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1. Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.

Author: Irja Lutsar, Corine Chazallon, Ursula Trafojer, Vincent Meiffredy de Cabre, Cinzia Auriti, Chiara Bertaina, Francesca Ippolita Calo Carducci, Fuat Emre Canpolat, Susanna Esposito, Isabelle Fournier, Maarja Hallik, Paul T Heath, Mari-Liis Ilmoja, Elias Iosifidis, Jelena Kuznetsova, Laurence Meyer, Tuuli Metsvaht, George Mitsiakos, Zoi Dorothea Pana, Fabio Mosca, Lorenza Pugni, Emmanuel Roilides, Paolo Rossi, Kosmas Sarafidis, Laura Sanchez, Michael Sharland, Vytautas Usonis, Adilia Warris, Jean-Pierre Aboulker, Carlo Giaquinto, and NeoMero Consortium
Subjects: Medicine, Science
Abstract: BackgroundThe early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged Methods and findingsNeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052).ConclusionsWithin this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.
Published: 2020
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2. Blunt cardiac rupture in a toddler

Author: Peep Talving, Mari-Liis Ilmoja, Günter Taal, Karl-Gunnar Isand, Sandra Teppo, Erast-Henri Noor, Rein Kruusat, Andrus Remmelgas, and Sten Saar
Subjects: Cardiac rupture, Blunt trauma, Toddler, Pediatrics, RJ1-570, Surgery, RD1-811
Abstract: Blunt cardiac rupture is typically a fatal injury with overall mortality exceeding 90%. Most of the patients never reach the hospital alive. In pediatric patients, only 0.03% of cases following blunt trauma admissions have a cardiac injury. This report presents a rare survivor of 16-months old toddler injured in a domestic accident suffering a right atrial rupture repaired through a median sternotomy. To the best of our knowledge this is the youngest case reported in the literature.
Published: 2016
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3. Neonates undergoing pyloric stenosis repair are at increased risk of difficult airway management

Author: Nicola Disma, Thomas Engelhardt, Tom G. Hansen, Jurgen C. de Graaff, Katalin Virag, Walid Habre, Christian Breschan, Rudolf Likar, Manuela Platzer, Isole Edelman, Johanes Eger, Stefan Heschl, Brigitte Messerer, Maria Vittinghof, Ruth Kroess, Martina Stichlberger, David Kahn, Thierry Pirotte, Caroline Pregardien, Francis Veyckemans, France Stevens, Johan Berghmans, Annemie Bauters, Luc De Baerdemaeker, Stefan De Hert, Koen Lapage, Aliaksandra Parashchanka, Jurgen Van Limmen, Piet Wyffels, Julie Lauweryns, Nadia Najafi, Joris Vundelinckx, Diana Butković, Ivana Kerovec Sorić, Sandra Kralik, Ana Markić, Josip Azman, Josko Markic, Daniela Pupacic, Michal Frelich, Petr Reimer, René Urbanec, Petra Cajková, Vladimír Mixa, Yvona Sedláčková, Lenka Knoppová, Alena Zlámalová (neé Květoňová), Martin Vavřina, Jiří Žurek, Tom Hansen, Arash Afshari, Anders Bastholm Bille, Marguerite Ellekvist, Mari-Liis Ilmoja, Reet Moor, Reet Kikas, Merle Väli, Kariantti Kallio, Elisa Reponen, Pertti Suominen, Sami Suvanto, Raisa Vähätalo, Hannu Kokki, Merja Kokki, Jarkko Harju, Miia Kokkonen, Jenni Vieri, Tuula Manner, Amory Catherine, Hugues Ludot, Dina Bert, Juliette Godart, Anne Laffargue, Hervé Dupont, Benjamin Urbina, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Maryline Bordes, Karine Nouette Gaulain, Yann Hamonic, François Semjen, Olivier Jacqmarcq, Caroline Lejus-Bourdeau Cécile Magne, Léa Petry, Lilica Ros, Aurélien Zang, Mehdi Bennis, Bernard Coustets, Rose Fesseau, Isabelle Constant, Eliane Khalil, Nada Sabourdin, Noemie Audren, Thomas Descarpentries, Fanny Fabre, Aurélien Legrand, Emilie Druot, Gilles Orliaguet, Lucie Sabau, Lynn Uhrig, François de la Brière, Karin Jonckheer, Jean-Paul Mission, Lucia Scordo, Caroline Couchepin, Christophe Dadure, Pablo De la Arena, Laurent Hertz, Philippe Pirat, Chrystelle Sola, Myriam Bellon, Souhayl Dahmani, Florence Julien-Marsollier, Daphne Michelet, Veronique Depret-Donatien, Anne Lesage, Jost Kaufmann, Michael Laschat, Frank Wappler, Karin Becke, Lena Brunner, Karin Oppenrieder, Gregor Badelt, Karin Hochmuth, Bernhard Koller, Anita Reil, Sebastian Richter, Thomas Fischer, Anja Diers, Clemens Schorer, Andreas Weyland, Ruth Cohausz, Franz-Josef Kretz, Michaela Löffler, Markus Wilbs, Claudia Hoehne, Johanna Ulrici, Christiane Goeters, Armin Flinspach, Matthias Klages, Simone Lindau, Leila Messroghli, Kai Zacharowski, Christoph Eisner, Thomas Mueller, Daniel Richter, Melanie Schäfer, Markus Weigand, Sebastian Weiterer, Miriam Ochsenreiter, Michael Schöler, Tom Terboven, Isabel Eggemann, Sascha Haussmann, Nicolas Leister, Christoph Menzel, Uwe Trieschmann, Sirin Yücetepe, Susanna Keilig, Peter Kranke, Yvonne Jelting, Torsten Baehner, Richard Ellerkmann, Shahab Ghamari, Claudia Neumann, Martin Söhle, Pelagia Chloropoulou, Vagia Ntritsou, Pinelopi Papagiannopoulou, Eleana Garini, Afroditi Karafotia, Panagoula Mammi, Evangelia Bali, Despoina Iordanidou, Anna Malisiova, Artemis Polyzoi, Adelais Tsiotou, Erzsebet Sapi, Edgar Székely, Nandor Kosik, Veronika Maráczi, Janos Schnur, Judit Csillag, János Gál, Gergely Göbl, Balázs Hauser, András Petróczy, Gyula Tövisházi, Stuart Blain, Sarah Gallagher, Sinead Harte, Mandy Jackson, Emma Meehan, Zeenat Nawoor, Brendan O’Hare, Mark Ross, Daniela Lerro, Marinella Astuto, Chiara Grasso, Rita Scalisi, Giulia Frasacco, Elena Lenares, Roberto Leone, Maurizia Grazzini, Carmelo Minardi, Nicola Zadra, Gilda Cinnella, Antonella Cotoia, Dario Galante, Brita De Lorenzo, Beate Kuppers, Giulia Bottazzi, Fabio Caramelli, Maria Cristina Mondardini, Emanuele Rossetti, Sergio Picardo, Alessandro Vittori, Anna Camporesi, Francesca Izzo, Edoardo Calderini, Laura Brigitta Colantonio, Simona Anna Finamore, Giuliana Anna Porro, Rachele Bonfiglio, Svetlana Kotzeva, Girolamo Mattioli, Camilla Micalizzi, Alessia Montaguti, Angela Pistorio, Anna Guddo, Gerald Rogan Neba, Moreno Favarato, Bruno Guido Locatelli, Micol Maffioletti, Valter Sonzogni, Rossella Garra, Maria Sammartino, Fabio Sbaraglia, Andrea Cortegiani, Alessandra Moscarelli, Elena Attanasi, Simonetta Tesoro, Cristina Agapiti, Francesca Pinzoni, Cesare Vezzoli, Bilotta Federico, Arta Barzdina, Zane Straume, Anda Zundane, Laura Lukosiene, Irena Maraulaite, Ilona Razlevice, Bernd Schmitz, Stephanie Mifsud, Carolin Aehling, Celia Allison, Rients De Boer, Dina Emal, Markus Stevens, Marielle Buitenhuis, Jurgen de Graaff, Inge De Liefde, Andreas Machotta, Gail Scoones, Lonneke Staals, Jeremy Tomas, Anouk Van der Knijff-van Dortmont, Marianne Veldhuizen, David Alders, Eva Schafrat, Jan Schreiber, Petronella Mari Vermeulen, Mark Hendriks, Sandra Lako, Marieke Voet-Lindner, Barbe Pieters, Gert-Jan Scheffer, Luc Tielens, Anthony R. Absalom, Margot Bergsma, Joke De Ruiter, Sascha Meier, Martin Volkers, Tjerk Zweers, Anne M. Beukers, Christa Boer, Jurgen Dertinger, Sandra Numan, Bas Van Zaane, Wenche B. Boerke, Nil Ekiz, Kristoffer Stensrud, Inger Marie Drage, Erik Ramon Isern, Alicja Bartkowska-Sniatkowska, Malgorzata Grzeskowiak, Magdalena Juzwa-Sobieraj, Jowita Rosada-Kurasińska, Artur Baranowski, Karina Jakubowska, Dorota Lewandowska, Magdalena Mierzewska-Schmidt, Piotr Sawicki, Magdalena Urban-Lechowicz, Pomianek Przemyslaw, Marzena Zielinska, Teresa Leal, Maria Soares, Pedro Pina, Sílvia Pinho, Maria Domingas Patuleia, Catarina Cruz Esteves, Helena Salgado, Maria João Santos, Rodica Badeti, Iulia Cindea, Loredana Oana, Adriana Gurita, Luminita Ilie, Gabriel Mocioiu, Radu Tabacaru, Irina Trante, Valentin Munteanu, Mihai Morariu, Emese Nyíri, Ivana Budic, Vesna Marjanovic, Biljana Drašković, Marina Pandurov, Jordanka Ilic, Ana Mandras, Zdenka Rados, Nikola Stankovic, Maja Suica, Sladjana Vasiljevic, Mirjana Knezevic, Irina Milojevic, Ivana Petrov, Selena Puric Racic, Dusica Simic, Irena Simic, Marija Stevic, Irena Vulicevic, Banská Bystrica, Barbora Cabanová, Miloslav Hanula, Jelena Berger, Darja Janjatovic, Špela Pirtovšek Štupnik, Dolores Méndez, Gema Pino, Paloma Rubio, Alberto Izquierdo, Silvia López, Cristina González Serrano, Jesús Cebrián, Ana Peleteiro, Pilar Del Rey de Diego, Ernesto Martínez García, Carolina Tormo de las Heras, Pablo Troncoso Montero, Celia Arbona, David Artés, Alicia Chamizo, Silvia Serrano, Montserrat Suarez Comas, Francisco Escribá, Cristina Auli, Osvaldo Pérez Pardo, Natalia Sierra Biddle, Ceferina Suárez Castaño, María Isabel Villalobos Rico, Susana Manrique Muñoz, Irene García Martínez, Nuria Montferrer Estruch, Elena Vilardell Ortíz, Rodrigo Poves-Álvarez, Ivan Kohn, Ulf Lindestam, Jarl Reinhard, Albert Castellheim, Kerstin Sandström, Sporre Bengt, Rainer Dörenberg, Peter Frykholm, Maria Garcia, Ann Kvarnström, Emma Pontén, Thomas Bruelisauer, Gabor Erdoes, Heiko Kaiser, Mathias Marchon, Thomas Riva, Stefan Seiler, Yann Bögli, Mirko Dolci, Carine Marcucci, Isabelle Pichon, Laszlo Vutskits, Mattias Casutt, Martin Hölzle, Thomas Hurni, Martin Jöhr, Anna-Ursina Malär, Jacqueline Mauch, Thomas Erb, Karin Oeinck, Mine Akin, Gulsen Keskin, Yesim Senayli, Guner Kaya, Pinar Kendigelen, Ayse Çiğdem Tutuncu, Zehra Hatipoğlu, Dilek Özcengiz, Hale Aksu Erdost, Elvan Öçmen, Çimen Olguner, Hilmi Ayanoglu, Pelin Corman Dincer, Tumay Umuroglu, Mustafa Azizoglu, Handan Birbiçer, Nurcan Doruk, Aslı Sagun, Sibel Baris, Dmytro Dmytriiev, Sridevi Kuchi, Nuria Masip, Peter Brooks, Alison Hare, Nargis Ahmad, Michelle Casey, Sam De Silva, Nadine Dobby, Prakash Krishnan, L. Amaki Sogbodjor, Ellie Walker, Suellen Walker, Stephanie King, Katy Nicholson, Michelle Quinney, Paul Stevens, Andrew Blevin, Mariangela Giombini, Chulananda Goonasekera, Sadia Adil, Stephanie Bew, Carol Bodlani, Dan Gilpin, Stephanie Jinks, Nalini Malarkkan, Alice Miskovic, Rebecca Pad, Juliet Wolfe Barry, Joy Abbott, James Armstrong, Natalie Cooper, Lindsay Crate, John Emery, Kathryn James, Hannah King, Paul Martin, Stefano Scalia Catenacci, Rob Bomont, Paul Smith, Sara Mele, Alessandra Verzelloni, Philippa Dix, Graham Bell, Elena Gordeva, Lesley McKee, Esther Ngan, Jutta Scheffczik, Li-En Tan, Mark Worrall, Carmel Cassar, Kevin Goddard, Victoria Barlow, Vimmi Oshan, Khairi Shah, Sarah Bell, Lisa Daniels, Monica Gandhi, David Pachter, Chris Perry, Andrew Robertson, Carmen Scott, Lynne Waring, David Barnes, Sophie Childs, Joanne Norman, Robin Sunderland, Dowell Julia, Feijten Prisca, Harlet Pierre, Herbineaux Sarah, Leva Brigitte, Plichon Benoît, Virág Katalin, and Anesthesiology
Subjects: Europe, Anesthesiology and Pain Medicine, Infant, Newborn, Intubation, Intratracheal, Humans, Infant, airway management, complications, difficult airway, neonatal anaesthesia, pyloric stenosis, tracheal intubation, Anesthesia, Pyloric Stenosis, Hypertrophic, Airway Management, Child, Hypoxia
Abstract: Background: Hypertrophic pyloric stenosis in otherwise healthy neonates frequently requires urgent surgical procedure but anaesthesia care may result in respiratory complications, such as hypoxaemia, pulmonary aspiration of gastric contents, and postoperative apnoea. The primary aim was to study whether or not the incidence of difficult airway management and of hypoxaemia in neonates undergoing pyloric stenosis repair was higher than that in neonates undergoing other surgeries. Methods: Data on neonates and infants undergoing anaesthesia and surgery for pyloric stenosis were extracted from the NEonate and Children audiT of Anesthesia pRactice In Europe (NECTARINE) database, for secondary analysis. Results: We identified 310 infants who had anaesthesia for surgery for pyloric stenosis. Difficult airway management (more than two attempts at laryngoscopy) was higher in children with pyloric stenosis when compared with the entire NECTARINE cohort (7.9% [95% confidence interval {CI}, 5.22–11.53] vs 4.4% [95% CI, 1.99–6.58]; relative risk [RR]=1.81 [95% CI, 1.21–2.69]; P=0.004), whereas transient hypoxaemia with oxygen saturation
Published: 2022

4. Pharmacogenetics may explain part of the interindividual variability of dobutamine pharmacodynamics in neonates

Author: Maarja Hallik, Hiie Soeorg, Tiina Kahre, Ülle Murumets, Mari-Liis Ilmoja, Karin Kipper, and Tuuli Metsvaht
Subjects: Pharmacology, Heart Rate, Pharmacogenetics, Pregnancy, Critical Illness, Dobutamine, Infant, Newborn, Humans, Female, Pharmacology (medical), Polymorphism, Single Nucleotide
Abstract: Aim: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the hemodynamic response to dobutamine in critically ill neonates. Methods: Alleles in the known genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Results: 26 neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8 – 60.7) bpm per AUC of 100 mg·h, p=0.0005. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C>T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2 – 42.9) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0116 and 33.2 (12.1 – 54.3) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0025, respectively. Conclusion: In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.
Published: 2022
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5. Difficult tracheal intubation in neonates and infants. NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE)

