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1. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020)

Author: Moritoki Egi, Hiroshi Ogura, Tomoaki Yatabe, Kazuaki Atagi, Shigeaki Inoue, Toshiaki Iba, Yasuyuki Kakihana, Tatsuya Kawasaki, Shigeki Kushimoto, Yasuhiro Kuroda, Joji Kotani, Nobuaki Shime, Takumi Taniguchi, Ryosuke Tsuruta, Kent Doi, Matsuyuki Doi, Taka-aki Nakada, Masaki Nakane, Seitaro Fujishima, Naoto Hosokawa, Yoshiki Masuda, Asako Matsushima, Naoyuki Matsuda, Kazuma Yamakawa, Yoshitaka Hara, Masaaki Sakuraya, Shinichiro Ohshimo, Yoshitaka Aoki, Mai Inada, Yutaka Umemura, Yusuke Kawai, Yutaka Kondo, Hiroki Saito, Shunsuke Taito, Chikashi Takeda, Takero Terayama, Hideo Tohira, Hideki Hashimoto, Kei Hayashida, Toru Hifumi, Tomoya Hirose, Tatsuma Fukuda, Tomoko Fujii, Shinya Miura, Hideto Yasuda, Toshikazu Abe, Kohkichi Andoh, Yuki Iida, Tadashi Ishihara, Kentaro Ide, Kenta Ito, Yusuke Ito, Yu Inata, Akemi Utsunomiya, Takeshi Unoki, Koji Endo, Akira Ouchi, Masayuki Ozaki, Satoshi Ono, Morihiro Katsura, Atsushi Kawaguchi, Yusuke Kawamura, Daisuke Kudo, Kenji Kubo, Kiyoyasu Kurahashi, Hideaki Sakuramoto, Akira Shimoyama, Takeshi Suzuki, Shusuke Sekine, Motohiro Sekino, Nozomi Takahashi, Sei Takahashi, Hiroshi Takahashi, Takashi Tagami, Goro Tajima, Hiroomi Tatsumi, Masanori Tani, Asuka Tsuchiya, Yusuke Tsutsumi, Takaki Naito, Masaharu Nagae, Ichiro Nagasawa, Kensuke Nakamura, Tetsuro Nishimura, Shin Nunomiya, Yasuhiro Norisue, Satoru Hashimoto, Daisuke Hasegawa, Junji Hatakeyama, Naoki Hara, Naoki Higashibeppu, Nana Furushima, Hirotaka Furusono, Yujiro Matsuishi, Tasuku Matsuyama, Yusuke Minematsu, Ryoichi Miyashita, Yuji Miyatake, Megumi Moriyasu, Toru Yamada, Hiroyuki Yamada, Ryo Yamamoto, Takeshi Yoshida, Yuhei Yoshida, Jumpei Yoshimura, Ryuichi Yotsumoto, Hiroshi Yonekura, Takeshi Wada, Eizo Watanabe, Makoto Aoki, Hideki Asai, Takakuni Abe, Yutaka Igarashi, Naoya Iguchi, Masami Ishikawa, Go Ishimaru, Shutaro Isokawa, Ryuta Itakura, Hisashi Imahase, Haruki Imura, Takashi Irinoda, Kenji Uehara, Noritaka Ushio, Takeshi Umegaki, Yuko Egawa, Yuki Enomoto, Kohei Ota, Yoshifumi Ohchi, Takanori Ohno, Hiroyuki Ohbe, Kazuyuki Oka, Nobunaga Okada, Yohei Okada, Hiromu Okano, Jun Okamoto, Hiroshi Okuda, Takayuki Ogura, Yu Onodera, Yuhta Oyama, Motoshi Kainuma, Eisuke Kako, Masahiro Kashiura, Hiromi Kato, Akihiro Kanaya, Tadashi Kaneko, Keita Kanehata, Ken-ichi Kano, Hiroyuki Kawano, Kazuya Kikutani, Hitoshi Kikuchi, Takahiro Kido, Sho Kimura, Hiroyuki Koami, Daisuke Kobashi, Iwao Saiki, Masahito Sakai, Ayaka Sakamoto, Tetsuya Sato, Yasuhiro Shiga, Manabu Shimoto, Shinya Shimoyama, Tomohisa Shoko, Yoh Sugawara, Atsunori Sugita, Satoshi Suzuki, Yuji Suzuki, Tomohiro Suhara, Kenji Sonota, Shuhei Takauji, Kohei Takashima, Sho Takahashi, Yoko Takahashi, Jun Takeshita, Yuuki Tanaka, Akihito Tampo, Taichiro Tsunoyama, Kenichi Tetsuhara, Kentaro Tokunaga, Yoshihiro Tomioka, Kentaro Tomita, Naoki Tominaga, Mitsunobu Toyosaki, Yukitoshi Toyoda, Hiromichi Naito, Isao Nagata, Tadashi Nagato, Yoshimi Nakamura, Yuki Nakamori, Isao Nahara, Hiromu Naraba, Chihiro Narita, Norihiro Nishioka, Tomoya Nishimura, Kei Nishiyama, Tomohisa Nomura, Taiki Haga, Yoshihiro Hagiwara, Katsuhiko Hashimoto, Takeshi Hatachi, Toshiaki Hamasaki, Takuya Hayashi, Minoru Hayashi, Atsuki Hayamizu, Go Haraguchi, Yohei Hirano, Ryo Fujii, Motoki Fujita, Naoyuki Fujimura, Hiraku Funakoshi, Masahito Horiguchi, Jun Maki, Naohisa Masunaga, Yosuke Matsumura, Takuya Mayumi, Keisuke Minami, Yuya Miyazaki, Kazuyuki Miyamoto, Teppei Murata, Machi Yanai, Takao Yano, Kohei Yamada, Naoki Yamada, Tomonori Yamamoto, Shodai Yoshihiro, Hiroshi Tanaka, and Osamu Nishida
Subjects: Evidence-based medicine, GRADE, Guidelines, Sepsis, Septic shock, Systematic review, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Abstract The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.
Published: 2021
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2. Posterior reversible encephalopathy syndrome (PRES) of the isolated brainstem

Author: Yosuke Hayashi, Tomoaki Hashida, Megumi Yazaki, Tomohiko Uchida, and Eizo Watanabe
Subjects: brain edema, emergency medicine, hypertension, magnetic resonance imaging, neurology, pons, Medicine, Medicine (General), R5-920
Abstract: Abstract A 71‐year‐old man had disordered consciousness whose Glasgow Coma Scale was E4V1M5. His blood pressure was high, but there was no abnormality in the cerebrospinal fluid examination. The MRI finding reveals a high‐intensity area at the pons without the blood flow interruption. Thus, he has diagnosed with brainstem PRES.
Published: 2022
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3. A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis

Author: Eizo Watanabe, Osamu Takasu, Youichi Teratake, Teruo Sakamoto, Toshiaki Ikeda, Joji Kotani, Nobuya Kitamura, Masaaki Ohmori, Ayako Teratani, Goichi Honda, Masahiko Hatano, Benjamin Mayer, E. Marion Schneider, and Shigeto Oda
Subjects: genetic predisposition to disease, genetic testing, multicenter studies, disseminated intravascular coagulation, single nucleotide polymorphisms, Medicine (General), R5-920
Abstract: Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (THBD). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis.Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis.Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (−1920*C/G; rs2239562) [odds ratio [OR] 2.709 (1.067–6.877), P = 0.033 and OR 1.768 (1.060–2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [OR 1.593 (1.086–2.338), P = 0.017].Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis.
Published: 2022
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4. Case Report: Lifesaving Hemostasis With Resuscitative Endovascular Balloon Occlusion of the Aorta in a Patient With Cardiac Arrest Caused by Upper Gastrointestinal Hemorrhage

Author: Tomoaki Hashida, Nanami Hata, Akiko Higashi, Yoshito Oka, Shunsuke Otani, and Eizo Watanabe
Subjects: cardiopulmonary arrest, cardiopulmonary resuscitation, radiology, interventional, shock, Medicine (General), R5-920
Abstract: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is performed to treat hemorrhagic shock, whose cause is located below the diaphragm. However, its use in patients with gastrointestinal hemorrhage is relatively rare. The 45-year-old man with a history of dilated cardiomyopathy had experienced epigastric discomfort and had an episode of presyncope. On his presentation, the patient's blood pressure was 82/64 mmHg, heart rate 140/min, and consciousness level GCS E4V5M6. Hemodynamics stabilized rapidly with a transfusion that was administered on an emergency basis, and a blood sample only showed mild anemia (Hb, 11.5 g/dL). The patient was admitted to investigating the presyncope episode, and the planned endoscopy was scheduled the following day. The patient had an episode of presyncope soon and was found in hemorrhagic shock resulting from a duodenal ulcer rapidly deteriorated to cardiac arrest. Although a spontaneous heartbeat was restored with cardiopulmonary resuscitation, the patient's hemodynamics were unstable despite the emergency blood transfusion administered by pumping. Consequently, a REBOA device was placed, resuscitation was continued, and hemostasis was achieved by vascular embolization for the gastroduodenal artery. The patient was subsequently discharged without complications. However, there is no established evidence regarding the REBOA use in upper gastrointestinal hemorrhage, and the investigations that have been reported have been limited. Further, one recent research suggests that appropriate patient selection and early use may improve survival in these life-threatening cases. As was seen in the present case, REBOA can effectively treat upper gastrointestinal hemorrhage by temporarily stabilizing hemodynamics and enabling a hemostatic procedure to be quickly performed during that time. This report also demonstrated the hemodynamics during the combination of intermittent and partial REBOA to avoid the complications of ischemic or reperfusion injury of the intestines or lower extremities.
Published: 2021
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5. Acquisition and Analysis of Microcirculation Image in Septic Model Rats

Author: Chen Ye, Mami Kawasaki, Kazuya Nakano, Takashi Ohnishi, Eizo Watanabe, Shigeto Oda, Taka-Aki Nakada, and Hideaki Haneishi
Subjects: microcirculation, sepsis, thrombomodulin (TM) alfa, blood velocity, vessel diameter, robust principal component analysis (RPCA), Chemical technology, TP1-1185
Abstract: Background: Microcirculation is a vital sign that supplies oxygen and nutrients to maintain normal life activities. Sepsis typically influences the operation of microcirculation, which is recovered by the administration of medicine injection. Objective: Sepsis-induced variation and recovery of microcirculation are quantitatively detected using microcirculation images acquired by a non-contact imaging setup, which might assist the clinical diagnosis and therapy of sepsis. Methods: In this study, a non-contact imaging setup was first used to record images of microcirculation on the back of model rats. Specifically, the model rats were divided into three groups: (i) the sham group as a control group; (ii) the cecum ligation and puncture (CLP) group with sepsis; and (iii) the CLP+thrombomodulin (TM) group with sepsis and the application of TM alfa therapy. Furthermore, considering the sparsity of red blood cells (RBCs), the blood velocity is estimated by robust principal component analysis (RPCA) and U-net, and the blood vessel diameter is estimated by the contrast difference between the blood vessel and tissue. Results and Effectiveness: In the experiments, the continuous degradation of the estimated blood velocity and blood vessel diameter in the CLP group and the recovery after degradation of those in the CLP+TM group were quantitatively observed. The variation tendencies of the estimated blood velocity and blood vessel diameter in each group suggested the effects of sepsis and its corresponding therapy.
Published: 2022
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6. Diagnosis of sepsis‐induced disseminated intravascular coagulation and coagulopathy

Author: Toshiaki Iba, Yutaka Umemura, Eizo Watanabe, Takeshi Wada, Kei Hayashida, Shigeki Kushimoto, and The Japanese Surviving Sepsis Campaign Guideline Working Group for disseminated intravascular coagulation
Subjects: Coagulopathy, diagnostic criteria, disseminated intravascular coagulation, sepsis/multiple organ failure, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Disseminated intravascular coagulation (DIC) is a frequent complication in sepsis. Once patients develop DIC, the mortality rate increases significantly. Moreover, recent studies have suggested that coagulation disorder plays a significant role in the development of organ dysfunction in sepsis. Thus, the early detection of DIC is vital in sepsis care, and the Japanese Association for Acute Medicine established a set of original diagnostic criteria in 2006 (JAAM DIC). Since then, the usefulness of the JAAM DIC has been repeatedly reported, and these criteria have been widely adopted in emergency and critical care settings in Japan. Different criteria have also been released by the International Society on Thrombosis and Haemostasis (ISTH overt‐DIC), and the latter criteria are presently considered to be the international standard. Compared with the JAAM DIC, the ISTH overt‐DIC criteria are stricter and the timing of diagnosis is later. This discrepancy is because of conceptual differences. As many physicians think sepsis‐associated DIC is the target of anticoagulant therapies in Japan, the JAAM DIC criteria were designed to allow the early initiation of treatment. As other countries do not provide DIC‐specific treatments, early diagnosis is not necessary, and this situation has led to a significant gap. However, as overt‐DIC is a late‐phase coagulation disorder, a need for early detection has been advocated, and members of the ISTH have recently proposed the category of sepsis‐induced coagulopathy. In this review, we introduce the strengths and weaknesses of the major criteria including JAAM‐DIC, ISTH overt‐DIC, sepsis‐induced coagulopathy, and Japanese Society on Thrombosis and Haemostasis‐DIC.
Published: 2019
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7. Sepsis-associated disseminated intravascular coagulation and its differential diagnoses

Author: Toshiaki Iba, Eizo Watanabe, Yutaka Umemura, Takeshi Wada, Kei Hayashida, Shigeki Kushimoto, Japanese Surviving Sepsis Campaign Guideline Working Group for disseminated intravascular coagulation, and Hideo Wada
Subjects: Disseminated intravascular coagulation, Sepsis, Thrombotic thrombocytopenic purpura, Hemolytic uremic syndrome, Heparin-induced thrombocytopenia, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Abstract Disseminated intravascular coagulation (DIC) is a common complication in sepsis. Since DIC not only promotes organ dysfunction but also is a strong prognostic factor, its diagnosis at the earliest possible timing is important. Thrombocytopenia is often present in patients with DIC but can also occur in a number of other critical conditions. Of note, many of the rare thrombocytopenic diseases require prompt diagnoses and specific treatments. To differentiate these diseases correctly, the phenotypic expressions must be considered and the different disease pathophysiologies must be understood. There are three major players in the background characteristics of thrombocytopenia: platelets, the coagulation system, and vascular endothelial cells. For example, the activation of coagulation is at the core of the pathogenesis of sepsis-associated DIC, while platelet aggregation is the essential mechanism in thrombotic thrombocytopenic purpura and endothelial damage is the hallmark of hemolytic uremic syndrome. Though each of the three players is important in all thrombocytopenic diseases, one of the three dominant players typically establishes the individual features of each disease. In this review, we introduce the pathogeneses, symptoms, diagnostic measures, and recent therapeutic advances for the major diseases that should be immediately differentiated from DIC in sepsis.
Published: 2019
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8. Thrombocytopenia in the ICU: disseminated intravascular coagulation and thrombotic microangiopathies—what intensivists need to know

Author: Jean-Louis Vincent, Pedro Castro, Beverley J. Hunt, Achim Jörres, Manuel Praga, Jose Rojas-Suarez, and Eizo Watanabe
Subjects: Disseminated intravascular coagulation, Hemolytic uremic syndrome, Intensive care unit, Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Published: 2018
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9. The Effects of Fasting and Massive Diarrhea on Absorption of Enteral Vancomycin in Critically Ill Patients: A Retrospective Observational Study

Author: Takehiko Oami, Noriyuki Hattori, Yosuke Matsumura, Eizo Watanabe, Ryuzo Abe, Taku Oshima, Waka Takahashi, Shingo Yamazaki, Tatsuya Suzuki, and Shigeto Oda
Subjects: vancomycin, enteral administration, therapeutic drug monitoring, Clostridium difficile infection, critical care, Medicine (General), R5-920
Abstract: PurposeAlthough vancomycin (VCM) is not absorbed from healthy intestinal mucosa, elevations in the serum VCM concentrations have been reported in some cases. The aims of this study are to evaluate the necessity of therapeutic drug monitoring (TDM) during enteral VCM administration in critically ill patients.Materials and methodsIn this retrospective study, we enrolled 19 patients admitted to our intensive care unit who were treated with enteral VCM from December 2006 to January 2014. Clinical factors were compared between two groups: Group E whose serum concentrations were detectable, and Group N whose concentrations were below the detection limit of the VCM assay.ResultsGroup E comprises 7 patients, and Group N comprises 12 patients. The fasting duration in Group E was significantly longer compared with that in Group N (17 vs. 8 days, p = 0.023). Furthermore, there was a significant correlation between the serum VCM concentrations and the fasting duration (r = 0.79, p
Published: 2017
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10. Autophagy-related IRGM polymorphism is associated with mortality of patients with severe sepsis.

Author: Tomonori Kimura, Eizo Watanabe, Teruo Sakamoto, Osamu Takasu, Toshiaki Ikeda, Kazumi Ikeda, Joji Kotani, Nobuya Kitamura, Tomohito Sadahiro, Yoshihisa Tateishi, Koichiro Shinozaki, and Shigeto Oda
Subjects: Medicine, Science
Abstract: ObjectiveAutophagy is the regulated catabolic process for recycling damaged or unnecessary organelles, which plays crucial roles in cell survival during nutrient deficiency, and innate immune defense against pathogenic microorganisms. Autophagy has been also reported to be involved in various conditions including inflammatory diseases. IRGM (human immunity-related GTPase) has an important function in eliminating Mycobacterium tuberculosis from host cells via autophagy. We examined the association between genetic polymorphism and clinical course/outcome in severely septic patients.MethodsThe study included 125 patients with severe sepsis/septic shock (SS) and 104 non-sepsis patients who were admitted to the intensive care unit (ICU) of Chiba University Hospital between October 2001 and September 2008 (discovery cohort) and 268 SS patients and 454 non-sepsis patients who were admitted to ICUs of five Japanese institutions including Chiba University Hospital between October 2008 and September 2012 (multi-center validation cohort). Three hundred forty seven healthy volunteers who consented to this study were also included. Genotyping was performed for a single-nucleotide polymorphism (SNP) within the coding region of IRGM, IRGM(+313) (rs10065172). Lipopolysaccharide challenge of whole blood from randomly selected healthy volunteers (n = 70) was performed for comparison of IRGM mRNA expression among different genotypes.ResultsNo significant difference in genotypic distributions (CC/CT/TT) at the IRGM(+313) locus was observed among the three subject groups (SS, non-sepsis, and healthy volunteers) in either cohort. When mortality were compared, no significant difference was observed in the non-sepsis group, while TT homozygotes exhibited a significantly higher mortality than the CC+CT genotype category in the SS group for both cohorts (P = 0.043, 0.037). Lipopolysaccharide challenge to whole blood showed a significant suppression of IRGM mRNA expression in TT compared with the CC+CT genotype category (P = 0.019).ConclusionsThe data suggest that the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation.
Published: 2014
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11. Investigation into Effect of Thrombomodulin Alfa for Septic Model Rats based on Microcirculation Image Analysis.

Author: Mami Kawasaki, Kazuya Nakano, Takashi Ohnishi, Masashi Sekine, Eizo Watanabe, Shigeto Oda, Taka-aki Nakada, and Hideaki Haneishi
Published: 2020
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12. Quantifying Myeloperoxidase-DNA and Neutrophil Elastase-DNA Complexes from Neutrophil Extracellular Traps by Using a Modified Sandwich ELISA

Author: Md. Monirul Islam, Umme Salma, Takayuki Irahara, Eizo Watanabe, and Naoshi Takeyama
Subjects: General Immunology and Microbiology, General Chemical Engineering, General Neuroscience, General Biochemistry, Genetics and Molecular Biology
Published: 2023

13. Mechanical ventilation in patients with cardiogenic pulmonary edema: a sub-analysis of the LUNG SAFE study

Author: Amado-Rodríguez, Laura, Rodríguez-Garcia, Raquel, Bellani, Giacomo, Pham, Tài, Fan, Eddy, Madotto, Fabiana, Laffey, John G, Albaiceta, Guillermo M, Antonio Pesenti, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, DanielF McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Fernando Rios, Frank Van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Sanatorio Las Lomas, San Isidro, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Joris Vermassen, Philippe Meersseman, Helga Ceunen, JonasI Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, MarlusM Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid BinHJAbul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, ShouH Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, ChristianM Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, BorisG Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, FrancescoL Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, DanieleM Combaux, Fabien Grelon, Charlene Le Moal, EliseP Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, RachanaV Rhayakar, Nagarajan Ramakrishnan, VallishK Bhardwaj, HeeraL Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, EimhinS Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, ColinS Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Sara Sher, Anna Rossi, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, RobertoR Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, EttoreR Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, YvesD Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, AsiscloJ Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Hellen M Van Wezel, SergeJ Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, DanielleJ Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, BritÅ Sjøbø, AnneB Guttormsen, Hector H LeonYoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, AnaM Araujo, NunoT Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, IsabelM Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, AhmedS AlJabbary, Edgardo Tabhan, YaseenM 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Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, AntonioG Jimenez, FranciscoP Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, CorcolesG Virgilio, NoeliaN Recio, Richard O Adamsson, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, KarinE Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, SilviaL Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, HervéO Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, OnatO Akyol, SuleymanS Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, ChristopherJ Scott, HelenE Ellis, Stuart Mckechnie, PaulaJ Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, MichaelN Dean, JuliusH Cranshaw, EmmaL Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, PieterD Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, SimonK Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, KatieH McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, DonaldA Irvine, Charing Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, SamanthaJ Hagan, JadeM Cole, Caroline C MacFie, AnnaT Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M BannerGoodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz Mesar, DaleJ Yeatts, Jessica Warren, MichaelJ Lanspa, Russel R Miller, ColinK Grissom, SamuelM Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Rebecca M Baro, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, RobertL Owens, Ashley Schomer, Amado-Rodríguez, Laura, Rodríguez-Garcia, Raquel, Bellani, Giacomo, Pham, Tài, Fan, Eddy, Madotto, Fabiana, Laffey, John G, Albaiceta, Guillermo M, Antonio Pesenti, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, DanielF McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Fernando Rios, Frank Van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, DanielF McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Sanatorio Las Lomas, San Isidro, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier 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Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, ShouH Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, ChristianM Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, BorisG Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, FrancescoL Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, DanieleM Combaux, Fabien Grelon, Charlene Le Moal, EliseP Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, RachanaV Rhayakar, Nagarajan Ramakrishnan, VallishK Bhardwaj, HeeraL Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, EimhinS Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, ColinS Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Sara Sher, Anna Rossi, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, RobertoR Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, EttoreR Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, YvesD Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, AsiscloJ Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Amine Ali Zeggwagh, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Leo M Heunks, Hellen M Van Wezel, SergeJ Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, DanielleJ Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, BritÅ Sjøbø, AnneB Guttormsen, Hector H LeonYoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, AnaM Araujo, NunoT Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, IsabelM Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, AhmedS AlJabbary, Edgardo Tabhan, YaseenM Arabi, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, JuanC Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, GuillermoM Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, AntonioL RuizAguilar, LuisM Claraco-Vega, Juan Alfonso Soler, Maria Del CarmenLorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, JuanB López-Messa, ManuelP Perez, CesarP Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana Temprano, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, M Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, AntonioG Jimenez, FranciscoP Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, CorcolesG Virgilio, NoeliaN Recio, Richard O Adamsson, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, KarinE Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, SilviaL Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, HervéO Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, OnatO Akyol, SuleymanS Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, ChristopherJ Scott, HelenE Ellis, Stuart Mckechnie, PaulaJ Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, MichaelN Dean, JuliusH Cranshaw, EmmaL Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, PieterD Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, SimonK Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, KatieH McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, DonaldA Irvine, Charing Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, SamanthaJ Hagan, JadeM Cole, Caroline C MacFie, 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Teresa, Arizmendi, Alfon, Piacentini, Enrique A., Franco, Nieve, Honrubia, Teresa, Cheng, Meisy Perez, Losada, Elena Perez, Blanco, Javier, Yuste, Luis J., Carbayo-Gorriz, Cecilia, Cazorla-Barranquero, Francisca G., Alonso, Javier G., Alda, Rosa S., Algaba, Ángela, Navarro, Gonzalo, Cereijo, Enrique, Diaz-Rodriguez, Esther, Marcos, Diego Pastor, Montero, Laura Alvarez, Para, Luis Herrera, Sanchez, Roberto Jimenez, Navalpotro, Miguel Angel Blasco, Abad, Ricardo Diaz, González, Raquel Montiel, Toribio, Dácil Parrilla, Castro, Alejandro G., Artiga, Maria Jose D., Penuelas, Oscar, Roser, Tomas P., Olga, Moreno F., Curto, Elena Gallego, Sánchez, Rocío Manzano, Imma, Vallverdu P., Elisabet, Garcia M., Claverias, Laura, Magret, Monica, Pellicer, Ana M., Rodriguez, Lucia L., Sánchez-Ballesteros, Jesú, González-Salamanca, Ángela, Jimenez, Antoniog, Huerta, Franciscop, Diaz, Juan Carlos J. Sotillo, Lopez, Esther Bermejo, Moya, David D. Llinare, Alfonso, Alec A. Tallet, Luis, Palazon Sanchez Eugenio, Cesar, Palazon Sanchez, Rafael, Sánchez I., Virgilio, Corcolesg, Recio, Noelian, Adamsson, Richard O., Rylander, Christian C., Holzgraefe, Bernhard, Broman, Lars M, Wessbergh, Joanna, Persson, Linnea, Schiöler, Fredrik, Kedelv, Han, Tibblin, Anna Oscarsson, Appelberg, Henrik, Hedlund, Lar, Helleberg, Johan, Eriksson, Karine, Glietsch, Rita, Larsson, Nikla, Nygren, Ingela, Nunes, Silvial, Morin, Anna-Karin, Kander, Thoma, Adolfsson, Anne, Zender, Hervéo, Leemann-Refondini, Corinne, Elatrous, Souheil, Bouchoucha, Slaheddine, Chouchene, Imed, Ouanes, Islem, Souissi, Asma Ben, Kamoun, Salma, Demirkiran, Oktay, Aker, Mustafa, Erbabacan, Emre, Ceylan, Ilkay, Girgin, Nermin Kelebek, Ozcelik, Menekse, Ünal, Necmettin, Meco, Basak Ceyda, Akyol, Onato, Derman, Suleyman, Kennedy, Barry, Parhar, Ken, Srinivasa, Latha, Mcauley, Danny, Hopkins, Phil, Mellis, Clare, Kakar, Vivek, Hadfield, Dan, Vercueil, Andre, Bhowmick, Kaushik, Humphreys, Sally K., Ferguson, Andrew, Mckee, Raymond, Raj, Ashok S., Fawkes, Danielle A., Watt, Philip, Twohey, Linda, Jha, Rajeev R., Thomas, Matthew, Morton, Alex, Kadaba, Varsha, Smith, Mark J., Hormis, Anil P., Kannan, Santhana G., Namih, Miriam, Reschreiter, Henrik, Camsooksai, Julie, Kumar, Alek, Rugonfalvi, Szabolc, Nutt, Christopher, Oneill, Orla, Seasman, Colette, Dempsey, Ged, Scott, Christopherj, Ellis, Helene, Mckechnie, Stuart, Hutton, Paulaj, Di Tomasso, Nora N., Vitale, Michela N., Griffin, Ruth O., Dean, Michaeln, Cranshaw, Juliush, Willett, Emmal, Ioannou, Nichola, Gillis, Sarah, Csabi, Peter, Macfadyen, Rosaleen, Dawson, Heidi, Preez, Pieterd, Williams, Alexandra J, Boyd, Owen, de Gordoa, Laura Ortiz-Ruiz, Bramall, Jon, Symmonds, Sophie, Chau, Simonk, Wenham, Tim, Szakmany, Tama, Toth-Tarsoly, Piroska, Mccalman, Katieh, Alexander, Peter, Stephenson, Lorraine, Collyer, Thoma, Chapman, Rhiannon, Cooper, Raphael, Allan, Russell M, Sim, Malcolm, Wrathall, David W, Irvine, Donalda, Zantua, Charing Kim S., Adams, John C., Burtenshaw, Andrew J., Sellors, Gareth P., Welters, Ingeborg D., Williams, Karen E., Hessell, Robert J., Oldroyd, Matthew G., Battle, Ceri E., Pillai, Suresh, Kajtor, Istvan, Sivashanmugavel, Mageswaran, Okane, Sinead C., Donnelly, Adrian, Frigyik, Aniko D., Careless, Jon P., May, Martin M, Stewart, Richard, Trinder, T. John, Hagan, Samanthaj, Cole, Jadem, Macfie, Caroline C., Dowling, Annat, Nin, Nicolá, Nuñez, Edgardo, Pittini, Gustavo, Rodriguez, Ruben, Imperio, María C., Santos, Cristina, França, Ana G, Ebeid, Alejandro, Deicas, Alberto, Serra, Carolina, Uppalapati, Aditya, Kamel, Ghassan, Bannergoodspeed, Valerie M., Beitler, Jeremy R., Mukkera, Satyanarayana Reddy, Kulkarni, Shreedhar, Shinn III, John O., Gomaa, Dina, Tainter, Christopher, Lee, Jarone, Mesar, Tomaz, Yeatts, Dalej, Warren, Jessica, Lanspa, Michaelj, Miller, Russel R., Grissom, Colink, Brown, Samuelm, Bauer, Philippe R., Gosselin, Ryan J., Kitch, Barrett T., Cohen, Jason E., Beegle, Scott H., Choudry, Shazia, Gueret, Renaud M., Tulaimat, Aiman, Stigler, William, Batra, Hitesh, Huff, Nidhi G., Lamb, Keith D., Oetting, Trevor W., Mohr, Nicholas M., Judy, Claine, Saito, Shigeki, Kheir, Fayez M., Kheir, Fayez, Schlichting, Adam B., Delsing, Angela, Crouch, Daniel R., Elmasri, Mary, Ismail, Dina, Dreyer, Kyle R., Blakeman, Thomas C., Baro, Rebecca M., Hou, Peter C., Seethala, Raghu, Aisiku, Imo, Henderson, Galen, Frendl, Gyorgy, Hou, Sen-Kuang, Owens, Robertl, Schomer, Ashley, Amado-Rodríguez, L, Rodríguez-Garcia, R, Bellani, G, Pham, T, Fan, E, Madotto, F, Laffey, J, and Albaiceta, G
Subjects: Ventilator-induced lung injury, Cardiogenic pulmonary edema, Driving pressure, Mechanical ventilation, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Settore MED/41 - ANESTESIOLOGIA, Critical Care and Intensive Care Medicine
Abstract: Supported by Centro de Investigación Biomédica en Red (CIBER)‑Enfermedades respiratorias, Madrid, Spain (CB17/06/00021) and Fundación para el Fomento en Asturias de la Investigación Científica aplicada y la tecnología (FICYT, AYUD2021/52014). RRG is the recipient of a grant from Instituto de Salud Carlos III, Madrid, Spain (CM20/00083)., Amado-Rodríguez L., Rodríguez-Garcia R., Bellani G., Pham T., Fan E., Madotto F., Laffey J.G., Albaiceta G.M., Pesenti A., Brochard L., Esteban A., Gattinoni L., van Haren F., Larsson A., McAuley D.F., Ranieri M., Rubenfeld G., Taylor Thompson B., Wrigge H., Slutsky A.S., Rios F., Van Haren F., Sottiaux T., Depuydt P., Lora F.S., Azevedo L.C., Bugedo G., Qiu H., Gonzalez M., Silesky J., Cerny V., Nielsen J., Jibaja M., Wrigge H., Matamis D., Ranero J.L., Amin P., Hashemian S.M., Clarkson K., Kurahashi K., Villagomez A., Zeggwagh A.A., Heunks L.M., Laake J.H., Palo J.E., do Vale Fernandes A., Sandesc D., Arabi Y.M., Bumbasierevic V., Nin N., Lorente J.A., Larsson A., Piquilloud L., Abroug F., McAuley D.F., McNamee L., Hurtado J., Bajwa E., Démpaire G., Sula H., Nunci L., Cani A., Zazu A., Dellera C., Insaurralde C.S., Las Lomas S., Isidro S., Alejandro R.V., Daldin J., Vinzio M., Fernandez R.O., Cardonnet L.P., Bettini L.R., Bisso M.C., Osman E.M., Setten M.G., Lovazzano P., Alvarez J., Villar V., Pozo N.C., Grubissich N., Plotnikow G.A., Vasquez D.N., Ilutovich S., Tiribelli N., Chena A., Pellegrini C.A., Saenz M.G., Estenssoro E., Brizuela M., Gianinetto H., Gomez P.E., Cerrato V.I., Bezzi M.G., Borello S.A., Loiacono F.A., Fernandez A.M., Knowles S., Reynolds C., Inskip D.M., Miller J.J., Kong J., Whitehead C., Bihari S., Seven A., Krstevski A., Rodgers H.J., Millar R.T., McKenna T.E., Bailey I.M., Hanlon G.C., Aneman A., Lynch J.M., Azad R., Neal J., Woods P.W., Roberts B.L., Kol M.R., Wong H.S., Riss K.C., Staudinger T., Wittebole X., Berghe C., Bulpa P.A., Dive A.M., Verstraete R., Lebbinck H., Depuydt P., Vermassen J., Meersseman P., Ceunen H., Rosa J.I., Beraldo D.O., Piras C., Rampinelli A.M., Nassar Jr A.P., Mataloun S., Moock M., Thompson M.M., Gonçalves C.H., Antônio A.C.P., Ascoli A., Biondi R.S., Fontenele D.C., Nobrega D., Sales V.M., BinHJAbul Wahab A.Y., Ismail M., Shindhe S., Laffey J., Beloncle F., Davies K.G., Cirone R., Manoharan V., Ismail M., Goligher E.C., Jassal M., Nishikawa E., Javeed A., Curley G., Rittayamai N., Parotto M., Ferguson N.D., Mehta S., Knoll J., Pronovost A., Canestrini S., Bruhn A.R., Garcia P.H., Aliaga F.A., Farías P.A., Yumha J.S., Ortiz C.A., Salas J.E., Saez A.A., Vega L.D., Labarca E.F., Martinez F.T., Carreño N.G., Lora P., Liu H., Qiu H., Liu L., Tang R., Luo X., An Y., Zhao H., Gao Y., Zhai Z., Ye Z.L., Wang W., Li W., Li Q., Zheng R., Yu W., Shen J., Li X., Yu T., Lu W., Wu Y.Q., Huang X.B., He Z., Lu Y., Han H., Zhang F., Sun R., Wang H.X., Qin S.H., Zhu B.H., Zhao J., Liu J., Li B., Liu J.L., Zhou F.C., Li Q.J., Zhang X.Y., Li-Xin Z., Xin-Hua Q., Jiang L., Gao Y.N., Zhao X.Y., Li Y.Y., Li X.L., Wang C., Yao Q., Yu R., Chen K., Shao H., Qin B., Huang Q.Q., Zhu W.H., Hang A.Y., Hua M.X., Li Y., Xu Y., Di Y.D., Ling L.L., Qin T.H., Wang S.H., Qin J., Han Y., Zhou S., Vargas M.P., Jimenez J.I.S., Rojas M.A.G., SolisQuesada J.E., Ramirez-Alfaro C.M., Máca J., Sklienka P., Gjedsted J., Christiansen A., Nielsen J., Villamagua B.G., Llano I., Burtin P., Buzancais G., Beuret P., Pelletier N., Mortaza S., Mercat A., Chelly J., Jochmans S., Terzi N., Daubin C., Carteaux G., de Prost N., Chiche J.-D., Daviaud F., Fartoukh M., Barberet G., Biehler J., Dellamonica J., Doyen D., Arnal J.-M., Briquet A., Hraiech S., Papazian L., Follin A., Roux D., Messika J., Kalaitzis E., Dangers L., Combes A., Béduneau G., Carpentier D., Zogheib E.H., Dupont H., Ricome S., Santoli F.L., Besset S.L., Michel P., Gelée B., Danin P.-E., Goubaux B., Crova P.J., Phan N.T., Berkelmans F., Badie J.C., Tapponnier R., Gally J., Khebbeb S., Herbrecht J.-E., Schneider F., Declercq P.L.M., Rigaud J.-P., Duranteau J., Harrois A., Chabanne R., Marin J., Bigot C., Thibault S., Ghazi M., Boukhazna M., Zein S.O., Richecoeur J.R., Combaux D.M., Grelon F., Le Moal C., Sauvadet E.P., Robine A., Lemiale V., Reuter D., Dres M., Demoule A., Goldgran-Toledano D., Baboi L., Guérin C., Lohner R., Kraßler J., Schäfer S., Zacharowski K.D., Meybohm P., Reske A.W., Simon P., Hopf H.B.F., Schuetz M., Baltus T., Papanikolaou M.N., Papavasilopoulou T.G., Zacharas G.A., Ourailogloy V., Mouloudi E.K., Massa E.V., Nagy E.O., Stamou E.E., Kiourtzieva E.V., Oikonomou M.A., Avila L.E., Cortez C.A., Citalán J.E., Jog S.A., Sable S.D., Shah B., Gurjar M., Baronia A.K., Memon M., Muthuchellappan R., Ramesh V.J., Shenoy A., Unnikrishnan R., Dixit S.B., Rhayakar R.V., Ramakrishnan N., Bhardwaj V.K., Mahto H.L., Sagar S.V., Palaniswamy V., Ganesan D., Jamaati H., Heidari F., Meaney E.A., Nichol A., Knapman K.M., O’Croinin D., Dunne E.S., Breen D.M., Jaafar R.F., Dwyer R., Amir F., Ajetunmobi O.O., O’Muircheartaigh A.C., Black C.S., Treanor N., Collins D.V., Altaf W., Zani G., Fusari M., Spadaro S., Volta C.A., Graziani R., Brunettini B., Palmese S., Formenti P., Umbrello M., Lombardo A., Pecci E., Botteri M., Savioli M., Protti A., Mattei A., Schiavoni L., Tinnirello A., Todeschini M., Giarratano A., Cortegiani A., Sher S., Rossi A., Antonelli M.M., Montini L.M., Casalena P., Scafetti S., Panarello G., Occhipinti G., Patroniti N., Pozzi M., Biscione R.R., Poli M.M., Raimondi F., Albiero D., Crapelli G., Beck E., Pota V., Schiavone V., Molin A., Tarantino F., Monti G., Frati E., Mirabella L., Cinnella G., Fossali T., Colombo R., Terragni P., Pattarino I., Mojoli F., Braschi A., Borotto E.E., Cracchiolo A.N., Palma D.M., Raponi F., Foti G., Vascotto E.R., Coppadoro A., Brazzi L., Floris L., Iotti G.A., Venti A., Yamaguchi O., Takagi S., Maeyama H.N., Watanabe E., Yamaji Y., Shimizu K., Shiozaki K., Futami S., Ryosuke S., Saito K., Kameyama Y., Ueno K., Izawa M., Okuda N., Suzuki H., Harasawa T., Nasu M., Takada T., Ito F., Nunomiya S., Koyama K., Abe T., Andoh K., Kusumoto K., Hirata A., Takaba A., Kimura H., Matsumoto S., Higashijima U., Honda H., Aoki N., Imai H., Ogino Y., Mizuguchi I., Ichikado K., Nitta K., Mochizuki K., Hashida T., Tanaka H., Nakamura T., Niimi D., Ueda T., Kashiwa Y., Uchiyama A., Sabelnikovs O., Oss P., Haddad Y., Liew K.Y., Ñamendys-Silva S.A., Jarquin-Badiola Y.D., Sanchez-Hurtado L.A., Gomez-Flores S.S., Marin M.C., Lemus J.S., Fierro J.M., Cervantes M.R., Mejia F.J.F., Dector D., Rojas A., Gonzalez D.R., Estrella C.R., Sanchez-Medina J.R., Ramirez-Gutierrez A., George F.G., Aguirre J.S., Buensuseso J.A., Poblano M., Dendane T., Zeggwagh A.A., Balkhi H., Elkhayari M., Samkaoui N., Ezzouine H., Benslama A., Amor M., Maazouzi W., Cimic N., Beck O., Bruns M.M., Schouten J.A., Rinia M., Raaijmakers M., Heunks L.M., Van Wezel H.M., Heines S.J., Strauch U., Buise M.P., Simonis F.D., Schultz M.J., Goodson J.C., Browne T.S., Navarra L., Hunt A., Hutchison R.A., Bailey M.B., Newby L., McArthur C., Kalkoff M., Mcleod A., Casement J., Hacking D.J., Andersen F.H., Dolva M.S., Laake J.H., Barratt-Due A., Noremark K.A.L., Søreide E., Sjøbø B.Å., Guttormsen A.B., LeonYoshido H.H., Aguilar R.Z., Oscanoa F.A.M., Alisasis A.U., Robles J.B., Pasanting-Lim R.A.B., Tan B.C., Andruszkiewicz P., Jakubowska K., Coxo C.M., Alvarez A.M., Oliveira B.S., Montanha G.M., Barros N.C., Pereira C.S., Messias A.M., Monteiro J.M., Araujo A.M., Catorze N.T., Marum S.M., Bouw M.J., Gomes R.M., Brito V.A., Castro S., Estilita J.M., Barros F.M., Serra I.M., Martinho A.M., Tomescu D.R., Marcu A., Bedreag O.H., Papurica M., Corneci D.E., Negoita S.I., Grigoriev E., Gritsan A.I., Gazenkampf A.A., Almekhlafi G., Albarrak M.M., Mustafa G.M., Maghrabi K.A., Salahuddin N., Aisa T.M., AlJabbary A.S., Tabhan E., Trinidad O.A., Al Dorzi H.M., Bumbasirevic V., Jovanovic B., Bolon S., Smith O., Mancebo J., Aguirre-Bermeo H., Lopez-Delgado J.C., Esteve F., Rialp G., Forteza C., De Haro C., Artigas A., Albaiceta G.M., De Cima-Iglesias S., Seoane-Quiroga L., Ceniceros-Barros A., RuizAguilar A.L., Claraco-Vega L.M., Soler J.A., del CarmenLorente M., Hermosa C., Gordo F., PrietoGonzález M., López-Messa J.B., Perez M.P., Perez C.P., Allue R.M., RocheCampo F., Ibañez-Santacruz M., Temprano S., Pintado M.C., De Pablo R., Gómez P.R.A., Ruiz S.R., Moles S.I., Jurado M.T., Arizmendi A., Piacentini E.A., Franco N., Honrubia T., Cheng M.P., Losada E.P., Blanco J., Yuste L.J., Carbayo-Gorriz C., Cazorla-Barranquero F.G., Alonso J.G., Alda R.S., Algaba Á., Navarro G., Cereijo E., Diaz-Rodriguez E., Marcos D.P., Montero L.A., Para L.H., Sanchez R.J., Navalpotro M.A.B., Abad R.D., González R.M., Toribio D.P., Castro A.G., Artiga M.J.D., Penuelas O., Roser T.P., Olga M.F., Curto E.G., Sánchez R.M., Imma V.P., Elisabet G.M., Claverias L., Magret M., Pellicer A.M., Rodriguez L.L., Sánchez-Ballesteros J., González-Salamanca Á., Jimenez A.G., Huerta F.P., Diaz J.C.J.S., Lopez E.B., Moya D.D.L., Alfonso A.A.T., Luis P.S.E., Cesar P.S., Rafael S.I., Virgilio C.G., Recio N.N., Adamsson R.O., Rylander C.C., Holzgraefe B., Broman L.M., Wessbergh J., Persson L., Schiöler F., Kedelv H., Tibblin A.O., Appelberg H., Hedlund L., Helleberg J., Eriksson K.E., Glietsch R., Larsson N., Nygren I., Nunes S.L., Morin A.-K., Kander T., Adolfsson A., Zender H.O., Leemann-Refondini C., Elatrous S., Bouchoucha S., Chouchene I., Ouanes I., Souissi A.B., Kamoun S., Demirkiran O., Aker M., Erbabacan E., Ceylan I., Girgin N.K., Ozcelik M., Ünal N., Meco B.C., Akyol O.O., Derman S.S., Kennedy B., Parhar K., Srinivasa L., McNamee L., McAuley D., Hopkins P., Mellis C., Kakar V., Hadfield D., Vercueil A., Bhowmick K., Humphreys S.K., Ferguson A., Mckee R., Raj A.S., Fawkes D.A., Watt P., Twohey L., Jha R.R., Thomas M., Morton A., Kadaba V., Smith M.J., Hormis A.P., Kannan S.G., Namih M., Reschreiter H., Camsooksai J., Kumar A., Rugonfalvi S., Nutt C., Oneill O., Seasman C., Dempsey G., Scott C.J., Ellis H.E., Mckechnie S., Hutton P.J., Di Tomasso N.N., Vitale M.N., Griffin R.O., Dean M.N., Cranshaw J.H., Willett E.L., Ioannou N., Gillis S., Csabi P., Macfadyen R., Dawson H., Preez P.D., Williams A.J., Boyd O., de Gordoa L.O.-R., Bramall J., Symmonds S., Chau S.K., Wenham T., Szakmany T., Toth-Tarsoly P., McCalman K.H., Alexander P., Stephenson L., Collyer T., Chapman R., Cooper R., Allan R.M., Sim M., Wrathall D.W., Irvine D.A., Zantua C.K.S., Adams J.C., Burtenshaw A.J., Sellors G.P., Welters I.D., Williams K.E., Hessell R.J., Oldroyd M.G., Battle C.E., Pillai S., Kajtor I., Sivashanmugavel M., Okane S.C., Donnelly A., Frigyik A.D., Careless J.P., May M.M., Stewart R., Trinder T.J., Hagan S.J., Cole J.M., MacFie C.C., Dowling A.T., Hurtado J., Nin N., Hurtado J., Nuñez E., Pittini G., Rodriguez R., Imperio M.C., Santos C., França A.G., Ebeid A., Deicas A., Serra C., Uppalapati A., Kamel G., BannerGoodspeed V.M., Beitler J.R., Mukkera S.R., Kulkarni S., Shinn III J.O., Gomaa D., Tainter C., Lee J., Mesar T., Yeatts D.J., Warren J., Lanspa M.J., Miller R.R., Grissom C.K., Brown S.M., Bauer P.R., Gosselin R.J., Kitch B.T., Cohen J.E., Beegle S.H., Choudry S., Gueret R.M., Tulaimat A., Stigler W., Batra H., Huff N.G., Lamb K.D., Oetting T.W., Mohr N.M., Judy C., Saito S., Kheir F.M., Kheir F., Schlichting A.B., Delsing A., Crouch D.R., Elmasri M., Crouch D.R., Ismail D., Dreyer K.R., Blakeman T.C., Baro R.M., Hou P.C., Seethala R., Aisiku I., Henderson G., Frendl G., Hou S.-K., Owens R.L., Schomer A.
Published: 2022

14. Outcome of acute hypoxaemic respiratory failure: insights from the LUNG SAFE Study

Author: Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andres, Gattinoni, Luciano, Larsson, Anders, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, 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Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan 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Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin 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Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, 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Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andre, Gattinoni, Luciano, Larsson, Ander, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tài Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L 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Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori 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C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Intensive Care Medicine, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Pham, T, Pesenti, A, Bellani, G, Rubenfeld, G, Fan, E, Bugedo, G, Lorente, J, Fernandes, A, Van Haren, F, Bruhn, A, Rios, F, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Thompson, B, Wrigge, H, Brochard, L, Laffey, J, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), St. Michael's Hospital, University of Toronto, Groupe de recherche clinique CARMAS, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano [Milano] (UNIMI), University of Milan, San Gerardo Hospital, Sunnybrook Health Sciences Center, Mount Sinai Hospital [Toronto, Canada] (MSH), Pontificia Universidad Católica de Chile (UC), University Hospital of Getafe, CIBER Enfermedades Respiratorias (CIBERES), Universidad Europea de Madrid, Hospital Garcia de Orta (EPE), Canberra Hospital, Medical School [Australian National University - ANU], Australian National University (ANU), University of Canberra, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Göttingen - Georg-August-Universität Göttingen, Uppsala University, Queen's University [Belfast] (QUB), Royal Victoria Hospital, McGill University Health Center [Montreal] (MUHC), Università degli Studi di Bologna, Massachusetts General Hospital [Boston], University Hospital Leipzig, Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, 06112, Halle, National University of Ireland [Galway] (NUI Galway), Bayer GlaxoSmithKline, GSK Baxter International Boehringer Ingelheim Wellcome Trust, WT National Institute for Health Research, NIHR Queen's University Belfast, QUB Medical Research Council Canada, MRC European Society of Intensive Care Medicine, ESICM, Support statement: This work was supported by the European Society of Intensive Care Medicine. Funding information for this article has been deposited with the Crossref Funder Registry., Conflict of interest: T. Pham has nothing to disclose. A. Pesenti reports personal fees from Maquet, Novalung/Xenios, Baxter, Gilead and Boehringer Ingelheim, outside the submitted work. G. Bellani reports grants and personal fees from Draeger Medical, personal fees from Getinge, Hamilton, GE Healthcare, Dimar SRL, Intersurgical and Flowmeter SPA, outside the submitted work. G. Rubenfeld has nothing to disclose. E. Fan reports personal fees from ALung Technologies, Getinge and MC3 Cardiopulmonary, grants, personal fees and non-financial support from Fresenius Medical Care, outside the submitted work. G. Bugedo has nothing to disclose. J.A. Lorente has nothing to disclose. A.D. V. Fernandes has nothing to disclose. F. Van Haren has nothing to disclose. A. Bruhn has nothing to disclose. F. Rios has nothing to disclose. A. Esteban has nothing to disclose. L. Gattinoni has nothing to disclose. A. Larsson reports grants from the Swedish Heart and Lung Foundation, during the conduct of the study. D.F. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work, in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK, NI HSC R&D Division, NI Chest Heart and Stroke, and MRC, is one of four named inventors on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution, The Queen’s University of Belfast (http://www.google.com/patents/US8962032), and is a Director of Research for the Intensive Care Society and NIHR EME Programme Director. M. Ranieri has nothing to disclose. B.T. Thompson reports personal fees from Bayer, Thetis and Novartis, outside the submitted work. H. Wrigge reports personal fees for consultancy from Dräger Medical, personal fees for advisory board work from Liberate Medical, grants and personal fees for lectures from InfectoPharm, personal fees for lectures from MSD and GE, outside the submitted work. L.J. Brochard reports grants from Medtronic Covidien, grants and non-financial support from Fisher Paykel, non-financial support from Air Liquide, Sentec and Philips, other (patent) from General Electric, outside the submitted work. J.G. Laffey reports grants and personal fees from Baxter, grants and non-financial support from Aerogen and Factor Biosciences, outside the submitted work., LUNG SAFE Investigators and the European Society of Intensive Care Medicine Trials Group: Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J 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Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Amine Ali Zeggwagh, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Leo M Heunks, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, and UCL - (SLuc) Service de soins intensifs
Subjects: Pulmonary and Respiratory Medicine, ARDS, Unidades de cuidados intensivos, [SDV]Life Sciences [q-bio], medicine.medical_treatment, mechanical ventilation, NO, law.invention, 03 medical and health sciences, Tratamiento médico, 0302 clinical medicine, law, Settore MED/41 - ANESTESIOLOGIA, Insuficiencia respiratoria, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Lung, Mechanical ventilation, Respiratory Distress Syndrome, business.industry, Respiration, Incidence (epidemiology), medicine.disease, Intensive care unit, Respiration, Artificial, 3. Good health, Intensive Care Units, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], medicine.anatomical_structure, 030228 respiratory system, Respiratory failure, Heart failure, Anesthesia, Artificial, ards, business, Respiratory Insufficiency, Enfermedad
Abstract: BackgroundCurrent incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).MethodsAn international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH2O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared.Findings12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved.InterpretationMore than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.
Published: 2021

15. Posterior reversible encephalopathy syndrome (PRES) of the brainstem

Author: Yosuke Hayashi, Tomoaki Hashida, Megumi Yazaki, Tomohiko Uchida, and Eizo Watanabe
Abstract: A 71-year-old man had disordered consciousness whose Glasgow Coma Scale was E4V1M5. His blood pressure was high, but there was no abnormality in the cerebrospinal fluid examination. The MRI finding reveals a high-intensity area at the pons without the blood flow interruption. Thus, he has diagnosed with brainstem PRES
Published: 2022

16. Lesão medular no Centro de Reabilitação e Readaptação Dr. Henrique Santillo (CRER- GO) Lesión medular en el Centro de Rehabilitación y Readaptación Dr. Henrique Santillo (CRER-GO) Spinal cord injury in Dr. Henrique Santillo Rehabilitation and Readaptation Center (CRER-GO)

Author: Natália Ribeiro de Oliveira Custódio, Maurício Rassi Carneiro, Caroline Campelo Feres, Gabriela Henrique Souza Lima, Maria Raquel Ramos Jubé, Leonardo Eizo Watanabe, Lívia Gabriela Rocha Santos de Oliveira Saliba, Sérgio Daher, and Ana Cristina Ferreira Garcia
Subjects: Traumatismos de la médula espinal, Salud pública, Accidentes de tráfico, Traumatismos da medula espinhal, Saúde pública, Acidentes de trânsito, Spinal cord injuries, Public health, Accidents, traffic, Orthopedic surgery, RD701-811, Diseases of the musculoskeletal system, RC925-935
Abstract: OBJETIVO: avaliação epidemiológica de pacientes com diagnóstico de lesão medular internados para reabilitação na enfermaria do Centro de Reabilitação e Readaptação Dr. Henrique Santillo (CRER) em Goiânia, Goiás. MÉTODOS: estudo epidemiológico retrospectivo baseado na coleta de dados dos prontuários médicos dos pacientes internados no período de Março de 2007 a Março de 2009. RESULTADOS: foram avaliados 208 pacientes, com predomínio do sexo masculino (78,85%) e idade média de 35,3 anos. O déficit neurológico mais prevalente foi paraplegia (64,90%), sendo 54,33% dos pacientes classificados como ASIA A (lesão completa) de acordo com a classificação da American Spinal Injury Association (ASIA). O tempo médio de lesão até a admissão no CRER foi de 129,7 dias, e o tempo médio de internação para reabilitação destes pacientes foi de 44,9 dias. A principal etiologia da lesão medular foi traumática, sendo 44,70% representadas por acidente de trânsito. A complicação mais comum na internação foi infecção do trato urinário. CONCLUSÃO: os dados epidemiológicos de pacientes com lesão medular, admitidos no CRER para reabilitação, se mostraram em conformidade com dados já descritos na literatura, demonstrando cada vez mais a importância da divulgação e realização de campanhas de prevenção do trauma raquimedular. Assim como a necessidade do encaminhamento precoce destes pacientes ao centro de reabilitação, uma vez que a grande maioria é jovem, com sequelas neurológicas graves e altamente incapacitantes.OBJETIVO: evaluación epidemiológica de pacientes con diagnóstico de lesión medular internados para rehabilitación en urgencias del Centro de Rehabilitación y Readaptación Dr. Henrique Santillo (CRER) en Goiânia, Goiás. MÉTODOS: estudio epidemiológico retrospectivo con base en la recogida de datos de las historias médica de los pacientes internados en el periodo de Marzo de 2007 a Marzo de 2009. RESULTADOS: fueron evaluados 208 pacientes, con predominio de sexo masculino (78.85%), edad promedio de 35.3 años. El déficit neurológico más relevante fue paraplejia (64.90%), siendo 54.33% clasificados como ASIA A (lesión completa) de acuerdo con la clasificación de la American Spinal Injury Association (ASIA). El tiempo promedio de una lesión a la admisión en el CRER fue de 129.7 días y media estancia en el hospital para la rehabilitación de estos pacientes fue de 44.9 días. La principal etiología de la lesión medular fue traumática, siendo 44.70% representados por accidente de tráfico. La complicación más común en la internación fue infección del tracto urinario. CONCLUSIÓN: los datos epidemiológicos de pacientes con lesión medular admitidos en el CRER para rehabilitación se mostraron en conformidad con aquellos ya descritos en la literatura, demostrando cada vez mayor importancia de la divulgación y realización de campañas de prevención del trauma raquimedular. También hay necesidad de remitir de forma precoz a estos pacientes al centro de rehabilitación, una vez que la gran mayoría son pacientes jóvenes, con secuelas neurológicas graves y altamente discapacitantes.OBJECTIVE: retrospective epidemiological analysis of spinal cord injury patients admitted to Centro de Reabilitação e Readaptação Dr. Henrique Santillo (CRER) in Goiânia, Goiás. METHODS: retrospective epidemiological study based on the analysis of medical records data of patients who were hospitalized in the period from March 2007 to March 2009. RESULTS: 208 patients were analyzed, predominantly male (78.85%) with a mean age of 35.3 years. The most neurological deficit was paraplegic (64.90%), and 54.33% of the patients were classified as ASIA A (complete lesion), according to the American Spinal Injury Association (ASIA). The average time from injury to admission was 129.7 days, and the mean time of hospitalization was 44.9 days. The main cause was traumatic spinal cord injury and of these, 44.70% were from traffic accidents. The main complication was urinary tract infection. CONCLUSION: the epidemiological data of spinal cord injury patients admitted to rehabilitation in CRER was in accordance with data already reported in literature, demonstrating the importance of dissemination and implementation campaigns for the prevention of spinal cord trauma. As well as the need for early referral of patients to a rehabilitation center, since most of them are young with severe neurological deficit and highly disabling.
Published: 2009
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17. Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: Insights from the LUNG SAFE study

Author: Madotto F, Rezoagli E, Pham T, Schmidt M, McNicholas B, Protti A, Panwar R, Bellani G, Fan E, van Haren F, Brochard L, Laffey JG, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Fernando Rios, T Sottiaux, P Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Uhc Mother Theresa, Hektor Sula, Lordian Nunci, Alma Cani, Villa Maria, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E Mckenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Suresh Shindhe, Dk Maizatul Aiman B Pg Hj Ismail, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E Solis-Quesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Miguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tai Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, Pierre-Louis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, Hans-Bernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Sara Sher, Anna Rossi, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin-Nunomiya Kansuke-Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Dulce M Dector, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra-Rinia, Monique Raaijmakers, Hellen M Van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, 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C., Cazorla-Barranquero, F. G., Alonso, J. G., Alda, R. S., Algaba, A., Navarro, G., Cereijo, E., Diaz-Rodriguez, E., Marcos, D. P., Montero, L. A., Para, L. H., Sanchez, R. J., Navalpotro, M. A. B., Abad, R. D., Gonz A Lez, R. M., Toribio, D. A. C. P., Castro, A. G., Artiga, M. J. D., Penuelas, O., Roser, T. P., Olga, M. F., Curto, E. G., Sanchez, R. M., Imma, V. P., Elisabet, G. M., Claverias, L., Magret, M., Pellicer, A. M., Rodriguez, L. L., Sanchez-Ballesteros, J., Gonzalez-Salamanca, A., Jimenez, A. G., Huerta, F. P., Sotillo Diaz, J. C. J., Lopez, E. B., Llinares Moya, D. D., Tallet Alfonso, A. A., Luis, P. S. E., Cesar, P. S., Rafael, S. I., Virgilio, C. G., Recio, N. N., Adamsson, R. O., Rylander, C. C., Holzgraefe, B., Broman, L. M., Wessbergh, J., Persson, L., Schioler, F., Kedelv, H., Tibblin, A. O., Appelberg, H., Hedlund, L., Helleberg, J., Eriksson, K. E., Glietsch, R., Larsson, N., Nygren, I., Nunes, S. L., Morin, A. -K., Kander, T., Adolfsson, A., Zender, H. O., Leemann-Refondini, C., Elatrous, S., Bouchoucha, S., Chouchene, I., Ouanes, I., Souissi, A. B., Kamoun, S., Demirkiran, O., Aker, M., Erbabacan, E., Ceylan, I., Girgin, N. K., Ozcelik, M., Unal, N., Meco, B. C., Akyol, O. O., Derman, S. S., Kennedy, B., Parhar, K., Srinivasa, L., Hopkins, P., Mellis, C., Kakar, V., Hadfield, D., Vercueil, A., Bhowmick, K., Humphreys, S. K., Ferguson, A., Mckee, R., Raj, A. S., Fawkes, D. A., Watt, P., Twohey, L., Jhamatthew Thomas, R. R., Morton, A., Kadaba, V., Smith, M. J., Hormis, A. P., Kannan, S. G., Namih, M., Reschreiter, H., Camsooksai, J., Kumar, A., Rugonfalvi, S., Nutt, C., O'Neill, O., Seasman, C., Dempsey, G., Scott, C. J., Ellis, H. E., Mckechnie, S., Hutton, P. J., Di Tomasso, N. N., Vitale, M. N., Griffin, R. O., Dean, M. N., Cranshaw, J. H., Willett, E. L., Ioannou, N., Gillis, S., Csabi, P., Macfadyen, R., Dawson, H., Preez, P. D., Williams, A. J., Boyd, O., De Gordoa, L. O. -R., Bramall, J., Symmonds, S., Chau, S. K., Wenham, T., Szakmany, T., Toth-Tarsoly, P., Mccalman, K. H., Alexander, P., Stephenson, L., Collyer, T., Chapman, R., Cooper, R., Allan, R. M., Sim, M., Wrathall, D. W., Irvine, D. A., Zantua, K. S., Adams, J. C., Burtenshaw, A. J., Sellors, G. P., Welters, I. D., Williams, K. E., Hessell, R. J., Oldroyd, M. G., Battle, C. E., Pillai, S., Kajtor, I., Sivashanmugavel, M., O'Kane, S. C., Donnelly, A., Frigyik, A. D., Careless, J. P., May, M. M., Stewart, R., Trinder, T. J., Hagan, S. J., Wise, M. P., Cole, J. M., Macfie, C. C., Dowling, A. T., Nunez, E., Pittini, G., Rodriguez, R., Imperio, M. C., Santos, C., Franca, A. G., Ebeid, A., Deicas, A., Serra, C., Uppalapati, A., Kamel, G., Banner-Goodspeed, V. M., Beitler, J. R., Mukkera, S. R., Kulkarni, S., Lee, J., Mesar, T., Shinn, J. O., Gomaa, D., Tainter, C., Yeatts, D. J., Warren, J., Lanspa, M. J., Miller, R. R., Grissom, C. K., Brown, S. M., Bauer, P. R., Gosselin, R. J., Kitch, B. T., Cohen, J. E., Beegle, S. H., Gueret, R. M., Tulaimat, A., Choudry, S., Stigler, W., Batra, H., Huff, N. G., Lamb, K. D., Oetting, T. W., Mohr, N. M., Judy, C., Saito, S., Kheir, F. M., Kheir, F., Schlichting, A. B., Delsing, A., Crouch, D. R., Elmasri, M., Ismail, D., Dreyer, K. R., Blakeman, T. C., Baron, R. M., Grijalba, C. Q., Hou, P. C., Seethala, R., Aisiku, I., Henderson, G., Frendl, G., Hou, S. -K., Owens, R. L., Schomer, A., Bumbasirevic, V., Jovanovic, B., Surbatovic, M., Veljovic, M., UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, UCL - (SLuc) Service de soins intensifs, Graduate School, Intensive Care Medicine, ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Madotto, F, Rezoagli, E, Pham, T, Schmidt, M, Mcnicholas, B, Protti, A, Panwar, R, Bellani, G, Fan, E, Van Haren, F, Brochard, L, Laffey, J, Pesenti, A, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Rubenfeld, G, Thompson, B, Wrigge, H, Slutsky, A, Rios, F, Sottiaux, T, Depuydt, P, Lora, F, Azevedo, L, Bugedo, G, Qiu, H, Gonzalez, M, Silesky, J, Cerny, V, Nielsen, J, Jibaja, M, Matamis, D, Ranero, J, Amin, P, Hashemian, S, Clarkson, K, Kurahashi, K, Villagomez, A, Zeggwagh, A, Heunks, L, Laake, J, Palo, J, Do Vale Fernandes, A, Sandesc, D, Arabi, Y, Bumbasierevic, V, Nin, N, Lorente, J, Piquilloud, L, Abroug, F, Mcnamee, L, Hurtado, J, Bajwa, E, Dempaire, G, Theresa, U, Sula, H, Nunci, L, Cani, A, Maria, V, Zazu, A, Dellera, C, Insaurralde, C, Alejandro, R, Daldin, J, Vinzio, M, Fernandez, R, Cardonnet, L, Bettini, L, Bisso, M, Osman, E, Setten, M, Lovazzano, P, Alvarez, J, Villar, V, Pozo, N, Grubissich, N, Plotnikow, G, Vasquez, D, Ilutovich, S, Tiribelli, N, Chena, A, Pellegrini, C, Saenz, M, Estenssoro, E, Brizuela, M, Gianinetto, H, Gomez, P, Cerrato, V, Bezzi, M, Borello, S, Loiacono, F, Fernandez, A, Knowles, S, Reynolds, C, Inskip, D, Miller, J, Kong, J, Whitehead, C, Bihari, S, Seven, A, Krstevski, A, Rodgers, H, Millar, R, Mckenna, T, Bailey, I, Hanlon, G, Aneman, A, Lynch, J, Azad, R, Neal, J, Woods, P, Roberts, B, Kol, M, Wong, H, Riss, K, Staudinger, T, Wittebole, X, Berghe, C, Bulpa, P, Dive, A, Verstraete, R, Lebbinck, H, Vermassen, J, Meersseman, P, Ceunen, H, Rosa, J, Beraldo, D, Piras, C, Rampinelli, A, Nassar, A, Mataloun, S, Moock, M, Thompson, M, Goncalves, C, Antonio, A, Ascoli, A, Biondi, R, Fontenele, D, Nobrega, D, Sales, V, Shindhe, S, Pg Hj Ismail, D, Beloncle, F, Davies, K, Cirone, R, Manoharan, V, Ismail, M, Goligher, E, Jassal, M, Nishikawa, E, Javeed, A, Curley, G, Rittayamai, N, Parotto, M, Ferguson, N, Mehta, S, Knoll, J, Pronovost, A, Canestrini, S, Bruhn, A, Garcia, P, Aliaga, F, Farias, P, Yumha, J, Ortiz, C, Salas, J, Saez, A, Vega, L, Labarca, E, Martinez, F, Carreno, N, Lora, P, Liu, H, Liu, L, Tang, R, Luo, X, An, Y, Zhao, H, Gao, Y, Zhai, Z, Ye, Z, Wang, W, Li, W, Li, Q, Zheng, R, Yu, W, Shen, J, Li, X, Yu, T, Lu, W, Wu, Y, Huang, X, He, Z, Lu, Y, Han, H, Zhang, F, Sun, R, Wang, H, Qin, S, Zhu, B, Zhao, J, Liu, J, Li, B, Zhou, F, Zhang, X, Li-Xin, Z, Xin-Hua, Q, Jiang, L, Zhao, X, Li, Y, Wang, C, Yao, Q, Yu, R, Chen, K, Shao, H, Qin, B, Huang, Q, Zhu, W, Hang, A, Hua, M, Xu, Y, Di, Y, Ling, L, Qin, T, Wang, S, Qin, J, Han, Y, Zhou, S, Vargas, M, Silesky Jimenez, J, Gonzalez Rojas, M, Solis-Quesada, J, 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S, Lee, J, Mesar, T, Shinn, J, Gomaa, D, Tainter, C, Yeatts, D, Warren, J, Lanspa, M, Miller, R, Grissom, C, Brown, S, Bauer, P, Gosselin, R, Kitch, B, Cohen, J, Beegle, S, Gueret, R, Tulaimat, A, Choudry, S, Stigler, W, Batra, H, Huff, N, Lamb, K, Oetting, T, Mohr, N, Judy, C, Saito, S, Kheir, F, Schlichting, A, Delsing, A, Crouch, D, Elmasri, M, Ismail, D, Dreyer, K, Blakeman, T, Baron, R, Grijalba, C, Hou, P, Seethala, R, Aisiku, I, Henderson, G, Frendl, G, Hou, S, Owens, R, Schomer, A, Bumbasirevic, V, Jovanovic, B, Surbatovic, M, Veljovic, M, Madotto F, Rezoagli E, Pham T, Schmidt M, McNicholas B, Protti A, Panwar R, Bellani G, Fan E, van Haren F, Brochard L, Laffey JG, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Fernando Rios, T Sottiaux, P Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Uhc Mother Theresa, Hektor Sula, Lordian Nunci, Alma Cani, Villa Maria, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E Mckenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Suresh Shindhe, Dk Maizatul Aiman B Pg Hj Ismail, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E Solis-Quesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Miguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tai Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, Pierre-Louis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, Hans-Bernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Sara Sher, Anna Rossi, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin-Nunomiya, Kansuke-Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Dulce M Dector, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra-Rinia, Monique Raaijmakers, Hellen M Van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin Mcarthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L Ruiz-Aguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam-Prieto-González, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran Roche-Campo, Marcos Ibañez-Santacruz, Susana-Temprano, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier-Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel Gonz Á Lez, D Á Cil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Richard O Adamsson, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R JhaMatthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla O'Neill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz De Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C O'Kane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Matt P Wise, Jade M Cole, Caroline C MacFie, Anna T Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, Jarone Lee, Tomaz Mesar, John O Shinn 3rd, Dina Gomaa, Christopher Tainter, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Madotto F, Rezoagli E, Pham T, Schmidt M, McNicholas B, Protti A, Panwar R, Bellani G, Fan E, van Haren F, Brochard L, Laffey JG, and LUNG SAFE Investigators and the ESICM Trials Group, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Renaud M Gueret, Aiman Tulaimat, Shazia Choudry, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Rebecca M Baron, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Vesna Bumbasirevic, Bojan Jovanovic, Maja Surbatovic, Milic Veljovic
Subjects: ARDS, medicine.medical_treatment, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Hyperoxemia, Hypoxemia, law.invention, 0302 clinical medicine, law, Fraction of inspired oxygen, Oxygen therapy, Prevalence, Medicine, Hypoxia, Acute respiratory distress syndrome, Hyperoxia, Invasive mechanical ventilation, Mortality, Respiratory Distress Syndrome, Hyperbaric Oxygenation, Respiration, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Intensive care unit, