Publications by authors named "Gerald Schlager"

9 Publications

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Hemadsorption as rescue therapy for patients with multisystem organ failure in pediatric intensive care-Two case reports and review of the literature.

Artif Organs 2021 Jul 31. Epub 2021 Jul 31.

Division of Neonatology, Pediatric Intensive Care & Neuropediatrics, Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Hemadsorption via the cytokine-adsorber CytoSorb (CytoSorbents Europe, Berlin, Germany) has successfully been used as an adjunctive method in adults, mainly for the purpose of immunomodulation under acute inflammatory conditions such as sepsis and cardiac surgery. In recent years, there has been growing interest in its use in pediatric intensive care to improve outcomes in patients with multiple organ failure following an inflammatory illness. Literature on the application of CytoSorb in neonatal and pediatric patients is scarce, though the implication is that it could be an effective last-resort treatment option in critically ill pediatric patients. Herein we present the clinical cases of two pediatric patients successfully treated with a combination of the CytoSorb hemadsorber, continuous renal replacement therapy, and extracorporeal membrane oxygenation due to multiple organ failure following different underlying medical conditions. Patient 1 was a 7-month-old male child with Down's syndrome admitted to the Pediatric Intensive Care Unit (PICU) after congenital heart surgery, who developed antimicrobial-resistant septic shock and severe acute respiratory distress syndrome. Patient 2 was a 2-year-old male child admitted to the PICU with influenza A-associated acute liver failure resulting in hyperammonemia, lactate acidosis, hemodynamic instability, and acute kidney failure. In both patients, hemadsorption with CytoSorb was initiated as an adjunctive rescue therapy to treat refractory multisystem organ failure. Improvement of laboratory and clinical parameters was observed within hours of treatment initiation. The application of the hemadsorber-developed for use in adults-proved simple and safe for use in both of our low-weight pediatric patients.
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http://dx.doi.org/10.1111/aor.14047DOI Listing
July 2021

Necessity of early and continuous monitoring for possible infectious complications in children undergoing therapeutic hypothermia.

Acta Paediatr 2021 03 12;110(3):805-810. Epub 2020 Aug 12.

Division of Neonatology, Paediatric Intensive Care & Neuropaediatrics, Department of Paediatric and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Aim: Since therapeutic hypothermia (TH) is known for its inhibitory effects on leucocyte migration and cytokine synthesis, our aim was to underline the necessity of early monitoring for potential immunomodulatory risks.

Methods: Using a 13-year retrospective case-control study at the paediatric intensive care unit (PICU) of the Medical University in Vienna, all newborn infants and children receiving TH were screened and compared with a diagnosis-matched control group undergoing conventional normothermic treatment (NT). TH was accomplished by using a non-invasive cooling device. Target temperature was 32-34°C. Children with evident infections, a medical history of an immunodeficiency or undergoing immunosuppressive therapy, were excluded.

Results: During the observational period, 108 patients were screened, 27 of which underwent TH. Culture-proven infections occurred in 22% of the TH group compared with 4% of the normothermic controls (P = .1). From the second day following PICU admission, median C-reactive protein (CRP) values were higher in the TH group (day two P = .002, day three P = .0002, day six P = .008).

Conclusion: Children undergoing TH showed earlier and higher increases in CRP levels when compared to normothermic controls. These data underline the necessity of early and continuous monitoring for possible infectious complications.
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http://dx.doi.org/10.1111/apa.15506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984159PMC
March 2021

Direct postoperative protein S100B and NIRS monitoring in infants after pediatric cardiac surgery enrich early mortality assessment at the PICU.

Heart Lung 2020 Nov - Dec;49(6):731-736. Epub 2020 Sep 4.

Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Austria. Electronic address:

Background: Neuromonitoring using plasmatic biomarkers such as S100B and near-infrared spectroscopy (NIRS) represents a standard procedure for detecting cerebral damage after cardiac surgery. Their use in pediatric clinical assessment, however, is negligible.

Objectives: The goal of this study was to evaluate the predictive role of S100B levels and cerebral oxygenation in postoperative pediatric cardiac patients for survival and potential cerebral injuries.