Author: Nicola Disma, Katalin Virag, Thomas Riva, Jost Kaufmann, Thomas Engelhardt, Walid Habre, Christian Breschan, Rudolf Likar, Manuela Platzer, Isole Edelman, Johanes Eger, Stefan Heschl, Brigitte Messerer, Maria Vittinghof, Ruth Kroess, Martina Stichlberger, David Kahn, Thierry Pirotte, Caroline Pregardien, Francis Veyckemans, France Stevens, Johan Berghmans, Annemie Bauters, Luc De Baerdemaeker, Stefan De Hert, Koen Lapage, Aliaksandra Parashchanka, Jurgen Van Limmen, Piet Wyffels, Julie Lauweryns, Nadia Najafi, Joris Vundelinckx, Diana Butković, Ivana Kerovec Sorić, Sandra Kralik, Ana Markić, Josip Azman, Josko Markic, Daniela Pupacic, Michal Frelich, Petr Reimer, René Urbanec, Petra Cajková, Vladimír Mixa, Yvona Sedláčková, Lenka Knoppová, Alena Zlámalová (neé Květoňová), Martin Vavřina, Jiří Žurek, Tom Hansen, Arash Afshari, Anders Bastholm Bille, Marguerite Ellekvist, Mari-Liis Ilmoja, Reet Moor, Reet Kikas, Merle Väli, Kariantti Kallio, Elisa Reponen, Pertti Suominen, Sami Suvanto, Raisa Vähätalo, Hannu Kokki, Merja Kokki, Jarkko Harju, Miia Kokkonen, Jenni Vieri, Tuula Manner, Catherine Amory, Hugues Ludot, Dina Bert, Juliette Godart, Anne Laffargue, Hervé Dupont, Benjamin Urbina, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Maryline Bordes, Karine Nouette Gaulain, Yann Hamonic, François Semjen, Olivier Jacqmarcq, Caroline Lejus-Bourdeau, Cécile Magne, Léa Petry, Lilica Ros, Aurélien Zang, Mehdi Bennis, Bernard Coustets, Rose Fesseau, Isabelle Constant, Eliane Khalil, Nada Sabourdin, Noemie Audren, Thomas Descarpentries, Fanny Fabre, Aurélien Legrand, Emilie Druot, Gilles Orliaguet, Lucie Sabau, Lynn Uhrig, François de la Brière, Karin Jonckheer, Jean-Paul Mission, Lucia Scordo, Caroline Couchepin, Christophe Dadure, Pablo De la Arena, Laurent Hertz, Philippe Pirat, Chrystelle Sola, Myriam Bellon, Souhayl Dahmani, Florence Julien-Marsollier, Daphne Michelet, Veronique Depret-Donatien, Anne Lesage, Michael Laschat, Frank Wappler, Karin Becke, Lena Brunner, Karin Oppenrieder, Gregor Badelt, Karin Hochmuth, Bernhard Koller, Anita Reil, Sebastian Richter, Thomas Fischer, Anja Diers, Clemens Schorer, Andreas Weyland, Ruth Cohausz, Franz-Josef Kretz, Michaela Löffler, Markus Wilbs, Claudia Hoehne, Johanna Ulrici, Christiane Goeters, Armin Flinspach, Matthias Klages, Simone Lindau, Leila Messroghli, Kai Zacharowski, Christoph Eisner, Thomas Mueller, Daniel Richter, Melanie Schäfer, Markus Weigand, Sebastian Weiterer, Miriam Ochsenreiter, Michael Schöler, Tom Terboven, Isabel Eggemann, Sascha Haussmann, Nicolas Leister, Christoph Menzel, Uwe Trieschmann, Sirin Yücetepe, Susanna Keilig, Peter Kranke, Yvonne Jelting, Torsten Baehner, Richard Ellerkmann, Shahab Ghamari, Claudia Neumann, Martin Söhle, Pelagia Chloropoulou, Vagia Ntritsou, Pinelopi Papagiannopoulou, Eleana Garini, Afroditi Karafotia, Panagoula Mammi, Evangelia Bali, Despoina Iordanidou, Anna Malisiova, Artemis Polyzoi, Adelais Tsiotou, Erzsebet Sapi, Edgar Székely, Nandor Kosik, Veronika Maráczi, Janos Schnur, Judit Csillag, János Gál, Gergely Göbl, Balázs Hauser, András Petróczy, Gyula Tövisházi, Stuart Blain, Sarah Gallagher, Sinead Harte, Mandy Jackson, Emma Meehan, Zeenat Nawoor, Brendan O’Hare, Mark Ross, Daniela Lerro, Marinella Astuto, Chiara Grasso, Rita Scalisi, Giulia Frasacco, Elena Lenares, Roberto Leone, Maurizia Grazzini, Carmelo Minardi, Nicola Zadra, Gilda Cinnella, Antonella Cotoia, Dario Galante, Brita De Lorenzo, Beate Kuppers, Giulia Bottazzi, Fabio Caramelli, Maria Cristina Mondardini, Emanuele Rossetti, Sergio Picardo, Alessandro Vittori, Anna Camporesi, Andrea Wolfler, Edoardo Calderini, Laura Brigitta Colantonio, Simona Anna Finamore, Giuliana Anna Porro, Rachele Bonfiglio, Svetlana Kotzeva, Leila Mameli, Girolamo Mattioli, Camilla Micalizzi, Alessia Montaguti, Angela Pistorio, Clelia Zanaboni, Anna Guddo, Gerald Rogan Neba, Moreno Favarato, Bruno Guido Locatelli, Micol Maffioletti, Valter Sonzogni, Rossella Garra, Maria Sammartino, Fabio Sbaraglia, Andrea Cortegiani, Alessandra Moscarelli, Elena Attanasi, Simonetta Tesoro, Cristina Agapiti, Francesca Pinzoni, Cesare Vezzoli, Federico Bilotta, Arta Barzdina, Zane Straume, Anda Zundane, Laura Lukosiene, Irena Maraulaite, Ilona Razlevice, Bernd Schmitz, Stephanie Mifsud, Carolin Aehling, Celia Allison, Rients De Boer, Dina Emal, Markus Stevens, Marielle Buitenhuis, Jurgen de Graaff, Inge De Liefde, Andreas Machotta, Gail Scoones, Lonneke Staals, Jeremy Tomas, Anouk Van der Knijff-van Dortmont, Marianne Veldhuizen, David Alders, Wolfgang Buhre, Eva Schafrat, Jan Schreiber, Petronella Mari Vermeulen, Mark Hendriks, Sandra Lako, Marieke Voet-Lindner, Barbe Pieters, Gert-Jan Scheffer, Luc Tielens, Anthony R. Absalom, Margot Bergsma, Joke De Ruiter, Sascha Meier, Martin Volkers, Tjerk Zweers, Anne M. Beukers, Christa Boer, Jurgen Dertinger, Sandra Numan, Bas Van Zaane, Wenche B. Boerke, Nil Ekiz, Kristoffer Stensrud, Inger Marie Drage, Erik Ramon Isern, Alicja Bartkowska-Sniatkowska, Malgorzata Grzeskowiak, Magdalena Juzwa-Sobieraj, Jowita Rosada-Kurasińska, Artur Baranowski, Karina Jakubowska, Dorota Lewandowska, Magdalena Mierzewska-Schmidt, Piotr Sawicki, Magdalena Urban-Lechowicz, Pomianek Przemyslaw, Marzena Zielinska, Teresa Leal, Maria Soares, Pedro Pina, Sílvia Pinho, Maria Domingas Patuleia, Catarina Cruz Esteves, Helena Salgado, Maria João Santos, Rodica Badeti, Iulia Cindea, Loredana Oana, Adriana Gurita, Luminita Ilie, Gabriel Mocioiu, Radu Tabacaru, Irina Trante, Valentin Munteanu, Mihai Morariu, Emese Nyíri, Ivana Budic, Vesna Marjanovic, Biljana Drašković, Marina Pandurov, Jordanka Ilic, Ana Mandras, Zdenka Rados, Nikola Stankovic, Maja Suica, Sladjana Vasiljevic, Mirjana Knezevic, Irina Milojevic, Ivana Petrov, Selena Puric Racic, Dusica Simic, Irena Simic, Marija Stevic, Irena Vulicevic, Barbora Cabanová, Miloslav Hanula, Jelena Berger, Darja Janjatovic, Špela Pirtovšek Štupnik, Dolores Méndez, Gema Pino, Paloma Rubio, Alberto Izquierdo, Silvia López, Cristina González Serrano, Jesús Cebrián, Ana Peleteiro, Pilar Del Rey de Diego, Ernesto Martínez García, Carolina Tormo de las Heras, Pablo Troncoso Montero, Celia Arbona, David Artés, Alicia Chamizo, Silvia Serrano, Montserrat Suarez Comas, Francisco Escribá, Cristina Auli, Osvaldo Pérez Pardo, Natalia Sierra Biddle, Ceferina Suárez Castaño, María Isabel Villalobos Rico, Susana Manrique Muñoz, Irene García Martínez, Nuria Montferrer Estruch, Elena Vilardell Ortíz, Rodrigo Poves-Álvarez, Ivan Kohn, Ulf Lindestam, Jarl Reinhard, Albert Castellheim, Kerstin Sandström, Sporre Bengt, Rainer Dörenberg, Peter Frykholm, Maria Garcia, Ann Kvarnström, Emma Pontén, Thomas Bruelisauer, Gabor Erdoes, Heiko Kaiser, Mathias Marchon, Stefan Seiler, Yann Bögli, Mirko Dolci, Carine Marcucci, Isabelle Pichon, Laszlo Vutskits, Mattias Casutt, Martin Hölzle, Thomas Hurni, Martin Jöhr, Anna-Ursina Malär, Jacqueline Mauch, Thomas Erb, Karin Oeinck, Mine Akin, Gulsen Keskin, Yesim Senayli, Guner Kaya, Pinar Kendigelen, Ayse Çiğdem Tutuncu, Zehra Hatipoğlu, Dilek Özcengiz, Hale Aksu Erdost, Elvan Öçmen, Çimen Olguner, Hilmi Ayanoglu, Pelin Corman Dincer, Tumay Umuroglu, Mustafa Azizoglu, Handan Birbiçer, Nurcan Doruk, Aslı Sagun, Sibel Baris, Dmytro Dmytriiev, Sridevi Kuchi, Nuria Masip, Peter Brooks, Alison Hare, Nargis Ahmad, Michelle Casey, Sam De Silva, Nadine Dobby, Prakash Krishnan, L. Amaki Sogbodjor, Ellie Walker, Suellen Walker, Stephanie King, Katy Nicholson, Michelle Quinney, Paul Stevens, Andrew Blevin, Mariangela Giombini, Chulananda Goonasekera, Sadia Adil, Stephanie Bew, Carol Bodlani, Dan Gilpin, Stephanie Jinks, Nalini Malarkkan, Alice Miskovic, Rebecca Pad, Juliet Wolfe Barry, Joy Abbott, James Armstrong, Natalie Cooper, Lindsay Crate, John Emery, Kathryn James, Hannah King, Paul Martin, Stefano Scalia Catenacci, Rob Bomont, Paul Smith, Sara Mele, Alessandra Verzelloni, Philippa Dix, Graham Bell, Elena Gordeva, Lesley McKee, Esther Ngan, Jutta Scheffczik, Li-En Tan, Mark Worrall, Carmel Cassar, Kevin Goddard, Victoria Barlow, Vimmi Oshan, Khairi Shah, Sarah Bell, Lisa Daniels, Monica Gandhi, David Pachter, Chris Perry, Andrew Robertson, Carmen Scott, Lynne Waring, David Barnes, Sophie Childs, Joanne Norman, Robin Sunderland, Dowell Julia, Feijten Prisca, Harlet Pierre, Herbineaux Sarah, Leva Brigitte, Plichon Benoît, Virág Katalin, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Anesthesiology, HUS Children and Adolescents, Children's Hospital, Clinicum, Anestesiologian yksikkö, Disma, Nicola, Virag, Katalin, Riva, Thoma, Kaufmann, Jost, Engelhardt, Thoma, Habre, Walid, Breschan, Christian, Likar, Rudolf, Platzer, Manuela, Edelman, Isole, Eger, Johane, Heschl, Stefan, Messerer, Brigitte, Vittinghof, Maria, Kroess, Ruth, Stichlberger, Martina, Kahn, David, Pirotte, Thierry, Pregardien, Caroline, Veyckemans, Franci, Stevens, France, Berghmans, Johan, Bauters, Annemie, De Baerdemaeker, Luc, De Hert, Stefan, Lapage, Koen, Parashchanka, Aliaksandra, Van Limmen, Jurgen, Wyffels, Piet, Lauweryns, Julie, Najafi, Nadia, Vundelinckx, Jori, Butković, Diana, Kerovec Sorić, Ivana, Kralik, Sandra, Markić, Ana, Azman, Josip, Markic, Josko, Pupacic, Daniela, Frelich, Michal, Reimer, Petr, Urbanec, René, Cajková, Petra, Mixa, Vladimír, Sedláčková, Yvona, Knoppová, Lenka, Zlámalová (neé Květoňová), Alena, Vavřina, Martin, Žurek, Jiří, Hansen, Tom, Afshari, Arash, Bille, Anders Bastholm, Ellekvist, Marguerite, Ilmoja, Mari-Lii, Moor, Reet, Kikas, Reet, Väli, Merle, Kallio, Kariantti, Reponen, Elisa, Suominen, Pertti, Suvanto, Sami, Vähätalo, Raisa, Kokki, Hannu, Kokki, Merja, Harju, Jarkko, Kokkonen, Miia, Vieri, Jenni, Manner, Tuula, Amory, Catherine, Ludot, Hugue, Bert, Dina, Godart, Juliette, Laffargue, Anne, Dupont, Hervé, Urbina, Benjamin, Baujard, Catherine, Roulleau, Philippe, Staiti, Giuseppe, Bordes, Maryline, Nouette Gaulain, Karine, Hamonic, Yann, Semjen, Françoi, Jacqmarcq, Olivier, Lejus-Bourdeau, Caroline, Magne, Cécile, Petry, Léa, Ros, Lilica, Zang, Aurélien, Bennis, Mehdi, Coustets, Bernard, Fesseau, Rose, Constant, Isabelle, Khalil, Eliane, Sabourdin, Nada, Audren, Noemie, Descarpentries, Thoma, Fabre, Fanny, Legrand, Aurélien, Druot, Emilie, Orliaguet, Gille, Sabau, Lucie, Uhrig, Lynn, de la Brière, Françoi, Jonckheer, Karin, Mission, Jean-Paul, Scordo, Lucia, Couchepin, Caroline, Dadure, Christophe, De la Arena, Pablo, Hertz, Laurent, Pirat, Philippe, Sola, Chrystelle, Bellon, Myriam, Dahmani, Souhayl, Julien-Marsollier, Florence, Michelet, Daphne, Depret-Donatien, Veronique, Lesage, Anne, Laschat, Michael, Wappler, Frank, Becke, Karin, Brunner, Lena, Oppenrieder, Karin, Badelt, Gregor, Hochmuth, Karin, Koller, Bernhard, Reil, Anita, Richter, Sebastian, Fischer, Thoma, Diers, Anja, Schorer, Clemen, Weyland, Andrea, Cohausz, Ruth, Kretz, Franz-Josef, Löffler, Michaela, Wilbs, Marku, Hoehne, Claudia, Ulrici, Johanna, Goeters, Christiane, Flinspach, Armin, Klages, Matthia, Lindau, Simone, Messroghli, Leila, Zacharowski, Kai, Eisner, Christoph, Mueller, Thoma, Richter, Daniel, Schäfer, Melanie, Weigand, Marku, Weiterer, Sebastian, Ochsenreiter, Miriam, Schöler, Michael, Terboven, Tom, Eggemann, Isabel, Haussmann, Sascha, Leister, Nicola, Menzel, Christoph, Trieschmann, Uwe, Yücetepe, Sirin, Keilig, Susanna, Kranke, Peter, Jelting, Yvonne, Baehner, Torsten, Ellerkmann, Richard, Ghamari, Shahab, Neumann, Claudia, Söhle, Martin, Chloropoulou, Pelagia, Ntritsou, Vagia, Papagiannopoulou, Pinelopi, Garini, Eleana, Karafotia, Afroditi, Mammi, Panagoula, Bali, Evangelia, Iordanidou, Despoina, Malisiova, Anna, Polyzoi, Artemi, Tsiotou, Adelai, Sapi, Erzsebet, Székely, Edgar, Kosik, Nandor, Maráczi, Veronika, Schnur, Jano, Csillag, Judit, Gál, Jáno, Göbl, Gergely, Hauser, Baláz, Petróczy, Andrá, Tövisházi, Gyula, Blain, Stuart, Gallagher, Sarah, Harte, Sinead, Jackson, Mandy, Meehan, Emma, Nawoor, Zeenat, O’Hare, Brendan, Ross, Mark, Lerro, Daniela, Astuto, Marinella, Grasso, Chiara, Scalisi, Rita, Frasacco, Giulia, Lenares, Elena, Leone, Roberto, Grazzini, Maurizia, Minardi, Carmelo, Zadra, Nicola, Cinnella, Gilda, Cotoia, Antonella, Galante, Dario, De Lorenzo, Brita, Kuppers, Beate, Bottazzi, Giulia, Caramelli, Fabio, Mondardini, Maria Cristina, Rossetti, Emanuele, Picardo, Sergio, Vittori, Alessandro, Camporesi, Anna, Wolfler, Andrea, Calderini, Edoardo, Colantonio, Laura Brigitta, Finamore, Simona Anna, Porro, Giuliana Anna, Bonfiglio, Rachele, Kotzeva, Svetlana, Mameli, Leila, Mattioli, Girolamo, Micalizzi, Camilla, Montaguti, Alessia, Pistorio, Angela, Zanaboni, Clelia, Guddo, Anna, Neba, Gerald Rogan, Favarato, Moreno, Locatelli, Bruno Guido, Maffioletti, Micol, Sonzogni, Valter, Garra, Rossella, Sammartino, Maria, Sbaraglia, Fabio, Cortegiani, Andrea, Moscarelli, Alessandra, Attanasi, Elena, Tesoro, Simonetta, Agapiti, Cristina, Pinzoni, Francesca, Vezzoli, Cesare, Bilotta, Federico, Barzdina, Arta, Straume, Zane, Zundane, Anda, Lukosiene, Laura, Maraulaite, Irena, Razlevice, Ilona, Schmitz, Bernd, Mifsud, Stephanie, Aehling, Carolin, Allison, Celia, De Boer, Rient, Emal, Dina, Stevens, Marku, Buitenhuis, Marielle, de Graaff, Jurgen, De Liefde, Inge, Machotta, Andrea, Scoones, Gail, Staals, Lonneke, Tomas, Jeremy, Van der Knijff-van Dortmont, Anouk, Veldhuizen, Marianne, Alders, David, Buhre, Wolfgang, Schafrat, Eva, Schreiber, Jan, Vermeulen, Petronella Mari, Hendriks, Mark, Lako, Sandra, Voet-Lindner, Marieke, Pieters, Barbe, Scheffer, Gert-Jan, Tielens, Luc, Absalom, Anthony R., Bergsma, Margot, De Ruiter, Joke, Meier, Sascha, Volkers, Martin, Zweers, Tjerk, Beukers, Anne M., Boer, Christa, Dertinger, Jurgen, Numan, Sandra, Van Zaane, Ba, Boerke, Wenche B., Ekiz, Nil, Stensrud, Kristoffer, Drage, Inger Marie, Isern, Erik Ramon, Bartkowska-Sniatkowska, Alicja, Grzeskowiak, Malgorzata, Juzwa-Sobieraj, Magdalena, Rosada-Kurasińska, Jowita, Baranowski, Artur, Jakubowska, Karina, Lewandowska, Dorota, Mierzewska-Schmidt, Magdalena, Sawicki, Piotr, Urban-Lechowicz, Magdalena, Przemyslaw, Pomianek, Zielinska, Marzena, Leal, Teresa, Soares, Maria, Pina, Pedro, Pinho, Sílvia, Patuleia, Maria Dominga, Esteves, Catarina Cruz, Salgado, Helena, Santos, Maria João, Badeti, Rodica, Cindea, Iulia, Oana, Loredana, Gurita, Adriana, Ilie, Luminita, Mocioiu, Gabriel, Tabacaru, Radu, Trante, Irina, Munteanu, Valentin, Morariu, Mihai, Nyíri, Emese, Budic, Ivana, Marjanovic, Vesna, Drašković, Biljana, Pandurov, Marina, Ilic, Jordanka, Mandras, Ana, Rados, Zdenka, Stankovic, Nikola, Suica, Maja, Vasiljevic, Sladjana, Knezevic, Mirjana, Milojevic, Irina, Petrov, Ivana, Puric Racic, Selena, Simic, Dusica, Simic, Irena, Stevic, Marija, Vulicevic, Irena, Cabanová, Barbora, Hanula, Miloslav, Berger, Jelena, Janjatovic, Darja, Pirtovšek Štupnik, Špela, Méndez, Dolore, Pino, Gema, Rubio, Paloma, Izquierdo, Alberto, López, Silvia, González Serrano, Cristina, Cebrián, Jesú, Peleteiro, Ana, Del Rey de Diego, Pilar, Martínez García, Ernesto, Tormo de las Heras, Carolina, Troncoso Montero, Pablo, Arbona, Celia, Artés, David, Chamizo, Alicia, Serrano, Silvia, Suarez Comas, Montserrat, Escribá, Francisco, Auli, Cristina, Pérez Pardo, Osvaldo, Sierra Biddle, Natalia, Suárez Castaño, Ceferina, Villalobos Rico, María Isabel, Manrique Muñoz, Susana, García Martínez, Irene, Montferrer Estruch, Nuria, Vilardell Ortíz, Elena, Poves-Álvarez, Rodrigo, Kohn, Ivan, Lindestam, Ulf, Reinhard, Jarl, Castellheim, Albert, Sandström, Kerstin, Bengt, Sporre, Dörenberg, Rainer, Frykholm, Peter, Garcia, Maria, Kvarnström, Ann, Pontén, Emma, Bruelisauer, Thoma, Erdoes, Gabor, Kaiser, Heiko, Marchon, Mathia, Seiler, Stefan, Bögli, Yann, Dolci, Mirko, Marcucci, Carine, Pichon, Isabelle, Vutskits, Laszlo, Casutt, Mattia, Hölzle, Martin, Hurni, Thoma, Jöhr, Martin, Malär, Anna-Ursina, Mauch, Jacqueline, Erb, Thoma, Oeinck, Karin, Akin, Mine, Keskin, Gulsen, Senayli, Yesim, Kaya, Guner, Kendigelen, Pinar, Tutuncu, Ayse Çiğdem, Hatipoğlu, Zehra, Özcengiz, Dilek, Erdost, Hale Aksu, Öçmen, Elvan, Olguner, Çimen, Ayanoglu, Hilmi, Dincer, Pelin Corman, Umuroglu, Tumay, Azizoglu, Mustafa, Birbiçer, Handan, Doruk, Nurcan, Sagun, Aslı, Baris, Sibel, Dmytriiev, Dmytro, Kuchi, Sridevi, Masip, Nuria, Brooks, Peter, Hare, Alison, Ahmad, Nargi, Casey, Michelle, De Silva, Sam, Dobby, Nadine, Krishnan, Prakash, Sogbodjor, L. Amaki, Walker, Ellie, Walker, Suellen, King, Stephanie, Nicholson, Katy, Quinney, Michelle, Stevens, Paul, Blevin, Andrew, Giombini, Mariangela, Goonasekera, Chulananda, Adil, Sadia, Bew, Stephanie, Bodlani, Carol, Gilpin, Dan, Jinks, Stephanie, Malarkkan, Nalini, Miskovic, Alice, Pad, Rebecca, Wolfe Barry, Juliet, Abbott, Joy, Armstrong, Jame, Cooper, Natalie, Crate, Lindsay, Emery, John, James, Kathryn, King, Hannah, Martin, Paul, Scalia Catenacci, Stefano, Bomont, Rob, Smith, Paul, Mele, Sara, Verzelloni, Alessandra, Dix, Philippa, Bell, Graham, Gordeva, Elena, McKee, Lesley, Ngan, Esther, Scheffczik, Jutta, Tan, Li-En, Worrall, Mark, Cassar, Carmel, Goddard, Kevin, Barlow, Victoria, Oshan, Vimmi, Shah, Khairi, Bell, Sarah, Daniels, Lisa, Gandhi, Monica, Pachter, David, Perry, Chri, Robertson, Andrew, Scott, Carmen, Waring, Lynne, Barnes, David, Childs, Sophie, Norman, Joanne, Sunderland, Robin, Julia, Dowell, Prisca, Feijten, Pierre, Harlet, Sarah, Herbineaux, Brigitte, Leva, Benoît, Plichon, Katalin, Virág, IOO, ACS - Microcirculation, APH - Quality of Care, and ANS - Neuroinfection & -inflammation
Subjects: Male, Time Factors, paediatric, medicine.medical_treatment, morbidity, Severity of Illness Index, 0302 clinical medicine, 030202 anesthesiology, Risk Factors, Clinical endpoint, Anesthesia, Prospective Studies, 610 Medicine & health, Hypoxia, Medical Audit, medicine.diagnostic_test, ddc:617, infants, Incidence (epidemiology), Incidence, Age Factors, anaesthesia, respiratory system, Europe, Treatment Outcome, Cohort, Female, medicine.symptom, Bradycardia, Laryngoscopy, Anesthesia/adverse effects/mortality, Risk Assessment, Europe/epidemiology, 03 medical and health sciences, Laryngoscopy/adverse effects/mortality, Hypoxia/diagnosis/epidemiology/mortality, medicine, Intubation, Intratracheal, Humans, difficult intubation, business.industry, Tracheal intubation, Infant, Newborn, Infant, Perioperative, Newborn, 3126 Surgery, anesthesiology, intensive care, radiology, mortality, neonates, Clinical trial, Intratracheal, Anesthesiology and Pain Medicine, airway, Intubation, Intratracheal/adverse effects/mortality, neonate, Intubation, business, airways
Abstract: Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences. Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes. Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1e6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2
Published: 2021
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6. Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

