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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Refractory septic shock in children: a European Society of Paediatric and Neonatal Intensive Care definition</title><author><name sortKey="Morin, Luc" sort="Morin, Luc" uniqKey="Morin L" first="Luc" last="Morin">Luc Morin</name><affiliation><nlm:aff id="Aff1">Paediatric Intensive Care Unit, Paris South University Hospitals, AP-HP, 78 Rue du General Leclerc, 94275 Le Kremlin-Bicêtre, France</nlm:aff></affiliation></author><author><name sortKey="Ray, Samiran" sort="Ray, Samiran" uniqKey="Ray S" first="Samiran" last="Ray">Samiran Ray</name><affiliation><nlm:aff id="Aff2">Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Wilson, Clare" sort="Wilson, Clare" uniqKey="Wilson C" first="Clare" last="Wilson">Clare Wilson</name><affiliation><nlm:aff id="Aff3">Paediatric Intensive Care Unit, Saint-Mary’s Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Remy, Solenn" sort="Remy, Solenn" uniqKey="Remy S" first="Solenn" last="Remy">Solenn Remy</name><affiliation><nlm:aff id="Aff4">Paediatric Intensive Care Unit, Lyon University Hospitals, Bron, France</nlm:aff></affiliation></author><author><name sortKey="Benissa, Mohamed Rida" sort="Benissa, Mohamed Rida" uniqKey="Benissa M" first="Mohamed Rida" last="Benissa">Mohamed Rida Benissa</name><affiliation><nlm:aff id="Aff1">Paediatric Intensive Care Unit, Paris South University Hospitals, AP-HP, 78 Rue du General Leclerc, 94275 Le Kremlin-Bicêtre, France</nlm:aff></affiliation></author><author><name sortKey="Jansen, Nicolaas J G" sort="Jansen, Nicolaas J G" uniqKey="Jansen N" first="Nicolaas J. G." last="Jansen">Nicolaas J. G. Jansen</name><affiliation><nlm:aff id="Aff5">Paediatric Intensive Care Unit, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Javouhey, Etienne" sort="Javouhey, Etienne" uniqKey="Javouhey E" first="Etienne" last="Javouhey">Etienne Javouhey</name><affiliation><nlm:aff id="Aff4">Paediatric Intensive Care Unit, Lyon University Hospitals, Bron, France</nlm:aff></affiliation></author><author><name sortKey="Peters, Mark J" sort="Peters, Mark J" uniqKey="Peters M" first="Mark J." last="Peters">Mark J. Peters</name><affiliation><nlm:aff id="Aff2">Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Kneyber, Martin" sort="Kneyber, Martin" uniqKey="Kneyber M" first="Martin" last="Kneyber">Martin Kneyber</name><affiliation><nlm:aff id="Aff6">Paediatric Intensive Care Unit, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7">Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), The University of Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="De Luca, Daniele" sort="De Luca, Daniele" uniqKey="De Luca D" first="Daniele" last="De Luca">Daniele De Luca</name><affiliation><nlm:aff id="Aff8">Neonatal Intensive Care Unit, Paris South University Hospitals, AP-HP, Clamart, France</nlm:aff></affiliation></author><author><name sortKey="Nadel, Simon" sort="Nadel, Simon" uniqKey="Nadel S" first="Simon" last="Nadel">Simon Nadel</name><affiliation><nlm:aff id="Aff3">Paediatric Intensive Care Unit, Saint-Mary’s Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Schlapbach, Luregn Jan" sort="Schlapbach, Luregn Jan" uniqKey="Schlapbach L" first="Luregn Jan" last="Schlapbach">Luregn Jan Schlapbach</name><affiliation><nlm:aff id="Aff9">Paediatric Intensive Care Unit, Lady Cilento Children’s Hospital, Children’s Health Queensland, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10">Paediatric Critical Care Research Group, Mater Research, The University of Queensland, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff11">Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Maclaren, Graeme" sort="Maclaren, Graeme" uniqKey="Maclaren G" first="Graeme" last="Maclaren">Graeme Maclaren</name><affiliation><nlm:aff id="Aff12">Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff13">Cardiothoracic Intensive Care Unit, National University Health System, Singapore, Singapore</nlm:aff></affiliation></author><author><name sortKey="Tissieres, Pierre" sort="Tissieres, Pierre" uniqKey="Tissieres P" first="Pierre" last="Tissieres">Pierre Tissieres</name><affiliation><nlm:aff id="Aff1">Paediatric Intensive Care Unit, Paris South University Hospitals, AP-HP, 78 Rue du General Leclerc, 94275 Le Kremlin-Bicêtre, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14">Institute of Integrative Biology of the Cell, Paris Saclay University, Saint-Aubin, France</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27709263</idno><idno type="pmc">5106490</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106490</idno><idno type="RBID">PMC:5106490</idno><idno type="doi">10.1007/s00134-016-4574-2</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000D41</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D41</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Refractory septic shock in children: a European Society of Paediatric and Neonatal Intensive Care definition</title><author><name sortKey="Morin, Luc" sort="Morin, Luc" uniqKey="Morin L" first="Luc" last="Morin">Luc Morin</name><affiliation><nlm:aff id="Aff1">Paediatric Intensive Care Unit, Paris South University Hospitals, AP-HP, 78 Rue du General Leclerc, 94275 Le Kremlin-Bicêtre, France</nlm:aff></affiliation></author><author><name sortKey="Ray, Samiran" sort="Ray, Samiran" uniqKey="Ray S" first="Samiran" last="Ray">Samiran Ray</name><affiliation><nlm:aff id="Aff2">Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Wilson, Clare" sort="Wilson, Clare" uniqKey="Wilson C" first="Clare" last="Wilson">Clare Wilson</name><affiliation><nlm:aff id="Aff3">Paediatric Intensive Care Unit, Saint-Mary’s Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Remy, Solenn" sort="Remy, Solenn" uniqKey="Remy S" first="Solenn" last="Remy">Solenn Remy</name><affiliation><nlm:aff id="Aff4">Paediatric Intensive Care Unit, Lyon University Hospitals, Bron, France</nlm:aff></affiliation></author><author><name sortKey="Benissa, Mohamed Rida" sort="Benissa, Mohamed Rida" uniqKey="Benissa M" first="Mohamed Rida" last="Benissa">Mohamed Rida Benissa</name><affiliation><nlm:aff id="Aff1">Paediatric Intensive Care Unit, Paris South University Hospitals, AP-HP, 78 Rue du General Leclerc, 94275 Le Kremlin-Bicêtre, France</nlm:aff></affiliation></author><author><name sortKey="Jansen, Nicolaas J G" sort="Jansen, Nicolaas J G" uniqKey="Jansen N" first="Nicolaas J. G." last="Jansen">Nicolaas J. G. Jansen</name><affiliation><nlm:aff id="Aff5">Paediatric Intensive Care Unit, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Javouhey, Etienne" sort="Javouhey, Etienne" uniqKey="Javouhey E" first="Etienne" last="Javouhey">Etienne Javouhey</name><affiliation><nlm:aff id="Aff4">Paediatric Intensive Care Unit, Lyon University Hospitals, Bron, France</nlm:aff></affiliation></author><author><name sortKey="Peters, Mark J" sort="Peters, Mark J" uniqKey="Peters M" first="Mark J." last="Peters">Mark J. Peters</name><affiliation><nlm:aff id="Aff2">Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK</nlm:aff></affiliation></author><author><name sortKey="Kneyber, Martin" sort="Kneyber, Martin" uniqKey="Kneyber M" first="Martin" last="Kneyber">Martin Kneyber</name><affiliation><nlm:aff id="Aff6">Paediatric Intensive Care Unit, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7">Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), The University of Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="De Luca, Daniele" sort="De Luca, Daniele" uniqKey="De Luca D" first="Daniele" last="De Luca">Daniele De Luca</name><affiliation><nlm:aff id="Aff8">Neonatal Intensive Care Unit, Paris South University Hospitals, AP-HP, Clamart, France</nlm:aff></affiliation></author><author><name sortKey="Nadel, Simon" sort="Nadel, Simon" uniqKey="Nadel S" first="Simon" last="Nadel">Simon Nadel</name><affiliation><nlm:aff id="Aff3">Paediatric Intensive Care Unit, Saint-Mary’s Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Schlapbach, Luregn Jan" sort="Schlapbach, Luregn Jan" uniqKey="Schlapbach L" first="Luregn Jan" last="Schlapbach">Luregn Jan Schlapbach</name><affiliation><nlm:aff id="Aff9">Paediatric Intensive Care Unit, Lady Cilento Children’s Hospital, Children’s Health Queensland, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10">Paediatric Critical Care Research Group, Mater Research, The University of Queensland, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff11">Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Maclaren, Graeme" sort="Maclaren, Graeme" uniqKey="Maclaren G" first="Graeme" last="Maclaren">Graeme Maclaren</name><affiliation><nlm:aff id="Aff12">Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff13">Cardiothoracic Intensive Care Unit, National University Health System, Singapore, Singapore</nlm:aff></affiliation></author><author><name sortKey="Tissieres, Pierre" sort="Tissieres, Pierre" uniqKey="Tissieres P" first="Pierre" last="Tissieres">Pierre Tissieres</name><affiliation><nlm:aff id="Aff1">Paediatric Intensive Care Unit, Paris South University Hospitals, AP-HP, 78 Rue du General Leclerc, 94275 Le Kremlin-Bicêtre, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff14">Institute of Integrative Biology of the Cell, Paris Saclay University, Saint-Aubin, France</nlm:aff></affiliation></author></analytic><series><title level="j">Intensive Care Medicine</title><idno type="ISSN">0342-4642</idno><idno type="eISSN">1432-1238</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Purpose</title><p>Although overall paediatric septic shock mortality is decreasing, refractory septic shock (RSS) is still associated with high mortality. A definition for RSS is urgently needed to facilitate earlier identification and treatment. We aim to establish a European society of paediatric and neonatal intensive care (ESPNIC) experts’ definition of paediatric RSS.</p></sec><sec><title>Methods</title><p>We conducted a two-round Delphi study followed by an observational multicentre retrospective study. One hundred and fourteen paediatric intensivists answered a clinical case-based, two-round Delphi survey, identifying clinical items consistent with RSS. Multivariate analysis of these items in a development single-centre cohort (70 patients, 30 % mortality) facilitated development of RSS definitions based on either a bedside or computed severity score. Both scores were subsequently tested in a validation cohort (six centres, 424 patients, 11.6 % mortality).</p></sec><sec><title>Results</title><p>From the Delphi process, the draft definition included evidence of myocardial dysfunction and high blood lactate levels despite high vasopressor treatment. When assessed in the development population, each item was independently associated with the need for extracorporeal life support (ECLS) or death. Resultant bedside and computed septic shock scores had high discriminative power against the need for ECLS or death, with areas under the receiver operating characteristics curve of 0.920 (95 % CI 0.89–0.94), and 0.956 (95 % CI 0.93–0.97), respectively. RSS defined by a bedside score equal to or higher than 2 and a computed score equal to or higher than 3.5 was associated with a significant increase in mortality.</p></sec><sec><title>Conclusions</title><p>This ESPNIC definition of RSS accurately identifies children with the most severe form of septic shock.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1007/s00134-016-4574-2) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Liu, L" uniqKey="Liu L">L Liu</name></author><author><name sortKey="Johnson, Hl" uniqKey="Johnson H">HL Johnson</name></author><author><name sortKey="Cousens, S" uniqKey="Cousens S">S Cousens</name></author><author><name sortKey="Perin, J" uniqKey="Perin J">J Perin</name></author><author><name sortKey="Scott, S" uniqKey="Scott S">S Scott</name></author><author><name sortKey="Lawn, Je" uniqKey="Lawn J">JE Lawn</name></author><author><name sortKey="Rudan, I" uniqKey="Rudan I">I Rudan</name></author><author><name sortKey="Campbell, H" uniqKey="Campbell H">H Campbell</name></author><author><name sortKey="Cibulskis, R" uniqKey="Cibulskis R">R Cibulskis</name></author><author><name sortKey="Li, M" uniqKey="Li M">M Li</name></author><author><name sortKey="Mathers, C" uniqKey="Mathers C">C Mathers</name></author><author><name sortKey="Black, Re" uniqKey="Black R">RE Black</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schlapbach, Lj" uniqKey="Schlapbach L">LJ Schlapbach</name></author><author><name sortKey="Straney, L" uniqKey="Straney L">L Straney</name></author><author><name sortKey="Alexander, J" uniqKey="Alexander J">J Alexander</name></author><author><name sortKey="Maclaren, G" uniqKey="Maclaren G">G MacLaren</name></author><author><name sortKey="Festa, M" uniqKey="Festa M">M Festa</name></author><author><name sortKey="Schibler, A" uniqKey="Schibler A">A Schibler</name></author><author><name sortKey="Slater, A" uniqKey="Slater A">A Slater</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Watson, Rs" uniqKey="Watson R">RS Watson</name></author><author><name sortKey="Carcillo, Ja" uniqKey="Carcillo J">JA Carcillo</name></author><author><name sortKey="Linde Zwirble, Wt" uniqKey="Linde Zwirble W">WT Linde-Zwirble</name></author><author><name sortKey="Clermont, G" uniqKey="Clermont G">G Clermont</name></author><author><name sortKey="Lidicker, J" uniqKey="Lidicker J">J Lidicker</name></author><author><name sortKey="Angus, Dc" uniqKey="Angus D">DC Angus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaukonen, K M" uniqKey="Kaukonen K">K-M Kaukonen</name></author><author><name sortKey="Bailey, M" uniqKey="Bailey M">M Bailey</name></author><author><name sortKey="Suzuki, S" uniqKey="Suzuki S">S Suzuki</name></author><author><name sortKey="Pilcher, D" uniqKey="Pilcher D">D Pilcher</name></author><author><name sortKey="Bellomo, R" uniqKey="Bellomo R">R Bellomo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bone, Rc" uniqKey="Bone R">RC Bone</name></author><author><name sortKey="Fisher, Cj" uniqKey="Fisher C">CJ Fisher</name></author><author><name sortKey="Clemmer, Tp" uniqKey="Clemmer T">TP Clemmer</name></author><author><name sortKey="Slotman, Gj" uniqKey="Slotman G">GJ Slotman</name></author><author><name sortKey="Metz, Ca" uniqKey="Metz C">CA Metz</name></author><author><name sortKey="Balk, Ra" uniqKey="Balk R">RA Balk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levy, Mm" uniqKey="Levy M">MM Levy</name></author><author><name sortKey="Fink, Mp" uniqKey="Fink M">MP Fink</name></author><author><name sortKey="Marshall, Jc" uniqKey="Marshall J">JC Marshall</name></author><author><name sortKey="Abraham, E" uniqKey="Abraham E">E Abraham</name></author><author><name sortKey="Angus, D" uniqKey="Angus D">D Angus</name></author><author><name sortKey="Cook, D" uniqKey="Cook D">D Cook</name></author><author><name sortKey="Cohen, J" uniqKey="Cohen J">J Cohen</name></author><author><name sortKey="Opal, Sm" uniqKey="Opal S">SM Opal</name></author><author><name sortKey="Vincent, Jl" uniqKey="Vincent J">JL Vincent</name></author><author><name sortKey="Ramsay, G" uniqKey="Ramsay G">G Ramsay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singer, M" uniqKey="Singer M">M Singer</name></author><author><name sortKey="Deutschman, Cs" uniqKey="Deutschman C">CS Deutschman</name></author><author><name sortKey="Seymour, C" uniqKey="Seymour C">C Seymour</name></author><author><name sortKey="Shankar Hari, M" uniqKey="Shankar Hari M">M Shankar-Hari</name></author><author><name sortKey="Annane, D" uniqKey="Annane D">D Annane</name></author><author><name sortKey="Bauer, M" uniqKey="Bauer M">M Bauer</name></author><author><name sortKey="Bellomo, R" uniqKey="Bellomo R">R Bellomo</name></author><author><name sortKey="Bernard, Gr" uniqKey="Bernard G">GR Bernard</name></author><author><name sortKey="Chiche, Jd" uniqKey="Chiche J">JD Chiche</name></author><author><name sortKey="Coopersmith, Cm" uniqKey="Coopersmith C">CM Coopersmith</name></author><author><name sortKey="Hotchkiss, Rs" uniqKey="Hotchkiss R">RS Hotchkiss</name></author><author><name sortKey="Levy, Mm" uniqKey="Levy M">MM Levy</name></author><author><name sortKey="Marshall, Jc" uniqKey="Marshall J">JC Marshall</name></author><author><name sortKey="Martin, Gs" uniqKey="Martin G">GS Martin</name></author><author><name sortKey="Opal, Sm" uniqKey="Opal S">SM Opal</name></author><author><name sortKey="Rubenfeld, Gd" uniqKey="Rubenfeld G">GD Rubenfeld</name></author><author><name sortKey="Van Der Poll, T" uniqKey="Van Der Poll T">T van der Poll</name></author><author><name sortKey="Vincent, Jl" uniqKey="Vincent