. Patients 378 CDH patients born and treated in Mannheim University Medical Center, Department for Neonatology, between 2010 and 2017 constituted our cohort. Therapy was based on the standardized protocol of the CDH EURO Consortium.

Method: General data (sex, birth weight, gestational age etc.) and therapy-related data (duration of iNO application, OI after 60 mins, need for ECMO support etc.) were collected from clinical reports and then conducted using SAS for both mono- and multivariate analyses.

Results: Out of 378 newborns with CDH, 265 received iNO (70.1%), of whom 82 (30.9%) showed a significant OI reduction of ≥5 pts after 60 mins (=responders), median OI improved by 1.85 pts overall. Among initial responders iNO, application reduced the need for ECMO support (p=0.0054), increased the time to ECMO initiation (p=0.005) and reduced mortality (p=0.0396).

Discussion: A group of 43 patients considerably benefited from iNO and thererfore as they did not need ECMO support. Even though iNO therapy has failed to prove significant beneficial effects for non-responders, the application is still to be considered an essential treatment method in the transitional period of CDH patients.

Conclusions: A more critical approach towards iNO application in nonresponders should be promoted. Further extensive multicenter studies on treatment alternatives for CDH-PAH are desirable.
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http://dx.doi.org/10.1055/a-0991-0455DOI Listing
November 2019

Extracorporeal Membrane Oxygenation in Congenital Diaphragmatic Hernia.

Front Pediatr 2019 8;7:336. Epub 2019 Aug 8.

Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Congenital diaphragmatic hernia (CDH) is characterized by failure of diaphragmatic development with lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). If conventional treatment with gentle ventilation and optimized vasoactive medication fails, extracorporeal membrane oxygenation (ECMO) may be considered. The benefits of ECMO in CDH are still controversial, since there are only few randomized trials demonstrating the advantages of this therapeutic option. At present, there is no precise prenatal and/or early postnatal prognostication parameter to predict reversibility of PPHN in CDH patients. Indications for initiating ECMO include either respiratory or circulatory parameters, which are also undergoing continuous refinement. Centers with higher case numbers and the availability of ECMO published promising survival rates, but data on long-term results, including morbidity and quality of life, are rare. Survival might be influenced by the timing of ECMO initiation and the timing of surgical repair. In this regard a trend toward early initiation of ECMO and early surgery on ECMO exists. The results concerning the cannulation modes are similar and a consensus on time limit for ECMO runs does not exist. The use of ECMO in CDH will continue to be evaluated, and prospective randomized trials and registry network are necessary to help answering the addressed questions of patient selection and management.
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http://dx.doi.org/10.3389/fped.2019.00336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694279PMC
August 2019

Remicade (infliximab): 20 years of contributions to science and medicine.

Biologics 2019 30;13:139-178. Epub 2019 Jul 30.

Medical Affairs, Janssen Pharmaceuticals, Horsham, PA, USA.

On August 24, 1998, Remicade (infliximab), the first tumor necrosis factor-α (TNF) inhibitor, received its initial marketing approval from the US Food and Drug Administration for the treatment of Crohn's disease. Subsequently, Remicade was approved in another five adult and two pediatric indications both in the USA and across the globe. In the 20 years since this first approval, Remicade has made several important contributions to the advancement of science and medicine: 1) clinical trials with Remicade established the proof of concept that targeted therapy can be effective in immune-mediated inflammatory diseases; 2) as the first monoclonal antibody approved for use in a chronic condition, Remicade helped in identifying methods of administering large, foreign proteins repeatedly while limiting the body's immune response to them; 3) the need to establish Remicade's safety profile required developing new methods and setting new standards for postmarketing safety studies, specifically in the real-world setting, in terms of approach, size, and duration of follow-up; 4) the study of Remicade has improved our understanding of TNF's role in the immune system, as well as our understanding of the pathophysiology of a range of diseases characterized by chronic inflammation; and 5) Remicade and other TNF inhibitors have transformed treatment practices in these chronic inflammatory diseases: remission has become a realistic goal of therapy and long-term disability resulting from structural damage can be prevented. This paper reviews how, over the course of its development and 20 years of use in clinical practice, Remicade was able to make these contributions.
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http://dx.doi.org/10.2147/BTT.S207246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679695PMC
July 2019

Active perinatal care of preterm infants in the German Neonatal Network.

Arch Dis Child Fetal Neonatal Ed 2020 Mar 27;105(2):190-195. Epub 2019 Jun 27.

Department of Neonatology and Pediatric Intensive Care, University Hospital Carl Gustav Carus, Dresden, Germany.

Objective: To determine if survival rates of preterm infants receiving active perinatal care improve over time.

Design: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016.

Setting: 43 German level III neonatal intensive care units (NICUs).

Patients: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care.

Interventions: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (
Main Outcome Measures: Death by any cause before discharge.

Results: Total survival increased from 85.8% in 2011-2013 to 87.4% in 2014-2016. This increase was due to reduced mortality of NICUs with low survival rates in 2011-2013. Survival increased in these centres from 53% to 64% in the 22-24 weeks strata and from 73% to 84% in the 25-26 weeks strata.

Conclusions: Our data support previous reports that active perinatal care of very immature infants improves outcomes at the border of viability and survival rates at higher gestational ages. The high total number of surviving infants below 24 weeks of gestation challenges national recommendations exclusively referring to gestational age as the single criterion for providing active care. However, more data are needed before recommendations for parental counselling should be reconsidered.

Trial Registration: Approval by the local institutional review board for research in human subjects of the University of Lübeck (file number 08-022) and by the local ethic committees of all participating centres has been given.
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http://dx.doi.org/10.1136/archdischild-2018-316770DOI Listing
March 2020

Cross-sectional analysis on publication status and age representation of clinical studies addressing mechanical ventilation and ventilator-induced lung injury in infants and children.

BMJ Open 2018 11 18;8(11):e023524. Epub 2018 Nov 18.

Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Objectives: We determined the number and time-to-public availability of study results of published and unpublished clinical studies in paediatric mechanical ventilation (MV) and ventilator-induced lung injury (VILI), which were registered as completed on ClinicalTrials.gov. Furthermore, we explored the pattern of represented research study subtopics and the corresponding study populations.

Setting: Literature search based on ClinicalTrials.gov, PubMed and Google Scholar from 9 July 2017 to 27 September 2017.

Primary And Secondary Outcome Measures: Assessment, if studies included in our analysis had been published. Assessment of primary research focus, patient enrolment and age representation of the analysed studies.

Results: We identified n=109 registered and completed clinical studies on paediatric MV and VILI (enrolment: 22 233 participants). 71% were published, including data from 18 647 subjects. 29% of studies were unpublished, containing data from 3586 subjects. Median time-to-public availability of study results was 22 (IQR, 12.8-41.5) months. The most important study subtopics were biophysical and technical aspects of MV (32 studies), administration of drugs to mitigate VILI through various mechanisms (40 studies) and diagnostic procedures (16 studies). n=66/109 (61%) studies exclusively focused on children below 1 year of age and n=2/109 (2%) exclusively on children between 1 and 14 years.

Conclusions: One-third of clinical studies in paediatric MV and VILI registered as completed on ClinicalTrials.gov remained unpublished and contained data on 3586 study participants. The overall median time-to-public availability of study results was longer than the deadline of 12 months mandated by the Food and Drug Administration Amendment Act of 2007. Important and clinically relevant research study subtopics were represented in the research questions investigated in paediatric MV and VILI. The study population was skewed towards children younger than 1 year which indicates, that there is a substantial need for clinical VILI research in older children.
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http://dx.doi.org/10.1136/bmjopen-2018-023524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252714PMC
November 2018
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