Discussion
This prospective, multicenter, observational study discloses that fungemia accounted for 8.3 % of the hospital-acquired BSI in patients admitted to the ICU. The mortality rate in HAF was high (40 %), but delayed adequate antifungal therapy was not an independent risk factor for death. The presence of septic shock and renal dysfunction on ICU admission and renal failure at BSI diagnosis were the only factors associated with fungemia in patients with BSI. In patients with HAF, multivariate logistic regression analysis identified liver SOFA score ≥3, need for mechanical ventilation and ICU admission for medical reasons as independent predictors of 28-day mortality.
Candidemia in critically ill patients is considered to be a severe and life-threatening condition. Recent data show that ICU and hospital mortality rates are usually between 36 % and 61 % [
5,
6,
14,
15,
18,
23‐
26]. In our study, we observed 28 day-mortality of 40.6 % which is in agreement with former findings [
27] and is lower than the rates observed in recent Australian [
19], Brazilian [
26] and Spanish-Italian [
18] studies.
Characteristics of bacteremic and fungemic patients at admission are remarkably similar, namely in terms of the comorbidity index, immunosuppression and chronic organ illnesses, and only the presence of septic shock and renal dysfunction on ICU admission and renal failure at diagnosis were more frequent in patients with HA-BSI and fungemia than in those with bacteremia. Although delay in appropriate treatment was significantly longer for HAF, the outcome was similar in patients with fungemia and those with bacteremia.
Kumar et al. [
28] observed strong correlation between shorter time to onset of antimicrobial treatment and reduced mortality in patients with septic shock. They showed that over the first 6 hours after the onset of persistent or recurrent hypotension, each hour of delay in initiating effective antimicrobial therapy was associated with a mean reduction in survival of 7.6 %, including the subgroup of patients with fungal infection. Nevertheless, the results of studies addressing the potential benefit of early antifungal therapy in patients with candidemia are conflicting.
In a small prospective multicenter study (n = 46 patients) [
14], there was a higher (though not significant,
p = 0.06) probability of survival among patients receiving early antifungal therapy (within ≤48 hours) compared with those treated 48 hours or more after the diagnosis of candidemia. A few years later, an independent association between delayed antifungal therapy (>48 hours) and in-hospital mortality (hazard ratio (HR) 2.1, 95 % CI 1.0–4.4,
p = 0.05) was reported by Blot et al. [
27]. According to Morrell et al. [
29], mortality doubles when antifungal agents are administered ≥12 hours after the collection of the first positive blood culture and in another retrospective analysis of 230 patients with candidemia [
30], initiation of fluconazole ≤24 hours after the first positive blood culture was associated with a significantly lower mortality rate. This positive effect of early antifungal therapy on survival was further confirmed in a group of patients with candidemia-associated septic shock who received treatment within 15 hours of blood culture collection [
31]. Finally, in 216 patients hospitalized in five teaching hospitals in Italy and Spain (18), who had septic shock attributable to candidemia, adequate antifungal therapy, meaning both infecting organism susceptibility and adequate antifungal dosage within the first 24 hours of culture positivity, was one of the factors associated with 30-day survival.
However, some recent studies did not observe this beneficial association between timing of antifungal therapy and mortality in patients with candidemia [
32‐
34]. Kludze-Forson et al. [
35] observed a higher in-hospital mortality rate in patients receiving antifungal therapy within the first 24 hours (50 %) compared to 24–48 hours (28 %) and more than 48 hours (32 %) after blood culture collection. More recently, in a large retrospective study that included 446 patients with candidemia [
36], there was neither a significant association between time from positive culture to administration of appropriate antifungal therapy and 30-day mortality, nor between timing of appropriate antifungal therapy and microbiological resolution of
Candida bloodstream infection. Studies addressing only ICU-acquired candidemia, also failed to show this positive impact [
19,
25,
37]. In the study of Marriott et al. [
19], mean time to initiation of antifungal therapy was similar for non-survivors and survivors (2.0 ± 1.3 days vs 2.3 ± 1.6 days,
p = 0.13), and Charles et al. [
37] also observed that early therapy (≤48 hours after onset of candidemia) did not improve the outcome of patients with candidemia. Finally, a prospective, Spanish multicenter study showed that inadequate antifungal therapy was a factor independently associated with early mortality (0–7 days) in candidemia, but it had no impact on late mortality (8–30 days) [
38].
In our study, four factors may contribute to the absence of impact of delayed adequate antifungal therapy on mortality. First, in critically ill patients, antifungal therapy is more likely to be started earlier than in non-ICU patients and, in fact, 22.9 % of the patients received adequate treatment within the first 24 hours and almost half of them within the first 48 hours after blood culture collection. Second, among critically ill patients any relationship between mortality and initiation of antifungal therapy may be hidden by the power of the patient’s acute illness as a determinant of outcome. Third, only half of our fungemia patients had septic shock at BSI diagnosis and the impact of early therapy is understandably higher in this subgroup of patients. Finally, timing to source control is a possible confounder that could not be analyzed, namely we did not collect data on the presence of a catheter, except on removal if it was deemed the source of the bloodstream infection.
Few prognostic factors have been identified in ICU patients with candidemia. In this cohort, the only independent prognostic factors associated with 28-day mortality were liver SOFA score ≥3, need for mechanical ventilation and ICU admission for medical reasons. Acute severity of illness is one important prognostic factor in candidemia. Among candidemic patients, the severity of organ dysfunction at fungemia onset evaluated by the SOFA score is a risk factor for mortality [
39]. In our study, only liver failure was independently associated with 28-day mortality. In
Candida bloodstream infection, this association between liver disease and outcome was previously reported but only for patients with chronic liver illness, which has a significant HR as an independent risk factor for 30-day mortality (HR 2.15, 95 % CI 1.48–3.13,
p <0.001) [
34]. There is also a relationship between other scores, such as the APACHE II score, and mortality in candidemic patients [
14,
23‐
25,
40]. In our study, we used the SAPS II score but despite being higher in non-survivors (52 vs 47,
p = 0.095), we could not prove it was an independent risk factor for mortality. A possible explanation is the fact that this score was calculated on admission and may not reflect the severity of the patients at the time of BSI diagnosis.
The need for mechanical ventilation as an independent risk factor for mortality has also been reported by several authors. In a prospective, multicenter, observational French study [
5], the use of mechanical ventilation increased the odds of dying in the ICU 2.54 times (95 % CI 1.33–4.82,
p = 0.0045). A similar result was reported in another large retrospective study (n = 987 patients with candidemia) [
41] that showed an independent association between mechanical ventilation and 30-day mortality (OR 2.61, 95 % CI 1.81–3.78,
p <0.001). An even higher impact was observed in a study with 173 ICU-acquired episodes of candidemia, in which the need of mechanical ventilation was associated with a four times increased risk of death (95 % CI 1.93–8.41,
p <0.001) [
19]. Almirante et al. also reported that intubation (OR 7.5, 95 % CI 2.6–21.1) was associated with higher odds of 30-day mortality in a cohort of 345 patients with candidemia, of whom 33 % were in the ICU at diagnosis [
42].
In our cohort, medical patients had a lower probability of survival. Interestingly, the same result was reported by Charles et al. [
37] a few years ago in a small study of 51 ICU patients with candidemia, in which medical patients had a higher mortality rate compared to surgical patients (85 % vs 45.2 %) and prior surgery was an independent factor associated with survival (HR 0.25, 95 % CI 0.09–0.67,
p <0.05). Other authors [
19] observed that the chances of dying with candidemia are 6.97 times higher in patients without multi-trauma (95 % CI 1.64–29.67,
p = 0.009).
Although our study is multicenter, prospective and includes a significant number of patients, it has some limitations. It is not representative of the populations of healthcare systems in the 24 participating countries, and in some countries the number of patients included was very small. Each participating ICU performed investigations and laboratory testing according to their local protocols. The data were entered into the electronic case report form by investigators at each center, which may have increased the risk of inconsistency. Finally, some important variables with potential impact on the outcome were not considered, namely the antifungal agent used, its appropriateness and the timing of central venous catheter removal.
Acknowledgements
The EUROBACT study was designed by the infection section of the ESICM. The study was endorsed by the European Critical Care Research Network (ECCRN) in May 2009 and received the Clinical Research Award with a research grant of €20,000 from the ECCRN in November 2011.
The manuscript was written on behalf of the EUROBACT study group listed below. Grants were obtained from Université Grenoble 1 and European Society of Intensive Care Medicine.
Members of the EUROBACT study group Steering Committee: Alexis Tabah, Despoina Koulenti, Stijn Blot, Jean-Ralph Zahar, Maité Garrouste-Orgeas, and Jean-François Timsit.
EUROBACT Scientific Committee: Jean Carlet, Christian Brun-Buisson, Georges Dimopoulos, Claude Martin, and Jordi Rello.
Statistics and methodology: Jean Francois Timsit, Alexis Tabah, and Kevin Laupland.
Biostatistician: Aurélien Vesin.
Study monitoring: Alexis Tabah and Sylvain Anselme.
Country coordinators: Australia: Jeffrey Lipman; Austria: Andreas Valentin; Belgium: Johan Decruyenaere; Brazil: Frederico Bruzzi de Carvalho; Canada: Kevin Laupland; China: Xiaochun Ma; Croatia: Ivan Gornik; France: Benoit Misset; Germany: Wolfgang A. Krueger; Greece: Despoina Koulenti; Hungary: Akos Csomos; Italy: Massimo Antonelli; Japan: Toshiki Mizobe; Morocco: Said Motaouakkil; The Netherlands: Marc J.M. Bonten; Poland: Adam Mikstacki; Portugal: José-Artur Paiva; Republic of Serbia: Uros Batranovic; Romania: Daniela Filipescu; Spain: Jordi Valles & Ricard Ferrer; Switzerland: Philippe Eggimann; Tunisia: Fekri Abroug; Turkey: Nahit Çakar; United Arab Emirates: Hussain Al Rahma.
ICU investigators, listed by ICU (by country): Jeffrey Lipman (Prof., MD) - Department of Intensive Care Medicine, Royal Brisbane & Women’s Hospital, Brisbane, Australia; Anne Leditschke (MD) and Helen Rodgers (RN) - Canberra Hospital Intensive Care Unit, Canberra Hospital, Canberra, Australia; David Milliss (ASC Prof.) and Thomas Gottlieb (ASC Prof.) - Intensive Care Services, Concord Hospital, NSW, Australia; Stuart Baker (MD) and Brigit Roberts (RN) - ICU, Sir Charles Gairdner Hospital, Perth, Australia; Peter Kraffft (MD) and Silvia Bernreiter (MD) - Intensiv 1b, Hospital Rudolfstiftung, Vienna, Austria; Pieter Depuydt (MD) - Intensieve Zorg, Universitair Ziekenhuis Gent, Ghent, Belgium; Philippe Jamaer (MD) - Icu A3 And C3, Jessa Hospital, Campus Virga Jesse, Hasselt, Belgium; Hervé Lebbinck (MD) - Iz, Az Sint Augustinus Veurne, Veurne, Belgium; Frederico Bruzzi De Carvalho (MD) and Juliana Pereira (MD) - Centro De Terapia Intensiva, Hospital Mater Dei, Belo Horizonte, Brazil; Aline Camille Yehia (MD), Felipe Carrhá Machado (MD), and Ana Luiza Horta de Sa Carneiro (MD) - Cti Hospital Julia Kubitschek, Julia Kubitschek, Belo Horizonte, Brazil; Antonio Fagundes Jr. (MD) - Unidade de Terapia Intensiva, Hospital do Coração do Brasil, Brasília - DF, Brazil; Fernando Rodriguez (MD) - Cti Geral, Hospital de Clínicas Niterói, Niterói, Brazil; Marcio Soares (MD, PhD) and Jorge Salluh (MD, PhD) - Cti, Instituto Nacional de Cancer, Rio De Janeiro, Brazil; Renata Beranger (MD) - ICU, São Lucas Hospital, Rio de Janeiro, Brazil; Marcelo Lugarinho (MD) - Cti Do Hospital De Clínicas Mario Lioni, Hospital De Clínicas Mario Lioni, Rio de Janeiro, Brazil; Alexandre Carvalho (MD) and Livia, Reis (RN) - Uti 1-2-3, Udi Hospital, São Luis - Ma, Brazil; Cyntia de Lima (MD) - Uti Clínica, Hospital Santa Izabel, Salvador, Brazil; Claudio Piras (Prof., MD, PhHD) - CPC, Vitoria Apart Hospital, Vitoria, Brazil; Eliana Caser (Prof.) and Jansen Falcão (MD) - Uti Geral Adulto, Centro Integrado De Atenção A Saúde - Cias Unimed Vitória, Vitória - ES, Brazil; Kevin B Laupland (MD) - ICU, Peter Lougheed Centre, Calgary, Canada; Kevin B. Laupland (MD) - ICU, Foothills Medical Centre, Calgary, Canada; Kevin B. Laupland (MD) - CVICU, Foothills Medical Centre, Calgary, Canada; Kevin B. Laupland (MD) - ICU, Rockyview General Hospital, Calgary, Canada; Zhidan Zhang (MD) and Xiaochun Ma (MD) - Department Of Critical Care Medicine, The First Affiliated Hospital Of China Medical University, Shenyang, China; Xian Yao Wan (Prof.) - Jiu Zhi Zhang (Prof.) - Department Of Intensive Care Medicine, The First Affiliated Hospital Of Dalian Medical University, Dalian, China; Ke-Jian Qian (Prof.) - Liang Xia (MD) - Intensive Care Unit, The First Affiliated Hospital Of Nan Chang University, Nan Chang, China; Congshan Yang (MD) - Department Of Critical Care Medicine, Zhongda Hospital, Southeast University, Nanjing, China; Deng Lijing (MD) - Central ICU, West China Hospital Of Sichuan University, Chengdu, China; Meili Duan (MD) - Department Of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Tang Zhanhong (Prof.) and Pan Yiping (MD) - Intensive Care Unit, The First Hospital Of Guangxi Medical University, Nanning, China; Wang Yongqiang (MD) - Luo Ning (MD) - ICU, Tianjin First Center Hospital, Tianjin, China; Zhou Li-Xin (Prof.) and Li Jin-Quan (MD) - Intensive Care Unit, The Affiliated Foshan Hospital Of Sun Yat-Sen University, Foshan, China; Xian Yao Wan (Prof.) - ICU, Beijing Tongren Hospital, Beijing, China; Ivan Gornik (MD) - Medical Intensive Care Unit, University Hospiral Centre Zagreb, Zagreb, Croatia; Vesna Degoricija (Prof., MD, PhD) - Medical ICU, University Hospital Sisters Of Mercy And University Of Zagreb School Of Medicine, Zagreb, Croatia; Achille Kouatchet (MD) - Département De Réanimation Médicale Et Médecine Hy, Chu Angers, Angers Cedex 9, France; Gaetan Plantefeve (MD) and Olivier Pajot (MD) - Réanimation Polyvalente, Ch Victor Dupouy, Argenteuil, France; Hatem Kallel (MD) - Polyvalent ICU, Andrée Rosemon, Cayenne, France; Lherm Thierry (MD) and Kalfon Pierre (MD) - Réanimation Polyvalente, Louis Pasteur, Chartres, France; David Petitpas (MD) - Réanimation polyvalente, Chg Châlons En Champagne, Châlons En Champagne, France; Henry Lessire (MD) - Réanimation Médicale, Ch Pasteur, Colmar, France; Christian Brun-Buisson (Prof., MD) - Tai Pham (MD) - Réanimation Médicale, Chu Henri Mondor, Créteil, France; Djillali Annane (Prof.) and Virginie Maxime (MD) - Réanimation Médicale, Chu, Garches, France; Herault Marie-Christine (MD) - Reanimation Polyvalente Chirurgicale, Chu Michallon, Grenoble, France; Sybille Merceron (MD) - Medico-Surgical ICU, André Mignot Versailles Hospital Centre, Le Chesnay, France; Eric Kipnis (ASC Prof., MD, PhD) and Marielle Boyer-Besseyre (ASC Prof., MD) - Réanimation Chirurgicale, CHRU De Lille, Lille, France; Benoit Tavernier (Prof., MD, PhD) and Sebastien Faivre (MD) - Réanimation Neurochirurgicale, CHRU de Lille, Lille, France; Voillet Francois (MD) and Renaud Lepaul Ercole (MD) - Medical Intensive Care Unit, Hopital North, Marseille, France; Vincent Willems (MD) - Réanimation Polyvalente, Centre Hospitalier De Meaux, Meaux, France; Kada Klouche (MD, PhD) and Jean Philippe Delabre (MD) - Medical Intensive Care Unit, Lapeyronie University Hospital, Montpellier, France; Cartier Julien (MD) and Gleyse Brigitte (RN) - Service De Réanimation Polyvalente, Ch De Montélimar, Montélimar, France; Sebastien Gibot (MD, PhD) - Réanimation Médicale, Hopital Central, Nancy, France; Bruno Mégarbane (Prof., MD, PhD) - Réanimation Médicale Et Toxicologique, Hôpital Lariboisière, Paris, France; Philippe Seguin (MD, PhD) - Réanimation Chirurgicale, Chu De Rennes, Rennes, France; Anne Launoy (MD) - Service De Réanimation Chirurgicale Hautepierre, Hôpitaux Universitaires De Strasbourg, Strasbourg, France; Tixier Vincent (MD) - Medical, Gabriel Montpied, Clermont-Ferrand, France; Samir Jamali (MD) - Usi (Unité De Soins Intensifs), Centre Hospitalier De Dourdan, Dourdan, France; Silvia Calvino (RN) and Alexis Tabah (MD) - Réanimation Médicale, Grenoble Teaching Hospital, Grenoble, France; Michel Durand (MD) and Marine Rossi-Blancher (MD) - Reanimation Cardiovasculaire et Thoracique, Hopital Michallon, Grenoble, France; Alexandre Debrumetz (MD) and Elie Azoulay (Prof.) - Service De Réanimation Médicale, CHU Saint Louis, Paris, France. Julien Charpentier (MD) and Jean-Daniel Chiche (Prof., MD, PhD) - Réanimation Médicale Polyvalente, Cochin, Paris, France; Maité Garrouste-Orgeas (MD) and Benoit Misset (MD) - Réanimation Polyvalente, Gh Paris Saint-Joseph, Paris, France; Gernot Marx (Prof., MD) - Klinik Für Operative Intensivmedizin Und Intermediate Care, University Hospital Aachen, Aachen, Germany; Wolfgang A. Krueger (MD, PhD) - Anaesthesiology and Intensive Care Medicine, Clinics Of Constance, Constance, Germany; Thomas Felbinger (MD, PhD) - Department of Anaesthesiology, The Munich Municipal Hospitals Ltd., Munich, Germany; Alexandra Heininger (MD, PhD) - ICU 20-22, Universitätsklinik Für Anaesthesiologie Und Intensivmedizin, Tuebingen, Germany; Ingo Voigt (MD) - Kardiologische Intensivstation, Elisabeth Krankenhaus Essen, Essen, Germany; Torsten Schroeder (MD) - Interdisziplinäre Intensivstation, Karl-Olga Krankenhaus, Stuttgart, Germany; Ioannis Pneumatikos (Prof., MD, PhD) - Vassiliki Theodorou (MD) - Critical Care Department, University Hospital of Alexandroupoli, Alexandroupoli, Greece; Despoina Koulenti (MD) - Apostolos Armaganidis (Prof., MD, PhD) - 2nd Critical Care Department, Attikon University Hospital, Athens, Greece; Pavlos Myrianthefs (ASC Prof., MD, PhD) - Alexandra Gavala (MD) - Athens University, School Of Nursing, ICU, “Kat” General Hospital, Athens, Greece; Chara Nikolaou (MD) - Katerina Kounougeri (MD) - Department of Critical Care Medicine, Konstantopouleion General Hospital of Nea Ionia, Athens, Greece; Christina Routsi (ASC Prof., MD, PhD) - Adamantia Liapikou (MD) - University ICU Department, Evangelismos General Hospital, Athens, Greece; Christodoulos Nathanail (MD, PhD) - Pirros Tsakas (MD) - Intensive Care Unit, General Hospital of Arta, Arta, Greece; Andreas Karabinis (MD, PhD) - Christos Tsakalakis (MD) - Critical Care Department, General Hospital “G. Genimatas”, Athens, Greece; Kostas Mandragos (MD,PhD) - Chrysostomos Katsenos (MD) - Intensive Care Unit, Red Cross (Erythros Stavros) Hospital, Athens, Greece; Georgios Anthopoulos (MD) - Georgios Choutas (MD) - Intensive Care Unit, 251 Air Force General Hospital, Athens, Greece; Anastasia Koutsikou (MD) - Ilona Nikolaidou (MD) - Intensive Care Unit (Surgical), General Hospital of Athens “Asklepieion Voulas”, Athens, Greece; Vasileios Bekos (MD) – Anna Spring (RN) - Intensive Care Unit, Naval Hospital of Athens, Athens, Greece; Haralambos Paskalis (MD) - Vassiliki Psallida (MD) - Intensive Care Unit, Hygeia General Hospital, Athens, Greece. Aikaterini Ioakeimidou (MD) - Alexandra Lahana (MD, PhD) - Intensive Care Unit, Athens Veterans Hospital (Nimits), Athens, Greece; Paraskevi Plantza (MD) - Aikaterini Nodarou (MD) - Icu Kaa Sotiria General Hospital, Sotiria General Hospital, Athens, Greece; Antonia Koutsoukou (ASC Prof., MD, PhD) - Magdalini Kyriakopoulou (MD) - ICU 1st Resp. Medicine Depart. Athens University, Sotiria General Hospital, Athens, Greece; Martha Michalia (MD) - Phyllis Clouva-Molyvdas (MD) - Department of Critical Care Medicine, “Thriassion” General Hospital of Eleusis, Elefsina, Athens, Greece; Dimitrios Sfyras (MD) - Christos Georgiadis (MD) - Intensive Care Unit, General Hospital of Lamia, Lamia, Greece; Pavlos Polakis (MD) - Spiros Papanikolaou (MD) - Intensive Care Unit, “Peiraiko Therapeftirio, Pireus, Greece; Christos Christopoulos (MD, PhD) - Efstratia Vrettou (MD) - Intensive Care Unit, General Hospital of Pyrgos, Pyrgos, Greece; Kostoula Arvaniti (MD, PhD) - Dimitrios Matamis (MD, PhD) - Critical Care Department, “Papageorgiou” General Hospital of Thessaloniki, Thessaloniki, Greece; Theoniki Paraforou (MD, PhD) - Kyriaki Spiropoulou (MD) - ICU, General Hospital Of Trikala, Trikala, Greece; Dimitris Georgopoulos (Prof., MD, PhD) - Maria Klimathianaki (MD) - Critical Care Department, University General Hospital of Heraklion, Crete, Heraklion, Greece; Georgios Nakos (Prof., MD, PhD) - Vasilios Koulouras (ASC Prof.F, MD, PhD) - Critical Care Department, University Hospital of Ioannina, Ioannina, Greece; Apostolos Komnos (MD, PhD) - Achilleas Chovas (MD, PhD) - Department Of Critical Care Medicine, General Hospital of Larisa, Larisa, Greece; Athanasios Prekates (MD, PhD) - Eleni Magira (MD, PhD) - Critical Care Department, “Tzaneion” General Hospital of Pireus, Pireus, Greece; Maria Giannakoy (MD, PhD) - Eleni Gkeka (MD) - Intensive Care Unit, “Ahepa” General Hospital, Thessaloniki, Greece; Eleni Antoniadou (MD, PhD) - Elli Antypa (MD,PhD) - Critical Care Department, General Hospital Of Thessaloniki “G. Genimatas”, Thessaloniki, Greece; Nikoletta Gritsi-Gerogianni (MD,PhD) - Christina Kydona (MD) - Critical Care Department, “Hippokrateion” General Hospital of Thessaloniki, Thessaloniki, Greece; Epaminondas Zakynthinos (ASC Prof., MD, PhD) - Nikolas Tzovaras (MD) - Critical Care Department, University Hospital of Larissa, Larissa, Greece; Akos Csomos (MD, PhD) - Surgical Intensive Care, Semmelweis University, Budapest, Hungary; Csóka Gábor (MD) - Sürgősségi Beteg Ellátó Egység, Fővárosi Önkormányzat Szent Imre Kórház, Budapest, Hungary; Borbala Mikos (MD) - György Velkey (MD) - Pediatric Anaesthesia And Intensive Care Unit, Bethesda Children’s Hospital of The Hungarian Reformed Church, Budapest, Hungary; Eszter Vitális (MD) - Auguszta Sebészet Intenzív, The Medical And Health Science Centre of the University of Debrecen, Debrecen, Hungary; Nóra, Ágota Kovács (MD) - Aito Flór Ferenc, Kistarcsa, Hungary; Lajos Bogar (Prof., MD, PHD) - Tamas Kiss (MD) - Department of Anaesthesia and Intensive Therapy, University Of Pécs 400 Bed Clinic, Pécs, Hungary; Zollei Eva (MD) - Medical ICU, University of Szeged, Szeged, Hungary; Valerio Mangani (MD) - Giorgio Tulli (Prof) - Intensive Care Unit, S.Giovanni Di Dio, Firenze, Italy. Guido Stefania (MD) - Ronco Chiara (student) - Centro Rianimazione, Maggiore Della Carità, Novara, Italy; Massimo Antonelli (Prof.) - Luca Montini (MD) - Rianimazione E Terapia Intensiva, Policlinico Universitario A. Gemelli, Rome, Italy; Monica Rocco (Prof., MD) - Giorgia Citterio (MD) - Centro Di Rianimazione, Policlinico Umberto I, Rome, Italy; Shigeki Fujitani (MD) - Emergency & Critical Care Medicine, St. Marianna University School of Medicine Hospital, Kanagawa, Japan; Koji Hosokawa (MD) - Intensive Care Unit, Kyoto Prefectural University Of Medicine, Kyoto, Japan; Motaouakkil Said (Prof.) - Charra Boubaker (Prof.) - Reanimation Medicale, CHU Ibn Rochd, Casablanca, Morocco; Marcus Schultz (Prof., MD, PhD, FCCP) - Annelou Van Der Veen (RN) - ICU, Academic Medical Center, Amsterdam, Netherlands; Heleen Aardema (MD) - Intensive and Respiratory Care Unit, University Medical Center Groningen, Groningen, Netherlands; Dennis Bergmans (MD, PhD) - Rik Schoemakers (BSc) - Department Of Intensive Care, Maastricht University Medical Centre, Maastricht, Netherlands; Ronald Wesselink (MD, PhD) - ICU, St. Antonius Ziekenhuis, Nieuwegein, Netherlands; Evelien A.N. Oostdijk (MD) - Marc J.M., Bonten (Prof., MD, PhD) - Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands; Iwona Dragan (MD) - ICU, General Hospital, Gniezno, Poland; Włodzimierz Kostyrka (MD) - Micu, Szpital Powiatowy, Ostrów Wielkopolski, Poland; Barbara Tamowicz (MD, PhD) - Adam Mikstacki (MD, PhD) - Department of Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, Regional Hospital, Poznan, Poland; Piotr Smuszkiewicz (MD, PhD) - Department of Anaesthesiology & Intensive Therapy, University Hospital, Poznan, Poland; Jacek Nadolski (MD, PhD) - Oa I It, Wielkopolska Center of Pulmonology and Thoracic surgery, Poznań, Poland; Robert Choma (MD) - Oddział Anestezjologii I Intensywnej Terapii, Szpital W Śremie, Śrem, Poland; Wladyslaw Koscielniak (MD) - Pawel Pietraszek (MD) - Oddzial Anestezjologii I Intesywnej Terapii, Regional Hospital Zielona Gora, Zielona Gora, Poland; Edward Maul (MD) - Serviço De Medicina Intensiva, Hospital Central Do Funchal, Funchal, Portugal. Anabela Bártolo (MD) - Salomé Martins - Ucip, Chaa - Guimarães, Guimarães, Portugal; Isabel Miranda (MD) - Mariana Oliveira - Ucip02, Hospital De St. António Dos Capuchos, Centro Hospitalar De Lisboa Central, E.P.E., Lisboa, Portugal; Carlos França (Prof.) - Ana Tornada (MD) - SMI, Hospital De Santa Maria, Lisbon, Portugal; Luís Telo (MD) - Leonardo Ferreira (MD) - Ucip, Pulido Valente, Lisboa, Portugal; Teresa Cardoso (MD) - Unidade De Cuidados Intensivos Polivalente, Hospital De Santo António, Porto, Portugal; Lurdes Santos (PhD) - Alcina Ferreira (MD) - Uci-Di, Hospital S. João, Porto, Portugal; José Manuel Pereira (MD) - Ucip Geral, Hospital S João, Porto, Portugal; Celeste Dias (MD) - UCI Neurocriticos, Hospital Sao Joao, Porto, Portugal; Maria Conceição Dias (MD) - UCIPU - Ucip Urgencia, Hospital De S. João, Porto, Portugal; Ana J. Marques (MD) - Paula Castelões (MD) - Ucipolivalente Do Chvngaia, Hospital Santos Silva - Centro Hospitalar Vila Nova De Gaia, Vila Nova Gaia, Portugal; Uros Batranovic (MD) - Srdjan Gavrilovic (MD) - Intensive Care Unit, Institute For Pulmonary Diseases of Vojvodina, Sremska Kamenica, Republic of Serbia; Daniela Filipescu (Prof., MD, PhD) - Cardiac Anesthesia And Intensive Care, Emergency Institute Of Cardiovascular Diseases, Bucharest, Romania; Francisco Alvarez-Lerma (PhD) - Maria Pilar Gracia (PhD) - Intensive Care Unit, Hospital Del Mar, Barcelona, Spain; Fernando Armestar-Rodriguez (MD) - Eduard, Mesalles-Sanjuán (MD) - Medicina Intensiva, Hospital Universitari Germans Trias I Pujol, Badalona, Spain; Nerea Lopez De Arbina (MD) - Josep Sirvent (MD) - Servicio De Medicina Intensiva, Hospital Universitari De Girona Dr Josep Trueta, Girona, Spain; Pau Garro (MD) - Uci General, Hospital General De Granollers, Granollers (Barcelona), Spain; Juan Ramón Cortés Cañones (MD) - Unidad Cuidados Intensivos, Complexo Hospitalario Ourense Cristal Piñor, Orense, Spain; Armando Blanco (MD, PhD) - Lara Marqués (MD, PhD) - Unidad De Medicna Intensiva I, Hospital Universitario Central De Asturias (Huca), Oviedo, Spain; Josu Insausti (MD) - Iñigo Martija (MD) - Uci, Hospital De Navarra, Pamplona, Spain; Jordi Valles (MD, PhD) - Ricard Ferrer (MD, PhD) - Critical Care Center, Hospital Sabadell, Sabadell, Spain; Alejandro Ubeda (MD) - Francisco Lucena (MD) - Polyvalent ICU, H.U Valme, Seville, Spain; Maricarmen Gilavert Cuevas (MD) - Uci, Hospital Universitario Joan Xxiii-Instituto Pere Virgili, Tarragona, Spain; Rafael Zaragoza (MD) - Susana Sancho (MD) – ICU, Hospital Univ. Dr. Peset, Hospital Universitario Dr. Peset, Valencia, Spain; Markus Laube (MD) - Madeleine Rothen (MD) - Intensivstation, Spitalzentrum, Biel, Switzerland; Philippe Eggimann (MD) - Jean-Luc Pagani (MD) - Service De Médecine Intensive Adulte, Chuv, Lausanne, Switzerland; Samia Ayed (MD) - Service De Reanimation Medicale, CHU Tahar Sfar, Mahdia, Tunisia; Islem Ouanes (MD) - Fekri Abroug (Prof.) - Réanimation Polyvalente, Chu Fattouma Bourguiba, Monastir, Tunisia; Dilek Özcengiz (Prof.) - Reanimation, Cukurova Medical University, Adana, Turkey; Seyhan Yağar (MD, PhD) - Cardiovascular Surgery, ICU, Türkiye Yüksek Ihtisas Hospital, Ankara, Turkey; Süheyla Ünver (MD, ASC Prof.) - Yeliz Irem Tunçel (MD) - Anestesia Intensive Care Unit, Ankara Dr Abdurrahman Yurtaslan Onkoloji E. A. Hastanesi, Ankara, Turkey; Unase Buyukkocak (Prof., MD) - Esra Aykac (Resident) - Intensive Care Unit and Anaesthesia, Kirikkale University, The School of Medicine Hospital, Kirikkale, Turkey; Ahmet COŞAR (Prof., MD) - Hüseyin Oğuz Yilmaz (MD) - Anesteziyoloji Ve Reanimasyon Ad Ybü, Gülhane Askeri Tıp Akademisi, Ankara, Turkey; Arash Pirat (ASC Prof.) - Pinar Zeyneloglu (ASC Prof.) - Surgical Intensive Care Unit, Baskent University Hospital, Ankara, Turkey; Nermin Kelebek Girgin (MD) - Halis Akalın (Prof., MD) - Anaesthesiology and ICU, Uludag University Medical Faculty, Bursa, Turkey; Hulya Sungurtekin (MD, Prof) - Simay Serin (Prof., MD) - Anaesthesiology and ICU, Pamukkale University, Denizli, Turkey; I. Ozkan Akinci (ASC Prof.) - Neuro Icu, Istanbul Medical Faculty, Istanbul, Turkey; Tayfun Adanir (MD) - Atilla Sencan (MD) - Anaesthesiology and ICU, Ataturk Training And Research Hospital, Izmir, Turkey; Ahmet Dilek (ASC Prof., MD) - Mikail Yüksel Intensive Care Unit, Ondokuz Mayis University, School of Medicine, Samsun, Turkey; Ismail KATI (ASC Prof.) - Ugur Goktas (ASC Prof.) - Anaesthesia and Intensive Care Unit, Yuzuncu Yil University Medical Faculty, Van, Turkey; Ashraf El Houfi (MD, MS, FRCP) - Micu-Sicu, Dubai Hospital, Dubai, United Arab Emirates.