Author: Fuchs A., Disma N., Virag K., Ulmer F., Habre W., de Graaff J. C., Riva T., NECTARINE Group of the European Society of Anaesthesiology and Intensive Care Clinical Trial Network: Christian Breschan, Rudolf Likar, Manuela Platzer, Isole Edelman, Johanes Eger, Stefan Heschl, Brigitte Messerer, Maria Vittinghof, Ruth Kroess, Martina Stichlberger, David Kahn, Thierry Pirotte, Caroline Pregardien, Francis Veyckemans, France Stevens, Johan Berghmans, Annemie Bauters, Luc De Baerdemaeker, Stefan De Hert, Koen Lapage, Aliaksandra Parashchanka, Jurgen Van Limmen, Piet Wyffels, Nadia Najafi, Joris Vundelinckx, Diana Butković, Ivana Kerovec Sorić, Sandra Kralik, Ana Markić, Josip Azman, Josko Markic, Daniela Pupacic, Michal Frelich, Petr Reimer, René Urbanec, Petra Cajková, Vladimír Mixa, Yvona Sedláčková, Lenka Knoppová, Alena Zlámalová, Martin Vavřina, Jiří Žurek, Tom Hansen, Arash Afshari, Anders Bastholm Bille, Marguerite Ellekvist, Mari-Liis Ilmoja, Reet Moor, Reet Kikas, Merle Väli, Kariantti Kallio, Elisa Reponen, Pertti Suominen, Sami Suvanto, Raisa Vähätalo, Hannu Kokki, Merja Kokki, Jarkko Harju, Miia Kokkonen, Jenni Vieri, Tuula Manner, Catherine Amory, Hugues Ludot, Dina Bert, Juliette Godart, Anne Laffargue, Hervé Dupont, Benjamin Urbina, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Maryline Bordes, Karine Nouette Gaulain, Yann Hamonic, François Semjen, Olivier Jacqmarcq, Caroline Lejus-Bourdeau, Cécile Magne, Léa Petry, Lilica Ros, Aurélien Zang, Mehdi Bennis, Bernard Coustets, Rose Fesseau, Isabelle Constant, Eliane Khalil, Nada Sabourdin, Noemie Audren, Thomas Descarpentries, Fanny Fabre, Aurélien Legrand, Emilie Druot, Gilles Orliaguet, Lucie Sabau, Lynn Uhrig, François de la Brière, Karin Jonckheer, Jean-Paul Mission, Lucia Scordo, Caroline Couchepin, Christophe Dadure, Pablo De la Arena, Laurent Hertz, Philippe Pirat, Chrystelle Sola, Myriam Bellon, Souhayl Dahmani, Florence Julien-Marsollier, Daphne Michelet, Veronique Depret-Donatien, Anne Lesage, Jost Kaufmann, Michael Laschat, Frank Wappler, Karin Becke, Lena Brunner, Karin Oppenrieder, Gregor Badelt, Karin Hochmuth, Bernhard Koller, Anita Reil, Sebastian Richter, Thomas Fischer, Anja Diers, Clemens Schorer, Andreas Weyland, Ruth Cohausz, Franz-Josef Kretz, Michaela Löffler, Markus Wilbs, Claudia Hoehne, Johanna Ulrici, Christiane Goeters, Armin Flinspach, Matthias Klages, Simone Lindau, Leila Messroghli, Kai Zacharowski, Christoph Eisner, Thomas Mueller, Daniel Richter, Melanie Schäfer, Markus Weigand, Sebastian Weiterer, Miriam Ochsenreiter, Michael Schöler, Tom Terboven, Isabel Eggemann, Sascha Haussmann, Nicolas Leister, Christoph Menzel, Uwe Trieschmann, Sirin Yücetepe, Susanna Keilig, Peter Kranke, Yvonne Jelting, Torsten Baehner, Richard Ellerkmann, Shahab Ghamari, Claudia Neumann, Martin Söhle, Pelagia Chloropoulou, Vagia Ntritsou, Pinelopi Papagiannopoulou, Eleana Garini, Afroditi Karafotia, Panagoula Mammi, Evangelia Bali, Despoina Iordanidou, Anna Malisiova, Artemis Polyzoi, Adelais Tsiotou, Erzsebet Sapi, Edgar Székely, Nandor Kosik, Veronika Maráczi, Janos Schnur, Judit Csillag, János Gál, Gergely Göbl, Balázs Hauser, András Petróczy, Gyula Tövisházi, Stuart Blain, Sarah Gallagher, Sinead Harte, Mandy Jackson, Emma Meehan, Zeenat Nawoor, Brendan O'Hare, Mark Ross, Daniela Lerro, Marinella Astuto, Chiara Grasso, Rita Scalisi, Giulia Frasacco, Elena Lenares, Roberto Leone, Maurizia Grazzini, Carmelo Minardi, Nicola Zadra, Gilda Cinnella, Antonella Cotoia, Dario Galante, Brita De Lorenzo, Beate Kuppers, Giulia Bottazzi, Fabio Caramelli, Maria Cristina Mondardini, Emanuele Rossetti, Sergio Picardo, Alessandro Vittori, Anna Camporesi, Andrea Wolfler, Edoardo Calderini, Laura Brigitta Colantonio, Simona Anna Finamore, Giuliana Anna Porro, Rachele Bonfiglio, Svetlana Kotzeva, Leila Mameli, Girolamo Mattioli, Camilla Micalizzi, Alessia Montaguti, Angela Pistorio, Clelia Zanaboni, Anna Guddo, Gerald Rogan Neba, Moreno Favarato, Bruno Guido Locatelli, Micol Maffioletti, Valter Sonzogni, Rossella Garra, Maria Sammartino, Fabio Sbaraglia, Andrea Cortegiani, Alessandra Moscarelli, Elena Attanasi, Simonetta Tesoro, Cristina Agapiti, Francesca Pinzoni, Cesare Vezzoli, Federico Bilotta, Arta Barzdina, Zane Straume, Anda Zundane, Laura Lukosiene, Irena Maraulaite, Ilona Razlevice, Bernd Schmitz, Stephanie Mifsud, Carolin Aehling, Celia Allison, Rients De Boer, Dina Emal, Markus Stevens, Marielle Buitenhuis, Inge De Liefde, Andreas Machotta, Gail Scoones, Lonneke Staals, Jeremy Tomas, Anouk Van der Knijff-van Dortmont, Marianne Veldhuizen, David Alders, Wolfgang Buhre, Eva Schafrat, Jan Schreiber, Petronella Mari Vermeulen, Mark Hendriks, Sandra Lako, Marieke Voet-Lindner, Barbe Pieters, Gert-Jan Scheffer, Luc Tielens, Anthony R Absalom, Margot Bergsma, Joke De Ruiter, Sascha Meier, Martin Volkers, Tjerk Zweers, Anne M Beukers, Christa Boer, Jurgen Dertinger, Sandra Numan, Bas Van Zaane, Wenche B Boerk, Nil Ekiz, Kristoffer Stensrud, Inger Marie Drage, Erik Ramon Isern, Alicja Bartkowska-Sniatkowska, Malgorzata Grzeskowiak, Magdalena Juzwa-Sobieraj, Jowita Rosada-Kurasińska, Artur Baranowski, Karina Jakubowska, Dorota Lewandowska, Magdalena Mierzewska-Schmidt, Piotr Sawicki, Magdalena Urban-Lechowicz, Pomianek Przemyslaw, Marzena Zielinska, Teresa Leal, Maria Soares, Pedro Pina, Sílvia Pinho, Maria Domingas Patuleia, Catarina Cruz Esteves, Helena Salgado, Maria João Santos, Rodica Badeti, Iulia Cindea, Loredana Oana, Adriana Gurita, Luminita Ilie, Gabriel Mocioiu, Radu Tabacaru, Irina Trante, Valentin Munteanu, Mihai Morariu, Emese Nyíri, Ivana Budic, Vesna Marjanovic, Biljana Drašković, Marina Pandurov, Jordanka Ilic, Ana Mandras, Zdenka Rados, Nikola Stankovic, Maja Suica, Sladjana Vasiljevic, Mirjana Knezevic, Irina Milojevic, Ivana Petrov, Selena Puric Racic, Dusica Simic, Irena Simic, Marija Stevic, Irena Vulicevic, Barbora Cabanová, Miloslav Hanula, Jelena Berger, Darja Janjatovic, Špela Pirtovšek Štupnik, Dolores Méndez, Gema Pino, Paloma Rubio, Alberto Izquierdo, Silvia López, Cristina González Serrano, Jesús Cebrián, Ana Peleteiro, Pilar Del Rey de Diego, Ernesto Martínez García, Carolina Tormo de Las Heras, Pablo Troncoso Montero, Celia Arbona, David Artés, Alicia Chamizo, Silvia Serrano, Montserrat Suarez Comas, Francisco Escribá, Cristina Auli, Osvaldo Pérez Pardo, Natalia Sierra Biddle, Ceferina Suárez Castaño, María Isabel Villalobos Rico, Susana Manrique Muñoz, Irene García Martínez, Nuria Montferrer Estruch, Elena Vilardell Ortíz, Rodrigo Poves-Álvarez, Ivan Kohn, Ulf Lindestam, Jarl Reinhard, Albert Castellheim, Kerstin Sandström, Sporre Bengt, Rainer Dörenberg, Peter Frykholm, Maria Garcia, Ann Kvarnström, Emma Pontén, Thomas Bruelisauer, Gabor Erdoes, Heiko Kaiser, Mathias Marchon, Stefan Seiler, Yann Bögli, Mirko Dolci, Carine Marcucci, Isabelle Pichon, Laszlo Vutskits, Mattias Casutt, Martin Hölzle, Thomas Hurni, Martin Jöhr, Anna-Ursina Malär, Jacqueline Mauch, Thomas Erb, Karin Oeinck, Mine Akin, Gulsen Keskin, Yesim Senayli, Guner Kaya, Pinar Kendigelen, Ayse Çiğdem Tutuncu, Zehra Hatipoğlu, Dilek Özcengiz, Hale Aksu Erdost, Elvan Öçmen, Çimen Olguner, Hilmi Ayanoglu, Pelin Corman Dincer, Tumay Umuroglu, Mustafa Azizoglu, Handan Birbiçer, Nurcan Doruk, Aslı Sagun, Sibel Baris, Dmytro Dmytriiev, Sridevi Kuchi, Nuria Masip, Peter Brooks, Alison Hare, Nargis Ahmad, Michelle Casey, Sam De Silva, Nadine Dobby, Prakash Krishnan, L Amaki Sogbodjor, Ellie Walker, Suellen Walker, Stephanie King, Katy Nicholson, Michelle Quinney, Paul Stevens, Andrew Blevin, Mariangela Giombini, Chulananda Goonasekera, Sadia Adil, Stephanie Bew, Carol Bodlani, Dan Gilpin, Stephanie Jinks, Nalini Malarkkan, Alice Miskovic, Rebecca Pad, Juliet Wolfe Barry, Joy Abbott, James Armstrong, Natalie Cooper, Lindsay Crate, John Emery, Kathryn James, Hannah King, Paul Martin, Stefano Scalia Catenacci, Rob Bomont, Paul Smith, Sara Mele, Alessandra Verzelloni, Philippa Dix, Graham Bell, Elena Gordeva, Lesley McKee, Esther Ngan, Jutta Scheffczik, Li-En Tan, Mark Worrall, Carmel Cassar, Kevin Goddard, Victoria Barlow, Vimmi Oshan, Khairi Shah, Sarah Bell, Lisa Daniels, Monica Gandhi, David Pachter, Chris Perry, Andrew Robertson, Carmen Scott, Lynne Waring, David Barnes, Sophie Childs, Joanne Norman, Robin Sunderland, Fuchs A., Disma N., Virag K., Ulmer F., Habre W., de Graaff J.C., Riva T., NECTARINE Group of the European Society of Anaesthesiology and Intensive Care Clinical Trial Network: Christian Breschan, Rudolf Likar, Manuela Platzer, Isole Edelman, Johanes Eger, Stefan Heschl, Brigitte Messerer, Maria Vittinghof, Ruth Kroess, Martina Stichlberger, David Kahn, Thierry Pirotte, Caroline Pregardien, Francis Veyckemans, France Stevens, Johan Berghmans, Annemie Bauters, Luc De Baerdemaeker, Stefan De Hert, Koen Lapage, Aliaksandra Parashchanka, Jurgen Van Limmen, Piet Wyffels, Nadia Najafi, Joris Vundelinckx, Diana Butković, Ivana Kerovec Sorić, Sandra Kralik, Ana Markić, Josip Azman, Josko Markic, Daniela Pupacic, Michal Frelich, Petr Reimer, René Urbanec, Petra Cajková, Vladimír Mixa, Yvona Sedláčková, Lenka Knoppová, Alena Zlámalová, Martin Vavřina, Jiří Žurek, Tom Hansen, Arash Afshari, Anders Bastholm Bille, Marguerite Ellekvist, Mari-Liis Ilmoja, Reet Moor, Reet Kikas, Merle Väli, Kariantti Kallio, Elisa Reponen, Pertti Suominen, Sami Suvanto, Raisa Vähätalo, Hannu Kokki, Merja Kokki, Jarkko Harju, Miia Kokkonen, Jenni Vieri, Tuula Manner, Catherine Amory, Hugues Ludot, Dina Bert, Juliette Godart, Anne Laffargue, Hervé Dupont, Benjamin Urbina, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Maryline Bordes, Karine Nouette Gaulain, Yann Hamonic, François Semjen, Olivier Jacqmarcq, Caroline Lejus-Bourdeau, Cécile Magne, Léa Petry, Lilica Ros, Aurélien Zang, Mehdi Bennis, Bernard Coustets, Rose Fesseau, Isabelle Constant, Eliane Khalil, Nada Sabourdin, Noemie Audren, Thomas Descarpentries, Fanny Fabre, Aurélien Legrand, Emilie Druot, Gilles Orliaguet, Lucie Sabau, Lynn Uhrig, François de la Brière, Karin Jonckheer, Jean-Paul Mission, Lucia Scordo, Caroline Couchepin, Christophe Dadure, Pablo De la Arena, Laurent Hertz, Philippe Pirat, Chrystelle Sola, Myriam Bellon, Souhayl Dahmani, Florence Julien-Marsollier, Daphne Michelet, Veronique Depret-Donatien, Anne Lesage, Jost Kaufmann, Michael Laschat, Frank Wappler, Karin Becke, Lena Brunner, Karin Oppenrieder, Gregor Badelt, Karin Hochmuth, Bernhard Koller, Anita Reil, Sebastian Richter, Thomas Fischer, Anja Diers, Clemens Schorer, Andreas Weyland, Ruth Cohausz, Franz-Josef Kretz, Michaela Löffler, Markus Wilbs, Claudia Hoehne, Johanna Ulrici, Christiane Goeters, Armin Flinspach, Matthias Klages, Simone Lindau, Leila Messroghli, Kai Zacharowski, Christoph Eisner, Thomas Mueller, Daniel Richter, Melanie Schäfer, Markus Weigand, Sebastian Weiterer, Miriam Ochsenreiter, Michael Schöler, Tom Terboven, Isabel Eggemann, Sascha Haussmann, Nicolas Leister, Christoph Menzel, Uwe Trieschmann, Sirin Yücetepe, Susanna Keilig, Peter Kranke, Yvonne Jelting, Torsten Baehner, Richard Ellerkmann, Shahab Ghamari, Claudia Neumann, Martin Söhle, Pelagia Chloropoulou, Vagia Ntritsou, Pinelopi Papagiannopoulou, Eleana Garini, Afroditi Karafotia, Panagoula Mammi, Evangelia Bali, Despoina Iordanidou, Anna Malisiova, Artemis Polyzoi, Adelais Tsiotou, Erzsebet Sapi, Edgar Székely, Nandor Kosik, Veronika Maráczi, Janos Schnur, Judit Csillag, János Gál, Gergely Göbl, Balázs Hauser, András Petróczy, Gyula Tövisházi, Stuart Blain, Sarah Gallagher, Sinead Harte, Mandy Jackson, Emma Meehan, Zeenat Nawoor, Brendan O'Hare, Mark Ross, Daniela Lerro, Marinella Astuto, Chiara Grasso, Rita Scalisi, Giulia Frasacco, Elena Lenares, Roberto Leone, Maurizia Grazzini, Carmelo Minardi, Nicola Zadra, Gilda Cinnella, Antonella Cotoia, Dario Galante, Brita De Lorenzo, Beate Kuppers, Giulia Bottazzi, Fabio Caramelli, Maria Cristina Mondardini, Emanuele Rossetti, Sergio Picardo, Alessandro Vittori, Anna Camporesi, Andrea Wolfler, Edoardo Calderini, Laura Brigitta Colantonio, Simona Anna Finamore, Giuliana Anna Porro, Rachele Bonfiglio, Svetlana Kotzeva, Leila Mameli, Girolamo Mattioli, Camilla Micalizzi, Alessia Montaguti, Angela Pistorio, Clelia Zanaboni, Anna Guddo, Gerald Rogan Neba, Moreno Favarato, Bruno Guido Locatelli, Micol Maffioletti, Valter Sonzogni, Rossella Garra, Maria Sammartino, Fabio Sbaraglia, Andrea Cortegiani, Alessandra Moscarelli, Elena Attanasi, Simonetta Tesoro, Cristina Agapiti, Francesca Pinzoni, Cesare Vezzoli, Federico Bilotta, Arta Barzdina, Zane Straume, Anda Zundane, Laura Lukosiene, Irena Maraulaite, Ilona Razlevice, Bernd Schmitz, Stephanie Mifsud, Carolin Aehling, Celia Allison, Rients De Boer, Dina Emal, Markus Stevens, Marielle Buitenhuis, Inge De Liefde, Andreas Machotta, Gail Scoones, Lonneke Staals, Jeremy Tomas, Anouk Van der Knijff-van Dortmont, Marianne Veldhuizen, David Alders, Wolfgang Buhre, Eva Schafrat, Jan Schreiber, Petronella Mari Vermeulen, Mark Hendriks, Sandra Lako, Marieke Voet-Lindner, Barbe Pieters, Gert-Jan Scheffer, Luc Tielens, Anthony R Absalom, Margot Bergsma, Joke De Ruiter, Sascha Meier, Martin Volkers, Tjerk Zweers, Anne M Beukers, Christa Boer, Jurgen Dertinger, Sandra Numan, Bas Van Zaane, Wenche B Boerk, Nil Ekiz, Kristoffer Stensrud, Inger Marie Drage, Erik Ramon Isern, Alicja Bartkowska-Sniatkowska, Malgorzata Grzeskowiak, Magdalena Juzwa-Sobieraj, Jowita Rosada-Kurasińska, Artur Baranowski, Karina Jakubowska, Dorota Lewandowska, Magdalena Mierzewska-Schmidt, Piotr Sawicki, Magdalena Urban-Lechowicz, Pomianek Przemyslaw, Marzena Zielinska, Teresa Leal, Maria Soares, Pedro Pina, Sílvia Pinho, Maria Domingas Patuleia, Catarina Cruz Esteves, Helena Salgado, Maria João Santos, Rodica Badeti, Iulia Cindea, Loredana Oana, Adriana Gurita, Luminita Ilie, Gabriel Mocioiu, Radu Tabacaru, Irina Trante, Valentin Munteanu, Mihai Morariu, Emese Nyíri, Ivana Budic, Vesna Marjanovic, Biljana Drašković, Marina Pandurov, Jordanka Ilic, Ana Mandras, Zdenka Rados, Nikola Stankovic, Maja Suica, Sladjana Vasiljevic, Mirjana Knezevic, Irina Milojevic, Ivana Petrov, Selena Puric Racic, Dusica Simic, Irena Simic, Marija Stevic, Irena Vulicevic, Barbora Cabanová, Miloslav Hanula, Jelena Berger, Darja Janjatovic, Špela Pirtovšek Štupnik, Dolores Méndez, Gema Pino, Paloma Rubio, Alberto Izquierdo, Silvia López, Cristina González Serrano, Jesús Cebrián, Ana Peleteiro, Pilar Del Rey de Diego, Ernesto Martínez García, Carolina Tormo de Las Heras, Pablo Troncoso Montero, Celia Arbona, David Artés, Alicia Chamizo, Silvia Serrano, Montserrat Suarez Comas, Francisco Escribá, Cristina Auli, Osvaldo Pérez Pardo, Natalia Sierra Biddle, Ceferina Suárez Castaño, María Isabel Villalobos Rico, Susana Manrique Muñoz, Irene García Martínez, Nuria Montferrer Estruch, Elena Vilardell Ortíz, Rodrigo Poves-Álvarez, Ivan Kohn, Ulf Lindestam, Jarl Reinhard, Albert Castellheim, Kerstin Sandström, Sporre Bengt, Rainer Dörenberg, Peter Frykholm, Maria Garcia, Ann Kvarnström, Emma Pontén, Thomas Bruelisauer, Gabor Erdoes, Heiko Kaiser, Mathias Marchon, Stefan Seiler, Yann Bögli, Mirko Dolci, Carine Marcucci, Isabelle Pichon, Laszlo Vutskits, Mattias Casutt, Martin Hölzle, Thomas Hurni, Martin Jöhr, Anna-Ursina Malär, Jacqueline Mauch, Thomas Erb, Karin Oeinck, Mine Akin, Gulsen Keskin, Yesim Senayli, Guner Kaya, Pinar Kendigelen, Ayse Çiğdem Tutuncu, Zehra Hatipoğlu, Dilek Özcengiz, Hale Aksu Erdost, Elvan Öçmen, Çimen Olguner, Hilmi Ayanoglu, Pelin Corman Dincer, Tumay Umuroglu, Mustafa Azizoglu, Handan Birbiçer, Nurcan Doruk, Aslı Sagun, Sibel Baris, Dmytro Dmytriiev, Sridevi Kuchi, Nuria Masip, Peter Brooks, Alison Hare, Nargis Ahmad, Michelle Casey, Sam De Silva, Nadine Dobby, Prakash Krishnan, L Amaki Sogbodjor, Ellie Walker, Suellen Walker, Stephanie King, Katy Nicholson, Michelle Quinney, Paul Stevens, Andrew Blevin, Mariangela Giombini, Chulananda Goonasekera, Sadia Adil, Stephanie Bew, Carol Bodlani, Dan Gilpin, Stephanie Jinks, Nalini Malarkkan, Alice Miskovic, Rebecca Pad, Juliet Wolfe Barry, Joy Abbott, James Armstrong, Natalie Cooper, Lindsay Crate, John Emery, Kathryn James, Hannah King, Paul Martin, Stefano Scalia Catenacci, Rob Bomont, Paul Smith, Sara Mele, Alessandra Verzelloni, Philippa Dix, Graham Bell, Elena Gordeva, Lesley McKee, Esther Ngan, Jutta Scheffczik, Li-En Tan, Mark Worrall, Carmel Cassar, Kevin Goddard, Victoria Barlow, Vimmi Oshan, Khairi Shah, Sarah Bell, Lisa Daniels, Monica Gandhi, David Pachter, Chris Perry, Andrew Robertson, Carmen Scott, Lynne Waring, David Barnes, Sophie Childs, Joanne Norman, Robin Sunderland, and Anesthesiology
Subjects: Red Blood Cell Transfusion, NEONATE, Haemoglobin levels, 610 Medicine & health, Peri-operative, red blood cell transfusion, neonates, infants, High morbidity, Hemoglobins, TRANSFUSION, medicine, Clinical endpoint, Humans, Anesthesia, Prospective Studies, business.industry, Postmenstrual Age, Infant, Newborn, Perioperative, Europe, Red blood cell, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Observational study, business, 610 Medizin und Gesundheit, Erythrocyte Transfusion
Abstract: BACKGROUND Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12��g��dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (��week 3) onwards. OBJECTIVE To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN A multicentre observational study. SETTING The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g��dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g��dl-1 in week 2 and 8.0 [7.3 to 9.0] g��dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml��kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g��dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION ClinicalTrials.gov, identifier: NCT02350348.
Published: 2021
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7. Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates

Author: Hiie Soeorg, Helgi Padari, Karin Kipper, Mari-Liis Ilmoja, Irja Lutsar, and Tuuli Metsvaht
Subjects: Kinetics, Infant, Newborn, Pharmaceutical Science, Humans, Gentamicins, Kidney, Anti-Bacterial Agents, Glomerular Filtration Rate
Abstract: Gentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age ≥ 32 weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of total gentamicin, C1, C1a, and C2/C2a/C2b was evaluated by simulations. A total of 30 neonates (median (range) gestational age 36.4 (32-42) weeks, postnatal age 3 (1-5) days, creatinine value 47.5 (17-78) µmol/L) were included. Pharmacokinetics of all components was best described by a two-compartment model. Clearance of C1 was smaller than clearances of C1a and C2/C2a/C2b, and other parameters were similar. The model with different K
Published: 2022

8. Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial

Author: Louise F Hill, Michelle N Clements, Mark A Turner, Daniele Donà, Irja Lutsar, Evelyne Jacqz-Aigrain, Paul T Heath, Emmanuel Roilides, Louise Rawcliffe, Clara Alonso-Diaz, Eugenio Baraldi, Andrea Dotta, Mari-Liis Ilmoja, Ajit Mahaveer, Tuuli Metsvaht, George Mitsiakos, Vassiliki Papaevangelou, Kosmas Sarafidis, A Sarah Walker, Michael Sharland, Michelle Clements, Basma Bafadal, Ana Alarcon Allen, Fani Anatolitou, Antonio Del Vecchio, Mario Giuffrè, Korina Karachristou, Paolo Manzoni, Stefano Martinelli, Paul Moriarty, Angeliki Nika, Vana Papaevangelou, Charles Roehr, Laura Sanchez Alcobendas, Tania Siahanidou, Chryssoula Tzialla, Luca Bonadies, Nicola Booth, Paola Catalina Morales-Betancourt, Malaika Cordeiro, Concha de Alba Romero, Javier de la Cruz, Maia De Luca, Daniele Farina, Caterina Franco, Dimitra Gialamprinou, Maarja Hallik, Laura Ilardi, Vincenzo Insinga, Elias Iosifidis, Riste Kalamees, Angeliki Kontou, Zoltan Molnar, Eirini Nikaina, Chryssoula Petropoulou, Mar Reyné, Kassandra Tataropoulou, Pinelopi Triantafyllidou, Adamantios Vontzalidis, Mike Sharland, Hill L.F., Clements M.N., Turner M.A., Dona D., Lutsar I., Jacqz-Aigrain E., Heath P.T., Roilides E., Rawcliffe L., Alonso-Diaz C., Baraldi E., Dotta A., Ilmoja M.-L., Mahaveer A., Metsvaht T., Mitsiakos G., Papaevangelou V., Sarafidis K., Walker A.S., Sharland M., Clements M., Bafadal B., Alarcon Allen A., Anatolitou F., Del Vecchio A., Giuffre M., Karachristou K., Manzoni P., Martinelli S., Moriarty P., Nika A., Roehr C., Sanchez Alcobendas L., Siahanidou T., Tzialla C., Bonadies L., Booth N., Catalina Morales-Betancourt P., Cordeiro M., de Alba Romero C., de la Cruz J., De Luca M., Farina D., Franco C., Gialamprinou D., Hallik M., Ilardi L., Insinga V., Iosifidis E., Kalamees R., Kontou A., Molnar Z., Nikaina E., Petropoulou C., Reyne M., Tataropoulou K., Triantafyllidou P., and Vontzalidis A.
Subjects: medicine.medical_specialty, Time Factors, Population, Equivalence Trials as Topic, Loading dose, Article, law.invention, Gram-positive, Randomized controlled trial, law, Vancomycin, Intensive care, Internal medicine, Intensive Care Units, Neonatal, Sepsis, Developmental and Educational Psychology, Clinical endpoint, Medicine, Humans, Dosing, education, Infusions, Intravenous, education.field_of_study, business.industry, Infant, Newborn, Infant, dosing, United Kingdom, Anti-Bacterial Agents, Europe, Regimen, Treatment Outcome, Spain, Relative risk, Pediatrics, Perinatology and Child Health, sepsi, business
Abstract: Summary Background Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. Methods NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov ( NCT02790996 ). Findings Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). Interpretation In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. Funding EU Seventh Framework Programme for research, technological development and demonstration.
Published: 2021

9. Corrigendum to ‘Difficult tracheal intubation in neonates and infants. NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE):a prospective European multicentre observational study’ (Br J Anaesth 2021; 126: 1173–81) (British Journal of Anaesthesia (2021) 126(6) (1173–1181), (S0007091221001161), (10.1016/j.bja.2021.02.021))

Author: Nicola Disma, Katalin Virag, Thomas Riva, Jost Kaufmann, Thomas Engelhardt, Walid Habre, Christian Breschan, Rudolf Likar, Manuela Platzer, Isole Edelman, Johanes Eger, Stefan Heschl, Brigitte Messerer, Maria Vittinghof, Ruth Kroess, Martina Stichlberger, David Kahn, Thierry Pirotte, Caroline Pregardien, Francis Veyckemans, France Stevens, Johan Berghmans, Annemie Bauters, Luc De Baerdemaeker, Stefan De Hert, Koen Lapage, Aliaksandra Parashchanka, Jurgen Van Limmen, Piet Wyffels, Julie Lauweryns, Nadia Najafi, Joris Vundelinckx, Diana Butković, Ivana Kerovec Sorić, Sandra Kralik, Ana Markić, Josip Azman, Josko Markic, Daniela Pupacic, Michal Frelich, Petr Reimer, René Urbanec, Petra Cajková, Vladimír Mixa, Yvona Sedláčková, Lenka Knoppová, Alena Zlámalová (neé Květoňová), Martin Vavřina, Jiří Žurek, Tom Hansen, Arash Afshari, Anders Bastholm Bille, Marguerite Ellekvist, Mari-Liis Ilmoja, Reet Moor, Reet Kikas, Merle Väli, Kariantti Kallio, Elisa Reponen, Pertti Suominen, Sami Suvanto, Raisa Vähätalo, Hannu Kokki, Merja Kokki, Jarkko Harju, Miia Kokkonen, Jenni Vieri, Tuula Manner, Catherine Amory, Hugues Ludot, Dina Bert, Juliette Godart, Anne Laffargue, Hervé Dupont, Benjamin Urbina, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Maryline Bordes, Karine Nouette Gaulain, Yann Hamonic, François Semjen, Olivier Jacqmarcq, Caroline Lejus-Bourdeau, Cécile Magne, Léa Petry, Lilica Ros, Aurélien Zang, Mehdi Bennis, Bernard Coustets, Rose Fesseau, Isabelle Constant, Eliane Khalil, Nada Sabourdin, Noemie Audren, Thomas Descarpentries, Fanny Fabre, Aurélien Legrand, Emilie Druot, Gilles Orliaguet, Lucie Sabau, Lynn Uhrig, François de la Brière, Karin Jonckheer, Jean-Paul Mission, Lucia Scordo, Caroline Couchepin, Christophe Dadure, Pablo De la Arena, Laurent Hertz, Philippe Pirat, Chrystelle Sola, Myriam Bellon, Souhayl Dahmani, Florence Julien-Marsollier, Daphne Michelet, Veronique Depret-Donatien, Anne Lesage, Michael Laschat, Frank Wappler, Karin Becke, Lena Brunner, Karin Oppenrieder, Gregor Badelt, Karin Hochmuth, Bernhard Koller, Anita Reil, Sebastian Richter, Thomas Fischer, Anja Diers, Clemens Schorer, Andreas Weyland, Ruth Cohausz, Franz-Josef Kretz, Michaela Löffler, Markus Wilbs, Claudia Hoehne, Johanna Ulrici, Christiane Goeters, Armin Flinspach, Matthias Klages, Simone Lindau, Leila Messroghli, Kai Zacharowski, Christoph Eisner, Thomas Mueller, Daniel Richter, Melanie Schäfer, Markus Weigand, Sebastian Weiterer, Miriam Ochsenreiter, Michael Schöler, Tom Terboven, Isabel Eggemann, Sascha Haussmann, Nicolas Leister, Christoph Menzel, Uwe Trieschmann, Sirin Yücetepe, Susanna Keilig, Peter Kranke, Yvonne Jelting, Torsten Baehner, Richard Ellerkmann, Shahab Ghamari, Claudia Neumann, Martin Söhle, Pelagia Chloropoulou, Vagia Ntritsou, Pinelopi Papagiannopoulou, Eleana Garini, Afroditi Karafotia, Panagoula Mammi, Evangelia Bali, Despoina Iordanidou, Anna Malisiova, Artemis Polyzoi, Adelais Tsiotou, Erzsebet Sapi, Edgar Székely, Nandor Kosik, Veronika Maráczi, Janos Schnur, Judit Csillag, János Gál, Gergely Göbl, Balázs Hauser, András Petróczy, Gyula Tövisházi, Stuart Blain, Sarah Gallagher, Sinead Harte, Mandy Jackson, Emma Meehan, Zeenat Nawoor, Brendan O’Hare, Mark Ross, Daniela Lerro, Marinella Astuto, Chiara Grasso, Rita Scalisi, Giulia Frasacco, Elena Lenares, Roberto Leone, Maurizia Grazzini, Carmelo Minardi, Nicola Zadra, Gilda Cinnella, Antonella Cotoia, Dario Galante, Brita De Lorenzo, Beate Kuppers, Giulia Bottazzi, Fabio Caramelli, Maria Cristina Mondardini, Emanuele Rossetti, Sergio Picardo, Alessandro Vittori, Anna Camporesi, Andrea Wolfler, Edoardo Calderini, Laura Brigitta Colantonio, Simona Anna Finamore, Giuliana Anna Porro, Rachele Bonfiglio, Svetlana Kotzeva, Leila Mameli, Girolamo Mattioli, Camilla Micalizzi, Alessia Montaguti, Angela Pistorio, Clelia Zanaboni, Anna Guddo, Gerald Rogan Neba, Moreno Favarato, Bruno Guido Locatelli, Micol Maffioletti, Valter Sonzogni, Rossella Garra, Maria Sammartino, Fabio Sbaraglia, Andrea Cortegiani, Alessandra Moscarelli, Elena Attanasi, Simonetta Tesoro, Cristina Agapiti, Francesca Pinzoni, Cesare Vezzoli, Federico Bilotta, Arta Barzdina, Zane Straume, Anda Zundane, Laura Lukosiene, Irena Maraulaite, Ilona Razlevice, Bernd Schmitz, Stephanie Mifsud, Carolin Aehling, Celia Allison, Rients De Boer, Dina Emal, Markus Stevens, Marielle Buitenhuis, Jurgen de Graaff, Inge De Liefde, Andreas Machotta, Gail Scoones, Lonneke Staals, Jeremy Tomas, Anouk Van der Knijff-van Dortmont, Marianne Veldhuizen, David Alders, Wolfgang Buhre, Eva Schafrat, Jan Schreiber, Petronella Mari Vermeulen, Mark Hendriks, Sandra Lako, Marieke Voet-Lindner, Barbe Pieters, Gert-Jan Scheffer, Luc Tielens, Anthony R. Absalom, Margot Bergsma, Joke De Ruiter, Sascha Meier, Martin Volkers, Tjerk Zweers, Anne M. Beukers, Christa Boer, Jurgen Dertinger, Sandra Numan, Bas Van Zaane, Wenche B. Boerke, Nil Ekiz, Kristoffer Stensrud, Inger Marie Drage, Erik Ramon Isern, Alicja Bartkowska-Sniatkowska, Malgorzata Grzeskowiak, Magdalena Juzwa-Sobieraj, Jowita Rosada-Kurasińska, Artur Baranowski, Karina Jakubowska, Dorota Lewandowska, Magdalena Mierzewska-Schmidt, Piotr Sawicki, Magdalena Urban-Lechowicz, Pomianek Przemyslaw, Marzena Zielinska, Teresa Leal, Maria Soares, Pedro Pina, Sílvia Pinho, Maria Domingas Patuleia, Catarina Cruz Esteves, Helena Salgado, Maria João Santos, Rodica Badeti, Iulia Cindea, Loredana Oana, Adriana Gurita, Luminita Ilie, Gabriel Mocioiu, Radu Tabacaru, Irina Trante, Valentin Munteanu, Mihai Morariu, Emese Nyíri, Ivana Budic, Vesna Marjanovic, Biljana Drašković, Marina Pandurov, Jordanka Ilic, Ana Mandras, Zdenka Rados, Nikola Stankovic, Maja Suica, Sladjana Vasiljevic, Mirjana Knezevic, Irina Milojevic, Ivana Petrov, Selena Puric Racic, Dusica Simic, Irena Simic, Marija Stevic, Irena Vulicevic, Barbora Cabanová, Miloslav Hanula, Jelena Berger, Darja Janjatovic, Špela Pirtovšek Štupnik, Dolores Méndez, Gema Pino, Paloma Rubio, Alberto Izquierdo, Silvia López, Cristina González Serrano, Jesús Cebrián, Ana Peleteiro, Pilar Del Rey de Diego, Ernesto Martínez García, Carolina Tormo de las Heras, Pablo Troncoso Montero, Celia Arbona, David Artés, Alicia Chamizo, Silvia Serrano, Montserrat Suarez Comas, Francisco Escribá, Cristina Auli, Osvaldo Pérez Pardo, Natalia Sierra Biddle, Ceferina Suárez Castaño, María Isabel Villalobos Rico, Susana Manrique Muñoz, Irene García Martínez, Nuria Montferrer Estruch, Elena Vilardell Ortíz, Rodrigo Poves-Álvarez, Ivan Kohn, Ulf Lindestam, Jarl Reinhard, Albert Castellheim, Kerstin Sandström, Sporre Bengt, Rainer Dörenberg, Peter Frykholm, Maria Garcia, Ann Kvarnström, Emma Pontén, Thomas Bruelisauer, Gabor Erdoes, Heiko Kaiser, Mathias Marchon, Stefan Seiler, Yann Bögli, Mirko Dolci, Carine Marcucci, Isabelle Pichon, Laszlo Vutskits, Mattias Casutt, Martin Hölzle, Thomas Hurni, Martin Jöhr, Anna-Ursina Malär, Jacqueline Mauch, Thomas Erb, Karin Oeinck, Mine Akin, Gulsen Keskin, Yesim Senayli, Guner Kaya, Pinar Kendigelen, Ayse Çiğdem Tutuncu, Zehra Hatipoğlu, Dilek Özcengiz, Hale Aksu Erdost, Elvan Öçmen, Çimen Olguner, Hilmi Ayanoglu, Pelin Corman Dincer, Tumay Umuroglu, Mustafa Azizoglu, Handan Birbiçer, Nurcan Doruk, Aslı Sagun, Sibel Baris, Dmytro Dmytriiev, Sridevi Kuchi, Nuria Masip, Peter Brooks, Alison Hare, Nargis Ahmad, Michelle Casey, Sam De Silva, Nadine Dobby, Prakash Krishnan, L. Amaki Sogbodjor, Ellie Walker, Suellen Walker, Stephanie King, Katy Nicholson, Michelle Quinney, Paul Stevens, Andrew Blevin, Mariangela Giombini, Chulananda Goonasekera, Sadia Adil, Stephanie Bew, Carol Bodlani, Dan Gilpin, Stephanie Jinks, Nalini Malarkkan, Alice Miskovic, Rebecca Pad, Juliet Wolfe Barry, Joy Abbott, James Armstrong, Natalie Cooper, Lindsay Crate, John Emery, Kathryn James, Hannah King, Paul Martin, Stefano Scalia Catenacci, Rob Bomont, Paul Smith, Sara Mele, Alessandra Verzelloni, Philippa Dix, Graham Bell, Elena Gordeva, Lesley McKee, Esther Ngan, Jutta Scheffczik, Li-En Tan, Mark Worrall, Carmel Cassar, Kevin Goddard, Victoria Barlow, Vimmi Oshan, Khairi Shah, Sarah Bell, Lisa Daniels, Monica Gandhi, David Pachter, Chris Perry, Andrew Robertson, Carmen Scott, Lynne Waring, David Barnes, Sophie Childs, Joanne Norman, Robin Sunderland, Dowell Julia, Feijten Prisca, Harlet Pierre, Herbineaux Sarah, Leva Brigitte, Plichon Benoît, Virág Katalin, Disma N., Virag K., Riva T., Kaufmann J., Engelhardt T., Habre W., Breschan C., Likar R., Platzer M., Edelman I., Eger J., Heschl S., Messerer B., Vittinghof M., Kroess R., Stichlberger M., Kahn D., Pirotte T., Pregardien C., Veyckemans F., Stevens F., Berghmans J., Bauters A., De Baerdemaeker L., De Hert S., Lapage K., Parashchanka A., Van Limmen J., Wyffels P., Lauweryns J., Najafi N., Vundelinckx J., Butkovic D., Kerovec Soric I., Kralik S., Markic A., Azman J., Markic J., Pupacic D., Frelich M., Reimer P., Urbanec R., Cajkova P., Mixa V., Sedlackova Y., Knoppova L., Zlamalova (nee Kvetonova) A., Vavrina M., Zurek J., Hansen T., Afshari A., Bille A.B., Ellekvist M., Ilmoja M.-L., Moor R., Kikas R., Vali M., Kallio K., Reponen E., Suominen P., Suvanto S., Vahatalo R., Kokki H., Kokki M., Harju J., Kokkonen M., Vieri J., Manner T., Amory C., Ludot H., Bert D., Godart J., Laffargue A., Dupont H., Urbina B., Baujard C., Roulleau P., Staiti G., Bordes M., Nouette Gaulain K., Hamonic Y., Semjen F., Jacqmarcq O., Lejus-Bourdeau C., Magne C., Petry L., Ros L., Zang A., Bennis M., Coustets B., Fesseau R., Constant I., Khalil E., Sabourdin N., Audren N., Descarpentries T., Fabre F., Legrand A., Druot E., Orliaguet G., Sabau L., Uhrig L., de la Briere F., Jonckheer K., Mission J.-P., Scordo L., Couchepin C., Dadure C., De la Arena P., Hertz L., Pirat P., Sola C., Bellon M., Dahmani S., Julien-Marsollier F., Michelet D., Depret-Donatien V., Lesage A., Laschat M., Wappler F., Becke K., Brunner L., Oppenrieder K., Badelt G., Hochmuth K., Koller B., Reil A., Richter S., Fischer T., Diers A., Schorer C., Weyland A., Cohausz R., Kretz F.-J., Loffler M., Wilbs M., Hoehne C., Ulrici J., Goeters C., Flinspach A., Klages M., Lindau S., Messroghli L., Zacharowski K., Eisner C., Mueller T., Richter D., Schafer M., Weigand M., Weiterer S., Ochsenreiter M., Scholer M., Terboven T., Eggemann I., Haussmann S., Leister N., Menzel C., Trieschmann U., Yucetepe S., Keilig S., Kranke P., Jelting Y., Baehner T., Ellerkmann R., Ghamari S., Neumann C., Sohle M., Chloropoulou P., Ntritsou V., Papagiannopoulou P., Garini E., Karafotia A., Mammi P., Bali E., Iordanidou D., Malisiova A., Polyzoi A., Tsiotou A., Sapi E., Szekely E., Kosik N., Maraczi V., Schnur J., Csillag J., Gal J., Gobl G., Hauser B., Petroczy A., Tovishazi G., Blain S., Gallagher S., Harte S., Jackson M., Meehan E., Nawoor Z., O'Hare B., Ross M., Lerro D., Astuto M., Grasso C., Scalisi R., Frasacco G., Lenares E., Leone R., Grazzini M., Minardi C., Zadra N., Cinnella G., Cotoia A., Galante D., De Lorenzo B., Kuppers B., Bottazzi G., Caramelli F., Mondardini M.C., Rossetti E., Picardo S., Vittori A., Camporesi A., Wolfler A., Calderini E., Colantonio L.B., Finamore S.A., Porro G.A., Bonfiglio R., Kotzeva S., Mameli L., Mattioli G., Micalizzi C., Montaguti A., Pistorio A., Zanaboni C., Guddo A., Neba G.R., Favarato M., Locatelli B.G., Maffioletti M., Sonzogni V., Garra R., Sammartino M., Sbaraglia F., Cortegiani A., Moscarelli A., Attanasi E., Tesoro S., Agapiti C., Pinzoni F., Vezzoli C., Bilotta F., Barzdina A., Straume Z., Zundane A., Lukosiene L., Maraulaite I., Razlevice I., Schmitz B., Mifsud S., Aehling C., Allison C., De Boer R., Emal D., Stevens M., Buitenhuis M., de Graaff J., De Liefde I., Machotta A., Scoones G., Staals L., Tomas J., Van der Knijff-van Dortmont A., Veldhuizen M., Alders D., Buhre W., Schafrat E., Schreiber J., Vermeulen P.M., Hendriks M., Lako S., Voet-Lindner M., Pieters B., Scheffer G.-J., Tielens L., Absalom A.R., Bergsma M., De Ruiter J., Meier S., Volkers M., Zweers T., Beukers A.M., Boer C., Dertinger J., Numan S., Van Zaane B., Boerke W.B., Ekiz N., Stensrud K., Drage I.M., Isern E.R., Bartkowska-Sniatkowska A., Grzeskowiak M., Juzwa-Sobieraj M., Rosada-Kurasinska J., Baranowski A., Jakubowska K., Lewandowska D., Mierzewska-Schmidt M., Sawicki P., Urban-Lechowicz M., Przemyslaw P., Zielinska M., Leal T., Soares M., Pina P., Pinho S., Patuleia M.D., Esteves C.C., Salgado H., Santos M.J., Badeti R., Cindea I., Oana L., Gurita A., Ilie L., Mocioiu G., Tabacaru R., Trante I., Munteanu V., Morariu M., Nyiri E., Budic I., Marjanovic V., Draskovic B., Pandurov M., Ilic J., Mandras A., Rados Z., Stankovic N., Suica M., Vasiljevic S., Knezevic M., Milojevic I., Petrov I., Puric Racic S., Simic D., Simic I., Stevic M., Vulicevic I., Cabanova B., Hanula M., Berger J., Janjatovic D., Pirtovsek Stupnik S., Mendez D., Pino G., Rubio P., Izquierdo A., Lopez S., Gonzalez Serrano C., Cebrian J., Peleteiro A., Del Rey de Diego P., Martinez Garcia E., Tormo de las Heras C., Troncoso Montero P., Arbona C., Artes D., Chamizo A., Serrano S., Suarez Comas M., Escriba F., Auli C., Perez Pardo O., Sierra Biddle N., Suarez Castano C., Villalobos Rico M.I., Manrique Munoz S., Garcia Martinez I., Montferrer Estruch N., Vilardell Ortiz E., Poves-Alvarez R., Kohn I., Lindestam U., Reinhard J., Castellheim A., Sandstrom K., Bengt S., Dorenberg R., Frykholm P., Garcia M., Kvarnstrom A., Ponten E., Bruelisauer T., Erdoes G., Kaiser H., Marchon M., Seiler S., Bogli Y., Dolci M., Marcucci C., Pichon I., Vutskits L., Casutt M., Holzle M., Hurni T., Johr M., Malar A.-U., Mauch J., Erb T., Oeinck K., Akin M., Keskin G., Senayli Y., Kaya G., Kendigelen P., Tutuncu A.C., Hatipoglu Z., Ozcengiz D., Erdost H.A., Ocmen E., Olguner C., Ayanoglu H., Dincer P.C., Umuroglu T., Azizoglu M., Birbicer H., Doruk N., Sagun A., Baris S., Dmytriiev D., Kuchi S., Masip N., Brooks P., Hare A., Ahmad N., Casey M., De Silva S., Dobby N., Krishnan P., Sogbodjor L.A., Walker E., Walker S., King S., Nicholson K., Quinney M., Stevens P., Blevin A., Giombini M., Goonasekera C., Adil S., Bew S., Bodlani C., Gilpin D., Jinks S., Malarkkan N., Miskovic A., Pad R., Wolfe Barry J., Abbott J., Armstrong J., Cooper N., Crate L., Emery J., James K., King H., Martin P., Scalia Catenacci S., Bomont R., Smith P., Mele S., Verzelloni A., Dix P., Bell G., Gordeva E., McKee L., Ngan E., Scheffczik J., Tan L.-E., Worrall M., Cassar C., Goddard K., Barlow V., Oshan V., Shah K., Bell S., Daniels L., Gandhi M., Pachter D., Perry C., Robertson A., Scott C., Waring L., Barnes D., Childs S., Norman J., Sunderland R., Julia D., Prisca F., Pierre H., Sarah H., Brigitte L., Benoit P., Katalin V., Anesthesiology, APH - Quality of Care, and Amsterdam Neuroscience - Neuroinfection & -inflammation
Subjects: Anesthesiology and Pain Medicine, business.industry, medicine.medical_treatment, Anesthesia, Tracheal intubation, Neonates, anaesthesia, medicine, MEDLINE, Observational study, Audit, business
Abstract: The authors regret that errors were present in the above article. On page 1174, in the second paragraph of the Statistical methods section, the second sentence should read as follows: The incidence of difficult intubation was determined including those whose tracheas were already intubated and is reported as a percentage with a 95% exact binomial CI. On page 1175, in the third paragraph of the Statistical methods section ‘mean standardised difference (MSD)’ should read ‘standardised mean difference (SMD)’ The authors would like to apologise for any inconvenience caused.
Published: 2021
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10. Population pharmacokinetics and pharmacodynamics of dobutamine in neonates on the first days of life

Author: Rūta Veigure, Joseph F. Standing, Kalev Takkis, Joel Starkopf, Kristel Köbas, Tuuli Metsvaht, Mari-Liis Ilmoja, Maarja Hallik, Margit Sõnajalg, Hiie Soeorg, Karin Kipper, Maila Raidmäe, Karin Uibo, and Tiiu Jalas
Subjects: medicine.medical_specialty, Mean arterial pressure, Cardiac output, Population, Gestational Age, 030226 pharmacology & pharmacy, Ventricular Function, Left, 03 medical and health sciences, 0302 clinical medicine, Dobutamine, Internal medicine, Intensive care, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, Cardiac Output, education, Pharmacology, Volume of distribution, education.field_of_study, Ejection fraction, business.industry, Infant, Newborn, Infant, Stroke Volume, Original Articles, cardiovascular pharmacology, intensive care, neonatology, NONMEM, pharmacokinetic–pharmacodynamic, Pharmacodynamics, Cardiology, Original Article, business, medicine.drug
Abstract: Aims To describe the pharmacokinetics (PK) and concentration‐related effects of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=535 in critically ill neonates in the first days of life, using nonlinear mixed effects modelling. Methods Dosing, plasma concentration and haemodynamic monitoring data from a dose‐escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5–20 μg kg−1 min−1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors. Results Twenty‐eight neonates with median (range) gestational age of 30.4 (22.7–41.0) weeks and birth weight (BW) of 1618 (465–4380) g were included. PK data were adequately described by 1‐compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h−1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model. Conclusion In the postnatal transitional period, PK of dobutamine was described by a 1‐compartmental linear model, CL related to BW and PMA. A concentration–response relationship with haemodynamic variables has been established.
Published: 2020
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11. Population Pharmacokinetics and Dosing of Milrinone After Patent Ductus Arteriosus Ligation in Preterm Infants

Author: Mari-Liis Ilmoja, Maarja Hallik, Tõnis Tasa, Rūta Veigure, Karin Kipper, Karin Uibo, Tiiu Jalas, Joseph F. Standing, Kalev Takkis, Maila Raidmäe, Joel Starkopf, and Tuuli Metsvaht
Subjects: Male, Cardiac function curve, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Cardiotonic Agents, Population pharmacokinetics, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Pharmacokinetics, Tachycardia, Internal medicine, Ductus arteriosus, Humans, Medicine, cardiovascular diseases, Dosing, Ductus Arteriosus, Patent, Ligation, business.industry, Infant, Newborn, Stroke Volume, 030208 emergency & critical care medicine, Syndrome, medicine.anatomical_structure, Echocardiography, Pediatrics, Perinatology and Child Health, cardiovascular system, Cardiology, Milrinone, Female, Hypotension, business, Infant, Premature, medicine.drug, Hemodynamic instability
Abstract: The postoperative course of patent ductus arteriosus ligation is often complicated by postligation cardiac syndrome, occurring in 10-45% of operated infants. Milrinone might prevent profound hemodynamic instability and improve the recovery of cardiac function in this setting. The present study aimed to describe the population pharmacokinetics of milrinone in premature neonates at risk of postligation cardiac syndrome and give dosing recommendations.A prospective single group open-label pharmacokinetics study.Two tertiary care neonatal ICUs: Tallinn Children's Hospital and Tartu University Hospital, Estonia.Ten neonates with postmenstrual age of 24.6-30.1 weeks and postnatal age of 5-27 days undergoing patent ductus arteriosus ligation and at risk of postligation cardiac syndrome, based on echocardiographic assessment of left ventricular output of less than 200 mL/kg/min 1 hour after the surgery.Milrinone at a dose of 0.73 μg/kg/min for 3 hours followed by 0.16 μg/kg/min for 21 hours. Four blood samples from each patient for milrinone plasma concentration measurements were collected.Concentration-time data of milrinone were analyzed with nonlinear mixed-effects modeling software (NONMEM Version 7.3 [ICON Development Solutions, Ellicott City, MD]). Probability of target attainment simulations gave a dosing schedule that maximally attains concentration targets of 150-250 μg/L. Milrinone pharmacokinetics was described by a one-compartmental linear model with allometric scaling to bodyweight and an age maturation function of glomerular filtration rate. Parameter estimates for a patient with the median weight were 0.350 (L/hr) for clearance and 0.329 (L) for volume of distribution. The best probability of target attainment was achieved with a loading dose of 0.50 μg/kg/min for 3 hours followed by 0.15 μg/kg/min (postmenstrual age27 wk) or 0.20 μg/kg/min (postmenstrual age ≥ 27 wk).Population pharmacokinetic modeling and simulations suggest a slow loading dose followed by maintenance infusion to reach therapeutic milrinone plasma concentrations within the timeframe of the postligation cardiac syndrome.
Published: 2019
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12. A sensitive method for the simultaneous UHPLC-MS/MS analysis of milrinone and dobutamine in blood plasma using NH4F as the eluent additive and ascorbic acid as a stabilizer

Author: Joel Starkopf, Kalev Takkis, Tuuli Metsvaht, Rūta Veigure, Maarja Hallik, Karin Kipper, and Mari-Liis Ilmoja
Subjects: 0303 health sciences, Analyte, Chromatography, Chemistry, 030302 biochemistry & molecular biology, 010401 analytical chemistry, Ascorbic acid, 01 natural sciences, 0104 chemical sciences, 03 medical and health sciences, Column chromatography, Pharmacokinetics, Pharmacodynamics, Blood plasma, medicine, Milrinone, Dobutamine, Spectroscopy, medicine.drug
Abstract: The purpose of this work was to develop and validate an HPLC-MS/MS method suitable for quantifying two important cardiovascular drugs, milrinone and dobutamine, in neonatal and paediatric patients’ blood plasma samples. Sufficiently low LLOQ levels were required to obtain adequate pharmacokinetic data for the evaluation of optimal dosing. Since the specifics of the patient group set some restrictions on the available sample volume, the method was designed to use only 20 µL of plasma for the analysis. Analytes were separated chromatographically in a biphenyl column using a conventional water-methanol-formic acid eluent with the addition of ammonium fluoride. The latter provided a significant signal enhancement in positive ion mode detection for both analytes allowing the LLOQ to reach below 1 ng/mL. Matrix matched calibration was linear in the range of 1–300 ng/mL, between-run accuracy remained within 107–115%, and precision within 4.8–7.4% for both analytes over the calibration range (including LLOQ level). Dobutamine degradation in plasma samples was prevented by the usage of ascorbic acid. The method was applied to plasma samples of neonates from two pharmacokinetic/pharmacodynamics studies (n = 38).
Published: 2019
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13. Genetic Relatedness of Staphylococcus haemolyticus in Gut and Skin of Preterm Neonates and Breast Milk of Their Mothers

Author: Hanna Kadri Metsvaht, Evamaria Elisabet Keränen, Tuuli Metsvaht, Irja Lutsar, Hiie Soeorg, Imbi Eelmäe, Mari-Liis Ilmoja, and Mirjam Merila
Subjects: Male, Microbiology (medical), Neonatal intensive care unit, Mothers, Physiology, Breast milk, 03 medical and health sciences, 0302 clinical medicine, Intensive Care Units, Neonatal, 030225 pediatrics, Genotype, Humans, Medicine, Longitudinal Studies, Prospective Studies, 030212 general & internal medicine, Skin, Milk, Human, biology, business.industry, SCCmec, Infant, Newborn, Staphylococcal Infections, biology.organism_classification, Staphylococcus haemolyticus, Bacterial Typing Techniques, Gastrointestinal Tract, Variable number tandem repeat, Breast Feeding, Infectious Diseases, Pediatrics, Perinatology and Child Health, Multilocus sequence typing, Female, Neonatal Sepsis, business, Breast feeding, Infant, Premature, Multilocus Sequence Typing
Abstract: BACKGROUND Staphylococcus haemolyticus is a common colonizer and cause of late-onset sepsis (LOS) in preterm neonates. By describing genetic relatedness, we aimed to determine whether mother's breast milk (BM) is a source of S. haemolyticus colonizing neonatal gut and skin and/or causing LOS. METHODS S. haemolyticus was isolated from stool and skin swabs of 49 BM-fed preterm neonates admitted to neonatal intensive care unit, 20 healthy BM-fed term neonates and BM of mothers once a week and typed by multilocus variable number tandem repeat analysis and multilocus sequence typing. Virulence-related genes were determined by polymerase chain reaction. RESULTS Compared with term neonates, S. haemolyticus colonized more commonly gut (35% vs. 89.9%; P < 0.001) and skin (50% vs. 91.8%; P < 0.001) of preterm neonates and mothers' BM (15% vs. 38.8%). Isolates from preterm compared with term neonates and their mothers carried more commonly the mecA gene (83.5% vs. 5.4%; P < 0.001) and IS256 (52.4% vs. 2.7%; P < 0.001) and belonged to clonal complex 29 (89.1% vs. 63%; P = 0.014). Only 7 (14.3%) preterm and 3 (15%) term neonates were colonized in gut or on skin with multilocus variable number tandem repeat analysis types indistinguishable from those in BM. Most frequent multilocus variable number tandem repeat analysis types belonged to sequence type 3 or 42, comprised 71.1%-78.4% of isolates from preterm neonates/mothers and caused all 7 LOS episodes. LOS-causing strain colonized the gut of 4/7 and the skin of 5/7 neonates, but not BM, before onset of LOS. CONCLUSIONS S. haemolyticus colonizing gut and skin or causing LOS in preterm neonates rarely originate from BM but are mecA-positive strains adapted to hospital environment.
Published: 2019
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14. Morbidity and mortality after anaesthesia in early life:results of the European prospective multicentre observational study, neonate and children audit of anaesthesia practice in Europe (NECTARINE)

Author: Nicola Disma, Francis Veyckemans, Katalin Virag, Tom G. Hansen, Karin Becke, Pierre Harlet, Laszlo Vutskits, Suellen M. Walker, Jurgen C. de Graaff, Marzena Zielinska, Dusica Simic, Thomas Engelhardt, Walid Habre, Christian Breschan, Rudolf Likar, Manuela Platzer, Isole Edelman, Johanes Eger, Stefan Heschl, Brigitte Messerer, Maria Vittinghof, Ruth Kroess, Martina Stichlberger, David Kahn, Thierry Pirotte, Caroline Pregardien, France Stevens, Johan Berghmans, Annemie Bauters, Luc De Baerdemaeker, Stefan De Hert, Koen Lapage, Aliaksandra Parashchanka, Jurgen Van Limmen, Piet Wyffels, Julie Lauweryns, Nadia Najafi, Joris Vundelinckx, Diana Butković, Ivana Kerovec Sorić, Sandra Kralik, Ana Markić, Josip Azman, Josko Markic, Daniela Pupacic, Michal Frelich, Petr Reimer, Rene Urbanec, Petra Cajkova, Vladimir Mixa, Yvona Sedlačkova, Lenka Knoppova, Alena Zlamalova (nee Květoňova), Martin Vavřina, Jiři Žurek, Tom Hansen, Arash Afshari, Anders B. Bille, Marguerite Ellekvist, Mari-Liis Ilmoja, Reet Moor, Reet Kikas, Merle Vali, Kariantti Kallio, Elisa Reponen, Pertti Suominen, Sami Suvanto, Raisa Vahatalo, Hannu Kokki, Merja Kokki, Jarkko Harju, Miia Kokkonen, Jenni Vieri, Tuula Manner, Catherine Amory, Hugues Ludot, Dina Bert, Juliette Godart, Anne Laffargue, Herve Dupont, Benjamin Urbina, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Maryline Bordes, Karine Nouette Gaulain, Yann Hamonic, Francois Semjen, Olivier Jacqmarcq, Caroline Lejus-Bourdeau, Cecile Magne, Lea Petry, Lilica Ros, Aurelien Zang, Mehdi Bennis, Bernard Coustets, Rose Fesseau, Isabelle Constant, Eliane Khalil, Nada Sabourdin, Noemie Audren, Thomas Descarpentries, Fanny Fabre, Aurelien Legrand, Emilie Druot, Gilles Orliaguet, Lucie Sabau, Lynn Uhrig, Francois de la Briere, Karin Jonckheer, Jean-Paul Mission, Lucia Scordo, Caroline Couchepin, Christophe Dadure, Pablo De la Arena, Laurent Hertz, Philippe Pirat, Chrystelle Sola, Myriam Bellon, Souhayl Dahmani, Florence Julien-Marsollier, Daphne Michelet, Veronique Depret-Donatien, Anne Lesage, Jost Kaufmann, Michael Laschat, Frank Wappler, Lena Brunner, Karin Oppenrieder, Gregor Badelt, Karin Hochmuth, Bernhard Koller, Anita Reil, Sebastian Richter, Thomas Fischer, Anja Diers, Clemens Schorer, Andreas Weyland, Ruth Cohausz, Franz-Josef Kretz, Michaela Loffler, Markus Wilbs, Claudia Hoehne, Johanna Ulrici, Christiane Goeters, Armin Flinspach, Matthias Klages, Simone Lindau, Leila Messroghli, Kai Zacharowski, Christoph Eisner, Thomas Mueller, Daniel Richter, Melanie Schafer, Markus Weigand, Sebastian Weiterer, Miriam Ochsenreiter, Michael Scholer, Tom Terboven, Isabel Eggemann, Sascha Haussmann, Nicolas Leister, Christoph Menzel, Uwe Trieschmann, Sirin Yucetepe, Susanna Keilig, Peter Kranke, Yvonne Jelting, Torsten Baehner, Richard Ellerkmann, Shahab Ghamari, Claudia Neumann, Martin Sohle, Pelagia Chloropoulou, Vagia Ntritsou, Pinelopi Papagiannopoulou, Eleana Garini, Afroditi Karafotia, Panagoula Mammi, Evangelia Bali, Despoina Iordanidou, Anna Malisiova, Artemis Polyzoi, Adelais Tsiotou, Erzsebet Sapi, Edgar Szekely, Nandor Kosik, Veronika Maraczi, Janos Schnur, Judit Csillag, Janos Gal, Gergely Gobl, Balazs Hauser, Andras Petroczy, Gyula Tovishazi, Stuart Blain, Sarah Gallagher, Sinead Harte, Mandy Jackson, Emma Meehan, Zeenat Nawoor, Brendan O’Hare, Mark Ross, Daniela Lerro, Marinella Astuto, Chiara Grasso, Rita Scalisi, Giulia Frasacco, Elena Lenares, Roberto Leone, Maurizia Grazzini, Carmelo Minardi, Nicola Zadra, Gilda Cinnella, Antonella Cotoia, Dario Galante, Brita De Lorenzo, Beate Kuppers, Giulia Bottazzi, Fabio Caramelli, Maria C. Mondardini, Emanuele Rossetti, Sergio Picardo, Alessandro Vittori, Anna Camporesi, Andrea Wolfler, Edoardo Calderini, Laura B. Colantonio, Simona A. Finamore, Giuliana A. Porro, Rachele Bonfiglio, Svetlana Kotzeva, Leila Mameli, Girolamo Mattioli, Camilla Micalizzi, Alessia Montaguti, Angela Pistorio, Clelia Zanaboni, Anna Guddo, Gerald R. Neba, Moreno Favarato, Bruno G. Locatelli, Micol Maffioletti, Valter Sonzogni, Rossella Garra, Maria Sammartino, Fabio Sbaraglia, Andrea Cortegiani, Alessandra Moscarelli, Elena Attanasi, Simonetta Tesoro, Cristina Agapiti, Francesca Pinzoni, Cesare Vezzoli, Federico Bilotta, Arta Barzdina, Zane Straume, Anda Zundane, Laura Lukosiene, Irena Maraulaite, Ilona Razlevice, Bernd Schmitz, Stephanie Mifsud, Carolin Aehling, Celia Allison, Rients De Boer, Dina Emal, Markus Stevens, Marielle Buitenhuis, Jurgen de Graaff, Inge De Liefde, Andreas Machotta, Gail Scoones, Lonneke Staals, Jeremy Tomas, Anouk Van der, Knijff-van Dortmont, Marianne Veldhuizen, David Alders, Wolfgang Buhre, Eva Schafrat, Jan Schreiber, Petronella M. Vermeulen, Mark Hendriks, Sandra Lako, Marieke Voet-Lindner, Barbe Pieters, Gert-Jan Scheffer, Luc Tielens, Anthony R. Absalom, Margot Bergsma, Joke De Ruiter, Sascha Meier, Martin Volkers, Tjerk Zweers, Anne M. Beukers, Christa Boer, Jurgen Dertinger, Sandra Numan, Bas Van Zaane, Wenche B. Boerke, Nil Ekiz, Kristoffer Stensrud, Inger M. Drage, Erik R. Isern, Alicja Bartkowska-Sniatkowska, Malgorzata Grzeskowiak, Magdalena Juzwa-Sobieraj, Jowita Rosada-Kurasińska, Artur Baranowski, Karina Jakubowska, Dorota Lewandowska, Magdalena Mierzewska-Schmidt, Piotr Sawicki, Magdalena Urban-Lechowicz, Pomianek Przemyslaw, Teresa Leal, Maria Soares, Pedro Pina, Silvia Pinho, Maria Domingas Patuleia, Catarina C. Esteves, Helena Salgado, Maria J. Santos, Rodica Badeti, Iulia Cindea, Loredana Oana, Adriana Gurita, Luminita Ilie, Gabriel Mocioiu, Radu Tabacaru, Irina Trante, Valentin Munteanu, Mihai Morariu, Emese Nyiri, Ivana Budic, Vesna Marjanovic, Biljana Drašković, Marina Pandurov, Jordanka Ilic, Ana Mandras, Zdenka Rados, Nikola Stankovic, Maja Suica, Sladjana Vasiljevic, Mirjana Knezevic, Irina Milojevic, Ivana Petrov, Selena Puric Racic, Irena Simic, Marija Stevic, Irena Vulicevic, Barbora Cabanova, Miloslav Hanula, Jelena Berger, Darja Janjatovic, Špela P. Štupnik, Ivan Kohn, Ulf Lindestam, Jarl Reinhard, Albert Castellheim, Kerstin Sandstrom, Sporre Bengt, Rainer Dorenberg, Peter Frykholm, Maria Garcia, Ann Kvarnstrom, Emma Ponten, Thomas Bruelisauer, Gabor Erdoes, Heiko Kaiser, Mathias Marchon, Thomas Riva, Stefan Seiler, Yann Bogli, Mirko Dolci, Carine Marcucci, Isabelle Pichon, Mattias Casutt, Martin Holzle, Thomas Hurni, Martin Johr, null Anna-Ursina, null Malar, Jacqueline Mauch, Thomas Erb, Karin Oeinck, Mine Akin, Gulsen Keskin, Yesim Senayli, Guner Kaya, Pinar Kendigelen, Ayse C. Tutuncu, Zehra Hatipoğlu, Dilek Ozcengiz, Hale Aksu Erdost, Elvan Ocmen, Cimen Olguner, Hilmi Ayanoglu, Pelin C. Dincer, Tumay Umuroglu, Mustafa Azizoglu, Handan Birbicer, Nurcan Doruk, Aslı Sagun, Sibel Baris, Dmytro Dmytriiev, Sridevi Kuchi, Nuria Masip, Peter Brooks, Alison Hare, Nargis Ahmad, Michelle Casey, Sam De Silva, Nadine Dobby, Prakash Krishnan, L. Amaki Sogbodjor, Ellie Walker, Suellen Walker, Stephanie King, Katy Nicholson, Michelle Quinney, Paul Stevens, Andrew Blevin, Mariangela Giombini, Chulananda Goonasekera, Sadia Adil, Stephanie Bew, Carol Bodlani, Dan Gilpin, Stephanie Jinks, Nalini Malarkkan, Alice Miskovic, Rebecca Pad, Juliet W. Barry, Joy Abbott, James Armstrong, Natalie Cooper, Lindsay Crate, John Emery, Kathryn James, Hannah King, Paul Martin, Stefano S. Catenacci, Rob Bomont, Paul Smith, Sara Mele, Alessandra Verzelloni, Philippa Dix, Graham Bell, Elena Gordeva, Lesley McKee, Esther Ngan, Jutta Scheffczik, Li-En Tan, Mark Worrall, Carmel Cassar, Kevin Goddard, Victoria Barlow, Vimmi Oshan, Khairi Shah, Sarah Bell, Lisa Daniels, Monica Gandhi, David Pachter, Chris Perry, Andrew Robertson, Carmen Scott, Lynne Waring, David Barnes, Sophie Childs, Joanne Norman, Robin Sunderland, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anesthésiologie, Tampere University, Department of Prehospital Emergency Care, Pain Management and Anaesthesiology, Anesthesiology, APH - Quality of Care, ANS - Neuroinfection & -inflammation, Disma, Nicola, Veyckemans, Franci, Virag, Katalin, Hansen, Tom G., Becke, Karin, Harlet, Pierre, Vutskits, Laszlo, Walker, Suellen M., de Graaff, Jurgen C., Zielinska, Marzena, Simic, Dusica, Engelhardt, Thoma, Habre, Walid, Breschan, Christian, Likar, Rudolf, Platzer, Manuela, Edelman, Isole, Eger, Johane, Heschl, Stefan, Messerer, Brigitte, Vittinghof, Maria, Kroess, Ruth, Stichlberger, Martina, Kahn, David, Pirotte, Thierry, Pregardien, Caroline, Stevens, France, Berghmans, Johan, Bauters, Annemie, De Baerdemaeker, Luc, De Hert, Stefan, Lapage, Koen, Parashchanka, Aliaksandra, Van Limmen, Jurgen, Wyffels, Piet, Lauweryns, Julie, Najafi, Nadia, Vundelinckx, Jori, Butković, Diana, Sorić, Ivana Kerovec, Kralik, Sandra, Markić, Ana, Azman, Josip, Markic, Josko, Pupacic, Daniela, Frelich, Michal, Reimer, Petr, Urbanec, Rene, Cajkova, Petra, Mixa, Vladimir, Sedlačkova, Yvona, Knoppova, Lenka, Zlamalova (nee Květoňova), Alena, Vavřina, Martin, Žurek, Jiři, Hansen, Tom, Afshari, Arash, Bille, Anders B., Ellekvist, Marguerite, Ilmoja, Mari-Lii, Moor, Reet, Kikas, Reet, Vali, Merle, Kallio, Kariantti, Reponen, Elisa, Suominen, Pertti, Suvanto, Sami, Vahatalo, Raisa, Kokki, Hannu, Kokki, Merja, Harju, Jarkko, Kokkonen, Miia, Vieri, Jenni, Manner, Tuula, Amory, Catherine, Ludot, Hugue, Bert, Dina, Godart, Juliette, Laffargue, Anne, Dupont, Herve, Urbina, Benjamin, Baujard, Catherine, Roulleau, Philippe, Staiti, Giuseppe, Bordes, Maryline, Gaulain, Karine Nouette, Hamonic, Yann, Semjen, Francoi, Jacqmarcq, Olivier, Lejus-Bourdeau, Caroline, Magne, Cecile, Petry, Lea, Ros, Lilica, Zang, Aurelien, Bennis, Mehdi, Coustets, Bernard, Fesseau, Rose, Constant, Isabelle, Khalil, Eliane, Sabourdin, Nada, Audren, Noemie, Descarpentries, Thoma, Fabre, Fanny, Legrand, Aurelien, Druot, Emilie, Orliaguet, Gille, Sabau, Lucie, Uhrig, Lynn, de la Briere, Francoi, Jonckheer, Karin, Mission, Jean-Paul, Scordo, Lucia, Couchepin, Caroline, Dadure, Christophe, De la Arena, Pablo, Hertz, Laurent, Pirat, Philippe, Sola, Chrystelle, Bellon, Myriam, Dahmani, Souhayl, Julien-Marsollier, Florence, Michelet, Daphne, Depret-Donatien, Veronique, Lesage, Anne, Kaufmann, Jost, Laschat, Michael, Wappler, Frank, Brunner, Lena, Oppenrieder, Karin, Badelt, Gregor, Hochmuth, Karin, Koller, Bernhard, Reil, Anita, Richter, Sebastian, Fischer, Thoma, Diers, Anja, Schorer, Clemen, Weyland, Andrea, Cohausz, Ruth, Kretz, Franz-Josef, Loffler, Michaela, Wilbs, Marku, Hoehne, Claudia, Ulrici, Johanna, Goeters, Christiane, Flinspach, Armin, Klages, Matthia, Lindau, Simone, Messroghli, Leila, Zacharowski, Kai, Eisner, Christoph, Mueller, Thoma, Richter, Daniel, Schafer, Melanie, Weigand, Marku, Weiterer, Sebastian, Ochsenreiter, Miriam, Scholer, Michael, Terboven, Tom, Eggemann, Isabel, Haussmann, Sascha, Leister, Nicola, Menzel, Christoph, Trieschmann, Uwe, Yucetepe, Sirin, Keilig, Susanna, Kranke, Peter, Jelting, Yvonne, Baehner, Torsten, Ellerkmann, Richard, Ghamari, Shahab, Neumann, Claudia, Sohle, Martin, Chloropoulou, Pelagia, Ntritsou, Vagia, Papagiannopoulou, Pinelopi, Garini, Eleana, Karafotia, Afroditi, Mammi, Panagoula, Bali, Evangelia, Iordanidou, Despoina, Malisiova, Anna, Polyzoi, Artemi, Tsiotou, Adelai, Sapi, Erzsebet, Szekely, Edgar, Kosik, Nandor, Maraczi, Veronika, Schnur, Jano, Csillag, Judit, Gal, Jano, Gobl, Gergely, Hauser, Balaz, Petroczy, Andra, Tovishazi, Gyula, Blain, Stuart, Gallagher, Sarah, Harte, Sinead, Jackson, Mandy, Meehan, Emma, Nawoor, Zeenat, O’Hare, Brendan, Ross, Mark, Lerro, Daniela, Astuto, Marinella, Grasso, Chiara, Scalisi, Rita, Frasacco, Giulia, Lenares, Elena, Leone, Roberto, Grazzini, Maurizia, Minardi, Carmelo, Zadra, Nicola, Cinnella, Gilda, Cotoia, Antonella, Galante, Dario, De Lorenzo, Brita, Kuppers, Beate, Bottazzi, Giulia, Caramelli, Fabio, Mondardini, Maria C., Rossetti, Emanuele, Picardo, Sergio, Vittori, Alessandro, Camporesi, Anna, Wolfler, Andrea, Calderini, Edoardo, Colantonio, Laura B., Finamore, Simona A., Porro, Giuliana A., Bonfiglio, Rachele, Kotzeva, Svetlana, Mameli, Leila, Mattioli, Girolamo, Micalizzi, Camilla, Montaguti, Alessia, Pistorio, Angela, Zanaboni, Clelia, Guddo, Anna, Neba, Gerald R., Favarato, Moreno, Locatelli, Bruno G., Maffioletti, Micol, Sonzogni, Valter, Garra, Rossella, Sammartino, Maria, Sbaraglia, Fabio, Cortegiani, Andrea, Moscarelli, Alessandra, Attanasi, Elena, Tesoro, Simonetta, Agapiti, Cristina, Pinzoni, Francesca, Vezzoli, Cesare, Bilotta, Federico, Barzdina, Arta, Straume, Zane, Zundane, Anda, Lukosiene, Laura, Maraulaite, Irena, Razlevice, Ilona, Schmitz, Bernd, Mifsud, Stephanie, Aehling, Carolin, Allison, Celia, De Boer, Rient, Emal, Dina, Stevens, Marku, Buitenhuis, Marielle, de Graaff, Jurgen, De Liefde, Inge, Machotta, Andrea, Scoones, Gail, Staals, Lonneke, Tomas, Jeremy, Van der, Anouk, Dortmont, Knijff-van, Veldhuizen, Marianne, Alders, David, Buhre, Wolfgang, Schafrat, Eva, Schreiber, Jan, Vermeulen, Petronella M., Hendriks, Mark, Lako, Sandra, Voet-Lindner, Marieke, Pieters, Barbe, Scheffer, Gert-Jan, Tielens, Luc, Absalom, Anthony R., Bergsma, Margot, De Ruiter, Joke, Meier, Sascha, Volkers, Martin, Zweers, Tjerk, Beukers, Anne M., Boer, Christa, Dertinger, Jurgen, Numan, Sandra, Van Zaane, Ba, Boerke, Wenche B., Ekiz, Nil, Stensrud, Kristoffer, Drage, Inger M., Isern, Erik R., Bartkowska-Sniatkowska, Alicja, Grzeskowiak, Malgorzata, Juzwa-Sobieraj, Magdalena, Rosada-Kurasińska, Jowita, Baranowski, Artur, Jakubowska, Karina, Lewandowska, Dorota, Mierzewska-Schmidt, Magdalena, Sawicki, Piotr, Urban-Lechowicz, Magdalena, Przemyslaw, Pomianek, Leal, Teresa, Soares, Maria, Pina, Pedro, Pinho, Silvia, Patuleia, Maria Dominga, Esteves, Catarina C., Salgado, Helena, Santos, Maria J., Badeti, Rodica, Cindea, Iulia, Oana, Loredana, Gurita, Adriana, Ilie, Luminita, Mocioiu, Gabriel, Tabacaru, Radu, Trante, Irina, Munteanu, Valentin, Morariu, Mihai, Nyiri, Emese, Budic, Ivana, Marjanovic, Vesna, Drašković, Biljana, Pandurov, Marina, Ilic, Jordanka, Mandras, Ana, Rados, Zdenka, Stankovic, Nikola, Suica, Maja, Vasiljevic, Sladjana, Knezevic, Mirjana, Milojevic, Irina, Petrov, Ivana, Racic, Selena Puric, Simic, Irena, Stevic, Marija, Vulicevic, Irena, Cabanova, Barbora, Hanula, Miloslav, Berger, Jelena, Janjatovic, Darja, Štupnik, Špela P., Kohn, Ivan, Lindestam, Ulf, Reinhard, Jarl, Castellheim, Albert, Sandstrom, Kerstin, Bengt, Sporre, Dorenberg, Rainer, Frykholm, Peter, Garcia, Maria, Kvarnstrom, Ann, Ponten, Emma, Bruelisauer, Thoma, Erdoes, Gabor, Kaiser, Heiko, Marchon, Mathia, Riva, Thoma, Seiler, Stefan, Bogli, Yann, Dolci, Mirko, Marcucci, Carine, Pichon, Isabelle, Casutt, Mattia, Holzle, Martin, Hurni, Thoma, Johr, Martin, Anna-Ursina, null, Malar, null, Mauch, Jacqueline, Erb, Thoma, Oeinck, Karin, Akin, Mine, Keskin, Gulsen, Senayli, Yesim, Kaya, Guner, Kendigelen, Pinar, Tutuncu, Ayse C., Hatipoğlu, Zehra, Ozcengiz, Dilek, Erdost, Hale Aksu, Ocmen, Elvan, Olguner, Cimen, Ayanoglu, Hilmi, Dincer, Pelin C., Umuroglu, Tumay, Azizoglu, Mustafa, Birbicer, Handan, Doruk, Nurcan, Sagun, Aslı, Baris, Sibel, Dmytriiev, Dmytro, Kuchi, Sridevi, Masip, Nuria, Brooks, Peter, Hare, Alison, Ahmad, Nargi, Casey, Michelle, De Silva, Sam, Dobby, Nadine, Krishnan, Prakash, Sogbodjor, L. Amaki, Walker, Ellie, Walker, Suellen, King, Stephanie, Nicholson, Katy, Quinney, Michelle, Stevens, Paul, Blevin, Andrew, Giombini, Mariangela, Goonasekera, Chulananda, Adil, Sadia, Bew, Stephanie, Bodlani, Carol, Gilpin, Dan, Jinks, Stephanie, Malarkkan, Nalini, Miskovic, Alice, Pad, Rebecca, Barry, Juliet W., Abbott, Joy, Armstrong, Jame, Cooper, Natalie, Crate, Lindsay, Emery, John, James, Kathryn, King, Hannah, Martin, Paul, Catenacci, Stefano S., Bomont, Rob, Smith, Paul, Mele, Sara, Verzelloni, Alessandra, Dix, Philippa, Bell, Graham, Gordeva, Elena, McKee, Lesley, Ngan, Esther, Scheffczik, Jutta, Tan, Li-En, Worrall, Mark, Cassar, Carmel, Goddard, Kevin, Barlow, Victoria, Oshan, Vimmi, Shah, Khairi, Bell, Sarah, Daniels, Lisa, Gandhi, Monica, Pachter, David, Perry, Chri, Robertson, Andrew, Scott, Carmen, Waring, Lynne, Barnes, David, Childs, Sophie, Norman, Joanne, Sunderland, Robin, HUS Children and Adolescents, Children's Hospital, and Clinicum
Subjects: Male, Time Factors, Health Status, Comorbidity, Intraoperative Complications/diagnosis/epidemiology/mortality/therapy, 0302 clinical medicine, Postoperative Complications, 030202 anesthesiology, Risk Factors, patient safety, Medicine, Anesthesia, Prospective Studies, Prospective cohort study, Intraoperative Complications, Medical Audit, ddc:617, Incidence (epidemiology), Incidence, Age Factors, Gestational age, critical events, Europe, Anesthetics/adverse effects, quality, Surgical Procedures, Operative, outcome, Female, Infant, Premature, Gestational Age, Anesthesia/adverse effects/mortality, Risk Assessment, Europe/epidemiology, 03 medical and health sciences, Humans, Anesthetics, business.industry, Postoperative Complications/diagnosis/epidemiology/mortality/therapy, Postmenstrual Age, Infant, Newborn, Infant, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, neonates, Clinical trial, Surgical Procedures, Operative/adverse effects/mortality, Anesthesiology and Pain Medicine, Blood pressure, Observational study, critical event, neonate, business
Abstract: Background: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. Methods: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. Results: Infants (n=5609) born at mean (standard deviation [SD]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2
Published: 2021
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15. Ampicillin Pharmacokinetics During First Week of Life in Preterm and Term Neonates

Author: Tuuli Metsvaht, Irja Lutsar, Helgi Padari, Tõnis Tasa, Karin Kipper, Koit Herodes, Hiie Soeorg, Kersti Oselin, Maarja Hallik, and Mari-Liis Ilmoja
Subjects: Microbiology (medical), medicine.medical_specialty, medicine.drug_class, Antibiotics, Population, Gestational Age, Microbial Sensitivity Tests, Gastroenterology, Group B, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, 030225 pediatrics, Internal medicine, Ampicillin, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, education, Volume of distribution, education.field_of_study, Models, Statistical, business.industry, Infant, Newborn, Gestational age, Anti-Bacterial Agents, Infectious Diseases, Pediatrics, Perinatology and Child Health, Epidemiological Models, Neonatal Sepsis, business, medicine.drug
Abstract: Background and aims Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term neonates by evaluating its PK in serum, cerebrospinal (CSF), and epithelial lining fluid. Methods A prospective study included neonates receiving ampicillin for suspected or proven early onset sepsis and pneumonia. PK samples were collected at steady state, at predose and 5 minutes, 1 hour, 3 hours, 8 hours, and 12 hours after ampicillin 3-minute infusion. Ampicillin concentrations were measured by ultra-high-performance liquid chromatography. Noncompartmental anaysis (NCA) and population pharmacokinetic (pop-PK) modeling were performed and probability of therapeutic target attainment was simulated. Results In 14 neonates (GA of 32-42 wks; mean BW 2873 g), PK parameters (mean ± SD) in NCA were the following: half-life 7.21 ± 7.97 hours; volume of distribution (Vd) 1.07 ± 0.51 L; clearance (CL) 0.20 ± 0.13 L/h; 24-hour area under the concentration-time curve 348.92 ± 114.86 mg*h/L. In pop-PK analysis, a 2-compartmental model described the data most adequately with the final parameter estimates of CL 15.15 (CV 40.47%) L/h/70kg; central Vd 24.87 (CV 37.91%) L/70kg; intercompartmental CL 0.39 (CV 868.56) L/h and peripheral Vd 1.039 (CV 69.32%) L. Peutic target attainment simulations demonstrated that a dosage of 50 mg/kg q 12 hours attained 100% fT > MIC 0.25 mg/L, group B streptococcal breakpoint. Conclusions We recommend ampicillin dosage 50 mg/kg q 12 hours for neonates with gestational age ≥32 weeks during the first week of life.
Published: 2021

16. Coagulase-Negative Staphylococci in Human Milk From Mothers of Preterm Compared With Term Neonates

Author: Hanna Kadri Metsvaht, Hiie Soeorg, Tuuli Metsvaht, Irja Lutsar, Imbi Eelmäe, Sirli Treumuth, Mirjam Merila, and Mari-Liis Ilmoja
Subjects: Adult, Coagulase, Estonia, 0301 basic medicine, medicine.medical_specialty, Pediatrics, Term Birth, Staphylococcus, 030106 microbiology, Breastfeeding, Mothers, Penicillins, 03 medical and health sciences, Intensive Care Units, Neonatal, Staphylococcus epidermidis, medicine, Humans, Longitudinal Studies, Prospective Studies, Cefuroxime, Milk, Human, Molecular epidemiology, Obstetrics, business.industry, Amoxicillin, Obstetrics and Gynecology, Term neonates, Staphylococcus haemolyticus, Anti-Bacterial Agents, Breast Feeding, Ampicillin, Female, business, Infant, Premature
Abstract: Background: Human milk is the preferred nutrition for neonates and a source of bacteria. Research aim: The authors aimed to characterize the molecular epidemiology and genetic content of staphylococci in the human milk of mothers of preterm and term neonates. Methods: Staphylococci were isolated once per week in the 1st month postpartum from the human milk of mothers of 20 healthy term and 49 preterm neonates hospitalized in the neonatal intensive care unit. Multilocus variable-number tandem-repeats analysis and multilocus sequence typing were used. The presence of the mecA gene, icaA gene of the ica-operon, IS 256, and ACME genetic elements was determined by PCR. Results: The human milk of mothers of preterm compared with term neonates had higher counts of staphylococci but lower species diversity. The human milk of mothers of preterm compared with term neonates more often contained Staphylococcus epidermidis mecA (32.7% vs. 2.6%), icaA (18.8% vs. 6%), IS 256 (7.9% vs. 0.9%), and ACME (15.4% vs. 5.1%), as well as Staphylococcus haemolyticus mecA (90.5% vs. 10%) and IS 256 (61.9% vs. 10%). The overall distribution of multilocus variable-number tandem-repeats analysis (MLVA) types and sequence types was similar between the human milk of mothers of preterm and term neonates, but a few mecA-IS 256-positive MLVA types colonized only mothers of preterm neonates. Maternal hospitalization within 1 month postpartum and the use of an arterial catheter or antibacterial treatment in the neonate increased the odds of harboring mecA-positive staphylococci in human milk. Conclusion: Limiting exposure of mothers of preterm neonates to the hospital could prevent human milk colonization with more pathogenic staphylococci.
Published: 2017
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17. Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): a randomised controlled trial

Author: George Mitsiakos, Vytautas Usonis, Carlo Giaquinto, Elias Iosifidis, Ursula Trafojer, Jelena Kuznetsova, Kosmas Sarafidis, Paul T. Heath, Laurence Meyer, Mari-Liis Ilmoja, Susanna Esposito, Adilia Warris, Laura Sanchez, Maarja Hallik, Isabelle Fournier, Fabio Mosca, Emmanuel Roilides, Vincent Meiffredy de Cabre, Cinzia Auriti, Chiara Bertaina, Francesca Ippolita Calò Carducci, Corine Chazallon, Jean-Pierre Aboulker, Zoi Dorothea Pana, Lorenza Pugni, Mike Sharland, Fuat Emre Canpolat, Paolo Rossi, Tuuli Metsvaht, and Irja Lutsar
Subjects: 0301 basic medicine, Male, Antibiotics, Pathology and Laboratory Medicine, law.invention, Efficacy, 0302 clinical medicine, Randomized controlled trial, law, Medicine and Health Sciences, 030212 general & internal medicine, Female, Humans, Infant, Meropenem, Neonatal Sepsis, Safety, Treatment Outcome, Standard of Care, Multidisciplinary, Neonatal sepsis, Antimicrobials, Mortality rate, Gram Positive Bacteria, Drugs, Settore MED/38, Clinical Laboratory Sciences, 3. Good health, Clinical Laboratories, Research Design, Population study, Medicine, Gentamicin, Research Article, medicine.drug, medicine.medical_specialty, Clinical Research Design, medicine.drug_class, Antibiotic sensitivity, Science, 030106 microbiology, Research and Analysis Methods, Microbiology, Sepsis, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, Microbial Control, 030225 pediatrics, Internal medicine, medicine, Adverse effect, Survival rate, Gram Negative Bacteria, Pharmacology, business.industry, Biology and Life Sciences, Bacteriology, medicine.disease, Regimen, Antibiotic Resistance, Antimicrobial Resistance, Adverse Events, business
Abstract: BackgroundThe early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged Methods and findingsNeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052).ConclusionsWithin this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.
Published: 2018
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18. A sensitive method for the simultaneous UHPLC-MS/MS analysis of milrinone and dobutamine in blood plasma using NH

Author: Kalev, Takkis, Rūta, Veigure, Tuuli, Metsvaht, Maarja, Hallik, Mari-Liis, Ilmoja, Joel, Starkopf, and Karin, Kipper
Subjects: Article
Abstract: The purpose of this work was to develop and validate an HPLC-MS/MS method suitable for quantifying two important cardiovascular drugs, milrinone and dobutamine, in neonatal and paediatric patients’ blood plasma samples. Sufficiently low LLOQ levels were required to obtain adequate pharmacokinetic data for the evaluation of optimal dosing. Since the specifics of the patient group set some restrictions on the available sample volume, the method was designed to use only 20 µL of plasma for the analysis. Analytes were separated chromatographically in a biphenyl column using a conventional water-methanol-formic acid eluent with the addition of ammonium fluoride. The latter provided a significant signal enhancement in positive ion mode detection for both analytes allowing the LLOQ to reach below 1 ng/mL. Matrix matched calibration was linear in the range of 1–300 ng/mL, between-run accuracy remained within 107–115%, and precision within 4.8–7.4% for both analytes over the calibration range (including LLOQ level). Dobutamine degradation in plasma samples was prevented by the usage of ascorbic acid. The method was applied to plasma samples of neonates from two pharmacokinetic/pharmacodynamics studies (n = 38).
Published: 2018

19. Genetic relatedness of Gram-negative bacteria colonizing gut and skin of neonates and mother's own milk

Author: Ülle Parm, Tuuli Metsvaht, Irja Lutsar, Hiie Soeorg, Jelena Štšepetova, Mari-Liis Ilmoja, Imbi Eelmäe, and Mirjam Merila
Subjects: 0301 basic medicine, Male, Gram-negative bacteria, Physiology, Mothers, Gestational Age, Sepsis, 03 medical and health sciences, Feces, 0302 clinical medicine, 030225 pediatrics, Gram-Negative Bacteria, Medicine, Humans, Colonization, Prospective Studies, Skin, biology, Milk, Human, business.industry, Transmission (medicine), Infant, Newborn, Obstetrics and Gynecology, Gestational age, biology.organism_classification, medicine.disease, Term neonates, 030104 developmental biology, Logistic Models, Pediatrics, Perinatology and Child Health, Female, Genetic relatedness, business, Gram-Negative Bacterial Infections, Bacteria, Infant, Premature
Abstract: We described colonization of mother’s own milk with Gram-negative bacteria and its relationship with neonatal colonization. Gram-negative bacteria isolated from weekly collected stool, skin and mother’s own milk of hospitalized preterm (n = 49) and healthy term neonates (n = 20) were genotyped. Colonization-related factors were determined by logistic regression. Gram-negative bacteria were isolated from mother’s own milk of 22.4% (n = 11) and 15% (n = 3) of mothers of preterm and term neonates, respectively. According to pulsed-field gel electrophoresis genetically similar strains were present in mother’s own milk and gut of 8.2% (n = 4) of mother–preterm neonate, but none of mother–term neonate pairs. In three of four late-onset sepsis caused by Gram-negative bacteria, colonization of gut, but not mother’s own milk, with invasive species preceded late-onset sepsis. Colonization of mother’s own milk with Gram-negative bacteria is uncommon and transmission to neonatal gut may occur in less than one-tenth of neonate–mother pairs.
Published: 2018

20. Higher intake of coagulase-negative staphylococci from maternal milk promotes gut colonization with mecA-negative Staphylococcus epidermidis in preterm neonates

Author: Hiie Soeorg, Hanna Kadri Metsvaht, Mari-Liis Ilmoja, Tuuli Metsvaht, Irja Lutsar, Mirjam Merila, Imbi Eelmäe, and Sirli Treumuth
Subjects: 0301 basic medicine, Adult, Coagulase, Term Birth, 030106 microbiology, Physiology, Enteral administration, Sepsis, 03 medical and health sciences, Feces, 0302 clinical medicine, Staphylococcus epidermidis, 030225 pediatrics, Intensive Care Units, Neonatal, medicine, Humans, Colonization, Longitudinal Studies, Prospective Studies, Proportional Hazards Models, Skin, biology, Milk, Human, business.industry, Hazard ratio, cons, Infant, Newborn, Obstetrics and Gynecology, biology.organism_classification, medicine.disease, Staphylococcus haemolyticus, Gastrointestinal Tract, Breast Feeding, Pediatrics, Perinatology and Child Health, Female, Neonatal Sepsis, business, Breast feeding, Infant, Premature, Multilocus Sequence Typing
Abstract: We aimed to determine factors associated with gut colonization of preterm neonates with coagulase-negative staphylococci (CoNS) from maternal milk (MM). CoNS isolated from weekly collected stool and MM of hospitalized preterm (n = 49) and healthy term neonates (n = 20) were genotyped. Colonization-related factors were determined by Cox proportional hazards regression. Gut colonization with mecA-negative Staphylococcus epidermidis from MM was less prevalent (40.8% vs. 95%) and delayed (median age 15.5 vs. 2 days) in preterm compared with term neonates. Enhanced colonization was associated with higher intake of CoNS from MM (hazard ratio (95% confidence interval) 1.006 (1.00–1.01) for 106 colony-forming units), lower proportion of mecA-positive predominant NICU strains in gut (0.09 (0.01–0.49) for 1%) and lower incidence of late-onset CoNS sepsis (5% vs. 34% in those without colonization). Enteral feeding with larger proportion of unpasteurized MM and limiting spread of predominant strains may promote colonization with CoNS from MM.
Published: 2018

21. The development of gut microbiota in critically ill extremely low birth weight infants assessed with 16S rRNA gene based sequencing

Author: Ülle Parm, Epp Sepp, Jelena Štšepetova, Tuuli Metsvaht, Tiina Drell, Irja Lutsar, Mari-Liis Ilmoja, and Jaak Simm
Subjects: DNA, Bacterial, Male, Microbiology (medical), Critical Illness, Molecular Sequence Data, Physiology, Biology, Gut flora, DNA, Ribosomal, Microbiology, Feces, RNA, Ribosomal, 16S, medicine, Cluster Analysis, Humans, Microbial colonization, Gene, Phylogeny, Genetics, Bacteria, Critically ill, Infant, Newborn, Gastroenterology, Infant, Genes, rRNA, Sequence Analysis, DNA, 16S ribosomal RNA, biology.organism_classification, Biota, Gastrointestinal Tract, Low birth weight, Infectious Diseases, Infant, Extremely Low Birth Weight, 16s rrna gene sequencing, Female, medicine.symptom, Research Paper
Abstract: An increasing number of studies that are using high-throughput molecular methods are rapidly extending our knowledge of gut microbial colonization in preterm infants whose immaturity and requirement for extensive treatment may result in altered colonization process. We aimed to describe the profile of gut microbiota in 50 extremely low birth weight (1200 g) critically ill infants at three different time points during the first two months of life by using 16S rRNA gene specific sequencing. Stool samples were collected at the age of one week, one month and two months. Bacterial community profiling was done using universal amplification of 16S rRNA gene and 454 pyrosequencing.The diversity of gut microbiota in preterm neonates in the first week of life was low but increased significantly over two months. The gut microbiota was dominated by facultative anaerobic bacteria (Staphylococcus spp. and Enterobacteriaceae) and lacked colonization with bacteria known to provide resistance against pathogens (Bacteroides, Bifidobacterium, and Lactobacillus) throughout the study. Colonization of Escherichia coli and uncultured Veillionella was positively correlated with maturity. Infants born to mothers with chorioamnionitis had significantly higher bacterial diversity than those without.High prevalence and abundance of potentially pathogenic Enterobacteriaceae and Staphylococcaceae with low prevalence and abundance of colonization resistance providing taxa bifidobacteria, Bacteroides and lactobacilli may lead to high infection risk via microbial translocation from the gut. Additionally, our data suggest that maternal chorioamnionitis may have an effect on the diversity of infants' gut microbiota; however, the mechanisms involved remain to be elucidated.
Published: 2014
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22. Different course of lung disease in two siblings with novel ABCA3 mutations

Author: Mari-Liis Ilmoja, Tarmo Annilo, and Maarja Hallik
Subjects: Genetic Markers, Male, Heterozygote, ABCA3, Gene mutation, Compound heterozygosity, Humans, Medicine, Epigenetics, Index case, Gene, biology, business.industry, Siblings, Infant, Newborn, Interstitial lung disease, medicine.disease, Phenotype, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Immunology, biology.protein, ATP-Binding Cassette Transporters, Female, Lung Diseases, Interstitial, business
Abstract: Mutations in the gene for adenosine triphosphate-binding cassette transporter subfamily A member 3 (ABCA3) have been reported in infants and children with surfactant deficiency and interstitial lung disease. We report a case of siblings found to be compound heterozygotes for two novel ABCA3 gene mutations but developing very different course of lung disease. The index case is a baby girl with severe interstitial lung disease that manifested on the first days of life. Her 4-year-old brother carrying the same mutations has no signs of lung disease so far. Our findings suggest the contribution of other genetic, epigenetic and environmental factors to discordant phenotype observed in patients carrying the same mutations in the ABCA3 gene. The clinical course of the index case suggests benefit of combined medical therapy in treating infants with ABCA3 deficiency.
Published: 2013
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23. Genetic Relatedness of Coagulase-negative Staphylococci From Gastrointestinal Tract and Blood of Preterm Neonates With Late-onset Sepsis