J">JL Vincent</name></author><author><name sortKey="Angus, Dc" uniqKey="Angus D">DC Angus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vincent, Jl" uniqKey="Vincent J">JL Vincent</name></author><author><name sortKey="Moreno, R" uniqKey="Moreno R">R Moreno</name></author><author><name sortKey="Takala, J" uniqKey="Takala J">J Takala</name></author><author><name sortKey="Willatts, S" uniqKey="Willatts S">S Willatts</name></author><author><name sortKey="De Mendonca, A" uniqKey="De Mendonca A">A De Mendonça</name></author><author><name sortKey="Bruining, H" uniqKey="Bruining H">H Bruining</name></author><author><name sortKey="Reinhart, Ck" uniqKey="Reinhart C">CK Reinhart</name></author><author><name sortKey="Suter, Pm" uniqKey="Suter P">PM Suter</name></author><author><name sortKey="Thijs, Lg" uniqKey="Thijs L">LG Thijs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leclerc, F" uniqKey="Leclerc F">F Leclerc</name></author><author><name sortKey="Leteurtre, S" uniqKey="Leteurtre S">S Leteurtre</name></author><author><name sortKey="Duhamel, A" uniqKey="Duhamel A">A Duhamel</name></author><author><name sortKey="Grandbastien, B" uniqKey="Grandbastien B">B Grandbastien</name></author><author><name sortKey="Proulx, F" uniqKey="Proulx F">F Proulx</name></author><author><name sortKey="Martinot, A" uniqKey="Martinot A">A Martinot</name></author><author><name sortKey="Gauvin, F" uniqKey="Gauvin F">F Gauvin</name></author><author><name sortKey="Hubert, P" uniqKey="Hubert P">P Hubert</name></author><author><name sortKey="Lacroix, J" uniqKey="Lacroix J">J Lacroix</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Brierley, J" uniqKey="Brierley J">J Brierley</name></author><author><name sortKey="Carcillo, Ja" uniqKey="Carcillo J">JA Carcillo</name></author><author><name sortKey="Choong, K" uniqKey="Choong K">K Choong</name></author><author><name sortKey="Cornell, T" uniqKey="Cornell T">T Cornell</name></author><author><name sortKey="Decaen, A" uniqKey="Decaen A">A Decaen</name></author><author><name sortKey="Deymann, A" uniqKey="Deymann A">A Deymann</name></author><author><name sortKey="Doctor, A" uniqKey="Doctor A">A Doctor</name></author><author><name sortKey="Davis, A" uniqKey="Davis A">A Davis</name></author><author><name sortKey="Duff, J" uniqKey="Duff J">J Duff</name></author><author><name sortKey="Dugas, Ma" uniqKey="Dugas M">MA Dugas</name></author><author><name sortKey="Duncan, A" uniqKey="Duncan A">A Duncan</name></author><author><name sortKey="Evans, B" uniqKey="Evans B">B Evans</name></author><author><name sortKey="Feldman, J" uniqKey="Feldman J">J Feldman</name></author><author><name sortKey="Felmet, K" uniqKey="Felmet K">K Felmet</name></author><author><name sortKey="Fisher, G" uniqKey="Fisher G">G Fisher</name></author><author><name sortKey="Frankel, L" uniqKey="Frankel L">L Frankel</name></author><author><name sortKey="Jeffries, H" uniqKey="Jeffries H">H Jeffries</name></author><author><name sortKey="Greenwald, B" uniqKey="Greenwald B">B Greenwald</name></author><author><name sortKey="Gutierrez, J" uniqKey="Gutierrez J">J Gutierrez</name></author><author><name sortKey="Hall, M" uniqKey="Hall M">M Hall</name></author><author><name sortKey="Han, Yy" uniqKey="Han Y">YY Han</name></author><author><name sortKey="Hanson, J" uniqKey="Hanson J">J Hanson</name></author><author><name sortKey="Hazelzet, J" uniqKey="Hazelzet J">J Hazelzet</name></author><author><name sortKey="Hernan, L" uniqKey="Hernan L">L Hernan</name></author><author><name sortKey="Kiff, J" uniqKey="Kiff J">J Kiff</name></author><author><name sortKey="Kissoon, N" uniqKey="Kissoon N">N Kissoon</name></author><author><name sortKey="Kon, A" uniqKey="Kon A">A Kon</name></author><author><name sortKey="Irazuzta, J" uniqKey="Irazuzta J">J Irazuzta</name></author><author><name sortKey="Lin, J" uniqKey="Lin J">J Lin</name></author><author><name sortKey="Lorts, A" uniqKey="Lorts A">A Lorts</name></author><author><name sortKey="Mariscalco, M" uniqKey="Mariscalco M">M Mariscalco</name></author><author><name sortKey="Mehta, R" uniqKey="Mehta R">R Mehta</name></author><author><name sortKey="Nadel, S" uniqKey="Nadel S">S Nadel</name></author><author><name sortKey="Nguyen, T" uniqKey="Nguyen T">T Nguyen</name></author><author><name sortKey="Nicholson, C" uniqKey="Nicholson C">C Nicholson</name></author><author><name sortKey="Peters, M" uniqKey="Peters M">M Peters</name></author><author><name sortKey="Okhuysen Cawley, R" uniqKey="Okhuysen Cawley R">R Okhuysen-Cawley</name></author><author><name sortKey="Poulton, T" uniqKey="Poulton T">T Poulton</name></author><author><name sortKey="Relves, M" uniqKey="Relves M">M Relves</name></author><author><name sortKey="Rodriguez, A" uniqKey="Rodriguez A">A Rodriguez</name></author><author><name sortKey="Rozenfeld, R" uniqKey="Rozenfeld R">R Rozenfeld</name></author><author><name sortKey="Schnitzler, E" uniqKey="Schnitzler E">E Schnitzler</name></author><author><name sortKey="Shanley, T" uniqKey="Shanley T">T Shanley</name></author><author><name sortKey="Kache, S" uniqKey="Kache S">S Kache</name></author><author><name sortKey="Skippen, P" uniqKey="Skippen P">P Skippen</name></author><author><name sortKey="Torres, A" uniqKey="Torres A">A Torres</name></author><author><name sortKey="Von Dessauer, B" uniqKey="Von Dessauer B">B von Dessauer</name></author><author><name sortKey="Weingarten, J" uniqKey="Weingarten J">J Weingarten</name></author><author><name sortKey="Yeh, T" uniqKey="Yeh T">T Yeh</name></author><author><name sortKey="Zaritsky, A" uniqKey="Zaritsky A">A Zaritsky</name></author><author><name sortKey="Stojadinovic, B" uniqKey="Stojadinovic B">B Stojadinovic</name></author><author><name sortKey="Zimmerman, J" uniqKey="Zimmerman J">J Zimmerman</name></author><author><name sortKey="Zuckerberg, A" uniqKey="Zuckerberg A">A Zuckerberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ranieri, Vm" uniqKey="Ranieri V">VM Ranieri</name></author><author><name sortKey="Thompson, Bt" uniqKey="Thompson B">BT Thompson</name></author><author><name sortKey="Barie, Ps" uniqKey="Barie P">PS Barie</name></author><author><name sortKey="Dhainaut, Jf" uniqKey="Dhainaut J">JF Dhainaut</name></author><author><name sortKey="Douglas, Is" uniqKey="Douglas I">IS Douglas</name></author><author><name sortKey="Finfer, S" uniqKey="Finfer S">S Finfer</name></author><author><name sortKey="G Rdlund, B" uniqKey="G Rdlund B">B Gårdlund</name></author><author><name sortKey="Marshall, Jc" uniqKey="Marshall J">JC Marshall</name></author><author><name sortKey="Rhodes, A" uniqKey="Rhodes A">A Rhodes</name></author><author><name sortKey="Artigas, A" uniqKey="Artigas A">A Artigas</name></author><author><name sortKey="Payen, D" uniqKey="Payen D">D Payen</name></author><author><name sortKey="Tenhunen, J" uniqKey="Tenhunen J">J Tenhunen</name></author><author><name sortKey="Al Khalidi, Hr" uniqKey="Al Khalidi H">HR Al-Khalidi</name></author><author><name sortKey="Thompson, V" uniqKey="Thompson V">V Thompson</name></author><author><name sortKey="Janes, J" uniqKey="Janes J">J Janes</name></author><author><name sortKey="Macias, Wl" uniqKey="Macias W">WL Macias</name></author><author><name sortKey="Vangerow, B" uniqKey="Vangerow B">B Vangerow</name></author><author><name sortKey="Williams, Md" uniqKey="Williams M">MD Williams</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nadel, S" uniqKey="Nadel S">S Nadel</name></author><author><name sortKey="Goldstein, B" uniqKey="Goldstein B">B Goldstein</name></author><author><name sortKey="Williams, Md" uniqKey="Williams M">MD Williams</name></author><author><name sortKey="Dalton, H" uniqKey="Dalton H">H Dalton</name></author><author><name sortKey="Peters, M" uniqKey="Peters M">M Peters</name></author><author><name sortKey="Macias, Wl" uniqKey="Macias W">WL Macias</name></author><author><name sortKey="Abd Allah, Sa" uniqKey="Abd Allah S">SA Abd-Allah</name></author><author><name sortKey="Levy, H" uniqKey="Levy H">H Levy</name></author><author><name sortKey="Angle, R" uniqKey="Angle R">R Angle</name></author><author><name sortKey="Wang, D" uniqKey="Wang D">D Wang</name></author><author><name sortKey="Sundin, Dp" uniqKey="Sundin D">DP Sundin</name></author><author><name sortKey="Giroir, B" uniqKey="Giroir B">B Giroir</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Investigators, Process" uniqKey="Investigators P">ProCESS Investigators</name></author><author><name sortKey="Yealy, Dm" uniqKey="Yealy D">DM Yealy</name></author><author><name sortKey="Kellum, Ja" uniqKey="Kellum J">JA Kellum</name></author><author><name sortKey="Huang, Dt" uniqKey="Huang D">DT Huang</name></author><author><name sortKey="Barnato, Ae" uniqKey="Barnato A">AE Barnato</name></author><author><name sortKey="Weissfeld, La" uniqKey="Weissfeld L">LA Weissfeld</name></author><author><name sortKey="Pike, F" uniqKey="Pike F">F Pike</name></author><author><name sortKey="Terndrup, T" uniqKey="Terndrup T">T Terndrup</name></author><author><name sortKey="Wang, He" uniqKey="Wang H">HE Wang</name></author><author><name sortKey="Hou, Pc" uniqKey="Hou P">PC Hou</name></author><author><name sortKey="Lovecchio, F" uniqKey="Lovecchio F">F LoVecchio</name></author><author><name sortKey="Filbin, Mr" uniqKey="Filbin M">MR Filbin</name></author><author><name sortKey="Shapiro, Ni" uniqKey="Shapiro N">NI Shapiro</name></author><author><name sortKey="Angus, Dc" uniqKey="Angus D">DC Angus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peake, Sl" uniqKey="Peake S">SL Peake</name></author><author><name sortKey="Bailey, M" uniqKey="Bailey M">M Bailey</name></author><author><name sortKey="Bellomo, R" uniqKey="Bellomo R">R Bellomo</name></author><author><name sortKey="Cameron, Pa" uniqKey="Cameron P">PA Cameron</name></author><author><name sortKey="Cross, A" uniqKey="Cross A">A Cross</name></author><author><name sortKey="Delaney, A" uniqKey="Delaney A">A Delaney</name></author><author><name sortKey="Finfer, S" uniqKey="Finfer S">S Finfer</name></author><author><name sortKey="Higgins, A" uniqKey="Higgins A">A Higgins</name></author><author><name sortKey="Jones, Da" uniqKey="Jones D">DA Jones</name></author><author><name sortKey="Myburgh, Ja" uniqKey="Myburgh J">JA Myburgh</name></author><author><name sortKey="Syres, Ga" uniqKey="Syres G">GA Syres</name></author><author><name sortKey="Webb, Sa" uniqKey="Webb S">SA Webb</name></author><author><name sortKey="Williams, P" uniqKey="Williams P">P Williams</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Daviaud, F" uniqKey="Daviaud F">F Daviaud</name></author><author><name sortKey="Grimaldi, D" uniqKey="Grimaldi D">D Grimaldi</name></author><author><name sortKey="Dechartres, A" uniqKey="Dechartres A">A Dechartres</name></author><author><name sortKey="Charpentier, J" uniqKey="Charpentier J">J Charpentier</name></author><author><name sortKey="Geri, G" uniqKey="Geri G">G Geri</name></author><author><name sortKey="Marin, N" uniqKey="Marin N">N Marin</name></author><author><name sortKey="Chiche, Jd" uniqKey="Chiche J">JD Chiche</name></author><author><name sortKey="Cariou, A" uniqKey="Cariou A">A Cariou</name></author><author><name sortKey="Mira, Jp" uniqKey="Mira J">JP Mira</name></author><author><name sortKey="Pene, F" uniqKey="Pene F">F Pène</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Parker, Mm" uniqKey="Parker M">MM Parker</name></author><author><name sortKey="Shelhamer, Jh" uniqKey="Shelhamer J">JH Shelhamer</name></author><author><name sortKey="Natanson, C" uniqKey="Natanson C">C Natanson</name></author><author><name sortKey="Alling, Dw" uniqKey="Alling D">DW Alling</name></author><author><name sortKey="Parrillo, Je" uniqKey="Parrillo J">JE Parrillo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pathan, N" uniqKey="Pathan N">N Pathan</name></author><author><name sortKey="Hemingway, Ca" uniqKey="Hemingway C">CA Hemingway</name></author><author><name sortKey="Alizadeh, Aa" uniqKey="Alizadeh A">AA Alizadeh</name></author><author><name sortKey="Stephens, Ac" uniqKey="Stephens A">AC Stephens</name></author><author><name sortKey="Boldrick, Jc" uniqKey="Boldrick J">JC Boldrick</name></author><author><name sortKey="Oragui, Ee" uniqKey="Oragui E">EE Oragui</name></author><author><name sortKey="Mccabe, C" uniqKey="Mccabe C">C McCabe</name></author><author><name sortKey="Welch, Sb" uniqKey="Welch S">SB Welch</name></author><author><name sortKey="Whitney, A" uniqKey="Whitney A">A Whitney</name></author><author><name sortKey="O Ara, P" uniqKey="O Ara P">P O’Gara</name></author><author><name sortKey="Nadel, S" uniqKey="Nadel S">S Nadel</name></author><author><name sortKey="Relman, Da" uniqKey="Relman D">DA Relman</name></author><author><name sortKey="Harding, Se" uniqKey="Harding S">SE Harding</name></author><author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deep, A" uniqKey="Deep A">A Deep</name></author><author><name sortKey="Goonasekera, Cda" uniqKey="Goonasekera C">CDA Goonasekera</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author><author><name sortKey="Brierley, J" uniqKey="Brierley J">J Brierley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hotchkiss, Rs" uniqKey="Hotchkiss R">RS Hotchkiss</name></author><author><name sortKey="Monneret, G" uniqKey="Monneret G">G Monneret</name></author><author><name sortKey="Payen, D" uniqKey="Payen D">D Payen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brechot, N" uniqKey="Brechot N">N Bréchot</name></author><author><name sortKey="Luyt, C E" uniqKey="Luyt C">C-E Luyt</name></author><author><name sortKey="Schmidt, M" uniqKey="Schmidt M">M Schmidt</name></author><author><name sortKey="Leprince, P" uniqKey="Leprince P">P Leprince</name></author><author><name sortKey="Trouillet, Jl" uniqKey="Trouillet J">JL Trouillet</name></author><author><name sortKey="Leger, P" uniqKey="Leger P">P Léger</name></author><author><name sortKey="Pavie, A" uniqKey="Pavie A">A Pavie</name></author><author><name sortKey="Chastre, J" uniqKey="Chastre J">J Chastre</name></author><author><name sortKey="Combes, A" uniqKey="Combes A">A Combes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maclaren, G" uniqKey="Maclaren G">G MacLaren</name></author><author><name sortKey="Butt, W" uniqKey="Butt W">W Butt</name></author><author><name sortKey="Best, D" uniqKey="Best D">D Best</name></author><author><name sortKey="Donath, S" uniqKey="Donath S">S Donath</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Goldstein, B" uniqKey="Goldstein B">B Goldstein</name></author><author><name sortKey="Giroir, B" uniqKey="Giroir B">B Giroir</name></author><author><name sortKey="Randolph, A" uniqKey="Randolph A">A Randolph</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Delong, Er" uniqKey="Delong E">ER DeLong</name></author><author><name sortKey="Delong, Dm" uniqKey="Delong D">DM DeLong</name></author><author><name sortKey="Clarke Pearson, Dl" uniqKey="Clarke Pearson D">DL Clarke-Pearson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Luca, D" uniqKey="De Luca D">D De Luca</name></author><author><name sortKey="Piastra, M" uniqKey="Piastra M">M Piastra</name></author><author><name sortKey="Chidini, G" uniqKey="Chidini G">G Chidini</name></author><author><name sortKey="Tissieres, P" uniqKey="Tissieres P">P Tissieres</name></author><author><name sortKey="Calderini, E" uniqKey="Calderini E">E Calderini</name></author><author><name sortKey="Essouri, S" uniqKey="Essouri S">S Essouri</name></author><author><name sortKey="Medina Villanueva, A" uniqKey="Medina Villanueva A">A Medina Villanueva</name></author><author><name sortKey="Vivanco Allende, A" uniqKey="Vivanco Allende A">A Vivanco Allende</name></author><author><name sortKey="Pons Odena, M" uniqKey="Pons Odena M">M Pons-Odena</name></author><author><name sortKey="Perez Baena, L" uniqKey="Perez Baena L">L Perez-Baena</name></author><author><name sortKey="Hermon, M" uniqKey="Hermon M">M Hermon</name></author><author><name sortKey="Tridente, A" uniqKey="Tridente A">A Tridente</name></author><author><name sortKey="Conti, G" uniqKey="Conti G">G Conti</name></author><author><name sortKey="Antonelli, M" uniqKey="Antonelli M">M Antonelli</name></author><author><name sortKey="Kneyber, M" uniqKey="Kneyber M">M Kneyber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Davidson, J" uniqKey="Davidson J">J Davidson</name></author><author><name sortKey="Tong, S" uniqKey="Tong S">S Tong</name></author><author><name sortKey="Hancock, H" uniqKey="Hancock H">H Hancock</name></author><author><name sortKey="Hauck, A" uniqKey="Hauck A">A Hauck</name></author><author><name sortKey="Da Cruz, E" uniqKey="Da Cruz E">E da Cruz</name></author><author><name sortKey="Kaufman, J" uniqKey="Kaufman J">J Kaufman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kalil, Ac" uniqKey="Kalil A">AC Kalil</name></author><author><name sortKey="Florescu, Df" uniqKey="Florescu D">DF Florescu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Slater, A" uniqKey="Slater A">A Slater</name></author><author><name sortKey="Shann, F" uniqKey="Shann F">F Shann</name></author><author><name sortKey="Pearson, G" uniqKey="Pearson G">G Pearson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leteurtre, S" uniqKey="Leteurtre S">S Leteurtre</name></author><author><name sortKey="Duhamel, A" uniqKey="Duhamel A">A Duhamel</name></author><author><name sortKey="Salleron, J" uniqKey="Salleron J">J Salleron</name></author><author><name sortKey="Grandbastien, B" uniqKey="Grandbastien B">B Grandbastien</name></author><author><name sortKey="Lacroix, J" uniqKey="Lacroix J">J Lacroix</name></author><author><name sortKey="Leclerc, F" uniqKey="Leclerc F">F Leclerc</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jhamb, U" uniqKey="Jhamb U">U Jhamb</name></author><author><name sortKey="Jat, K" uniqKey="Jat K">K Jat</name></author><author><name sortKey="Gupta, V" uniqKey="Gupta V">V Gupta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bakker, J" uniqKey="Bakker J">J Bakker</name></author><author><name sortKey="Gris, P" uniqKey="Gris P">P Gris</name></author><author><name sortKey="Coffernils, M" uniqKey="Coffernils M">M Coffernils</name></author><author><name sortKey="Kahn, Rj" uniqKey="Kahn R">RJ Kahn</name></author><author><name sortKey="Vincent, Jl" uniqKey="Vincent J">JL Vincent</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levraut, J" uniqKey="Levraut J">J Levraut</name></author><author><name sortKey="Ichai, C" uniqKey="Ichai C">C Ichai</name></author><author><name sortKey="Petit, I" uniqKey="Petit I">I Petit</name></author><author><name sortKey="Ciebiera, Jp" uniqKey="Ciebiera J">JP Ciebiera</name></author><author><name sortKey="Perus, O" uniqKey="Perus O">O Perus</name></author><author><name sortKey="Grimaud, D" uniqKey="Grimaud D">D Grimaud</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gaies, Mg" uniqKey="Gaies M">MG Gaies</name></author><author><name sortKey="Gurney, Jg" uniqKey="Gurney J">JG Gurney</name></author><author><name sortKey="Yen, Ah" uniqKey="Yen A">AH Yen</name></author><author><name sortKey="Napoli, Ml" uniqKey="Napoli M">ML Napoli</name></author><author><name sortKey="Gajarski, Rj" uniqKey="Gajarski R">RJ Gajarski</name></author><author><name sortKey="Ohye, Rg" uniqKey="Ohye R">RG Ohye</name></author><author><name sortKey="Charpie, Jr" uniqKey="Charpie J">JR Charpie</name></author><author><name sortKey="Hirsch, Jc" uniqKey="Hirsch J">JC Hirsch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Horton, S" uniqKey="Horton S">S Horton</name></author><author><name sortKey="D Dekem, Y" uniqKey="D Dekem Y">Y d’Udekem</name></author><author><name sortKey="Shann, F" uniqKey="Shann F">F Shann</name></author><author><name sortKey="Butt, W" uniqKey="Butt W">W Butt</name></author><author><name sortKey="Bennett, M" uniqKey="Bennett M">M Bennett</name></author><author><name sortKey="Best, D" uniqKey="Best D">D Best</name></author><author><name sortKey="Brizard, C" uniqKey="Brizard C">C Brizard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goldman, Ap" uniqKey="Goldman A">AP Goldman</name></author><author><name sortKey="Kerr, Sj" uniqKey="Kerr S">SJ Kerr</name></author><author><name sortKey="Butt, W" uniqKey="Butt W">W Butt</name></author><author><name sortKey="Marsh, Mj" uniqKey="Marsh M">MJ Marsh</name></author><author><name sortKey="Murdoch, Ia" uniqKey="Murdoch I">IA Murdoch</name></author><author><name sortKey="Paul, T" uniqKey="Paul T">T Paul</name></author><author><name sortKey="Firmin, Rk" uniqKey="Firmin R">RK Firmin</name></author><author><name sortKey="Tasker, Rc" uniqKey="Tasker R">RC Tasker</name></author><author><name sortKey="Macrae, Dj" uniqKey="Macrae D">DJ Macrae</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Torgersen, C" uniqKey="Torgersen C">C Torgersen</name></author><author><name sortKey="Dunser, Mw" uniqKey="Dunser M">MW Dünser</name></author><author><name sortKey="Wenzel, V" uniqKey="Wenzel V">V Wenzel</name></author><author><name sortKey="Jochberger, S" uniqKey="Jochberger S">S Jochberger</name></author><author><name sortKey="Mayr, V" uniqKey="Mayr V">V Mayr</name></author><author><name sortKey="Schmittinger, Ca" uniqKey="Schmittinger C">CA Schmittinger</name></author><author><name sortKey="Lorenz, I" uniqKey="Lorenz I">I Lorenz</name></author><author><name sortKey="Schmid, S" uniqKey="Schmid S">S Schmid</name></author><author><name sortKey="Westphal, M" uniqKey="Westphal M">M Westphal</name></author><author><name sortKey="Grander, W" uniqKey="Grander W">W Grander</name></author><author><name sortKey="Luckner, G" uniqKey="Luckner G">G Luckner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takasu, O" uniqKey="Takasu O">O Takasu</name></author><author><name sortKey="Gaut, Jp" uniqKey="Gaut J">JP Gaut</name></author><author><name sortKey="Watanabe, E" uniqKey="Watanabe E">E Watanabe</name></author><author><name sortKey="To, K" uniqKey="To K">K To</name></author><author><name sortKey="Fagley, Re" uniqKey="Fagley R">RE Fagley</name></author><author><name sortKey="Sato, B" uniqKey="Sato B">B Sato</name></author><author><name sortKey="Jarman, S" uniqKey="Jarman S">S Jarman</name></author><author><name sortKey="Efimov, Ir" uniqKey="Efimov I">IR Efimov</name></author><author><name sortKey="Janks, Dl" uniqKey="Janks D">DL Janks</name></author><author><name sortKey="Srivastava, A" uniqKey="Srivastava A">A Srivastava</name></author><author><name sortKey="Bhayani, Sb" uniqKey="Bhayani S">SB Bhayani</name></author><author><name sortKey="Drewry, A" uniqKey="Drewry A">A Drewry</name></author><author><name sortKey="Swanson, Pe" uniqKey="Swanson P">PE Swanson</name></author><author><name sortKey="Hotchkiss, Rs" uniqKey="Hotchkiss R">RS Hotchkiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vieillard Baron, A" uniqKey="Vieillard Baron A">A Vieillard-Baron</name></author><author><name sortKey="Prin, S" uniqKey="Prin S">S Prin</name></author><author><name sortKey="Chergui, K" uniqKey="Chergui K">K Chergui</name></author><author><name sortKey="Dubourg, O" uniqKey="Dubourg O">O Dubourg</name></author><author><name sortKey="Jardin, F" uniqKey="Jardin F">F Jardin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cvetkovic, M" uniqKey="Cvetkovic M">M Cvetkovic</name></author><author><name sortKey="Lutman, D" uniqKey="Lutman D">D Lutman</name></author><author><name sortKey="Ramnarayan, P" uniqKey="Ramnarayan P">P Ramnarayan</name></author><author><name sortKey="Pathan, N" uniqKey="Pathan N">N Pathan</name></author><author><name sortKey="Inwald, Dp" uniqKey="Inwald D">DP Inwald</name></author><author><name sortKey="Peters, Mj" uniqKey="Peters M">MJ Peters</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Intensive Care Med</journal-id><journal-id journal-id-type="iso-abbrev">Intensive Care Med</journal-id><journal-title-group><journal-title>Intensive Care Medicine</journal-title></journal-title-group><issn pub-type="ppub">0342-4642</issn><issn pub-type="epub">1432-1238</issn><publisher><publisher-name>Springer Berlin Heidelberg</publisher-name><publisher-loc>Berlin/Heidelberg</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27709263</article-id><article-id pub-id-type="pmc">5106490</article-id><article-id pub-id-type="publisher-id">4574</article-id><article-id pub-id-type="doi">10.1007/s00134-016-4574-2</article-id><article-categories><subj-group subj-group-type="heading"><subject>Pediatric Original</subject></subj-group></article-categories><title-group><article-title>Refractory septic shock in children: a European Society of Paediatric and Neonatal Intensive Care definition</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Morin</surname><given-names>Luc</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ray</surname><given-names>Samiran</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wilson</surname><given-names>Clare</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Remy</surname><given-names>Solenn</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Benissa</surname><given-names>Mohamed Rida</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Jansen</surname><given-names>Nicolaas J. G.</given-names></name><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Javouhey</surname><given-names>Etienne</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Peters</surname><given-names>Mark J.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Kneyber</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="Aff6">6</xref><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>De Luca</surname><given-names>Daniele</given-names></name><xref ref-type="aff" rid="Aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Nadel</surname><given-names>Simon</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Schlapbach</surname><given-names>Luregn Jan</given-names></name><xref ref-type="aff" rid="Aff9">9</xref><xref ref-type="aff" rid="Aff10">10</xref><xref ref-type="aff" rid="Aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Maclaren</surname><given-names>Graeme</given-names></name><xref ref-type="aff" rid="Aff12">12</xref><xref ref-type="aff" rid="Aff13">13</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5423-5532</contrib-id><name><surname>Tissieres</surname><given-names>Pierre</given-names></name><address><phone>+33 1 45 21 32 05</phone><email>pierre.tissieres@aphp.fr</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff14">14</xref></contrib><contrib contrib-type="author"><collab>ESPNIC Refractory Septic Shock Definition Taskforce the Infection Systemic Inflammation Sepsis section of ESPNIC </collab><xref ref-type="aff" rid="Aff15">15</xref></contrib><aff id="Aff1"><label>1</label>Paediatric Intensive Care Unit, Paris South University Hospitals, AP-HP, 78 Rue du General Leclerc, 94275 Le Kremlin-Bicêtre, France</aff><aff id="Aff2"><label>2</label>Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK</aff><aff id="Aff3"><label>3</label>Paediatric Intensive Care Unit, Saint-Mary’s Hospital, London, UK</aff><aff id="Aff4"><label>4</label>Paediatric Intensive Care Unit, Lyon University Hospitals, Bron, France</aff><aff id="Aff5"><label>5</label>Paediatric Intensive Care Unit, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands</aff><aff id="Aff6"><label>6</label>Paediatric Intensive Care Unit, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands</aff><aff id="Aff7"><label>7</label>Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), The University of Groningen, Groningen, The Netherlands</aff><aff id="Aff8"><label>8</label>Neonatal Intensive Care Unit, Paris South University Hospitals, AP-HP, Clamart, France</aff><aff id="Aff9"><label>9</label>Paediatric Intensive Care Unit, Lady Cilento Children’s Hospital, Children’s Health Queensland, Brisbane, Australia</aff><aff id="Aff10"><label>10</label>Paediatric Critical Care Research Group, Mater Research, The University of Queensland, Brisbane, Australia</aff><aff id="Aff11"><label>11</label>Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland</aff><aff id="Aff12"><label>12</label>Department of Paediatrics, Royal Children’s Hospital, University of Melbourne, Melbourne, Australia</aff><aff id="Aff13"><label>13</label>Cardiothoracic Intensive Care Unit, National University Health System, Singapore, Singapore</aff><aff id="Aff14"><label>14</label>Institute of Integrative Biology of the Cell, Paris Saclay University, Saint-Aubin, France</aff><aff id="Aff15"><label>15</label>European Society of Paediatric and Neonatal Intensive Care, Geneva, Switzerland</aff></contrib-group><pub-date pub-type="epub"><day>5</day><month>10</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>5</day><month>10</month><year>2016</year></pub-date><pub-date pub-type="ppub"><year>2016</year></pub-date><volume>42</volume><issue>12</issue><fpage>1948</fpage><lpage>1957</lpage><history><date date-type="received"><day>16</day><month>6</month><year>2016</year></date><date date-type="accepted"><day>22</day><month>9</month><year>2016</year></date></history><permissions><copyright-statement>© The Author(s) 2016</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.</license-p></license></permissions><abstract id="Abs1"><sec><title>Purpose</title><p>Although overall paediatric septic shock mortality is decreasing, refractory septic shock (RSS) is still associated with high mortality. A definition for RSS is urgently needed to facilitate earlier identification and treatment. We aim to establish a European society of paediatric and neonatal intensive care (ESPNIC) experts’ definition of paediatric RSS.</p></sec><sec><title>Methods</title><p>We conducted a two-round Delphi study followed by an observational multicentre retrospective study. One hundred and fourteen paediatric intensivists answered a clinical case-based, two-round Delphi survey, identifying clinical items consistent with RSS. Multivariate analysis of these items in a development single-centre cohort (70 patients, 30 % mortality) facilitated development of RSS definitions based on either a bedside or computed severity score. Both scores were subsequently tested in a validation cohort (six centres, 424 patients, 11.6 % mortality).</p></sec><sec><title>Results</title><p>From the Delphi process, the draft definition included evidence of myocardial dysfunction and high blood lactate levels despite high vasopressor treatment. When assessed in the development population, each item was independently associated with the need for extracorporeal life support (ECLS) or death. Resultant bedside and computed septic shock scores had high discriminative power against the need for ECLS or death, with areas under the receiver operating characteristics curve of 0.920 (95 % CI 0.89–0.94), and 0.956 (95 % CI 0.93–0.97), respectively. RSS defined by a bedside score equal to or higher than 2 and a computed score equal to or higher than 3.5 was associated with a significant increase in mortality.</p></sec><sec><title>Conclusions</title><p>This ESPNIC definition of RSS accurately identifies children with the most severe form of septic shock.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1007/s00134-016-4574-2) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Shock</kwd><kwd>Septic</kwd><kwd>Paediatrics</kwd><kwd>Acidosis</kwd><kwd>Lactic</kwd><kwd>Resuscitation</kwd><kwd>Failure</kwd><kwd>Cardiac</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer-Verlag Berlin Heidelberg and ESICM 2016</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Introduction</title><p>Infection remains the leading cause of paediatric mortality worldwide [<xref ref-type="bibr" rid="CR1">1</xref>]. In most high-income countries, access to care, vaccination campaigns and improvement in intensive care have drastically decreased deaths from infection. Similar to adults, recent paediatric studies have shown an increase in the incidence of invasive infection and septic shock and a relative decrease in mortality [<xref ref-type="bibr" rid="CR2">2</xref>–<xref ref-type="bibr" rid="CR4">4</xref>].</p><p>Recently, sepsis and septic shock definitions in adults were revised [<xref ref-type="bibr" rid="CR4">4</xref>–<xref ref-type="bibr" rid="CR7">7</xref>]. The aim of the Sepsis-3 definition was to help the clinician in the detection of septic shock patients and to treat them according to their risk of death. The sepsis-related organ failure assessment (SOFA) [<xref ref-type="bibr" rid="CR8">8</xref>] has a prominent place in this definition, but is neither adapted nor validated in paediatric patients. The clinical course of septic shock is affected by the age and immune state of the patient, the virulence of the pathogen, and the haemodynamic adaptation to circulatory failure. Paediatric logistic organ dysfunction (PELOD) is a paediatric organ dysfunction score validated in the severity classification of patients with sepsis [<xref ref-type="bibr" rid="CR9">9</xref>]. However, similar to the SOFA score, it does not impact patient management at the bedside.