Methods: A retrospective cohort study of infants after cardiac surgery. Primary outcome was survival until discharge. Intra/postoperative vital signs and laboratory data were measured and statistically analyzed.

Results: Seven out of 226 infants were non-survivors. Non-survivors had significantly lower cerebral saturation than survivors, as well as elevated S100B values at admission, associated with lower arterial pressure and higher serum lactate levels.

Conclusion: Although significant differences of S100B and crO values between survivors and non-survivors were found, no critical thresholds could be established from the data. Nevertheless, changes from the norm in these parameters should raise awareness for critical clinical development.
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http://dx.doi.org/10.1016/j.hrtlng.2020.08.014DOI Listing
March 2021

Chylothorax and Chylous-Like Diseases in Children: Clinical Management.

Front Pediatr 2019 27;7:258. Epub 2019 Jun 27.

Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Vienna, Austria.

Chylothorax and chylous-like diseases are rare conditions and difficult to treat. But they may represent potentially life-threatening disorders and important causes of morbidity and prolonged hospitalization, especially in critically ill children. Conservative as well as surgical therapeutic management strategies are continuously performed at our institution, however the results have never been evaluated and no guidelines for treatment recommendations have been put into practice so far. The objective of this retrospective study was to present a comprehensive and substantial evaluation of all relevant demographic data from children with the chylothorax and chylous-like diseases and their clinical management. We retrospectively analyzed data from all children with diagnoses of chylothorax and chylous-like diseases admitted to our pediatric intensive care unit between the years 1999 and 2012. Data of 34 patients were analyzed for this study. Gender distribution (M/F) was almost equal (19/15; 56%/44%). Thirty-one children (91%) developed chylothorax after surgery. Two children (6%) had idiopathic chylothorax and in one child (3%) congenital chylothorax was diagnosed. All study patients ( = 34; 100%) received MBF/MCT therapy. We were quite successful in treating 14 children who received only this therapy, with chest tube output dropping from 100 to 4.7%. But only 11 (32%) children received somatostatin and 7 (20%) children received beta-isodona. Different surgical interventions were performed in 6 patients (17%). All study patients received chest tubes to drain the pleural fluid and hence to relieve the chyle related symptoms. A combination of different conservative therapies was successful in most of our patients. Prevention, early diagnosis and treatment of potential complications may further improve the success rate of conservative therapy especially in patients with postoperative chylothorax. In summary, appropriate therapy of this condition may be lengthy but can prevent significant morbidity and mortality.
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http://dx.doi.org/10.3389/fped.2019.00258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610320PMC
June 2019

Effect of propofol in the immature rat brain on short- and long-term neurodevelopmental outcome.

PLoS One 2013 30;8(5):e64480. Epub 2013 May 30.

Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Background: Propofol is commonly used as sedative in newborns and children. Recent experimental studies led to contradictory results, revealing neurodegenerative or neuroprotective properties of propofol on the developing brain. We investigated neurodevelopmental short- and long-term effects of neonatal propofol treatment.

Methods: 6-day-old Wistar rats (P6), randomised in two groups, received repeated intraperitoneal injections (0, 90, 180 min) of 30 mg/kg propofol or normal saline and sacrificed 6, 12 and 24 hrs following the first injection. Cortical and thalamic areas were analysed by Western blot and quantitative real-time PCR (qRT-PCR) for expression of apoptotic and neurotrophin-dependent signalling pathways. Long-term effects were assessed by Open-field and Novel-Object-Recognition at P30 and P120.

Results: Western blot analyses revealed a transient increase of activated caspase-3 in cortical, and a reduction of active mitogen-activated protein kinases (ERK1/2, AKT) in cortical and thalamic areas. qRT-PCR analyses showed a down-regulation of neurotrophic factors (BDNF, NGF, NT-3) in cortical and thalamic regions. Minor impairment in locomotive activity was observed in propofol treated adolescent animals at P30. Memory or anxiety were not impaired at any time point.

Conclusion: Exposing the neonatal rat brain to propofol induces acute neurotrophic imbalance and neuroapoptosis in a region- and time-specific manner and minor behavioural changes in adolescent animals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064480PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667818PMC
January 2014

CEACAM1 expression in oligodendrocytes of the developing rat brain shows a spatiotemporal relation to myelination and is altered in a model of encephalopathy of prematurity.

Dev Neurosci 2013 3;35(2-3):226-40. Epub 2013 May 3.

Department of Pediatrics 1, Neonatology, University Hospital Essen, Essen, Germany.

CEACAM1 is the founder molecule of the family of 'carcinoembryonic antigen-related cell adhesion molecules' and part of the immunoglobulin superfamily. Due to its role as a coreceptor to many other receptors (e.g. Toll-like receptor 2, Toll-like receptor 4, T-cell receptor, B-cell receptor, epidermal growth factor receptor and vascular endothelial growth factor receptor) and its different isoforms, CEACAM1 is a multifunctional protein with an impact on proliferation and differentiation of multiple cell types. Although different modes of action in other tissues are described, the role of CEACAM1 in the developing brain remains elusive. Here we report for the first time that CEACAM1 is expressed ontogenetically in oligodendrocytes of the developing rat brain, and that CEACAM1 expression has a spatiotemporal relation to myelination. In addition, CEACAM1 expression is altered in a model of hyperoxia- and inflammation-induced encephalopathy of prematurity, a myelination disorder of children born preterm. Furthermore, primary oligodendrocytes stimulated with CEACAM1 show increased myelination. Therefore, we postulate that CEACAM1 is, at least in part, involved in hyperoxia- and inflammation-induced disruption of myelination, but may also play a role in intact myelination as it is ontogenetically expressed in myelinating oligodendrocytes.
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http://dx.doi.org/10.1159/000348436DOI Listing
March 2014

Interaction of inflammation and hyperoxia in a rat model of neonatal white matter damage.

PLoS One 2012 14;7(11):e49023. Epub 2012 Nov 14.

Department of Neonatology, Charité University Medical Center, Berlin, Germany.

Intrauterine infection and inflammation are major reasons for preterm birth. The switch from placenta-mediated to lung-mediated oxygen supply during birth is associated with a sudden rise of tissue oxygen tension that amounts to relative hyperoxia in preterm infants. Both infection/inflammation and hyperoxia have been shown to be involved in brain injury of preterm infants. Hypothesizing that they might be additive or synergistic, we investigated the influence of a systemic lipopolysaccharide (LPS) application on hyperoxia-induced white matter damage (WMD) in newborn rats. Three-day-old Wistar rat pups received 0.25 mg/kg LPS i.p. and were subjected to 80% oxygen on P6 for 24 h. The extent of WMD was assessed by immunohistochemistry, western blots, and diffusion tensor (DT) magnetic resonance imaging (MRI). In addition, the effects of LPS and hyperoxia were studied in an in vitro co-culture system of primary rat oligodendrocytes and microglia cells. Both noxious stimuli, hyperoxia, and LPS caused hypomyelination as revealed by western blot, immunohistochemistry, and altered WM microstructure on DT-MRI. Even so, cellular changes resulting in hypomyelination seem to be different. While hyperoxia induces cell death, LPS induces oligodendrocyte maturity arrest without cell death as revealed by TUNEL-staining and immunohistological maturation analysis. In the two-hit scenario cell death is reduced compared with hyperoxia treated animals, nevertheless white matter alterations persist. Concordantly with these in vivo findings we demonstrate that LPS pre-incubation reduced premyelinating-oligodendrocyte susceptibility towards hyperoxia in vitro. This protective effect might be caused by upregulation of interleukin-10 and superoxide dismutase expression after LPS stimulation. Reduced expression of transcription factors controlling oligodendrocyte development and maturation further indicates oligodendrocyte maturity arrest. The knowledge about mechanisms that triggered hypomyelination contributes to a better understanding of WMD in premature born infants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049023PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498343PMC
May 2013

Role of p75NTR in NMDAR-mediated excitotoxic brain injury in neonatal mice.

Brain Res 2010 Oct 6;1355:31-40. Epub 2010 Aug 6.

Department of Paediatrics IV, Neonatology, Neuropaediatrics and Metabolic Diseases, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.

Background: Perinatal brain injury in preterm infants is a major cause of neurological handicap. The role of the neurotrophin receptor p75 (p75(NTR)) in the pathogenesis and repair of neonatal excitotoxic brain injury is unknown. Depending on a complex interplay of neurotrophin signalling, p75(NTR) can, in addition to its trophic function, also induce apoptosis.

Hypothesis: We hypothesised that excitotoxicity increases p75(NTR) expression and p75(NTR) knockout (KO) mice have a significantly smaller lesion size upon excitotoxicity as compared to wild-type (WT) mice.

Methods: We used an established animal model of neonatal excitotoxic brain injury mimicking several key aspects of human preterm brain damage. We subjected five-day-old WT and KO mice to excitotoxic injury by means of a single intracranial ibotenate injection (N-methyl-D-aspartate receptor agonist, NMDAR) into one brain hemisphere. Lesion size, number of activated caspase-3- and apoptosis-inducing factor (AIF)-positive cells were determined as outcome parameters. Gender analyses were taken into account retrospectively.

Results: NMDAR-mediated excitotoxicity induced an upregulation of p75(NTR) expression in the peri-lesion area. Lesion size was significantly increased in female KO as compared to male KO animals. Knockout of p75(NTR) reduced the number of activated caspase-3 but not AIF-positive cells after NMDAR-mediated excitotoxic injury independently of gender.

Conclusion: Since NMDAR-mediated excitotoxic brain injury induced p75(NTR) expression and caspase-3-activated apoptosis in p75(NTR) KO animals was decreased, we conclude that activation of p75(NTR) contributes to NMDAR-mediated apoptosis in the neonatal brain. An increase in lesion size in female animals after excitotoxic brain injury suggests that in females p75(NTR) seems to play a dual role.
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http://dx.doi.org/10.1016/j.brainres.2010.07.095DOI Listing
October 2010

Dextromethorphan is protective against sensitized N-methyl-D-aspartate receptor-mediated excitotoxic brain damage in the developing mouse brain.

Eur J Neurosci 2008 Feb 13;27(4):874-83. Epub 2008 Feb 13.

Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.

Enhanced glutamate release and inflammation play an important role in the pathogenesis of developmental brain injury. Although N-methyl-d-aspartate receptor (NMDAR) antagonists potently attenuate neonatal brain damage in several animal models, they can also impact trophic functions in the developing brain. As a consequence, high-affinity NMDAR antagonists have been shown to trigger widespread apoptotic neurodegeneration in the newborn brain. Dextromethorphan (DM), a low-affinity NMDAR antagonist with anti-inflammatory properties, may be neuroprotective against excitotoxic and inflammation-enhanced excitotoxic brain injury, without the associated stimulation of apoptotic degeneration. Using an established newborn mouse model of excitotoxic brain damage, we determined whether systemic injection of DM significantly attenuates excitotoxic lesion size. We investigated several doses and time regimens; a dose of 5 microg/g DM given in a combination of both pre-injury and repetitive post-injury treatment proved most effective. DM treatment significantly reduced lesion size in gray and white matter by reducing cell death as shown by a decreased Fluoro-Jade B staining and caspase-3 activation. Pre-treatment with interleukin-1beta and lipopolysaccharide enhanced NMDAR-mediated excitotoxic brain injury and microglial cell activation. This sensitizing effect was abolished by DM treatment, as the effectiveness of DM in reducing lesion size and microglial cell activation was similar to phosphate-buffered saline-pre-treated controls. In all cases, no gender-specific differences were detected. DM treatment did not trigger any apoptotic neurodegeneration (caspase-3 cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Fluoro-Jade B staining). Although functional parameters were not measured, our data corroborate reports that DM is neuroprotective and that it may therefore improve functional outcome following perinatal brain injury.
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http://dx.doi.org/10.1111/j.1460-9568.2008.06062.xDOI Listing
February 2008
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