Author: Tuuli Metsvaht, Ülle Parm, Irja Lutsar, Hiie Soeorg, Mari-Liis Ilmoja, Kristi Huik, and Natalja Metelskaja
Subjects: Male, Microbiology (medical), Genotype, Staphylococcus hominis, Sepsis, Staphylococcus epidermidis, medicine, Humans, Prospective Studies, Typing, Age of Onset, biology, business.industry, Infant, Newborn, Staphylococcal Infections, biology.organism_classification, medicine.disease, Staphylococcus haemolyticus, Gastrointestinal Tract, Molecular Typing, Infectious Diseases, Bacteremia, Pediatrics, Perinatology and Child Health, Immunology, Multilocus sequence typing, Female, Coagulase, business, Infant, Premature
Abstract: Background Coagulase-negative staphylococci (CoNS) are the first colonizers of gastrointestinal tract (GIT) and the commonest cause of late-onset sepsis (LOS) in preterm neonates. Intravascular catheters are considered a major source of CoNS bacteremia. However, several cases of LOS remain without an identified source. To elucidate whether GIT could be a potential source of invasive strains, we aimed to assess the molecular similarity between CoNS from blood and GIT in preterm neonates with LOS. Methods Altogether 22 blood and 53 GIT isolates collected from 22 neonates with LOS caused by CoNS (Staphylococcus haemolyticus in 13, Staphylococcus epidermidis in 7 and Staphylococcus hominis in 2 patients) were included. Rectal swabs were collected twice weekly from birth, but only isolates obtained before LOS were analyzed. S. epidermidis isolates were typed by multilocus variable number of tandem repeats analysis and multilocus sequence typing, S. haemolyticus by pulsed-field gel electrophoresis. Results Eighteen of 22 neonates had the same CoNS species in GIT and bloodstream; all these isolates from them (altogether 18 blood and 28 GIT isolates) underwent typing. The genotypic similarity between bloodstream and ≥1 antecedent GIT isolates was observed in 13 of 18 patients-3 of 7 with S. epidermidis and 10 of 11 with S. haemolyticus infection. The concordant GIT isolates were collected 0-7 days before the positive blood culture. Conclusions The similarity between CoNS from GIT and bloodstream indicates that preterm neonates harbour invasive strains in GIT before LOS. Whether there is a causal relationship between GIT colonization and LOS remains to be elucidated in further studies.
Published: 2013
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24. Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Author: Walid Habre, Nicola Disma, Katalin Virag, Karin Becke, Tom G Hansen, Martin Jöhr, Brigitte Leva, Neil S Morton, Petronella M Vermeulen, Marzena Zielinska, Krisztina Boda, Francis Veyckemans, Walter Klimscha, Regina Konecny, Robert Luntzer, Ulrike Morawk-Wintersperger, Franz Neiger, Lydia Rustemeyer, Christian Breschan, Denise Frey, Manuela Platzer, Reinhard Germann, Joachim Oeding, Birgit Stoegermüller, Bernhard Ziegler, Philipp Brotatsch, Anton Gutmann, Gerlinde Mausser, Brigitte Messerer, Wolfgang Toller, Maria Vittinghoff, Gregor Zangl, Natascha Seidel-Ahyai, Christoph Hochhold, Ruth Kroess, Peter Paal, Steven Cnudde, Patricia Coucke, Birgit Loveniers, John Mitchell, David Kahn, Thierry Pirotte, Caroline Pregardien, Marc Coppens, Stefan De Hert, Björn Heyse, Martine Neckebroek, Aliaksandra Parashchanka, Jurgen Van Limmen, Nancy Van Den Eynde, Caroline Vanpeteghem, Piet Wyffels, Michaël Lalot, Jean-Paul Lechat, France Stevens, Sari Casaer, Françoise De Groote, Françoise De Pooter, Andrée De Villé, Marc Gerin, Natalia Magasich, Cristel Sanchez Torres, Denise Van Deenen, Johan Berghmans, Dirk Himpe, Eva Roofthooft, Ellen Joukes, Carine Smitz, Veronique Van Reeth, Christel Huygens, Julie Lauweryns, Karen De Smet, Nadia Najafi, Jan Poelaert, Anne Van de Velde, Veerle Van Mossevelde, Ivan Bekavac, Diana Butkovic, Dubravka Heli Litvic, Ivana Kerovec Soric, Hrvoje Maretic, Djurdjica Moscatello, Ljiljana Popovic, Slobodan Micici, Ivana Stuck Tus, Lada Kalagac Fabris, Tatjana Simurina, Nina Sulen, Gordana Kesic-Valpotic, Dajana Djapic, Jirí Žurek, Lucie Jureckova, Iveta Mackova, Monika Skacel, Stanislava Weinlichova, Jan Divák, Michal Frelich, René Urbanec, Vera Biskupova, Vladimir Mixa, Jana Pavlickova, Arash Afshari, Morten Bøttger, Marguerite B. Ellekvist, Mathias Johansen, Birgitte Ingeborg Madsen, Jens Christian Nilsson, Birgitte MB Schousboe, Nicola G. Clausen, Tom G. Hansen, Nick Phaff Steen, Mari-Liis Ilmoja, Virge Tonise, Juri Karjagin, Reet Kikas, Mika Isohanni, Anniina Lyly, Annika Takala, Johanna Happo, Kai Kiviluoma, Kati Martikainen, Riku Aantaa, Tuula Manner, Sanna Vilo, Catherine Amory, Hugues Ludot, Patricia Lambotte, René Busche, Olivier Jacqmarcq, Corinne Lejus, Julien Corouge, Christian Erb, Delphine Garrigue, Patricia Gillet, Anne Laffargue, Veronique Lambelin, Hélène Le Freche, Daliana Peresbota, Pierre Richart, Jerome Berton, Catherine Chapotte, Laurent Colbus, Thierry Lehousse, Jean Monrigal, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Hélène Batoz, Maryline Bordes, Anne Didier, Yann Hamonic, Sylvaine Lagarde, Karine Nouette-Gaulain, François Semjen, Brigitte Zaghet, Jacky Dekens, Axelle Delcuze, Hervé Dupont, Aurélien Legrand, Celine Raffoflandreur, Noémie Audren, Blandine Camus, Marielle Cartal, Chantal Chazelet, Isabelle Davin, Marion Guillier, Luc Desjeux, Claire Larcher, Elodie Grein, Mickeal Leclercq, Roxana Levitchi, Lilica Rosu, Dominique Simon, Aurélien Zang, Anne Migeon, Anne-Charlotte Gagey, Nathalie Bourdaud, Anne-Charlotte Carre, Frédéric Duflo, Jean-Claude Riche, Philippe Robert, Emilie Druot, Olivier Maupain, Gilles Orliaguet, Lucie Sabau, Hanna Taright, Lynn Uhrig, Juliette Verchere-Montmayeur, Lise Debrabant, Clotaire Pilla, Alexandre Podvin, Benjamin Roth, Souhayl Dahmani, Florence Julien-Marsollier, Nada Sabourdin, Bogdan Alexandri, Gilles Brezac, Francois de la Brière, Catherine Hayem, Elizabeth Lhubat, Jean Paul Mission, Charlotte Rémond, Christophe Dadure, Maud Maniora, Anais Marie, Philippe Pirat, Anne-Charlotte Saour, Chrystelle Sola, Claude Ecoffey, Eric Wodey, Christian Adam, Thomas Standl, Ehrenfried Schindler, Tomohiro Yamamoto, Michael Brackhahn, Christoph Bernhard Eich, Holger Guericke, Petra Kindermann, Michael Laschat, Cornel Schink, Frank Wappler, Claudia Hoehne, Natalia Skordou, Johanna Ulrici, Martin Jetzek-Zader, Peter Kienbaum, Tanja Meyer-Treschan, Olaf Picker, Maximilian S. Schaefer, Golo Mielke, Sabine Baethge, Axel Ramminger, Martin Bauer, Matthias Bollinger, José Hinz, Michael Quintel, Sebastian G. Russo, Michael Bauer, Dfominik Geil, Andreas Kortgen, Niels-Peter Preussler, Ulrich Hofmann, Manfred Raber, Doris Reindl, Karin Oppenrieder, Bettina Schierlinger, Jens Roth, Wolfgang Funk, Thomas Fischer, Christian Gernoth, Christina Wiefelspütz, Hauke Volger, Nicole Zederer, Anja Diers, Matthias Huber, Clemens Schorer, Andreas Weyland, Konrad Schwarzkopf, Catharina Grau, Winfried Roth, Rolf Holy, Thomas Mader, Laura Peter, Hauke Supthut, Thomas Kuehhirt, Alexander Milde, Fritz Fiedler, Carsten Isselhorst, Ulrich Grundmann, Alexander Pattar, Jennifer Reinert, Birgit Ehm, Katrin Fritzsche, Ralf Gaebler, Patrick Meybohm, Maximilian Hein, Ines Guzman, Johanna Jokinen, Peter Kranke, Ulrich Goebel, Sarah Harris, Christoph Eisner, Miriam Ochsenreiter, Michael Schoeler, Elke Thil, Richard Ellerkmann, Andreas Hoeft, Claudia Neumann, Stefan Weber, Julia Keilhauer, Jan Kloessing, Michael Schramm, Uwe Trieschmann, Kristina Knauss, Barbara Sinner, Johannes Steinmann, Herbert Koessler, Evagelia Kalliardou, Anna Malisiova, Adelais Tsiotou, Pelagia Chloropoulou, Mpratzou Chrysi, Despoina Iordanidou, Merkourios Ntavlis, Krisztina B Boda, Christilynn Guerin, Janice Irwin, Claire Magner, Solmaz Nakhjavani, Brendan O'Hare, Deborah Galvin, Yosry Jamil, Carlos Lesmes, Yuri Barak, Haran Fisher, Ludmyla Kachko, Jacob Katz, Dmitry Kirilov, Michael Levinzon, Yair Manevich, Konstantin Nekrasov, Elia Peled, Elena Sanko, Dmitri Schmain, Olga Sheinkin, Eliahu Simhi, Alex Tarabikin, Evelina Trabkin, Irena Yagudaev, Yelena Zeitlin, Igor Zunser, Elisabetta Cerutti, Maria Maddalena Schellino, Silvia Valzan, Rosa Lucia Pinciroli, Luciano Bortone, Giorgia Cerati, Fabiana Salici, Leonardo Bussolin, Giuliana Rizzo, Francesca Rossetti, Laura Marchesini, Simonetta Tesoro, Brita De Lorenzo, Fabio Guarracino, Beate Kuppers, Marinella Astuto, Sofia Pitino, Rita Scalisi, Lucia Scordo, Sandra D'Alessandro, Luigi Dei Giudici, Ivano Farinelli, Giuseppe Lofino, Giuliano Marchetti, Sergio Giuseppe Picardo, Simone Reali, Alessandro Vittori, Francesco Antonio Idone, Maria Sammartino, Fabio Sbaraglia, Cinzia Barbera, Michela Bevilacqua, Valeria Cento, Svetlana Kotzeva, Leila Mameli, Giovanni Montobbio, Leandro Passariello, Cinzia Punzo, Rosanna Sileo, Rosanna Viacava, Claudia Volpe, Clelia Zanaboni, Edoardo Calderini, Daniele Genco, Simona Neri, Davide Ottolina, Anna Camporesi, Francesca Izzo, Ida Salvo, Andrea Wolfler, Andrea Sanna, Angela Sciascia, Paolo Stoia, Annamaria Guddo, Maria Lapi, Giorgio Ivani, Annalisa Longobardo, Valeria Mossetti, Dino Pedrotti, Maurizia Grazzini, Luisa Meneghini, Salvatore Metrangolo, Stefania Michelon, Carmelo Minardi, Costanza Tognon, Nicola Zadra, Ilaria Busi, Magda Khotcholava, Bruno Guido Locatelli, Valter Sonzogni, Giusi Starita, Nicole Almenrader, Caterina Aurilio, Pasquale Sansone, Raffaella Albarello, Paolo Bracci, Mariateresa Cecini, Maria Cristina Mondardini, Lorena Pasini, Milo Vason, Gianluca Zani, Roberto Zoppellari, Laura Pistidda, Andrea Cortegiani, Santi Maurizio Raineri, Antigona Hasani, Medita Hashimi, Agris Ancupans, Arta Barzdina, Zane Straume, Anda Zundane, Mikhail Chlopin, Dalia Gestautaite, Laura Lukosiene, Evelina Paliokaite, Ilona Razlevice, Inesa Armoniene, Aurelija Bernotiene, Vidunas Daugelavicius, Ilona Dockiene, Lina Gaidelyte, Nijole Saviciene, Jolita Krikstaponiene, Dominika Sidlovskaite-Baltake, Vladyslav Stasevski, Agne Vaitoskaite, David Gatt, Stephanie Mifsud, Simone Zammit, Celia Allison, Hamid Aslami, Susanne Eberl, Mireille F M van Stijn, Markus F Stevens, Kees Punt, Rob van Osch, Arthur Bauwman, Harm Scholten, Vesna Svircevic, Veronique Adriaens, Maaike Dirckx, Jaap Dogger, Ilse Dons-Sinke, Andreas Machotta, Xavier Moors, Mandana Rad, Lonneke Staals, Anouk van der Knijff - van Dortmont, Caroline van der Marel, Anne Sieben, Tim van der Zwan, Marianne Veldhuizen, David Alders, Wolfgang Buhre, Nicole Engel, Carine Vossen, Ravin Mahadewsing, Patrick Meijer, Volker Gerling, Roelof van der Schatte Olivier, Thea van Doorn, Kristy Vons Mark Hendriks, Sandra Lako, Gert jan Scheffer, Luc Tielens, Marieke Voet, Anthony Absalom, Margot Bergsma, Vera Spanjer, Rob Spanjersberg, Yvette van de Riet, Martin Volkers, Jurgen C. de Graaff, Geranne A.J. Hopman, Teus H. Kappen, J. Hannie, A.M. Megens, Sandra C. Numan, Anton N.J. Schouten, Nigel M. Turner, Désirée B.M. Van Der Werff, Renee T.M. Wensing, Erik Ephraim, Claire Nolte, Tore Reikvam, Ole Fredrik Lund, Lene Skaaden, Kari Marthe Ballovarre, Wenche Bakken Boerke, Guro Grindheim, Pal H H Lindenskov, Anne Beate Solas, Sjur Sponheim, Kyrre Ullensvang, Oddbjorn Viken, Inger Marie Drage, Kasper Gymoese Berthelsen, Bjørn Anders Kroken, Unni Bergland, Miroslaw Pryzmont, Mariola Talalaj, Malgorzata Wasiluk, Dorota Zalewska, Maria Damps, Jadzia Siemek-Mitela, Pawel Wieczorek, Magdalena Juzwa, Jowita Rosada-Kurasinska, Alicja Bartkowska-Sniatkowska, Maciej Cettler, Renata Kopycinska, Iwona Rudewicz, Jaek Sobczyk, Dariusz Wojciechowski, Artur Baranowski, Ewa Basiewicz, Magdalena Mierzewska-Schmidt, Wlodzimierz Retka, Piotr Sawicki, Magdalena Checinska, Magdalena Zurawska, Teresa Leal, Catia Mascarenhas, António Pedro Pina, Maria Joao Susano, Antonio Moniz, Maria Teresa Rocha, Carolina Calvao Santos, M Domingas Patuleia, Ricardo Pereira, Helena Roxo, Rosa Amaral, Isabel Guedes, Cristina Gomes, Marta Gonçalves, Helena Salgado, 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M., Ephraim, Erik, Nolte, Claire, Reikvam, Tore, Fredrik Lund, Ole, Skaaden, Lene, Marthe Ballovarre, Kari, Bakken Boerke, Wenche, Grindheim, Guro, Lindenskov, Pal H. H, Beate Solas, Anne, Sponheim, Sjur, Ullensvang, Kyrre, Viken, Oddbjorn, Marie Drage, Inger, Gymoese Berthelsen, Kasper, Anders Kroken, Bjørn, Bergland, Unni, Pryzmont, Miroslaw, Talalaj, Mariola, Wasiluk, Malgorzata, Zalewska, Dorota, Damps, Maria, Siemek Mitela, Jadzia, Wieczorek, Pawel, Juzwa, Magdalena, Rosada Kurasinska, Jowita, Bartkowska Sniatkowska, Alicja, Cettler, Maciej, Kopycinska, Renata, Rudewicz, Iwona, Sobczyk, Jaek, Wojciechowski, Dariusz, Baranowski, Artur, Basiewicz, Ewa, Mierzewska Schmidt, Magdalena, Retka, Wlodzimierz, Sawicki, Piotr, Checinska, Magdalena, Zurawska, Magdalena, Leal, Teresa, Mascarenhas, Catia, Pedro Pina, António, Joao Susano, Maria, Moniz, Antonio, Teresa Rocha, Maria, Calvao Santos, Carolina, Domingas Patuleia, M., Pereira, Ricardo, Roxo, Helena, Amaral, Rosa, Guedes, Isabel, Gomes, Cristina, Gonçalves, Marta, Salgado, Helena, Santos, Maria, Rodrigues, Sara, Sa, Angela, Machado, Elvira, Pé d'Arca, Sandra, Seabra, Manuel, Mihaela Gheorghe, Ligia, Ivascu, Constantin, Moraru Draghici, Lucia, Suvejan, Mirela, Babici, Remu, Eniko, Kovac, Hogea, Cristiana, Mihaela, Dubau, Nicoleta, Daraban, Barbunc, Danut, Maria Nistor, Alina, Stefan, Violeta, Catalina Ionescu, Gabriela, Davidescu, Irina, Teodora Nastase, Alina, Dumitru Rusu, Florin, Badarau, Victoria, Cindea, Iulia, Moscaliuc, Melania, Olteanu, Dana, Petrescu, Luxita, Ceuca, Daniela, Galinescu, Irena, Badeti, Rodica, Capusan, Alin, Cucui Cozma, Cosmina, Popescu, Barbura, Cimpeanu, Luminita, Birliba, Mihaela Petronela, Miulescu, Magdalena, Balamat, Stefania, Gurita, Adriana, Ilie, Luminita, Mocioiu, Gabriel, Pick, Darina, Sirghie, Rodica, Tabacaru, Radu, Trante, Irinel, Horhota, Lucian, Bandrabur, Daniela, Ciobanu, Tudor, Cuciuc, Veaceslav, Munteanu, Valentin, Olaru, Valentin, Paiu, Corneliu, Savu, Anca, Trifan, Oana, Elena Malos, Anca, Glazunov, Anton, Ivanov, Alexander, Poduskov, Evgeny, Popov, Alexander, Guskov, Igor, Lugovoy, Alexander, Nechaev, Vladislav, Ovezov, Alexey, Basov, Mikhail, Kochkin, Vladimir, Lazarev, Vladimir, Chizhov, Dmitri, Ostreikov, Ivan, Tolasov, Konstantin, Budic, Ivana, Marjanovic, Vesna, Draskovic, Biljana, Pandurov, Marina, Simin, Jovana, Dolinaj, Vladimir, Janjevic, Dusanka, Mandras, Ana, Mircetic, Maja, Petrovic, Sladjana, Rebac, Vlatka, Slavkovic, Bojana, Stevanovic, Vesna, Velcev, Ana, Knezevic, Mirjana, Milojevic, Irina, Puric, Selena, Simic, Irena, Stevic, Marija, Stranjanac, Vladimir, Simic, Dusica, Cabanova, Barbora, Hanula, Miloslav, Grynyuk, Andry, Berger, Jelena, Cerne, Uro, Nastran, Andraz, Pirc, Dejan, Popic, Rok, Stupnik, Spela, Rubio, Paloma, del Río, Cristina, Benito, Pilar, Pino, Gema, Gutierrez, Ignacio, Gutierrez Valcarcel, Andrea, León Carsi, Irene, Perez Garcia, Anibal, López Galera, Sílvia, Marco Valls, Joan, Ricol Lainez, Laura, Vallejo Tarrat, Andrea, Artes, David, Banus, Ester, Chirichiello, Luca, De Abreu, Leidy, De Josemaria, Belen, Helena Gaitan, M., Garces, Antonio, Lazaro, Juan J, Manen Berga, Ferran, Molies, Dolor, Monclus, Enric, Navaro, Montserrat, Pamies, Carmen, Perelló, Marina, Prat, Mar, Ribo, Laura, Angeles Sanz, M., Serrano, Silvia, Sola Ruiz, Eva, Anuncia Escontrela Rodríguez, Blanca, Maria Gago Martinez, Andrea, Martínez Ruiz, Alberto, De La Cruz Benito, Fausto, Gabilondo Garcia, Gustavo, Martinez Maldonado, Ever, Noriega, Bryant, Oller Duque, Lara, Olmos Mendez, Alberto, Perez Ferrer, Antonio, Reinoso Barbero, Francisco, Acevedo Bambaren, Ismael, Domínguez, Fernando, Franco, Teresa, Jiménez, Anabel, Melero, Alicia, Feliu, Montserrat, García, Irene, Montferrer, Núria, Munar, Francisca, Muro, Cristina, Nuño, Rosario, Perera, Remel, Schmucker, Erika, Börjesson, Glenda, Gillberg, Lar, Castellheim, Albert, Sandström, Kerstin, Bauer, Annette, Roos, Torbjörn, Hedlund, Lar, Boegli, Yann, Dolci, Mirko, Marcucci, Carine, Spahr Schopfer, Isabelle, Pellegrini, Michel, Book, Malte, Errass, Loreen, Riggenbach, Christine, Casutt, Mattia, Hölzle, Martin, Hurni, Thoma, Mauch, Jacqueline, Anselmi, Luciano, Anselmi, Irene, Jacomet, Alfred, Oberhauser, Marku, Wossner, Stephanie, Zettl, Angelika, Erb, Thoma, Mackiewicz, Tomasz, Simitzes, Helena, Ozer, Yetkin, Takil, Arzu, Alanoglu, Zekeriyya, Bermede, Onat, Cakar Turhan, K. Sanem, Alkis, Neslihan, Yildirim Guclu, Cigdem, Ceyda Meco, Basak, Hatipoglu, Zehra, Ozcengiz, Dilek, Begec, Zekine, Ilksen Toprak, Huseyin, Kendigelen, Pinar, Cigdem Tütüncü, Ayse, Karadeniz, Meltem Savran, Seyhan Ozkan, Tulay, Sivrikoz, Nuket, Kemal Arslantas, Mustafa, Hizal, Ayse, Tore Altun, Gülbin, Umuroglu, Tumay, Baris, Sibel, Kazak Bengisun, Zuleyha, Goncharenko, Galyna, Khrapak, Maksym, Klymenko, Tetyana, Pavlenko, Vitaliy, Prysiazhniuk, Dmytro, Rudio, Olga, Varyvoda, Mykhailo, Vodianytskyi, Sergii, Boryshkevych, Ivanna, Kyselova, Iryna, Trikash, Nikolay, Albokrinov, Andrew, Perova Sharonova, Valentina, Sklyar, Vitaliy, Surkov, Deni, Abdelaal, Amr, Barber, Nicola, Checuti, Sarah, Godsiff, Leisha, Johanne, Lynch, Simpson, Joanna, Underhill, Helen, Diwan, Rishi, Kelgeri, Nivedita, Masip, Nuria, Ravi, Radha, Roberts, Steve, Cillis, Annagrazia, Marcus, Ritchie, Merella, Federica, Love, David, Baraggia, Paolo, Bird, Victoria, Hussey, Joseph, Alderson, Peter, Bartholomew, Karen, Moncreiff, Michael, Davidson, Sarah, Hare, Alison, Kotecha, Ami, Lee, Corina, Liyanage, Ganga, Patel, Shivali, Samani, Amee, Abou Samra, Mark, Boyd, Matthew, Hullatt, Laurence, Levy, David, Pauling, Mark, Sharman, Sarah Jane, Smith, Natalie, Rutherford, John, Cavalier, Alison, Locke, Christie, Sage, Frederic, Bapat, Smita, Hammerschlag, Jacinda, Ioannou, Ioanni, King, Stephanie, Pegg, Rachel, Salota, Vishal, Sketcher, Jonathan, Thadsad, Muthu, Zeitlin, Deborah, Jack, Ewan, Lang, Colin, Ahmed, Samira, Ayyash, Reema, Bari, Francoise, Bell, Sarah J, Elizabeth Biercamp, Claire, Briggs, Sandra, Gabriella Elena Clement, Maria, Dalton, Mark, Ali Eissa Eid, Mohamed, Gandhi, Monica, Harmen Herrema, Idse, Khaffaf, Ranj, Jeng Min Law, Savio, Mcclintock, Joanna, Ireland, Nichola, Majid Saleem, Mohammed, Smith, Fiona, Cohen, Marc, Lee, Clover Ann, O'Donahue, Lizanne, Powell, Alex, Rawlinson, Ellen, Snoek, Aarjan, Weiss, Katja, Wellesley, Hugo, Crawford, Michael, Abdel Hafiz, Mostafa, Day, Alexandra, Rajamani, Balaji, Saha, Rita, Wright, Dave, Chee, Lew Chin, Bew, Stephanie, Homer, Rachel, Malarkkan, Nalini, Wolfe Barry, Juliet, Angadi, Pradeep, Cagney, Brid, De Melo, Eric, Dekker, Elsa, Helm, Emma, Jones, Gareth, Peiris, Kawshala, Russell, William, Slater, Patricia, Sodhi, Puja, Browning, Mike, Phillips, Trudie, Van Hecke, Rachel, Muir, Vimty, Singh, Piyush, Soskova, Tereza, Cumming, Craig, Farquharson, Pamela, Pearson, Karen, Shaw, Neil, Whiteside, Jonathan, Whyte, Emma, Byers, Gordon, Davies, Kay, Engelhardt, Thoma, Faliszewski, Isabella, Johnston, Graham, Kaufmann, Nil, Kusnirikova, Zuzana, Wilson, Graham, Carachi, Peter, Makin, Andrew, Foster, Brian, Lipczynski, Dariusz, Mawer, Rebecca, Rutherford, William, Rogerson, David, Rushman, Sarah, Taylor, Christopher, Tomlinson, William, Dix, Philippa, Woodward, Tom, Bell, Graham, Boyle, David, Cloherty, Marianne, Cullen, Julia, Cullen, Pauline, Fairgrieve, Ro, Ghent, Robert, Glasgow, Russell, Gordeeva, Elena, Harden, Alison, Hivey, Sarah, Jerome, Kevin, Mckee, Lesley, Morton, Neil, Pribul, Vicky, Sinclair, John, Steiner, Maria, Steward, Heather, Sweeney, Lorraine, Thomson, Wendy, Whiteside, Jeanette, Dalton, Andrew, Ross, Mark, Smith, Carolyn, Allen, Claire, Anders, Nicola, Barlow, Victoria, Bassett, Mike, Darwin, Leanne, Davison, Rachel, Diacono, Jacque, Hobbs, Amy, Hutchinson, Adel, Lomas, Bernadette, Lonsdale, Hannah, Nasser, Leila, Oshan, Vimmi, Patel, Pradip, Raistrick, Christopher, Scott Warren, Victoria, Talbot, Laura, Wai, Carolynn, Childs, Sophie, Dickinson, Matthew, Bloomfield, Tom, Garrioch, Sweyn, Watson, Karen, Gaynor, Jame, Harrison, Richard, Lee, Juliette, Blythe, Elizabeth, Dorman, Teresa, Eissa, Ayman, Ellwood, Jame, Gooch, Ingrid, Hearn, Robert, Hodgetts, Vanessa, John, Robert, Kirton, Christine, Ladak, Nadia, Morgan, Judith, Plant, Nina, Shepherd, Elizabeth, Short, Judith, Stack, Charle, Steel, Simon, Taylor, Matthew, Thomas, Deborah, Wilson, Catharine, Wilson Smith, Elaine, Bradbury, Carol L., Hussain, Nageena, Mayell, Antonia, Mesbah, Ahmed, Qureshi, Arif, Vaidyanath, Chandra, Geary, Tim, Hawksworth, Chri, Parasuraman, Tamaraichelvi, Perry, Nicole, Banerjee, Indrani, Barr, Katharine, Butler, Patrick, Davies, Jack, Flewin, Lisa, Gande, Richard, Montague, Jame, Plumb, Jame, Pratt, Thoma, Sutherland, Paul, Vail, Hannah, Wilkins, Andrew, Hunter, Catherine, Russell, Susan, Thomas, Alun, Mifsud, Mark, Strachan, Dominic, Plichon, Benoit, Harlet, Pierre, Child and Adolescent Psychiatry / Psychology, Morawk-Wintersperger, Ulrike, Seidel-Ahyai, Natascha, Lechat, Jean-Paul, Kesic-Valpotic, Gordana, Ilmoja, Mari-Lii, Nouette-Gaulain, Karine, Gagey, Anne-Charlotte, Carre, Anne-Charlotte, Riche, Jean-Claude, Verchere-Montmayeur, Juliette, Julien-Marsollier, Florence, Saour, Anne-Charlotte, Jetzek-Zader, Martin, Meyer-Treschan, Tanja, Preussler, Niels-Peter, Sidlovskaite-Baltake, Dominika, van Stijn, Mireille F M, Dons-Sinke, Ilse, van der Knijff - van Dortmont, Anouk, Hopman, Geranne A.J., Megens, A.M., Schouten, Anton N.J., Van Der Werff, Désirée B.M., Wensing, Renee T.M., Lindenskov, Pal H H, Siemek-Mitela, Jadzia, Rosada-Kurasinska, Jowita, Bartkowska-Sniatkowska, Alicja, Mierzewska-Schmidt, Magdalena, Moraru-Draghici, Lucia, Cucui-Cozma, Cosmina, Birliba, Mihaela-Petronela, Perez- Ferrer, Antonio, Spahr-Schopfer, Isabelle, Cakar Turhan, K.Sanem, Perova-Sharonova, Valentina, Abou-Samra, Mark, Sharman, Sarah-Jane, McClintock, Joanna, Lee, Clover-Ann, Abdel-Hafiz, Mostafa, Chee, Lew-Chin, McKee, Lesley, Scott-Warren, Victoria, and Wilson-Smith, Elaine
Subjects: Male, Pediatrics, Health Status, OPERATING-ROOM, Respiratory Tract Diseases, CHILDREN, 0302 clinical medicine, REGIONAL ANESTHESIA, Postoperative Complications, 030202 anesthesiology, CARDIAC-ARREST, Medicine, General anaesthesia, Prospective Studies, Prospective cohort study, Child, Intraoperative Complications, COMPLICATIONS, ddc:617, Incidence (epidemiology), Mortality rate, musculoskeletal, neural, and ocular physiology, Incidence, Age Factors, Hospitals, Europe, Cardiovascular Diseases, Child, Preschool, RESPIRATORY ADVERSE EVENTS, Female, Clinical Competence, Cohort study, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Adolescent, macromolecular substances, Anesthesia, General, Drug Hypersensitivity, 03 medical and health sciences, MORBIDITY, Journal Article, Humans, business.industry, Infant, Newborn, Infant, 030208 emergency & critical care medicine, Perioperative, nervous system, PROSPECTIVE COHORT, Relative risk, RISK-FACTORS, Observational study, Human medicine, Nervous System Diseases, business, SYSTEM
Abstract: Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31â127 anaesthetic procedures in 30â874 children with a mean age of 6Â·35 years (SD 4Â·50) were included. The incidence of perioperative severe critical events was 5Â·2% (95% CI 5Â·0â5Â·5) with an incidence of respiratory critical events of 3Â·1% (2Â·9â3Â·3). Cardiovascular instability occurred in 1Â·9% (1Â·7â2Â·1), with an immediate poor outcome in 5Â·4% (3Â·7â7Â·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10â000. This was independent of type of anaesthesia. Age (relative risk 0Â·88, 95% CI 0Â·86â0Â·90; p
Published: 2017
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25. The role of breast milk in the colonization of neonatal gut and skin with coagulase-negative staphylococci

Author: Kristi Huik, Marika Jürna-Ellam, Imbi Eelmäe, Sirli Treumuth, Tuuli Metsvaht, Irja Lutsar, Hiie Soeorg, Mari-Liis Ilmoja, and Mirjam Merila
Subjects: 0301 basic medicine, DNA, Bacterial, Male, Neonatal intensive care unit, Genotype, Term Birth, 030106 microbiology, Gestational Age, Minisatellite Repeats, Breast milk, Microbiology, 03 medical and health sciences, Feces, Child Development, Bacterial Proteins, Staphylococcus epidermidis, Pregnancy, medicine, Humans, Colonization, Skin, biology, Milk, Human, Virulence, Age Factors, Infant, Newborn, Gestational age, Infant, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, Gastrointestinal Tract, Hospitalization, Phenotype, Pediatrics, Perinatology and Child Health, Female, Coagulase, Infant, Premature
Abstract: BackgroundWe aimed to determine the genetic relatedness between Staphylococcus epidermidis colonizing breast milk (BM) and BM-fed neonates during the first month of life.MethodsS. epidermidis was isolated from the stool and skin swabs of 20 healthy term and 49 preterm neonates hospitalized in the neonatal intensive care unit and from the BM of mothers once a week and typed by multilocus variable-number tandem-repeat analysis. Virulence-related genes were determined by PCR.ResultsThe gut (95%) and skin (100%) of term neonates were colonized with strains genetically similar to those in BM and carrying mecA and IS256 at low rate (both6.7%). In preterm neonates, colonization with strains genetically similar to those in BM was low on the skin (34.7%) and in the gut in the first week of life (14.3%), but the prevalence of mecA (90.6%) and IS256 (61.7%) was high. By the fourth week, in the gut of preterm neonates the prevalence of mecA (73.8%) and IS256 (18.4%) decreased, but colonization with strains genetically similar to those in BM increased (83.7%).ConclusionDuring early life, the skin and gut of preterm neonates is colonized with S. epidermidis that is distinct from strains found in BM, but gradually the gut is enriched with strains genetically similar to those in BM, as in term neonates.
Published: 2016

26. Molecular epidemiology of Staphylococcus epidermidis in neonatal intensive care units

Author: Irja Lutsar, Mari-Liis Ilmoja, Kristi Huik, Ülle Parm, Hiie Soeorg, and Tuuli Metsvaht
Subjects: 0301 basic medicine, Microbiology (medical), Male, Genotype, Virulence Factors, 030106 microbiology, Microbial Sensitivity Tests, Minisatellite Repeats, Multiple Loci VNTR Analysis, Pathology and Forensic Medicine, Microbiology, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Staphylococcus epidermidis, Intensive care, Arginine catabolic mobile element, Intensive Care Units, Neonatal, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Prospective Studies, Molecular Epidemiology, Molecular epidemiology, biology, SCCmec, Infant, Newborn, Rectum, General Medicine, Staphylococcal Infections, bacterial infections and mycoses, biology.organism_classification, medicine.disease, Carrier State, Multilocus sequence typing, Female, Multilocus Sequence Typing
Abstract: Late-onset sepsis (LOS) in preterm neonates is increasingly reported to be associated with gut-colonizing Staphylococcus epidermidis. We aimed to describe the molecular epidemiology of S. epidermidis colonizing the gut of neonates hospitalized in two neonatal intensive care units. S. epidermidis from rectal swabs were typed by multilocus variable-number tandem-repeat analysis (MLVA), randomly chosen isolates of predominant MLVA types additionally by multilocus sequence typing. Antimicrobial susceptibility, the presence of icaA, IS256, arginine catabolic mobile element (ACME), agr type, and SCCmec type were determined. Of 276 neonates (38.4%), 106 were colonized with S. epidermidis, yielding a total of 139 isolates (62 in one unit and 77 in another unit). Of the 55 MLVA types identified, the five predominant detected in both units corresponded to sequence type (ST) 2, ST5, and ST59 or its single locus variant ST81 and formed three major MLVA clonal complexes accounting for 74.8% of all isolates. Overall, the prevalence of mecA, icaA, IS256, and ACME was 91.4%, 28.1%, 64%, and 77%, respectively. Of the mecA-positive isolates (n = 127), 43.9% carried SCCmec type IV. Of eight episodes of LOS, four were caused by ST2 and two by ST5. Preventing gut colonization with nosocomial epidemic S. epidermidis in hospitalized neonates could contribute to the prevention of LOS.
Published: 2016

27. Changes in care and short-term outcome for very preterm infants in Estonia

Author: Inge Ringmets, Pille Andresson, Heili Varendi, Liis Toome, Pille Saik, and Mari-Liis Ilmoja
Subjects: Mechanical ventilation, Pediatrics, medicine.medical_specialty, education.field_of_study, business.industry, medicine.medical_treatment, Population, Gestational age, General Medicine, Surfactant therapy, medicine.disease, Intraventricular hemorrhage, Pediatrics, Perinatology and Child Health, Cohort, medicine, Caesarean section, business, education, Cohort study
Abstract: Aim: To identify recent changes in short-term outcome and care for very preterm infants in Estonia. Methods: Comparison of two population-based cohorts of very preterm infants born alive at 22–31 gestational weeks. In 2007–2008, data were recorded prospectively in a neonatal register. For the cohort born in 2002–2003, the same variables were extracted retrospectively from the hospital records. Infants were followed up to discharge or death. Results: The cohort of 2007−2008 contained a higher proportion of infants born by caesarean section and of infants who received antenatal corticosteroids, maternal antibiotics, or surfactant therapy than the earlier cohort. A higher proportion of infants was admitted for care in 2007–2008 (98% vs. 94%; p = 0.013). During the study period, survival until discharge increased (85% vs. 78%; p = 0.041), although the length of hospital stay was unchanged. The use of mechanical ventilation, inotropes, and postnatal antibiotics decreased. Neonatal morbidity remained unchanged, except for a decrease in severe periventricular/intraventricular hemorrhage. Conclusion: The outcome for very preterm infants in Estonia has improved since 2002. With proactive perinatal management and less invasive neonatal care, survival until discharge increased without concomitant increases in neonatal morbidity and the length of hospital stay.
Published: 2012
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28. Short versus Long Infusion of Meropenem in Very-Low-Birth-Weight Neonates

Author: Helgi Padari, Karin Kipper, Lenne-Triin Kõrgvee, Kersti Oselin, Tuuli Metsvaht, Koit Herodes, Irja Lutsar, Mari-Liis Ilmoja, Joseph F. Standing, and Eva Germovsek
Subjects: Male, Population, Infant, Premature, Diseases, Meropenem, Drug Administration Schedule, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Enterocolitis, Necrotizing, Sepsis, Gram-Negative Bacteria, Medicine, Humans, Infant, Very Low Birth Weight, Pharmacology (medical), Drug Dosage Calculations, 030212 general & internal medicine, education, Infusions, Intravenous, Chromatography, High Pressure Liquid, Pharmacology, 0303 health sciences, Creatinine, education.field_of_study, Models, Statistical, Dose-Response Relationship, Drug, 030306 microbiology, business.industry, Postmenstrual Age, Infant, Newborn, Gestational age, Liter, Pneumonia, NONMEM, Anti-Bacterial Agents, Infectious Diseases, chemistry, Anesthesia, Female, Thienamycins, business, Infant, Premature, Software, medicine.drug
Abstract: Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, n = 9) or prolonged ( n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum ( C max ) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume ( V ss ) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a V ss of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high C max with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life.
Published: 2012
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29. Ampicillin versus penicillin in the empiric therapy of extremely low-birthweight neonates at risk of early onset sepsis

Author: Ülle Parm, Piia Müürsepp, Lea Maipuu, Mirjam Merila, Tuuli Metsvaht, Irja Lutsar, Kadri Julge, Mari-Liis Ilmoja, and Epp Sepp
Subjects: Pediatrics, medicine.medical_specialty, Neonatal intensive care unit, business.industry, medicine.drug_class, Antibiotics, Gestational age, medicine.disease, Penicillin, Sepsis, Ampicillin, Pediatrics, Perinatology and Child Health, medicine, Gentamicin, business, Empiric therapy, medicine.drug
Abstract: Background: There are no comparative data on the impact of different empiric antibiotic regimens on early bowel colonization as well as on clinical efficacy in extremely low-birthweight (ELBW) neonates at risk of early onset sepsis (EOS). Methods: A subgroup analysis was carried out of ELBW neonates recruited into a two-center, prospective, cluster randomized study comparing ampicillin and penicillin both combined with gentamicin, within the first 72 h of life. A composite primary end-point (need for change of antibiotics within 72 h and/or 7 day all-cause mortality) and the rate and duration of colonization by opportunistic aerobic microorganisms were assessed using hierarchical models corrected for study center and period. Results: In the ampicillin (n= 36) and penicillin (n= 39) groups change of antibiotics, 7 day mortality and the composite end-point occurred at similar rates. Neonatal intensive care unit mortality for infants with gestational age
Published: 2011
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30. Risk factors associated with gut and nasopharyngeal colonization by common Gram-negative species and yeasts in neonatal intensive care units patients

Author: Ülle Parm, Epp Sepp, Tuuli Metsvaht, Irja Lutsar, Merit Pauskar, Heti Pisarev, and Mari-Liis Ilmoja
Subjects: Male, medicine.medical_specialty, Pediatrics, Neonatal intensive care unit, Gestational Age, law.invention, Catheters, Indwelling, Risk Factors, law, Intensive Care Units, Neonatal, Nasopharynx, Internal medicine, Intensive care, Drug Resistance, Bacterial, Gram-Negative Bacteria, Humans, Medicine, Colonization, Prospective Studies, Risk factor, Candida albicans, Cross Infection, biology, Vaginal delivery, business.industry, Candidiasis, Infant, Newborn, Rectum, Obstetrics and Gynecology, Acinetobacter, biology.organism_classification, Intensive care unit, Breast Feeding, Pediatrics, Perinatology and Child Health, Equipment Contamination, Female, Gram-Negative Bacterial Infections, business
Abstract: Aim To characterize dynamics of mucosal colonization of neonates by common aerobic Gram negative species and Candida spp. and to identify independent perinatal, neonatal, and environmental factors influencing the colonization process. Study design The nasopharyngeal (n = 1145) and rectal (n = 1242) swabs were collected on admission and thereafter twice a week in neonates with risk factors of early onset sepsis (n = 276) admitted within the first 72 h of life. The association between colonization by different microbes and a total of 22 predefined risk factors was assessed using univariate and multiple logistic regression analyses. Results Throughout the study about half of the patients had rectal (55.8%) or nasopharyngeal colonization (42.8%) with common Gram-negative microorganisms. Colonization dynamics and risk factors were in general similar for a given bacterial species in both mucosal sites; nonfermentative microbes more often found in nasopharyngeal swabs and Enterobacteriaceae in rectal swabs. All organisms except Escherichia coli were influenced by the duration of intensive care unit stay but other risk factors were species specific, perhaps reflecting their mode of acquisition. While colonization by E. coli and Candida albicans was associated with perinatal factors like term birth, vaginal delivery, and breast milk feeding; colonization by Klebsiella pneumoniae, Enteribacter cloacae, Acinetobacter spp. and non-albicans Candida spp. were mostly determined by hospital environment (treatment unit and period, artificial interventions and their duration) and gestation age ≤ 28 weeks. Conclusions The knowledge of risk factor profiles may permit the development of strategies to prevent heavy colonization and subsequent invasive disease in high risk infants.
Published: 2011
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31. Impact of empiric antibiotic regimen on bowel colonization in neonates with suspected early onset sepsis

Author: Ülle Parm, Tuuli Metsvaht, Epp Sepp, Irja Lutsar, Mari-Liis Ilmoja, Heti Pisarev, and Merit Pauskar
Subjects: Estonia, Male, Microbiology (medical), medicine.medical_specialty, medicine.drug_class, Antibiotics, Penicillins, Biology, Microbiology, Medical microbiology, Amp resistance, Ampicillin, medicine, Humans, Candida, Antibacterial agent, Cross-Over Studies, Bacteria, Infant, Newborn, Rectum, General Medicine, Acinetobacter, medicine.disease, biology.organism_classification, Anti-Bacterial Agents, Gastrointestinal Tract, Penicillin, Infectious Diseases, Bacteremia, Female, medicine.drug
Abstract: The purpose of this study was to compare the impact of ampicillin and penicillin used for empiric treatment of early onset sepsis (EOS) on initial gut colonization by aerobic and facultative anaerobic microorganisms. A cluster-randomized, two-center, switch-over study was conducted in two paediatric intensive care units in Estonia and included 276 neonates. Rectal swabs were collected twice a week until discharge or day 60. Colonizing microbes were identified on species level and tested for ampicillin resistance (AR). The number of patients colonized with Gram negative microorganisms and Candida spp was similar in both treatment arms but ampicillin resulted in longer colonization duration (CD) of K. pneumonia (p = 0.012), AR Serratia spp (p = 0.012) and Candida spp (p = 0.02) and penicillin in that of AR Acinetobacter spp (p = 0.001). As for Gram positive microorganisms penicillin treatment was associated with a greater number of colonized patients and higher CD of Enterococcus spp and S. aureus but lower ones of S. haemolyticus and S. hominis. Influence of ampicillin and penicillin on initial gut colonization is somewhat different but these differences are of low clinical relevance and should not be a limiting step when choosing between these two antibiotics for the empiric treatment of EOS.
Published: 2010
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32. Comparison of ampicillin plus gentamicin vs. penicillin plus gentamicin in empiric treatment of neonates at risk of early onset sepsis

Author: I. Lutsar, M. Merila, L. Maipuu, Ü. Parm, Mari-Liis Ilmoja, and Tuuli Metsvaht
Subjects: medicine.medical_specialty, Pediatrics, Neonatal sepsis, business.industry, medicine.drug_class, Antibiotics, General Medicine, medicine.disease, Penicillin, Internal medicine, Ampicillin, Intensive care, Bacteremia, Pediatrics, Perinatology and Child Health, medicine, Gentamicin, business, Antibacterial agent, medicine.drug
Abstract: Aim: We aimed to compare the clinical efficacy of ampicillin (AMP) vs. penicillin (PEN) both combined with gentamicin in the empirical treatment of neonates at risk of early onset neonatal sepsis (EOS). Methods: We performed an open label cluster randomized equivalence study in both Estonian neonatal intensive care units, including neonates with suspected EOS, aged less than 72 h. Primary end-point was clinical failure rate, expressed by need for change of antibiotic regimen within 72 h and/or 7-day all cause mortality. Bowel colonization was followed with biweekly perineal swab cultures. Results: Incidence of proven EOS was 4.9%. Among neonates receiving AMP (n = 142) or PEN (n = 141) change of antibiotic regimen within 72 h (10/142 vs. 10/141; OR 1.02; 95% CI 0.40–2.59), 7-day mortality (11/142 vs. 14/141; OR 0.76; 95% CI 0.33–1.75) and over-all treatment failure (20/142 vs. 20/141; OR 1.01; 95% CI 0.52–1.97) occurred at similar rates. The only differences in gut colonization were lower number of patients colonised with enterococci, S. aureus and AMP resistant Acinetobacter spp. in AMP and lower number of those with S. haemolyticus and S. hominis in PEN arm. Conclusions: AMP and PEN combined with gentamicin have similar effectiveness in the empiric treatment of suspected neonatal EOS.
Published: 2010
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33. Sedation and Analgesia Practices in Neonatal Intensive Care Units (EUROPAIN): Results from a Prospective Cohort Study

Author: Tarja Pölkki, Randi Dovland Andersen, Paola Lago, Michael Schroth, T. Papadouri, Lena Bergqvist, Kosmas Sarafidis, Kanwaljeet J. S. Anand, Emilie Courtois, Ricardo Carbajal, Rasa Tameliene, Mari-Liis Ilmoja, Anna Dobrzanska, Simon Attard Montalto, Alejandro Avila-Alvarez, Angelika Berger, Mats Eriksson, Elaine M. Boyle, Sinno H.P. Simons, Bart Van Overmeire, C. Matos, Hugo Lagercrantz, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Örebro University Hospital [Örebro, Sweden], University of Leicester, Complexo Hospitalario Universitario A Coruña (CHUAC). 15006. A Coruña, Telemark Hospital, Neonatal Intensive Care Unit (NICU - THESSALONIKI), Aristotle University of Thessaloniki, Oulu University Hospital [Oulu], Maternidade Dr Alfredo da Costa (MDrAdC - LISBONNE), Maternidade Dr Alfredo da Costa (MDrAdC), Universita degli Studi di Padova, Archbishop Makarios Hospital, Mater Dei Hospital, Mater Dei Hospital [Malta], Paediatric Intensive Care, Tallinn Children's Hospital, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Kaunas Perinatal Center (KPC - KAUNAS), Lithuanian University of health Sciences, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Children's Memorial Health Institute, Cnopf’sche Kinderklinik, Karolinska Institutet [Stockholm], Departments of Woman & Child Health, University of Tennessee Memphis, The University of Tennessee Health Science Center [Memphis] (UTHSC), Abdus Salam International Centre for Theoretical Physics [Trieste] (ICTP), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pédiatrie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service des Urgences Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Örebro University Hospital, Örebro, Erasme Hospital, Centre d'Investigation Clinique INSERM 1412 (CIC 1412 - BREST), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neonatal Intensive Care Unit ( NICU - THESSALONIKI ), Maternidade Dr Alfredo da Costa ( MDrAdC - LISBONNE ), Maternidade Dr Alfredo da Costa ( MDrAdC ), Erasmus Medical Center, University Medical Center Rotterdam, Kaunas Perinatal Center ( KPC - KAUNAS ), International Center for Theoretical Physics [Trieste] ( ICTP ), Centre d'Investigation Clinique INSERM 1412 ( CIC 1412 - BREST ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), ARD - Amsterdam Reproduction and Development, Neonatology, and Pediatrics
Subjects: Male, MESH: Analgesics, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MESH : Prospective Studies, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Conscious Sedation, MESH : Analgesics, Opioid, MESH: Analgesics, Opioid, Pediatrics, law.invention, law, MESH: Hypnotics and Sedatives, Hypnotics and Sedatives/therapeutic use, MESH: Gestational Age, Hypnotics and Sedatives, Birth Weight, MESH : Female, Prospective Studies, MESH: Respiration, Artificial, Prospective cohort study, MESH : Propensity Score, Analgesics, Analgesics, Opioid/therapeutic use, MESH: Infant, Newborn, Pediatrik, Gestational age, MAC PED, Intensive care unit, 3. Good health, Analgesics, Opioid, Europe, Anesthesia, MESH : Analgesics, Analgesics/therapeutic use, Female, medicine.symptom, medicine.drug, Pulmonary and Respiratory Medicine, Respiration, Artificial/statistics & numerical data, MESH : Male, Sedation, Midazolam, MESH : Europe, Pain, Respiration, Artificial/methods, Conscious Sedation/statistics & numerical data, Gestational Age, MESH : Intensive Care Units, Neonatal, MESH : Hypnotics and Sedatives, MESH : Infant, Newborn, MESH : Conscious Sedation, Drug withdrawal, Intensive Care Units, Neonatal/statistics & numerical data, Intensive care, Intensive Care Units, Neonatal, medicine, Humans, MESH : Respiration, Artificial, MESH: Birth Weight, Propensity Score, Conscious Sedation/methods, Mechanical ventilation, MESH: Conscious Sedation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, [ SDV ] Life Sciences [q-bio], business.industry, MESH : Humans, Infant, Newborn, MESH : Birth Weight, MESH: Propensity Score, Newborn, medicine.disease, Respiration, Artificial, MESH: Male, MESH: Prospective Studies, Midazolam/therapeutic use, MESH: Midazolam, MESH : Midazolam, MESH: Europe, business, MESH: Female, MESH: Intensive Care Units, Neonatal, MESH : Gestational Age
Abstract: 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, NeoOpioid, EUROPAIN
Published: 2015

34. Severe Trauma in Estonia: 256 consecutive cases analysed and the impact on outcomes comparing two regions

Author: Thomas Lustenberger, Mari-Liis Ilmoja, Joel Starkopf, L. Kukk, Peep Talving, Tuuli Metsvaht, Urmas Lepner, T. Asser, Sten Saar, and I. Merioja
Subjects: Adult, Estonia, Male, medicine.medical_specialty, Poison control, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, Age Distribution, Trauma Centers, Epidemiology, Injury prevention, Outcome Assessment, Health Care, medicine, Humans, Orthopedics and Sports Medicine, Glasgow Coma Scale, 030212 general & internal medicine, Hospital Mortality, Sex Distribution, Retrospective Studies, Trauma Severity Indices, business.industry, Incidence (epidemiology), 030208 emergency & critical care medicine, Retrospective cohort study, Length of Stay, Middle Aged, medicine.disease, Benchmarking, Emergency medicine, Cohort, Emergency Medicine, Injury Severity Score, Wounds and Injuries, Surgery, Female, Medical emergency, business, human activities
Abstract: The purpose of this study was to investigate epidemiology of severe injuries in Estonia while comparing outcomes at regional trauma facilities.After the ethics review board approval, all consecutive trauma admissions with Injury Severity Score (ISS) 15 to North Estonia Medical Center/Tallinn Children's Hospital (NEMC + TCH) and Tartu University Hospital (TUH) were identified between 1/1/2013 and 31/12/2013. Data collection included demographics, admission data, injury severity variables, interventions, and in-hospital outcomes. Primary outcome was in-hospital mortality. Secondary outcomes were complications per Clavien-Dindo and hospital length of stay (HLOS). Logistic regression analysis was used to compare adjusted mortality between the two regional hospitals.A total of 256 patients met inclusion criteria. The mean ISS for the cohort was 23.6 ± 7.8, 13.3 % were hypotensive on admission, and 44.1 % had a Glasgow Coma Scale 9. Overall rate of complications was 40.2 % that did not differ between the facilities. The mean HLOS at the NEMC + TCH and the TUH were 20.1 ± 25.1 and 10.5 ± 11.2 days (p 0.001), respectively. Overall mortality was 20.7 % (n = 53). Mortality was 25.4 and 14.9 % for the NEMC + TCH and the TUH, respectively (p = 0.04). Logistic regression analysis resulted in comparable mortality at the regional trauma facilities (adj. OR 1.38; 95 % CI 0.66-2.92; p value 0.39).The annual incidence of injuries with ISS 15 was 256 cases with overall mortality at 20.7 % in Estonia. We observed comparable adjusted outcomes at the major regional trauma facilities. This study contains benchmarking data on severely injured patients in Estonia providing potential for future trauma care evaluation and regional outcome comparisons.
Published: 2015

35. Gut colonization by aerobic microorganisms is associated with route and type of nutrition in premature neonates

Author: Ülle Parm, Tuuli Metsvaht, Irja Lutsar, and Mari-Liis Ilmoja
Subjects: Male, medicine.medical_specialty, Pediatrics, Neonatal intensive care unit, Endocrinology, Diabetes and Metabolism, Perinatal Death, Nutritional Status, Breast milk, Gastroenterology, Enteral administration, Sepsis, Endocrinology, Enteral Nutrition, Enterocolitis, Necrotizing, Internal medicine, medicine, Odds Ratio, Animals, Humans, Prospective Studies, Intestinal Mucosa, Nutrition and Dietetics, Bacteria, Milk, Human, business.industry, Infant, Newborn, Odds ratio, medicine.disease, Infant Formula, Diet, Gastrointestinal Microbiome, Regimen, Parenteral nutrition, Logistic Models, Necrotizing enterocolitis, Female, Parenteral Nutrition, Total, business
Abstract: We hypothesized that the beneficial effects of early enteral compared with parenteral feeding are related to the increased variety of aerobic microorganisms that colonize the gut. Our aim was to describe the relationship, first, between the type of feeding and mucosal colonization and, second, between the type of feeding and the development of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm neonates. In total, 159 neonates aged 72 hours or less with risk factors for early-onset sepsis were recruited to a prospective 2-center s tudy. Rectal swabs were collected on admission and twice per week thereafter. The feeding regimen was recorded for the first 7 days and categorized into total parenteral nutrition (TPN) and 2 regimens of enteral nutrition, that is, breast milk containing regimen (BMCR), for which breast milk constituted at least 11% of the enteral diet, or formula. Herein, 70 neonates received formula, 48 received BMCR, and 41 received TPN; 69 cases of LOS and 15 cases of NEC were observed in 50 neonates. A multiple logistic regression analysis indicated that formula and BMCR were associated with 4- to 5-fold increases in colonization by Gram-negative bacteria (odds ratio [OR], 4.52; 1.87-10.95, and OR, 4.95; 1.90-12.87, respectively) and 5 to 9 times higher odds of colonization by Gram-positive microorganisms (OR, 5.75; 1.89-16.72, and OR, 8.61; 2.52-29.36, respectively) compared with TPN. The only difference between BMCR and the other feeding groups was the higher colonization with Staphylococcus haemolyticus in the latter (formula—OR, 6.24; 1.73-22.50; TPN—OR, 2.75; 1.08-6.97). Compared with BMCR, TPN was associated with an increased odds of LOS (OR, 3.04; 1.02-9.07) and an increased odds of death (19.75; 3.64-107.12) compared with formula. Although early enteral feeding is associated with a higher odds of colonization with opportunistic microorganisms, it should be preferred over TPN whenever feasible, due to the favorable effect on the prevention of LOS.
Published: 2014

36. Changes in care and short-term outcome for very preterm infants in Estonia

Author: Liis, Toome, Inge, Ringmets, Pille, Andresson, Mari-Liis, Ilmoja, Pille, Saik, and Heili, Varendi
Subjects: Cohort Studies, Estonia, Male, Survival Rate, Perinatal Care, Time Factors, Treatment Outcome, Infant, Newborn, Humans, Female, Gestational Age, Infant, Premature
Abstract: To identify recent changes in short-term outcome and care for very preterm infants in Estonia.Comparison of two population-based cohort of very preterm infants born alive at 22-31 gestational weeks. In 2007-2008, data were recorded prospectively in a neonatal register. For the cohort born in 2002-2003, the same variables were extracted retrospectively from the hospital records. Infants were followed up to discharge or death.The cohort of 2007-2008 contained a higher proportion of infants born by caesarean section and of infants who received antenatal corticosteroids, maternal antibiotics, or surfactant therapy than the earlier cohort. A higher proportion of infants was admitted for care in 2007-2008 (98% vs. 94%; p = 0.013). During the study period, survival until discharge increased (85% vs. 78%; p = 0.041), although the length of hospital stay was unchanged. The use of mechanical ventilation, inotropes, and postnatal antibiotics decreased. Neonatal morbidity remained unchanged, except for a decrease in severe periventricular/intraventricular haemorrhage.The outcome for very preterm infants in Estonia has improved since 2002. With proactive perinatal management and less invasive neonatal care, survival until discharge increased without concomitant increases in neonatal morbidity and the length of hospital stay.
Published: 2011

37. Ampicillin versus penicillin in the empiric therapy of extremely low-birthweight neonates at risk of early onset sepsis

Author: Tuuli, Metsvaht, Mari-Liis, Ilmoja, Ulle, Parm, Mirjam, Merila, Lea, Maipuu, Piia, Müürsepp, Kadri, Julge, Epp, Sepp, and Irja, Lutsar
Subjects: Male, Dose-Response Relationship, Drug, Incidence, Infant, Newborn, Penicillins, Anti-Bacterial Agents, Klebsiella Infections, Intestines, Klebsiella pneumoniae, Treatment Outcome, Infant, Extremely Low Birth Weight, Risk Factors, Intensive Care Units, Neonatal, Sepsis, Infant Mortality, Humans, Ampicillin, Female, Prospective Studies, Age of Onset, Follow-Up Studies
Abstract: There are no comparative data on the impact of different empiric antibiotic regimens on early bowel colonization as well as on clinical efficacy in extremely low-birthweight (ELBW) neonates at risk of early onset sepsis (EOS).A subgroup analysis was carried out of ELBW neonates recruited into a two-center, prospective, cluster randomized study comparing ampicillin and penicillin both combined with gentamicin, within the first 72 h of life. A composite primary end-point (need for change of antibiotics within 72 h and/or 7 day all-cause mortality) and the rate and duration of colonization by opportunistic aerobic microorganisms were assessed using hierarchical models corrected for study center and period.In the ampicillin (n= 36) and penicillin (n= 39) groups change of antibiotics, 7 day mortality and the composite end-point occurred at similar rates. Neonatal intensive care unit mortality for infants with gestational age26 weeks was lower in the ampicillin group. Ampicillin treatment was associated with a higher colonization rate by Klebsiella pneumoniae, including ampicillin-resistant strains.Preliminary data indicate an urgent need for adequately powered studies of early antibiotic therapy in the subpopulation of ELBW neonates at risk of EOS.
Published: 2011

38. Pharmacokinetics of penicillin g in very-low-birth-weight neonates

Author: Mari-Liis Ilmoja, Kersti Oselin, Tuuli Metsvaht, Irja Lutsar, and Kaili Anier
Subjects: Male, medicine.medical_specialty, Renal function, Urine, Infant, Premature, Diseases, Benzylpenicillin, Streptococcus agalactiae, Animal science, Pharmacokinetics, Intensive Care Units, Neonatal, Streptococcal Infections, medicine, Humans, Infant, Very Low Birth Weight, Pharmacology (medical), Antibacterial agent, Pharmacology, Dose-Response Relationship, Drug, business.industry, Infant, Newborn, Half-life, Penicillin G, Surgery, Anti-Bacterial Agents, Dose–response relationship, Infectious Diseases, Quartile, Female, business, Infant, Premature, medicine.drug, Half-Life
Abstract: Data on the pharmacokinetics (PKs) of penicillin G (PEN) in neonates date back to the 1970s and do not include data for very-low-birth-weight (VLBW) neonates. The aim of this study was to describe the steady-state PKs and to establish an optimal regimen for the dosing of PEN in neonates with gestational ages of less than 28 weeks and birth weights of less than 1,200 g. Two PEN dosing regimens were studied: 50,000 IU (30 mg)/kg of body weight every 12 h (q12h) (group 1; n = 9) and 25,000 IU (15 mg)/kg q12h (group 2; n = 9). Samples for PK analysis were drawn before the injection of PEN and at 2 and 30 min and 1.5, 4, 8, and 12 h after intravenous injection of the third to eighth PEN doses. The PEN concentration was measured by a high-performance liquid chromatography with UV detection technique. The median peak and trough concentrations of PEN were 147 μg/ml (lower and upper quartiles, 109 and 157 μg/ml, respectively) and 7 μg/ml (lower and upper quartiles, 5 and 13 μg/ml, respectively) after administration of the dose of 50,000 IU and 59 μg/ml (lower and upper quartiles, 53 and 78 μg/ml, respectively) and 3 μg/ml (lower and upper quartiles, 3 and 4 μg/ml, respectively) after administration of the dose of 25,000 IU. The PEN half-life (median and lower and upper quartiles for group 1, 3.9 h and 3.3 and 7.0 h, respectively; median and lower and upper quartiles for group 2, 4.6 h and 3.8 and 5.6 h, respectively) was longer in VLBW neonates than in adults and term infants. PEN renal clearance correlated with creatinine clearance ( R 2 = 0.309596; P = 0.038). Only a median of 34% (lower and upper quartiles, 28 and 37%, respectively) of the administered dose was excreted in urine within the following 12 h. We conclude that in VLBW infants a PEN dose of 25,000 IU (15 mg)/kg q12h is safe and sufficient to achieve serum concentrations above the MIC 90 for group B streptococci for the entire dosing interval.
Published: 2007

39. ABSTRACT 526

Author: Tuuli Metsvaht, Joel Starkopf, Maarja Hallik, and Mari-Liis Ilmoja
Subjects: medicine.medical_specialty, business.industry, CARDIOVASCULAR MEDICATIONS, Intensive care, Critical care nursing, Pediatrics, Perinatology and Child Health, Medicine, Critical Care and Intensive Care Medicine, business, Intensive care medicine
Published: 2014
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40. Clinical parameters predicting failure of empirical antibacterial therapy in early onset neonatal sepsis, identified by classification and regression tree analysis

Author: Mirjam Merila, Tuuli Metsvaht, Ülle Parm, Irja Lutsar, Piia Müürsepp, Mari-Liis Ilmoja, Heti Pisarev, and Lea Maipuu
Subjects: Estonia, medicine.medical_specialty, Pediatrics, Time Factors, Neonatal intensive care unit, medicine.drug_class, Antibiotics, Logistic regression, Sepsis, Predictive Value of Tests, Risk Factors, Internal medicine, Ampicillin, Research article, Infant Mortality, medicine, Humans, Treatment Failure, Pediatrics, Perinatology, and Child Health, Retrospective Studies, Univariate analysis, Neonatal sepsis, business.industry, Infant, Newborn, lcsh:RJ1-570, Infant, lcsh:Pediatrics, medicine.disease, Anti-Bacterial Agents, Child, Preschool, Predictive value of tests, Pediatrics, Perinatology and Child Health, Regression Analysis, business, Follow-Up Studies, medicine.drug
Abstract: Background About 10-20% of neonates with suspected or proven early onset sepsis (EOS) fail on the empiric antibiotic regimen of ampicillin or penicillin and gentamicin. We aimed to identify clinical and laboratory markers associated with empiric antibiotic treatment failure in neonates with suspected EOS. Methods Maternal and early neonatal characteristics predicting failure of empiric antibiotic treatment were identified by univariate logistic regression analysis from a prospective database of 283 neonates admitted to neonatal intensive care unit within 72 hours of life and requiring antibiotic therapy with penicillin or ampicillin and gentamicin. Variables, identified as significant by univariate analysis, were entered into stepwise multiple logistic regression (MLR) analysis and classification and regression tree (CRT) analysis to develop a decision algorithm for clinical application. In order to ensure the earliest possible timing separate analysis for 24 and 72 hours of age was performed. Results At 24 hours of age neonates with hypoglycaemia ≤ 2.55 mmol/L together with CRP values > 1.35 mg/L or those with BW ≤ 678 g had more than 30% likelihood of treatment failure. In normoglycaemic neonates with higher BW the best predictors of treatment failure at 24 hours were GA ≤ 27 weeks and among those, with higher GA, WBC ≤ 8.25 × 109 L-1 together with platelet count ≤ 143 × 109 L-1. The algorithm allowed capture of 75% of treatment failure cases with a specificity of 89%. By 72 hours of age minimum platelet count ≤ 94.5 × 109 L-1 with need for vasoactive treatment or leukopaenia ≤ 3.5 × 109 L-1 or leukocytosis > 39.8 × 109 L-1 or blood glucose ≤ 1.65 mmol/L allowed capture of 81% of treatment failure cases with the specificity of 88%. The performance of MLR and CRT models was similar, except for higher specificity of the CRT at 72 h, compared to MLR analysis. Conclusion There is an identifiable group of neonates with high risk of EOS, likely to fail on conventional antibiotic therapy.
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