</p><p>The Surviving Sepsis Campaign [<xref ref-type="bibr" rid="CR10">10</xref>] and the American College of Critical Care Medicine (ACCM) guidelines for hemodynamic support in neonates and children [<xref ref-type="bibr" rid="CR11">11</xref>] remain the most recognized standards of care. Specific therapies such as activated protein C [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR13">13</xref>] or early goal-directed therapy [<xref ref-type="bibr" rid="CR14">14</xref>, <xref ref-type="bibr" rid="CR15">15</xref>] have not been associated with a consistent decrease in mortality. The term septic shock encompasses various aetiologies and immune states for which specific interventions may have variable results [<xref ref-type="bibr" rid="CR16">16</xref>]. However, the subset of patients who are unresponsive to standard resuscitation are often labelled as having ‘refractory septic shock’ (RSS). RSS is typified by circulatory failure due to septic cardiomyopathy [<xref ref-type="bibr" rid="CR17">17</xref>–<xref ref-type="bibr" rid="CR19">19</xref>] with or without vasoplegia [<xref ref-type="bibr" rid="CR19">19</xref>]. Importantly, effective short-term support of the circulation with newer vasoactive agents or extracorporeal life support (ECLS) [<xref ref-type="bibr" rid="CR20">20</xref>] means that RSS is potentially reversible [<xref ref-type="bibr" rid="CR21">21</xref>, <xref ref-type="bibr" rid="CR22">22</xref>]. To maximise the impact of these rescue therapies, a robust tool for early identification of RSS is required,</p><p>The Infection, Systemic Inflammation and Sepsis section of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) designated a taskforce to define paediatric RSS [<xref ref-type="bibr" rid="CR23">23</xref>]. We performed a study linking a two-round Delphi survey with the development of septic shock scores. These scores aimed at an early indentification of RSS patients with a high risk of mortality at any moment during clinical care. The scores were subsequently validated in a multicentre international retrospective cohort.</p></sec><sec id="Sec2"><title>Materials and methods</title><sec id="Sec3"><title>Definition drafting</title><p>The first part of the Delphi study was a clinical case-based questionnaire. Two members (L.M. and P.T.) of the Infection, Systemic Inflammation and Sepsis section of ESPNIC were assigned to create four clinical cases of septic shock patients with varying levels of shock and organ dysfunction.</p><p>The characteristics of the clinical cases were set following a review of the literature on septic shock and a case analysis of septic shock patients, and covered the whole clinical spectrum of disease severity. Five members from the taskforce (G.M., S.N., M.P., M.K., N.J.G.J.) reviewed the cases for consistency and objectivity. All clinical cases were composed of vignettes with specific clinical and biological parameters (later described as criteria and corresponding cut-offs), encompassing the evolution of sepsis. For each vignette, responders were asked to grade the occurrence of RSS (0 = no RSS to 10 = yes) (see supplementary file 1). The questionnaire was then sent to all ESPNIC members via an Internet survey supplier (SurveyMonkey Inc., Palo Alto, CA, USA).</p><p>Criteria extracted from the clinical vignettes were ranged according to the distribution of their strength of association with RSS. Criteria graded A (first quartile) and B (second quartile) were selected and compiled in four draft definitions constituted by a minimal definition alone or with up to three additional organ failures. Preliminary definitions were then tested in the second part of the Delphi study. Participants of this second part had access to the results of the first study. They were asked to choose one of the four definitions and to re-score the definition cut-off values issued from the first part’s results. Based on this second round, criteria graded A or B were incorporated into the selected RSS draft definition. (See supplementary file 2 for additional information on methodology).</p></sec><sec id="Sec4"><title>Development population application and definition adjustment</title><p>The RSS draft definition was first tested in a development population. All patients less than 18 years old admitted to the Paediatric Intensive Care Unit (PICU) at Centre A for septic shock, according to consensus definition [<xref ref-type="bibr" rid="CR24">24</xref>], and requiring vasopressor or inotrope therapy between January 1, 2010 and December 31, 2013 were analysed. Exclusion criteria were: (1) the presence of limitations of life support at septic shock onset; (2) postmenstrual corrected age <37 weeks; and (3) perinatal sepsis defined as sepsis occurring in the first 7 days of life.</p><p>Protocols for clinical care of septic shock patients did not change during the 3-year study period. Patients were retrospectively identified using hospital records and data collected. The French Intensive Care Society ethics committee approved this study (CE SRLF 14-38). Clinical variables included in the definition or used to describe the populations or outcomes, and occurring before the occurrence of the composite endpoint PICU mortality and/or ECLS, were recorded (see supplementary file 2). Draft definition criteria identified in the Delphi study were evaluated against two outcomes: PICU mortality, and the composite endpoint PICU mortality and/or ECLS. Multivariable Cox regression was performed to study the association between the variables used in the definition and these two outcomes, to define two RSS scores. An easy to calculate score was named “bedside RSS score” and a more complex one was named “computed RSS score”.</p></sec><sec id="Sec5"><title>RSS definition assessment in a validation population</title><p>Both bedside and computed RSS scores were tested to evaluate their association with mortality and the composite endpoint mortality/need for ECLS. This was done on a validation population consisting of a cohort of PICU-admitted patients, retrospectively enrolled in 6 PICUs in four countries (Australia, France, Netherlands and United Kingdom; Table <xref rid="Tab1" ref-type="table">1</xref>). Inclusion and exclusion criteria were identical in the development and validation population. Data were collected retrospectively (C.W., E.J., L.J.S., L.M., M.K., M.P., N.J.G.J., S.N., S.R., S.R.). L.M. independently reviewed the consistency of the collected data. All six centres obtained local ethical approval for the retrospective analysis of the patient data and waiver of informed consent from legal representatives.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Hospitals and patients</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Hospitals</th><th align="left">Type of PICU</th><th align="left">PICU admissions and mortality</th><th align="left">Number of septic shock cases and mortality</th><th align="left">Weight in the cohort (cases/deaths)</th></tr></thead><tbody><tr><td align="left" colspan="5">Development population</td></tr><tr><td align="left"> Centre A</td><td align="left">M, S, ECLS</td><td align="left">3109 (4.2 %)</td><td char="(" align="char">70 (30 %)</td><td align="left">100 %/100 %</td></tr><tr><td align="left" colspan="5">Validation population</td></tr><tr><td align="left"> Centre B</td><td align="left">M, S, ECLS</td><td align="left">4608 (3.4 %)</td><td char="(" align="char">40 (7.5 %)</td><td align="left">9.4 %/6.1 %</td></tr><tr><td align="left"> Centre C</td><td align="left">M, S</td><td align="left">3875 (7.1 %)</td><td char="(" align="char">165 (13.9 %)</td><td align="left">38.9 %/46.9 %</td></tr><tr><td align="left"> Centre D</td><td align="left">M</td><td align="left">1288 (5.6 %)</td><td char="(" align="char">101 (6.9 %)</td><td align="left">23.8 %/14.3 %</td></tr><tr><td align="left"> Centre E</td><td align="left">M, S, C</td><td align="left">3145 (2.7 %)</td><td char="(" align="char">18 (33.3 %)</td><td align="left">4.2 %/12.2 %</td></tr><tr><td align="left"> Centre F</td><td align="left">M, S, C, ECLS</td><td align="left">3117 (4.7 %)</td><td char="(" align="char">57 (3.5 %)</td><td align="left">13.4 %/4.1 %</td></tr><tr><td align="left"> Centre G</td><td align="left">M, S</td><td align="left">3150 (1.9 %)</td><td char="(" align="char">44 (18.2 %)</td><td align="left">10.4 %/16.3 %</td></tr></tbody></table><table-wrap-foot><p><italic>PICU</italic> paediatric intensive care unit, <italic>M</italic> Medical, <italic>S</italic> Surgical, <italic>ECLS</italic> Extra-Corporeal Life Support, <italic>C</italic> Cardiac</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec6"><title>Statistical analysis</title><p>Continuous variables were tested for normality with Kolmogorov–Smirnov test and compared with Student’s <italic>t</italic> test or Mann–Whitney test, as appropriate. Non-continuous variables were tested with Chi-squared test or Fisher’s exact test, as appropriate. Data were described as frequencies and percentages, means and standard deviations or median and interquartile range, as appropriate. Multivariable Cox’s regression with backward-stepwise method was performed having as outcomes mortality or the composite endpoint mortality/need for ECLS. Covariates inserted in the models were the variables identified through the Delphi process and the patients’ age [<xref ref-type="bibr" rid="CR3">3</xref>]. Adjusted hazard ratios were used to weight covariates and included in the scores. The model goodness of fit was evaluated with Omnibus test. Receiver operating characteristics (ROC) analysis was then performed with the validation population for both scores and areas under the curves (AUC) were calculated to assess for the discriminative power of these scores. The best thresholds for these scores were obtained with the calculation of sensitivity, specificity, positive and negative predictive values and the Youden’s index (sensitivity + specificity – 1). The DeLong test was used to compare the AUC of both scores [<xref ref-type="bibr" rid="CR25">25</xref>]. Survival of RSS patients according to both scores have been evaluated by Kaplan–Meier curves and these latter have been tested using Logrank test. A <italic>p</italic> value of less than 0.05 was considered statistically significant. Statistical analyses were performed with SPSS for Macintosh, v.22.0 (SPSS, Chicago, IL, USA) and GraphPad Prism<sup>®</sup>, v. 5.0a (GraphPad Software, La Jolla, CA, USA) softwares.</p></sec></sec><sec id="Sec7"><title>Results</title><sec id="Sec8"><title>Draft of the definition</title><p>From April 9 to July 2 2014, 114/170 (67 %) physicians members of the ESPNIC representing 27 countries and 75 PICUs answered the first round of the Delphi study. The physicians PICU experience was less than 10 years for 35.6 %, 10–20 years for 44.1 % and more than 20 years for 20.3 %. Results from this first round are presented in Table <xref rid="Tab2" ref-type="table">2</xref>. Items graded A (first quartile of association with diagnosis of RSS) or B (second quartile) were selected for the second round. They were condensed into a minimal definition (lactic acidosis with vaso-inotrope dependency and myocardial dysfunction) with additional organ failures graded A or B [hepatic insufficiency, severe acute respiratory distress syndrome (ARDS) with the Berlin definition [<xref ref-type="bibr" rid="CR26">26</xref>] or failure to achieve effective continuous renal replacement therapy (CRRT)]. The vaso-inotrope dependency was assessed with the use of the vaso-inotrope score [VIS = (epinephrine + norepinephrine in mcg/kg min) × 100 + (dobutamine + dopamine in mcg/kg min) + (vasopressin in mcg/kg min) × 10,000 + (milrinone in mcg/kg min) × 20] [<xref ref-type="bibr" rid="CR27">27</xref>]. In the second round of the Delphi study, from September 23 to November 21 2014, 61 physicians answered the survey and 37 (60.6 %) selected the minimal definition without additional organ failure. They validated six items determined in the first round as important with a grade A or B for the diagnosis of RSS. The draft definition for RSS was the association of: (1) blood lactate >8 mmol/L or a 1 mmol/L lactate increase after 6 h of resuscitation, (2) vaso-inotrope dependency (VIS >200 mcg/kg min), and (3) myocardial dysfunction, defined as the occurrence of a resuscitation-responsive cardiac arrest in PICU or cardiac ultrasound findings with left ventricle ejection fraction (LVEF) <25 % or a cardiac index <2.2 L/min m<sup>2</sup>.<table-wrap id="Tab2"><label>Table 2</label><caption><p>Results of the first round of the Delphi study: association of clinical criteria with refractory septic shock diagnosis</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Criteria and cut-offs</th><th align="left">Scores<sup>b</sup></th><th align="left">Number of iteration</th><th align="left">Grade<sup>c</sup></th></tr></thead><tbody><tr><td align="left" colspan="4">Blood lactates</td></tr><tr><td align="left"> >4 mmol/L</td><td char="(" align="char">8 (7–9.5)</td><td char="." align="char">11</td><td align="left">C</td></tr><tr><td align="left"> >6 mmol/L</td><td char="(" align="char">9 (8–10)</td><td char="." align="char">9</td><td align="left">B</td></tr><tr><td align="left"> >8 mmol/L</td><td char="(" align="char">9.5 (9–10)</td><td char="." align="char">6</td><td align="left">A</td></tr><tr><td align="left"> >10 mmol/L</td><td char="(" align="char">9.5 (9–10)</td><td char="." align="char">4</td><td align="left">A</td></tr><tr><td align="left"> Stable<sup>a</sup></td><td char="(" align="char">9 (8.5–9.5)</td><td char="." align="char">2</td><td align="left">B</td></tr><tr><td align="left"> Increase<sup>a</sup></td><td char="(" align="char">8 (6.5–8.8)</td><td char="." align="char">3</td><td align="left">B</td></tr><tr><td align="left">ScvO2 < 70 %</td><td char="(" align="char">8 (6.5–8.8)</td><td char="." align="char">6</td><td align="left">C</td></tr><tr><td align="left" colspan="4">Vaso-inotrope score (mcg/kg min)</td></tr><tr><td align="left"> >50</td><td char="(" align="char">8 (6–8)</td><td char="." align="char">11</td><td align="left">C</td></tr><tr><td align="left"> >100</td><td char="(" align="char">8 (7.5–8.5)</td><td char="." align="char">8</td><td align="left">C</td></tr><tr><td align="left"> >125</td><td char="(" align="char">8 (8–9)</td><td char="." align="char">7</td><td align="left">C</td></tr><tr><td align="left"> >150</td><td char="(" align="char">8 (8–9.5)</td><td char="." align="char">6</td><td align="left">C</td></tr><tr><td align="left"> >175</td><td char="(" align="char">9 (8–10)</td><td char="." align="char">4</td><td align="left">B</td></tr><tr><td align="left"> >200</td><td char="(" align="char">9 (8.5–9.5)</td><td char="." align="char">2</td><td align="left">B</td></tr><tr><td align="left">Vaso-inotrope association bitherapy</td><td char="(" align="char">8 (8–8.5)</td><td char="." align="char">6</td><td align="left">C</td></tr><tr><td align="left">Vaso-inotrope association tritherapy</td><td char="(" align="char">9 (8.5–9.5)</td><td char="." align="char">2</td><td align="left">B</td></tr><tr><td align="left" colspan="4">ARDS</td></tr><tr><td align="left"> Mild (P/F 200–299)</td><td char="(" align="char">8 (6.8–8.5)</td><td char="." align="char">8</td><td align="left">C</td></tr><tr><td align="left"> Moderate (P/F 100–199)</td><td char="(" align="char">8 (7.3–9.5)</td><td char="." align="char">6</td><td align="left">C</td></tr><tr><td align="left"> Severe (P/F < 100)</td><td char="(" align="char">8.5 (7.8–9.3)</td><td char="." align="char">2</td><td align="left">B</td></tr><tr><td align="left">Arterial hypotension</td><td char="(" align="char">8 (8–9.8)</td><td char="." align="char">10</td><td align="left">C</td></tr><tr><td align="left" colspan="4">Cardiac index (L/min m<sup>2</sup>)</td></tr><tr><td align="left"> <6</td><td char="(" align="char">8 (6–9)</td><td char="." align="char">13</td><td align="left">C</td></tr><tr><td align="left"> <4.5</td><td char="(" align="char">8 (6–9.3)</td><td char="." align="char">12</td><td align="left">C</td></tr><tr><td align="left"> <3.3</td><td char="(" align="char">8 (8–9.8)</td><td char="." align="char">10</td><td align="left">C</td></tr><tr><td align="left"> <2.2</td><td char="(" align="char">10 (9–10)</td><td char="." align="char">3</td><td align="left">A</td></tr><tr><td align="left">Cardio circulatory arrest</td><td char="(" align="char">10 (10–10)</td><td char="." align="char">1</td><td align="left">A</td></tr><tr><td align="left" colspan="4">Left ventricle ejection fraction (%)</td></tr><tr><td align="left"> <45</td><td char="(" align="char">8 (5.3–8.3)</td><td char="." align="char">12</td><td align="left">C</td></tr><tr><td align="left"> <35</td><td char="(" align="char">8 (8–9.2)</td><td char="." align="char">8</td><td align="left">C</td></tr><tr><td align="left"> <25</td><td char="(" align="char">9.5 (9.3–9.8)</td><td char="." align="char">2</td><td align="left">A</td></tr><tr><td align="left" colspan="4">Cardiac arrest</td></tr><tr><td align="left"> Prior PICU admission</td><td char="(" align="char">9 (9–9)</td><td char="." align="char">1</td><td align="left">B</td></tr><tr><td align="left"> In PICU</td><td char="(" align="char">10 (10–10)</td><td char="." align="char">1</td><td align="left">A</td></tr><tr><td align="left">Hepatic insufficiency (prothrombin time/factor <italic>V</italic> <50 % or INR<sup>e</sup> >2)</td><td char="(" align="char">10 (10–10)</td><td char="." align="char">1</td><td align="left">A</td></tr><tr><td align="left">Need for CRRT</td><td char="(" align="char">6 (6–8)</td><td char="." align="char">5</td><td align="left">D</td></tr><tr><td align="left">CRRT dysfunction</td><td char="(" align="char">10 (10)</td><td char="." align="char">1</td><td align="left">A</td></tr><tr><td align="left" colspan="4">Procalcitonin at admission (ng/mL)</td></tr><tr><td align="left"> >50</td><td char="(" align="char">8 (4.5–9)</td><td char="." align="char">3</td><td align="left">D</td></tr><tr><td align="left"> >200</td><td char="(" align="char">6 (4.5–8)</td><td char="." align="char">3</td><td align="left">D</td></tr><tr><td align="left" colspan="4">Time since PICU admission (h)</td></tr><tr><td align="left"> >6</td><td char="(" align="char">8 (4.5–9)</td><td char="." align="char">7</td><td align="left">C</td></tr><tr><td align="left"> >24</td><td char="(" align="char">6 (4.5–8)</td><td char="." align="char">3</td><td align="left">D</td></tr></tbody></table><table-wrap-foot><p>Scores are expressed as medians and interquartile</p><p><italic>ScvO2</italic> central venous saturation of oxygen, <italic>ARDS</italic> acute respiratory distress syndrome graded with the Berlin definition, <italic>PICU</italic> paediatric intensive care unit, <italic>INR</italic> international normalized ratio, <italic>CRRT</italic> continuous renal replacement therapy</p><p><sup>a</sup>Blood lactates: stable defined as less than 1 mmol/L change between two consecutive samples, increase defined as more than 1 mmol/L increase between two samples</p><p><sup>b</sup>Scores represents the association of each criteria with the clinical diagnosis of RSS (0 = no RSS to 10 = RSS)</p><p><sup>c</sup>Each criteria was graded from A (first quartile—most associated with diagnosis of refractory septic shock) to D (fourth quartile—least associated with diagnosis of refractory septic shock)</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec9"><title>Development population application and definition adjustment</title><p>During a 4-year period between January 1, 2010 and December 31, 2013, 78 patients were admitted at the Centre A PICU for septic shock requiring inotropes or vasopressors. Eight were excluded because of limitations of life support on admission. Of the remaining 70 patients, 21 (30 %) died during PICU stay, of whom 11 (15.7 %) were classified in RSS by the draft definition with a mortality rate of 100 % (sensitivity = 52.4 %, specificity = 100 %) and a median delay from shock onset to death of 19 (12–72) h. No comorbidity was found in 47.1 % of the patients while 22 patients (31.4 %) were immunocompromised.</p><p>In the multivariable analysis, the model goodness of fit was satisfying for each step (<italic>p</italic> = 0.577 and <italic>p</italic> = 0.717 at the first and second steps, respectively). Data from the last step were selected and used to create septic shock scores. Mortality or the need for ECLS was independently associated with the worst VIS [HR = 1.001 (95 % CI: 1.0009–1.0011) <italic>p</italic> = 0.01], worst arterial lactate [HR = 1.1 (95 % CI: 1.01–1.23), <italic>p</italic> = 0.032] and presence of myocardial dysfunction [HR = 18, (95 % CI: 3.4–95.4), <italic>p</italic> = 0.001]. Lactates and VIS (<italic>ρ</italic> = 0.34; <italic>p</italic> = 0.008) as well as LVEF and lactates (<italic>ρ</italic> = –0.67; <italic>p</italic> < 0.001) were correlated. Age was not significantly associated with the outcome [HR = 0.99, (95 % CI: 0.98–1.01), <italic>p</italic> = 0.50]. Following this, two septic shock scores (SSS) were constituted:<list list-type="bullet"><list-item><p>Computed SSS calculated as follows, (cSSS) = 1.001<sup>VIS in mcg/kg min</sup> + 1.1<sup>arterial lactate in mmol/L</sup> + 18 (in the presence of myocardial dysfunction).</p></list-item><list-item><p>Bedside SSS (bSSS) based on 5 points with coefficient ranked and rounded to have a user-friendly score:</p></list-item><list-item><p>VIS > 200 mcg/kg min = 1 point</p></list-item><list-item><p>Arterial lactate >8 mmol/L or its increase of 1 mmol/L after 6 h of care = 1 point</p></list-item><list-item><p>Myocardial dysfunction as defined above = 3 points.</p></list-item></list></p></sec><sec id="Sec10"><title>Validation population</title><p>The validation population consisted of 456 patients admitted for septic shock requiring inotropes or vasopressors, with a mortality rate of 17.8 % (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). Thirty-two of these patients had limitations of life support on admission and were excluded from analysis. The mortality for the remaining 424 patients was 11.6 %. The main characteristics of both development and validation populations are compared in Table <xref rid="Tab3" ref-type="table">3</xref>. The two studied populations differed significantly in terms of prognostic factors and outcomes. The paediatric index of mortality score (PIM2) [17 (11–21) vs. 7.6 (3–15), <italic>p</italic> < 0.001], peak blood lactates [4.7 (2.3–7.8) vs. 2.6 (1.6–5.2), <italic>p</italic> < 0.01] and mortality (30 vs. 11.6 %, <italic>p</italic> < 0.001) were significantly higher in the development cohort. No comorbidity was found in 52 % of the patients while 60 patients (16.3 %) were immunocompromised. The origin of infection was nosocomial in 27.6 % and community-acquired in 72.4 % of the patients in the validation cohort. A microbiological diagnosis was positive for 317 patients (74.8 %; bacterial in 83.9 %, viral in 12.9 %, fungal in 2.5 % and parasitic in 0.6 %). The most prevalent pathogens were <italic>Neisseria meningitidis</italic> in 70 patients (22.4 %), Group-A <italic>Streptococcus</italic> in 38 patients (12 %), <italic>Streptococcus pneumoniae</italic> in 16 patients (5 %) and <italic>Staphylococcus aureus</italic> in 29 patients (9.1 %). The pathogen was a Gram-negative bacillus in 73 patients (23 %), including <italic>E. coli</italic> for 34 patients (10.7 %). Patients intubated for septic shock reached 87 %, and severe ARDS was present in 27.8 % of all patients.<fig id="Fig1"><label>Fig. 1</label><caption><p>Flow chart of the validation cohort</p></caption><graphic xlink:href="134_2016_4574_Fig1_HTML" id="MO1"></graphic></fig><table-wrap id="Tab3"><label>Table 3</label><caption><p>Patient characteristics in the development and validation populations</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left"></th><th align="left">Development population (<italic>n</italic> = 70)</th><th align="left">Validation population (<italic>n</italic> = 424)</th><th align="left"><italic>p</italic> value</th></tr></thead><tbody><tr><td align="left">Age (months)</td><td align="left">28 (8–76)</td><td align="left">32 (10–87.8)</td><td char="." align="char">0.60</td></tr><tr><td align="left">Sex ratio M/F</td><td align="left">1.92</td><td align="left">1.27</td><td char="." align="char">0.16</td></tr><tr><td align="left">PIM2 score</td><td align="left">17 (11–21)</td><td align="left">7.6 (3–15)</td><td char="." align="char"><0.001</td></tr><tr><td align="left">Nosocomial infection</td><td align="left">25 (35.7 %)</td><td align="left">117 (27.6 %)</td><td char="." align="char">0.21</td></tr><tr><td align="left">Absence of comorbidity</td><td align="left">33 (47.1 %)</td><td align="left">220 (52 %)</td><td char="." align="char">0.53</td></tr><tr><td align="left">Immunocompromised patients</td><td align="left">22 (31.4 %)</td><td align="left">69 (16.3 %)</td><td char="." align="char"><0.001</td></tr><tr><td align="left">Use of mechanical ventilation</td><td align="left">54 (77.1 %)</td><td align="left">369 (87 %)</td><td char="." align="char">0.04</td></tr><tr><td align="left">Severe ARDS</td><td align="left">14 (20 %)</td><td align="left">118 (27.8 %)</td><td char="." align="char">0.22</td></tr><tr><td align="left">Cardiac arrest</td><td align="left">14 (20 %)</td><td align="left">48 (11.3 %)</td><td char="." align="char">0.06</td></tr><tr><td align="left">Use of CRRT</td><td align="left">11 (15.7 %)</td><td align="left">47 (11.1 %)</td><td char="." align="char">0.36</td></tr><tr><td align="left">Maximal blood lactates (mmol/L)</td><td align="left">4.7 (2.3–7.8)</td><td align="left">2.6 (1.6–5.2)</td><td char="." align="char"><0.01</td></tr><tr><td align="left">Lactate increase<sup>a</sup></td><td align="left">25 (35.7 %)</td><td align="left">100 (23.6 %)</td><td char="." align="char">0.06</td></tr><tr><td align="left">ScvO2 <70 %</td><td align="left">25 (35.7 %)</td><td align="left">141 (33.2 %)</td><td char="." align="char">0.84</td></tr><tr><td align="left">Use of ECLS</td><td align="left">2 (2.9 %)</td><td align="left">2 (0.6 %)</td><td char="." align="char">0.15</td></tr><tr><td align="left">PICU mortality</td><td align="left">21 (30.0 %)</td><td align="left">49 (11.6 %)</td><td char="." align="char"><0.01</td></tr><tr><td align="left">Number of days in PICU</td><td align="left">6 (2–11)</td><td align="left">4 (1.4–8.3)</td><td char="." align="char">0.02</td></tr><tr><td align="left">Delay from septic shock onset to death (days)</td><td align="left">2 (0.6–4.5)</td><td align="left">1 (0.5–4)</td><td char="." align="char">0.61</td></tr></tbody></table><table-wrap-foot><p>All characteristics are during PICU stay. Continuous data are expressed as medians (interquartile). Categorial data are expressed as number (percent)</p><p><italic>PIM2</italic> paediatric index of mortality 2, <italic>ARDS</italic> acute respiratory distress syndrome graded with the Berlin definition, <italic>CRRT</italic> continuous renal replacement therapy, <italic>ScvO2</italic> central venous saturation of oxygen, <italic>ECLS</italic> extra-corporeal life support, <italic>PICU</italic> paediatric intensive care unit</p><p><sup>a</sup>Blood lactates: stable defined as less than 1 mmol/L change between two consecutive samples, increase defined as more than 1 mmol/L increase between two samples</p></table-wrap-foot></table-wrap></p><p>Both scores were calculated for all patients and performance analysed with ROC curves (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). The discriminative power for association with mortality or need for ECLS was calculated for computed and bedside scores, with AUC = 0.956 (95 % CI: 0.93–0.97) and 0.920 (95 % CI: 0.89–0.94), respectively. The computed score had a higher AUC as compared to the bedside score (<italic>p</italic> = 0.0092). The performances of both scores for association with death or use of ECLS are presented in Table <xref rid="Tab4" ref-type="table">4</xref>. The bedside SSS with a cut-off at 2 was associated with a positive predictive value of 60.3 % and a negative predictive value of 97.8 % (positive likelihood ratio = 11.6, Youden’s index = 0.765). The computed SSS with a cut-off at 3.5 was associated with a positive predictive value of 55 % and a negative predictive value of 98.5 % (positive likelihood ratio = 9.4, Youden’s index = 0.802). Mortality rate were compared for RSS populations defined by the bedside and the computed scores, with, respectively, 41 deaths among 68 RSS patients (mortality 60.3 %) versus 8 deaths among 356 non-RSS patients (mortality 2.2 %) for the bedside score and 44 deaths among 80 RSS patients (mortality 55 %) versus 5 deaths among 344 non-RSS patients (mortality 1.5 %). Survival curves for each score are presented in Fig. <xref rid="Fig3" ref-type="fig">3</xref> and mortality is significantly higher in RSS patients for both scores (<italic>p</italic> < 0.001 and <italic>p</italic> < 0.001).<fig id="Fig2"><label>Fig. 2</label><caption><p>Receiver operating characteristics curves for the computed septic shock score (cSSS) and the bedside septic shock score (bSSS). Area under the ROC curve in the validation population was 0.956 (95 % CI = 0.93–0.97, <italic>p</italic> < 0.01) for the cSSS and 0.920 (95 % CI = 0.89–0.94, <italic>p</italic> < 0.01) for the bSSS</p></caption><graphic xlink:href="134_2016_4574_Fig2_HTML" id="MO2"></graphic></fig><table-wrap id="Tab4"><label>Table 4</label><caption><p>Predictive performance of septic shock scores and their best threshold values</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left"></th><th align="left">Sensitivity (%)</th><th align="left">Specificity (%)</th><th align="left">Positive predictive value (%)</th><th align="left">Negative predictive value (%)</th><th align="left">Likelihood ratio</th></tr></thead><tbody><tr><td align="left" colspan="6">Bedside septic shock score (bSSS)</td></tr><tr><td align="left"> ≥1</td><td align="left">91.8</td><td align="left">78.9</td><td align="left">36.3</td><td align="left">98.7</td><td char="." align="char">4.4</td></tr><tr><td align="left"> ≥2</td><td align="left">83.7</td><td align="left">92.8</td><td align="left">60.3</td><td align="left">97.8</td><td char="." align="char">11.6</td></tr><tr><td align="left"> ≥3</td><td align="left">63.3</td><td align="left">95.2</td><td align="left">63.3</td><td align="left">95.2</td><td char="." align="char">13.2</td></tr><tr><td align="left"> ≥4</td><td align="left">59.2</td><td align="left">98.1</td><td align="left">80.6</td><td align="left">94.8</td><td char="." align="char">31.7</td></tr><tr><td align="left" colspan="6">Computed septic shock score (cSSS)</td></tr><tr><td align="left"> ≥2.5</td><td align="left">98</td><td align="left">71.7</td><td align="left">31.2</td><td align="left">99.6</td><td char="." align="char">3.5</td></tr><tr><td align="left"> ≥3.5</td><td align="left">89.8</td><td align="left">90.4</td><td align="left">55</td><td align="left">98.5</td><td char="." align="char">9.4</td></tr><tr><td align="left"> ≥5.0</td><td align="left">81.6</td><td align="left">94.7</td><td align="left">66.7</td><td align="left">97.5</td><td char="." align="char">15.3</td></tr><tr><td align="left"> ≥21</td><td align="left">57.1</td><td align="left">98.7</td><td align="left">84.8</td><td align="left">94.6</td><td char="." align="char">42.9</td></tr></tbody></table></table-wrap><fig id="Fig3"><label>Fig. 3</label><caption><p>Survival curve of refractory septic shock defined by <bold>a</bold> a bedside septic shock score ≥2.5, and <bold>b</bold> a computed septic shock score ≥3.5</p></caption><graphic xlink:href="134_2016_4574_Fig3_HTML" id="MO3"></graphic></fig></p></sec></sec><sec id="Sec11"><title>Discussion</title><p>The septic shock scores (bedside and computed) are the first scores that aim at diagnosing refractory septic shock in paediatric patients admitted in PICU for septic shock. The scores were effective to identify the most severely ill patients. A bedside score ≥2 or computed score ≥3.5 defined RSS with a mortality higher than 55 %. Although statistically different, the diagnostic accuracy of both scores seems clinically equivalent with an absolute difference of 0.035 in the AUC. The clinical utility for each score is different. The bSSS is a bedside tool potentially useful for stratifying the severity and assessing the imminent risk of death, helping clinicians to implement rescue therapies. Its simplicity to use may counter-balance the small loss in accuracy. The cSSS is a potentially powerful and discriminating epidemiological tool and its calculation needs a computer or a smartphone application.</p><p>Defining a study population has implications on trials outcomes and may explain contradictory outcomes from historical large-scale randomized trials [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR28">28</xref>]. Recently, the sepsis-3 adult definition has refined the identification of septic shock patients [<xref ref-type="bibr" rid="CR7">7</xref>]. However, although focusing exclusively on adults, the main advance of the sepsis-3 definition is the stratification of patients into two categories: sepsis and septic shock. In adults, the SOFA score assesses organ failures after sepsis with good correlation to mortality [<xref ref-type="bibr" rid="CR8">8</xref>]. This adult score is not adapted for paediatric patients. The paediatric index of mortality (PIM2) [<xref ref-type="bibr" rid="CR29">29</xref>] and the PELOD-2 [<xref ref-type="bibr" rid="CR30">30</xref>] score are paediatric scores that can be used to compare population of patients but are not specific for sepsis. In our study, the two scores were built with arterial lactate, vaso-inotrope score and septic cardiomyopathy and were associated with poor outcome. Each of those criteria was independently associated with mortality or the need for ECLS. Blood lactate is a widely used biomarker in septic shock patients. The highest value during the first 24 h of PICU was associated with mortality in paediatric septic shock patients [<xref ref-type="bibr" rid="CR31">31</xref>]. Dynamic values, such as lactime [<xref ref-type="bibr" rid="CR32">32</xref>] or lactate clearance [<xref ref-type="bibr" rid="CR33">33</xref>], are better predictors of mortality in adult patients, but they are not used routinely. Interestingly, the best predictor of survival to ECLS therapy in children with septic shock was a low pre-ECLS arterial lactate value [<xref ref-type="bibr" rid="CR22">22</xref>].</p><p>Use of vasopressors or inotropes to treat fluid-unresponsive shock is still the first line of treatment [<xref ref-type="bibr" rid="CR10">10</xref>, <xref ref-type="bibr" rid="CR11">11</xref>]. The VIS is a score used to assess the responsiveness and dependency to vasopressor in cardiac ICUs [<xref ref-type="bibr" rid="CR27">27</xref>], with a VIS >200 being associated with mortality or need for ECLS in post-operative paediatric cardiac patients with low cardiac output syndrome [<xref ref-type="bibr" rid="CR34">34</xref>]. In our study, norepinephrine was used in 77.2 % of the patients and an inotrope (dobutamine, dopamine, epinephrine or milrinone) added in 80.2 %. The cut-off chosen in the definition by the two-round survey is higher than the VIS scores found in the literature in patients under ECLS therapy for other indications [<xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR35">35</xref>, <xref ref-type="bibr" rid="CR36">36</xref>] or alternative vasopressors [<xref ref-type="bibr" rid="CR37">37</xref>], but similar to calculated inotrope scores in adult patients needing ECLS support for septic shock [<xref ref-type="bibr" rid="CR21">21</xref>].</p><p>The presence of a septic cardiomyopathy was independently associated with increased mortality or need for ECLS in the development population [OR = 18, (95 % CI: 3.4–95.4)]. Septic cardiomyopathy is the component carrying the highest weight in the septic shock scores. Although the pathogenesis of septic cardiomyopathy is multifactorial, it is known to be reversible [<xref ref-type="bibr" rid="CR36">36</xref>, <xref ref-type="bibr" rid="CR37">37</xref>, <xref ref-type="bibr" rid="CR38">38</xref>]. LVEF has proven to be sufficient for the diagnosis of low cardiac output with a LVEF <40 % [<xref ref-type="bibr" rid="CR39">39</xref>]. Diastolic dysfunction and right ventricle dysfunction in sepsis are less studied but their role in septic cardiomyopathy seems to precede systolic left ventricular dysfunction [<xref ref-type="bibr" rid="CR39">39</xref>]. Cardiac arrest is the ultimate evolution of septic shock. In our study, in both cohorts, 59.7 % of the deceased patients had a resuscitated cardiac arrest in the course of the septic shock. Patients in cardiac arrest due to septic shock can benefit from ECLS therapy with an overall survival of 75 % in one series [<xref ref-type="bibr" rid="CR22">22</xref>], compared to 32.7 % in our cohort. Improved assessment of septic cardiomyopathy before cardiac arrest occurs is mandatory. Regular evaluation of cardiac output and function can be based on invasive and non-invasive criteria. Non-invasive quantification relies mostly on continuous oesophageal or supra-sternal Doppler or cardiac ultrasound. Importantly, it is well recognized that children with septic shock without apparent need for inotropes can subsequently develop septic cardiomyopathy and low cardiac output [<xref ref-type="bibr" rid="CR19">19</xref>]. This haemodynamic pattern can be explained by the unmasking of septic cardiomyopathy by restoration of vasomotor tone in resuscitated shock after norepinephrine infusions, as well as over-enthusiastic fluid resuscitation [<xref ref-type="bibr" rid="CR17">17</xref>].</p><p>This study has some limitations. First, the data collection was retrospective and thus is at risk of missing data and information bias. Second, data were collected during the whole septic shock care period with selection of a unique worst value for each item. Thus, the maximal values could be at varying time points in the clinical course. Calculation of the score was based on worst values for each criterion that may not be synchronous. This could have increased the estimated risk of death for patients in the validation population as well as overestimating the AUCROC. However, most patients died shortly after admission (median time to death = 1 day) and the highest values were mostly collected within the first 24 h after admission. Similarly, a delay to death of less than 24 h was also shown in more than 13,000 paediatric sepsis admissions in the North Thames, UK, region [<xref ref-type="bibr" rid="CR40">40</xref>]. Other scores used similar methodology during their creation, including SOFA and PELOD [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR30">30</xref>]. Evaluating the kinetics of both scores as well as its composing criteria in the course of the disease is important and needs prospective evaluation. Third, there were significant baseline differences in the characteristics of the two populations (development and validation) and between centres included in the validation cohort. These may be explained by differences in patients’ recruitment and severity. Some of them were known prognostic factors in septic shock such as PIM2 scores and immunosuppression or were part of either the definition (blood lactates) or the outcome (mortality), outlining the patients’ recruitment and severity difference between both cohorts. The high mortality rate in the development cohort ensured the high power of this study to select the criteria associated with refractory septic shock. Meanwhile, the scores have an excellent discriminative value in the validation cohort. This reinforces the quality of the scores in various patients. Finally, this definition is based on a draft definition that has been developed using fictitious clinical cases and an international PICU physician opinion survey. The risk of opinion bias has been adjusted with the modification of this definition and the constitution of the septic shock scores tailored to an actual patient population. This definition is very coherent in real life, shown by the excellent discriminative power of both scores in the validation cohort. In regard of these limitations, a prospective study is warranted for refinement and external validation of this definition.</p></sec><sec id="Sec12"><title>Conclusion</title><p>In conclusion, we have defined refractory septic shock in children as the association of high blood lactate with high vaso-inotrope doses associated with myocardial dysfunction. This definition is based on two septic shock scores showing excellent discriminative power in a multicentre validation population. The RSS Computed Score is a powerful and potentially useful tool to compare patients in future interventional randomized multicenter studies on septic shock. The RSS Bedside Score is easy to calculate and may assist in determining patients who would be suitable for inclusion in clinical trials of rescue therapies.</p></sec><sec sec-type="supplementary-material"><title>Electronic supplementary material</title><sec id="Sec13"><p>Below is the link to the electronic supplementary material.
<supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="134_2016_4574_MOESM1_ESM.docx"><caption><p>Supplementary material 1 (DOCX 39 kb)</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM2"><media xlink:href="134_2016_4574_MOESM2_ESM.docx"><caption><p>Supplementary material 2 (DOCX 18 kb)</p></caption></media></supplementary-material></p></sec></sec></body><back><fn-group><fn><p><bold>Take-home message:</bold> The absence of a reliable definition for refractory septic shock in children represents a barrier to planning and interpretation of clinical trials of the use of specific and targeted therapeutics. The ESPNIC definition comprising lactic acidosis, vaso-inotrope dependency and septic cardiomyopathy is a highly discriminating definition and was validated on a large multicenter international cohort of patients in septic shock.</p></fn></fn-group><ack><p>We acknowledge Ella Nkanagu from the ESPNIC secretariat for her assistance. We would like to thank Anthony Slater, Tara Williams, and Katie Moynihan, Children`s Health Queensland, for their support and help in data extraction.</p></ack><notes notes-type="COI-statement"><title>Compliance with ethical standards</title><sec id="FPar1"><title>Funding</title><p>None.</p></sec><sec id="FPar2"><title>Conflicts of interest</title><p>Dr. Javouhey reports grants from CSL Behring, personal fees from Gambro-Baxter, outside the submitted work. Dr. Tissieres reports grants from Merieux Foundation, non-financial support from Chiesi Inc, outside the submitted work. All other authors declare that they have no conflict of interest.</p></sec></notes><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>L</given-names></name><name><surname>Johnson</surname><given-names>HL</given-names></name><name><surname>Cousens</surname><given-names>S</given-names></name><name><surname>Perin</surname><given-names>J</given-names></name><name><surname>Scott</surname><given-names>S</given-names></name><name><surname>Lawn</surname><given-names>JE</given-names></name><name><surname>Rudan</surname><given-names>I</given-names></name><name><surname>Campbell</surname><given-names>H</given-names></name><name><surname>Cibulskis</surname><given-names>R</given-names></name><name><surname>Li</surname><given-names>M</given-names></name><name><surname>Mathers</surname><given-names>C</given-names></name><name><surname>Black</surname><given-names>RE</given-names></name></person-group><article-title>Child health epidemiology reference group of WHO and UNICEF global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000</article-title><source>Lancet</source><year>2012</year><volume>379</volume><fpage>2151</fpage><lpage>2161</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(12)60560-1</pub-id><pub-id pub-id-type="pmid">22579125</pub-id></element-citation></ref><ref id="CR2"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schlapbach</surname><given-names>LJ</given-names></name><name><surname>Straney</surname><given-names>L</given-names></name><name><surname>Alexander</surname><given-names>J</given-names></name><name><surname>MacLaren</surname><given-names>G</given-names></name><name><surname>Festa</surname><given-names>M</given-names></name><name><surname>Schibler</surname><given-names>A</given-names></name><name><surname>Slater</surname><given-names>A</given-names></name><collab>ANZICS Paediatric Study Group</collab></person-group><article-title>Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study</article-title><source>Lancet Infect Dis</source><year>2015</year><volume>15</volume><fpage>46</fpage><lpage>54</lpage><pub-id pub-id-type="doi">10.1016/S1473-3099(14)71003-5</pub-id><pub-id pub-id-type="pmid">25471555</pub-id></element-citation></ref><ref id="CR3"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Watson</surname><given-names>RS</given-names></name><name><surname>Carcillo</surname><given-names>JA</given-names></name><name><surname>Linde-Zwirble</surname><given-names>WT</given-names></name><name><surname>Clermont</surname><given-names>G</given-names></name><name><surname>Lidicker</surname><given-names>J</given-names></name><name><surname>Angus</surname><given-names>DC</given-names></name></person-group><article-title>The epidemiology of severe sepsis in children in the United States</article-title><source>Am J Respir Crit Care Med</source><year>2003</year><volume>167</volume><fpage>695</fpage><lpage>701</lpage><pub-id pub-id-type="doi">10.1164/rccm.200207-682OC</pub-id><pub-id pub-id-type="pmid">12433670</pub-id></element-citation></ref><ref id="CR4"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kaukonen</surname><given-names>K-M</given-names></name><name><surname>Bailey</surname><given-names>M</given-names></name><name><surname>Suzuki</surname><given-names>S</given-names></name><name><surname>Pilcher</surname><given-names>D</given-names></name><name><surname>Bellomo</surname><given-names>R</given-names></name></person-group><article-title>Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012</article-title><source>JAMA</source><year>2014</year><volume>311</volume><fpage>1308</fpage><lpage>1316</lpage><pub-id pub-id-type="doi">10.1001/jama.2014.2637</pub-id><pub-id pub-id-type="pmid">24638143</pub-id></element-citation></ref><ref id="CR5"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bone</surname><given-names>RC</given-names></name><name><surname>Fisher</surname><given-names>CJ</given-names></name><name><surname>Clemmer</surname><given-names>TP</given-names></name><name><surname>Slotman</surname><given-names>GJ</given-names></name><name><surname>Metz</surname><given-names>CA</given-names></name><name><surname>Balk</surname><given-names>RA</given-names></name></person-group><article-title>Sepsis syndrome: a valid clinical entity. Methylprednisolone Severe Sepsis Study Group</article-title><source>Crit Care Med</source><year>1989</year><volume>17</volume><fpage>389</fpage><lpage>393</lpage><pub-id pub-id-type="doi">10.1097/00003246-198905000-00002</pub-id><pub-id pub-id-type="pmid">2651003</pub-id></element-citation></ref><ref id="CR6"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Levy</surname><given-names>MM</given-names></name><name><surname>Fink</surname><given-names>MP</given-names></name><name><surname>Marshall</surname><given-names>JC</given-names></name><name><surname>Abraham</surname><given-names>E</given-names></name><name><surname>Angus</surname><given-names>D</given-names></name><name><surname>Cook</surname><given-names>D</given-names></name><name><surname>Cohen</surname><given-names>J</given-names></name><name><surname>Opal</surname><given-names>SM</given-names></name><name><surname>Vincent</surname><given-names>JL</given-names></name><name><surname>Ramsay</surname><given-names>G</given-names></name><collab>SCCM, ESICM, ACCP, ATS, SIS</collab></person-group><article-title>2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference</article-title><source>Crit Care Med</source><year>2003</year><volume>31</volume><fpage>1250</fpage><lpage>1256</lpage><pub-id pub-id-type="doi">10.1097/01.CCM.0000050454.01978.3B</pub-id><pub-id pub-id-type="pmid">12682500</pub-id></element-citation></ref><ref id="CR7"><label>7.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Singer</surname><given-names>M</given-names></name><name><surname>Deutschman</surname><given-names>CS</given-names></name><name><surname>Seymour</surname><given-names>C</given-names></name><name><surname>Shankar-Hari</surname><given-names>M</given-names></name><name><surname>Annane</surname><given-names>D</given-names></name><name><surname>Bauer</surname><given-names>M</given-names></name><name><surname>Bellomo</surname><given-names>R</given-names></name><name><surname>Bernard</surname><given-names>GR</given-names></name><name><surname>Chiche</surname><given-names>JD</given-names></name><name><surname>Coopersmith</surname><given-names>CM</given-names></name><name><surname>Hotchkiss</surname><given-names>RS</given-names></name><name><surname>Levy</surname><given-names>MM</given-names></name><name><surname>Marshall</surname><given-names>JC</given-names></name><name><surname>Martin</surname><given-names>GS</given-names></name><name><surname>Opal</surname><given-names>SM</given-names></name><name><surname>Rubenfeld</surname><given-names>GD</given-names></name><name><surname>van der Poll</surname><given-names>T</given-names></name><name><surname>Vincent</surname><given-names>JL</given-names></name><name><surname>Angus</surname><given-names>DC</given-names></name></person-group><article-title>The third international consensus definitions for sepsis and septic shock (sepsis-3)</article-title><source>JAMA</source><year>2016</year><volume>315</volume><fpage>801</fpage><lpage>810</lpage><pub-id pub-id-type="doi">10.1001/jama.2016.0287</pub-id><pub-id pub-id-type="pmid">26903338</pub-id></element-citation></ref><ref id="CR8"><label>8.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vincent</surname><given-names>JL</given-names></name><name><surname>Moreno</surname><given-names>R</given-names></name><name><surname>Takala</surname><given-names>J</given-names></name><name><surname>Willatts</surname><given-names>S</given-names></name><name><surname>De Mendonça</surname><given-names>A</given-names></name><name><surname>Bruining</surname><given-names>H</given-names></name><name><surname>Reinhart</surname><given-names>CK</given-names></name><name><surname>Suter</surname><given-names>PM</given-names></name><name><surname>Thijs</surname><given-names>LG</given-names></name></person-group><article-title>The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine</article-title><source>Intensive Care Med</source><year>1996</year><volume>22</volume><fpage>707</fpage><lpage>710</lpage><pub-id pub-id-type="doi">10.1007/BF01709751</pub-id><pub-id pub-id-type="pmid">8844239</pub-id></element-citation></ref><ref id="CR9"><label>9.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leclerc</surname><given-names>F</given-names></name><name><surname>Leteurtre</surname><given-names>S</given-names></name><name><surname>Duhamel</surname><given-names>A</given-names></name><name><surname>Grandbastien</surname><given-names>B</given-names></name><name><surname>Proulx</surname><given-names>F</given-names></name><name><surname>Martinot</surname><given-names>A</given-names></name><name><surname>Gauvin</surname><given-names>F</given-names></name><name><surname>Hubert</surname><given-names>P</given-names></name><name><surname>Lacroix</surname><given-names>J</given-names></name></person-group><article-title>Cumulative influence of organ dysfunctions and septic state on mortality of critically ill children</article-title><source>Am J Respir Crit Care Med</source><year>2005</year><volume>171</volume><fpage>348</fpage><lpage>353</lpage><pub-id pub-id-type="doi">10.1164/rccm.200405-630OC</pub-id><pub-id pub-id-type="pmid">15516535</pub-id></element-citation></ref><ref id="CR10"><label>10.</label><mixed-citation publication-type="other">Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R (2013) Surviving sepsis campaign guidelines committee including The pediatric subgroup surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Intensive Care Med 39:165–228</mixed-citation></ref><ref id="CR11"><label>11.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brierley</surname><given-names>J</given-names></name><name><surname>Carcillo</surname><given-names>JA</given-names></name><name><surname>Choong</surname><given-names>K</given-names></name><name><surname>Cornell</surname><given-names>T</given-names></name><name><surname>Decaen</surname><given-names>A</given-names></name><name><surname>Deymann</surname><given-names>A</given-names></name><name><surname>Doctor</surname><given-names>A</given-names></name><name><surname>Davis</surname><given-names>A</given-names></name><name><surname>Duff</surname><given-names>J</given-names></name><name><surname>Dugas</surname><given-names>MA</given-names></name><name><surname>Duncan</surname><given-names>A</given-names></name><name><surname>Evans</surname><given-names>B</given-names></name><name><surname>Feldman</surname><given-names>J</given-names></name><name><surname>Felmet</surname><given-names>K</given-names></name><name><surname>Fisher</surname><given-names>G</given-names></name><name><surname>Frankel</surname><given-names>L</given-names></name><name><surname>Jeffries</surname><given-names>H</given-names></name><name><surname>Greenwald</surname><given-names>B</given-names></name><name><surname>Gutierrez</surname><given-names>J</given-names></name><name><surname>Hall</surname><given-names>M</given-names></name><name><surname>Han</surname><given-names>YY</given-names></name><name><surname>Hanson</surname><given-names>J</given-names></name><name><surname>Hazelzet</surname><given-names>J</given-names></name><name><surname>Hernan</surname><given-names>L</given-names></name><name><surname>Kiff</surname><given-names>J</given-names></name><name><surname>Kissoon</surname><given-names>N</given-names></name><name><surname>Kon</surname><given-names>A</given-names></name><name><surname>Irazuzta</surname><given-names>J</given-names></name><name><surname>Lin</surname><given-names>J</given-names></name><name><surname>Lorts</surname><given-names>A</given-names></name><name><surname>Mariscalco</surname><given-names>M</given-names></name><name><surname>Mehta</surname><given-names>R</given-names></name><name><surname>Nadel</surname><given-names>S</given-names></name><name><surname>Nguyen</surname><given-names>T</given-names></name><name><surname>Nicholson</surname><given-names>C</given-names></name><name><surname>Peters</surname><given-names>M</given-names></name><name><surname>Okhuysen-Cawley</surname><given-names>R</given-names></name><name><surname>Poulton</surname><given-names>T</given-names></name><name><surname>Relves</surname><given-names>M</given-names></name><name><surname>Rodriguez</surname><given-names>A</given-names></name><name><surname>Rozenfeld</surname><given-names>R</given-names></name><name><surname>Schnitzler</surname><given-names>E</given-names></name><name><surname>Shanley</surname><given-names>T</given-names></name><name><surname>Kache</surname><given-names>S</given-names></name><name><surname>Skippen</surname><given-names>P</given-names></name><name><surname>Torres</surname><given-names>A</given-names></name><name><surname>von Dessauer</surname><given-names>B</given-names></name><name><surname>Weingarten</surname><given-names>J</given-names></name><name><surname>Yeh</surname><given-names>T</given-names></name><name><surname>Zaritsky</surname><given-names>A</given-names></name><name><surname>Stojadinovic</surname><given-names>B</given-names></name><name><surname>Zimmerman</surname><given-names>J</given-names></name><name><surname>Zuckerberg</surname><given-names>A</given-names></name></person-group><article-title>Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine</article-title><source>Crit Care Med</source><year>2009</year><volume>37</volume><fpage>666</fpage><lpage>688</lpage><pub-id pub-id-type="doi">10.1097/CCM.0b013e31819323c6</pub-id><pub-id pub-id-type="pmid">19325359</pub-id></element-citation></ref><ref id="CR12"><label>12.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ranieri</surname><given-names>VM</given-names></name><name><surname>Thompson</surname><given-names>BT</given-names></name><name><surname>Barie</surname><given-names>PS</given-names></name><name><surname>Dhainaut</surname><given-names>JF</given-names></name><name><surname>Douglas</surname><given-names>IS</given-names></name><name><surname>Finfer</surname><given-names>S</given-names></name><name><surname>Gårdlund</surname><given-names>B</given-names></name><name><surname>Marshall</surname><given-names>JC</given-names></name><name><surname>Rhodes</surname><given-names>A</given-names></name><name><surname>Artigas</surname><given-names>A</given-names></name><name><surname>Payen</surname><given-names>D</given-names></name><name><surname>Tenhunen</surname><given-names>J</given-names></name><name><surname>Al-Khalidi</surname><given-names>HR</given-names></name><name><surname>Thompson</surname><given-names>V</given-names></name><name><surname>Janes</surname><given-names>J</given-names></name><name><surname>Macias</surname><given-names>WL</given-names></name><name><surname>Vangerow</surname><given-names>B</given-names></name><name><surname>Williams</surname><given-names>MD</given-names></name><collab>PROWESS-SHOCK Study Group</collab></person-group><article-title>Drotrecogin alfa (activated) in adults with septic shock</article-title><source>N Engl J Med</source><year>2012</year><volume>366</volume><fpage>2055</fpage><lpage>2064</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa1202290</pub-id><pub-id pub-id-type="pmid">22616830</pub-id></element-citation></ref><ref id="CR13"><label>13.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nadel</surname><given-names>S</given-names></name><name><surname>Goldstein</surname><given-names>B</given-names></name><name><surname>Williams</surname><given-names>MD</given-names></name><name><surname>Dalton</surname><given-names>H</given-names></name><name><surname>Peters</surname><given-names>M</given-names></name><name><surname>Macias</surname><given-names>WL</given-names></name><name><surname>Abd-Allah</surname><given-names>SA</given-names></name><name><surname>Levy</surname><given-names>H</given-names></name><name><surname>Angle</surname><given-names>R</given-names></name><name><surname>Wang</surname><given-names>D</given-names></name><name><surname>Sundin</surname><given-names>DP</given-names></name><name><surname>Giroir</surname><given-names>B</given-names></name><collab>REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study group</collab></person-group><article-title>Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial</article-title><source>Lancet</source><year>2007</year><volume>369</volume><fpage>836</fpage><lpage>843</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(07)60411-5</pub-id><pub-id pub-id-type="pmid">17350452</pub-id></element-citation></ref><ref id="CR14"><label>14.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Investigators</surname><given-names>ProCESS</given-names></name><name><surname>Yealy</surname><given-names>DM</given-names></name><name><surname>Kellum</surname><given-names>JA</given-names></name><name><surname>Huang</surname><given-names>DT</given-names></name><name><surname>Barnato</surname><given-names>AE</given-names></name><name><surname>Weissfeld</surname><given-names>LA</given-names></name><name><surname>Pike</surname><given-names>F</given-names></name><name><surname>Terndrup</surname><given-names>T</given-names></name><name><surname>Wang</surname><given-names>HE</given-names></name><name><surname>Hou</surname><given-names>PC</given-names></name><name><surname>LoVecchio</surname><given-names>F</given-names></name><name><surname>Filbin</surname><given-names>MR</given-names></name><name><surname>Shapiro</surname><given-names>NI</given-names></name><name><surname>Angus</surname><given-names>DC</given-names></name></person-group><article-title>A randomized trial of protocol-based care for early septic shock</article-title><source>N Engl J Med</source><year>2014</year><volume>370</volume><fpage>1683</fpage><lpage>1693</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa1401602</pub-id><pub-id pub-id-type="pmid">24635773</pub-id></element-citation></ref><ref id="CR15"><label>15.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Peake</surname><given-names>SL</given-names></name><name><surname>Bailey</surname><given-names>M</given-names></name><name><surname>Bellomo</surname><given-names>R</given-names></name><name><surname>Cameron</surname><given-names>PA</given-names></name><name><surname>Cross</surname><given-names>A</given-names></name><name><surname>Delaney</surname><given-names>A</given-names></name><name><surname>Finfer</surname><given-names>S</given-names></name><name><surname>Higgins</surname><given-names>A</given-names></name><name><surname>Jones</surname><given-names>DA</given-names></name><name><surname>Myburgh</surname><given-names>JA</given-names></name><name><surname>Syres</surname><given-names>GA</given-names></name><name><surname>Webb</surname><given-names>SA</given-names></name><name><surname>Williams</surname><given-names>P</given-names></name><collab>ARISE Investigators, for the Australian and New Zealand Intensive Care Society Clinical Trials Group</collab></person-group><article-title>Australasian resuscitation of sepsis evaluation (ARISE): a multi-centre, prospective, inception cohort study</article-title><source>Resuscitation</source><year>2009</year><volume>80</volume><fpage>811</fpage><lpage>818</lpage><pub-id pub-id-type="doi">10.1016/j.resuscitation.2009.03.008</pub-id><pub-id pub-id-type="pmid">19467755</pub-id></element-citation></ref><ref id="CR16"><label>16.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Daviaud</surname><given-names>F</given-names></name><name><surname>Grimaldi</surname><given-names>D</given-names></name><name><surname>Dechartres</surname><given-names>A</given-names></name><name><surname>Charpentier</surname><given-names>J</given-names></name><name><surname>Geri</surname><given-names>G</given-names></name><name><surname>Marin</surname><given-names>N</given-names></name><name><surname>Chiche</surname><given-names>JD</given-names></name><name><surname>Cariou</surname><given-names>A</given-names></name><name><surname>Mira</surname><given-names>JP</given-names></name><name><surname>Pène</surname><given-names>F</given-names></name></person-group><article-title>Timing and causes of death in septic shock</article-title><source>Ann Intensive Care</source><year>2015</year><volume>5</volume><fpage>58</fpage><pub-id pub-id-type="doi">10.1186/s13613-015-0058-8</pub-id><pub-id pub-id-type="pmid">26714808</pub-id></element-citation></ref><ref id="CR17"><label>17.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Parker</surname><given-names>MM</given-names></name><name><surname>Shelhamer</surname><given-names>JH</given-names></name><name><surname>Natanson</surname><given-names>C</given-names></name><name><surname>Alling</surname><given-names>DW</given-names></name><name><surname>Parrillo</surname><given-names>JE</given-names></name></person-group><article-title>Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis</article-title><source>Crit Care Med</source><year>1987</year><volume>15</volume><fpage>923</fpage><lpage>929</lpage><pub-id pub-id-type="doi">10.1097/00003246-198710000-00006</pub-id><pub-id pub-id-type="pmid">3652707</pub-id></element-citation></ref><ref id="CR18"><label>18.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pathan</surname><given-names>N</given-names></name><name><surname>Hemingway</surname><given-names>CA</given-names></name><name><surname>Alizadeh</surname><given-names>AA</given-names></name><name><surname>Stephens</surname><given-names>AC</given-names></name><name><surname>Boldrick</surname><given-names>JC</given-names></name><name><surname>Oragui</surname><given-names>EE</given-names></name><name><surname>McCabe</surname><given-names>C</given-names></name><name><surname>Welch</surname><given-names>SB</given-names></name><name><surname>Whitney</surname><given-names>A</given-names></name><name><surname>O’Gara</surname><given-names>P</given-names></name><name><surname>Nadel</surname><given-names>S</given-names></name><name><surname>Relman</surname><given-names>DA</given-names></name><name><surname>Harding</surname><given-names>SE</given-names></name><name><surname>Levin</surname><given-names>M</given-names></name></person-group><article-title>Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock</article-title><source>Lancet</source><year>2004</year><volume>363</volume><fpage>203</fpage><lpage>209</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(03)15326-3</pub-id><pub-id pub-id-type="pmid">14738793</pub-id></element-citation></ref><ref id="CR19"><label>19.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Deep</surname><given-names>A</given-names></name><name><surname>Goonasekera</surname><given-names>CDA</given-names></name><name><surname>Wang</surname><given-names>Y</given-names></name><name><surname>Brierley</surname><given-names>J</given-names></name></person-group><article-title>Evolution of haemodynamics and outcome of fluid-refractory septic shock in children</article-title><source>Intensive Care Med</source><year>2013</year><volume>39</volume><fpage>1602</fpage><lpage>1609</lpage><pub-id pub-id-type="doi">10.1007/s00134-013-3003-z</pub-id><pub-id pub-id-type="pmid">23812341</pub-id></element-citation></ref><ref id="CR20"><label>20.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hotchkiss</surname><given-names>RS</given-names></name><name><surname>Monneret</surname><given-names>G</given-names></name><name><surname>Payen</surname><given-names>D</given-names></name></person-group><article-title>Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy</article-title><source>Nat Rev Immunol</source><year>2013</year><volume>13</volume><fpage>862</fpage><lpage>874</lpage><pub-id pub-id-type="doi">10.1038/nri3552</pub-id><pub-id pub-id-type="pmid">24232462</pub-id></element-citation></ref><ref id="CR21"><label>21.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bréchot</surname><given-names>N</given-names></name><name><surname>Luyt</surname><given-names>C-E</given-names></name><name><surname>Schmidt</surname><given-names>M</given-names></name><name><surname>Leprince</surname><given-names>P</given-names></name><name><surname>Trouillet</surname><given-names>JL</given-names></name><name><surname>Léger</surname><given-names>P</given-names></name><name><surname>Pavie</surname><given-names>A</given-names></name><name><surname>Chastre</surname><given-names>J</given-names></name><name><surname>Combes</surname><given-names>A</given-names></name></person-group><article-title>Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock</article-title><source>Crit Care Med</source><year>2013</year><volume>41</volume><fpage>1616</fpage><lpage>1626</lpage><pub-id pub-id-type="doi">10.1097/CCM.0b013e31828a2370</pub-id><pub-id pub-id-type="pmid">23563585</pub-id></element-citation></ref><ref id="CR22"><label>22.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>MacLaren</surname><given-names>G</given-names></name><name><surname>Butt</surname><given-names>W</given-names></name><name><surname>Best</surname><given-names>D</given-names></name><name><surname>Donath</surname><given-names>S</given-names></name></person-group><article-title>Central extracorporeal membrane oxygenation for refractory pediatric septic shock</article-title><source>Pediatr Crit Care Med</source><year>2011</year><volume>12</volume><fpage>133</fpage><lpage>136</lpage><pub-id pub-id-type="doi">10.1097/PCC.0b013e3181e2a4a1</pub-id><pub-id pub-id-type="pmid">20453704</pub-id></element-citation></ref><ref id="CR23"><label>23.</label><mixed-citation publication-type="other">French Intensive Care Society, International congress- Réanimation 2016 (2016) Ann Intensive Care 6 (Suppl1):S50</mixed-citation></ref><ref id="CR24"><label>24.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goldstein</surname><given-names>B</given-names></name><name><surname>Giroir</surname><given-names>B</given-names></name><name><surname>Randolph</surname><given-names>A</given-names></name><collab>International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics</collab></person-group><article-title>International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics</article-title><source>Pediatr Crit Care Med</source><year>2005</year><volume>6</volume><fpage>2</fpage><lpage>8</lpage><pub-id pub-id-type="doi">10.1097/01.PCC.0000149131.72248.E6</pub-id><pub-id pub-id-type="pmid">15636651</pub-id></element-citation></ref><ref id="CR25"><label>25.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>DeLong</surname><given-names>ER</given-names></name><name><surname>DeLong</surname><given-names>DM</given-names></name><name><surname>Clarke-Pearson</surname><given-names>DL</given-names></name></person-group><article-title>Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach</article-title><source>Biometrics</source><year>1988</year><volume>44</volume><fpage>837</fpage><lpage>845</lpage><pub-id pub-id-type="doi">10.2307/2531595</pub-id><pub-id pub-id-type="pmid">3203132</pub-id></element-citation></ref><ref id="CR26"><label>26.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>De Luca</surname><given-names>D</given-names></name><name><surname>Piastra</surname><given-names>M</given-names></name><name><surname>Chidini</surname><given-names>G</given-names></name><name><surname>Tissieres</surname><given-names>P</given-names></name><name><surname>Calderini</surname><given-names>E</given-names></name><name><surname>Essouri</surname><given-names>S</given-names></name><name><surname>Medina Villanueva</surname><given-names>A</given-names></name><name><surname>Vivanco Allende</surname><given-names>A</given-names></name><name><surname>Pons-Odena</surname><given-names>M</given-names></name><name><surname>Perez-Baena</surname><given-names>L</given-names></name><name><surname>Hermon</surname><given-names>M</given-names></name><name><surname>Tridente</surname><given-names>A</given-names></name><name><surname>Conti</surname><given-names>G</given-names></name><name><surname>Antonelli</surname><given-names>M</given-names></name><name><surname>Kneyber</surname><given-names>M</given-names></name><collab>Respiratory Section of the European Society for Pediatric Neonatal Intensive Care (ESPNIC)</collab></person-group><article-title>The use of the Berlin definition for acute respiratory distress syndrome during infancy and early childhood: multicenter evaluation and expert consensus</article-title><source>Intensive Care Med</source><year>2013</year><volume>39</volume><fpage>2083</fpage><lpage>2091</lpage><pub-id pub-id-type="doi">10.1007/s00134-013-3110-x</pub-id><pub-id pub-id-type="pmid">24100946</pub-id></element-citation></ref><ref id="CR27"><label>27.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Davidson</surname><given-names>J</given-names></name><name><surname>Tong</surname><given-names>S</given-names></name><name><surname>Hancock</surname><given-names>H</given-names></name><name><surname>Hauck</surname><given-names>A</given-names></name><name><surname>da Cruz</surname><given-names>E</given-names></name><name><surname>Kaufman</surname><given-names>J</given-names></name></person-group><article-title>Prospective validation of the vasoactive-inotropic score and correlation to short-term outcomes in neonates and infants after cardiothoracic surgery</article-title><source>Intensive Care Med</source><year>2012</year><volume>38</volume><fpage>1184</fpage><lpage>1190</lpage><pub-id pub-id-type="doi">10.1007/s00134-012-2544-x</pub-id><pub-id pub-id-type="pmid">22527067</pub-id></element-citation></ref><ref id="CR28"><label>28.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kalil</surname><given-names>AC</given-names></name><name><surname>Florescu</surname><given-names>DF</given-names></name></person-group><article-title>Severe sepsis: are PROWESS and PROWESS-SHOCK trials comparable? a clinical and statistical heterogeneity analysis</article-title><source>Crit Care</source><year>2013</year><volume>17</volume><fpage>167</fpage><pub-id pub-id-type="doi">10.1186/cc12752</pub-id><pub-id pub-id-type="pmid">23826709</pub-id></element-citation></ref><ref id="CR29"><label>29.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Slater</surname><given-names>A</given-names></name><name><surname>Shann</surname><given-names>F</given-names></name><name><surname>Pearson</surname><given-names>G</given-names></name><collab>Paediatric Index of Mortality (PIM) Study Group</collab></person-group><article-title>PIM2: a revised version of the paediatric index of mortality</article-title><source>Intensive Care Med</source><year>2003</year><volume>29</volume><fpage>278</fpage><lpage>285</lpage><pub-id pub-id-type="doi">10.1007/s00134-002-1601-2</pub-id><pub-id pub-id-type="pmid">12541154</pub-id></element-citation></ref><ref id="CR30"><label>30.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leteurtre</surname><given-names>S</given-names></name><name><surname>Duhamel</surname><given-names>A</given-names></name><name><surname>Salleron</surname><given-names>J</given-names></name><name><surname>Grandbastien</surname><given-names>B</given-names></name><name><surname>Lacroix</surname><given-names>J</given-names></name><name><surname>Leclerc</surname><given-names>F</given-names></name><collab>Groupe Francophone de Réanimation et d’Urgences Pédiatriques (GFRUP)</collab></person-group><article-title>PELOD-2: an update of the PEdiatric logistic organ dysfunction score</article-title><source>Crit Care Med</source><year>2013</year><volume>41</volume><fpage>1761</fpage><lpage>1773</lpage><pub-id pub-id-type="doi">10.1097/CCM.0b013e31828a2bbd</pub-id><pub-id pub-id-type="pmid">23685639</pub-id></element-citation></ref><ref id="CR31"><label>31.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jhamb</surname><given-names>U</given-names></name><name><surname>Jat</surname><given-names>K</given-names></name><name><surname>Gupta</surname><given-names>V</given-names></name></person-group><article-title>Serum lactate levels as the predictor of outcome in pediatric septic shock</article-title><source>Indian J Crit Care Med</source><year>2011</year><volume>15</volume><fpage>102</fpage><pub-id pub-id-type="doi">10.4103/0972-5229.83017</pub-id><pub-id pub-id-type="pmid">21814374</pub-id></element-citation></ref><ref id="CR32"><label>32.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bakker</surname><given-names>J</given-names></name><name><surname>Gris</surname><given-names>P</given-names></name><name><surname>Coffernils</surname><given-names>M</given-names></name><name><surname>Kahn</surname><given-names>RJ</given-names></name><name><surname>Vincent</surname><given-names>JL</given-names></name></person-group><article-title>Serial blood lactate levels can predict the development of multiple organ failure following septic shock</article-title><source>Am J Surg</source><year>1996</year><volume>171</volume><fpage>221</fpage><lpage>226</lpage><pub-id pub-id-type="doi">10.1016/S0002-9610(97)89552-9</pub-id><pub-id pub-id-type="pmid">8619454</pub-id></element-citation></ref><ref id="CR33"><label>33.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Levraut</surname><given-names>J</given-names></name><name><surname>Ichai</surname><given-names>C</given-names></name><name><surname>Petit</surname><given-names>I</given-names></name><name><surname>Ciebiera</surname><given-names>JP</given-names></name><name><surname>Perus</surname><given-names>O</given-names></name><name><surname>Grimaud</surname><given-names>D</given-names></name></person-group><article-title>Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients</article-title><source>Crit Care Med</source><year>2003</year><volume>31</volume><fpage>705</fpage><lpage>710</lpage><pub-id pub-id-type="doi">10.1097/01.CCM.0000045561.85810.45</pub-id><pub-id pub-id-type="pmid">12626973</pub-id></element-citation></ref><ref id="CR34"><label>34.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gaies</surname><given-names>MG</given-names></name><name><surname>Gurney</surname><given-names>JG</given-names></name><name><surname>Yen</surname><given-names>AH</given-names></name><name><surname>Napoli</surname><given-names>ML</given-names></name><name><surname>Gajarski</surname><given-names>RJ</given-names></name><name><surname>Ohye</surname><given-names>RG</given-names></name><name><surname>Charpie</surname><given-names>JR</given-names></name><name><surname>Hirsch</surname><given-names>JC</given-names></name></person-group><article-title>Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass</article-title><source>Pediatr Crit Care Med</source><year>2010</year><volume>11</volume><fpage>234</fpage><lpage>238</lpage><pub-id pub-id-type="doi">10.1097/PCC.0b013e3181b806fc</pub-id><pub-id pub-id-type="pmid">19794327</pub-id></element-citation></ref><ref id="CR35"><label>35.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Horton</surname><given-names>S</given-names></name><name><surname>d’Udekem</surname><given-names>Y</given-names></name><name><surname>Shann</surname><given-names>F</given-names></name><name><surname>Butt</surname><given-names>W</given-names></name><name><surname>Bennett</surname><given-names>M</given-names></name><name><surname>Best</surname><given-names>D</given-names></name><name><surname>Brizard</surname><given-names>C</given-names></name></person-group><article-title>Extracorporeal membrane oxygenation via sternotomy for circulatory shock</article-title><source>J Thorac Cardiovasc Surg</source><year>2010</year><volume>139</volume><fpage>e12</fpage><lpage>e13</lpage><pub-id pub-id-type="doi">10.1016/j.jtcvs.2008.07.029</pub-id><pub-id pub-id-type="pmid">19660260</pub-id></element-citation></ref><ref id="CR36"><label>36.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goldman</surname><given-names>AP</given-names></name><name><surname>Kerr</surname><given-names>SJ</given-names></name><name><surname>Butt</surname><given-names>W</given-names></name><name><surname>Marsh</surname><given-names>MJ</given-names></name><name><surname>Murdoch</surname><given-names>IA</given-names></name><name><surname>Paul</surname><given-names>T</given-names></name><name><surname>Firmin</surname><given-names>RK</given-names></name><name><surname>Tasker</surname><given-names>RC</given-names></name><name><surname>Macrae</surname><given-names>DJ</given-names></name></person-group><article-title>Extracorporeal support for intractable cardiorespiratory failure due to meningococcal disease</article-title><source>Lancet</source><year>1997</year><volume>349</volume><fpage>466</fpage><lpage>469</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(96)12106-1</pub-id><pub-id pub-id-type="pmid">9040577</pub-id></element-citation></ref><ref id="CR37"><label>37.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Torgersen</surname><given-names>C</given-names></name><name><surname>Dünser</surname><given-names>MW</given-names></name><name><surname>Wenzel</surname><given-names>V</given-names></name><name><surname>Jochberger</surname><given-names>S</given-names></name><name><surname>Mayr</surname><given-names>V</given-names></name><name><surname>Schmittinger</surname><given-names>CA</given-names></name><name><surname>Lorenz</surname><given-names>I</given-names></name><name><surname>Schmid</surname><given-names>S</given-names></name><name><surname>Westphal</surname><given-names>M</given-names></name><name><surname>Grander</surname><given-names>W</given-names></name><name><surname>Luckner</surname><given-names>G</given-names></name></person-group><article-title>Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial</article-title><source>Intensive Care Med</source><year>2010</year><volume>36</volume><fpage>57</fpage><lpage>65</lpage><pub-id pub-id-type="doi">10.1007/s00134-009-1630-1</pub-id><pub-id pub-id-type="pmid">19756505</pub-id></element-citation></ref><ref id="CR38"><label>38.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takasu</surname><given-names>O</given-names></name><name><surname>Gaut</surname><given-names>JP</given-names></name><name><surname>Watanabe</surname><given-names>E</given-names></name><name><surname>To</surname><given-names>K</given-names></name><name><surname>Fagley</surname><given-names>RE</given-names></name><name><surname>Sato</surname><given-names>B</given-names></name><name><surname>Jarman</surname><given-names>S</given-names></name><name><surname>Efimov</surname><given-names>IR</given-names></name><name><surname>Janks</surname><given-names>DL</given-names></name><name><surname>Srivastava</surname><given-names>A</given-names></name><name><surname>Bhayani</surname><given-names>SB</given-names></name><name><surname>Drewry</surname><given-names>A</given-names></name><name><surname>Swanson</surname><given-names>PE</given-names></name><name><surname>Hotchkiss</surname><given-names>RS</given-names></name></person-group><article-title>Mechanisms of cardiac and renal dysfunction in patients dying of sepsis</article-title><source>Am J Respir Crit Care Med</source><year>2013</year><volume>187</volume><fpage>509</fpage><lpage>517</lpage><pub-id pub-id-type="doi">10.1164/rccm.201211-1983OC</pub-id><pub-id pub-id-type="pmid">23348975</pub-id></element-citation></ref><ref id="CR39"><label>39.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vieillard-Baron</surname><given-names>A</given-names></name><name><surname>Prin</surname><given-names>S</given-names></name><name><surname>Chergui</surname><given-names>K</given-names></name><name><surname>Dubourg</surname><given-names>O</given-names></name><name><surname>Jardin</surname><given-names>F</given-names></name></person-group><article-title>Hemodynamic instability in sepsis: bedside assessment by Doppler echocardiography</article-title><source>Am J Respir Crit Care Med</source><year>2003</year><volume>168</volume><fpage>1270</fpage><lpage>1276</lpage><pub-id pub-id-type="doi">10.1164/rccm.200306-816CC</pub-id><pub-id pub-id-type="pmid">14644922</pub-id></element-citation></ref><ref id="CR40"><label>40.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cvetkovic</surname><given-names>M</given-names></name><name><surname>Lutman</surname><given-names>D</given-names></name><name><surname>Ramnarayan</surname><given-names>P</given-names></name><name><surname>Pathan</surname><given-names>N</given-names></name><name><surname>Inwald</surname><given-names>DP</given-names></name><name><surname>Peters</surname><given-names>MJ</given-names></name></person-group><article-title>Timing of death in children referred for intensive care with severe sepsis: implications for interventional studies</article-title><source>Pediatr Crit Care Med</source><year>2015</year><volume>1</volume><fpage>410</fpage><lpage>417</lpage><pub-id pub-id-type="doi">10.1097/PCC.0000000000000385</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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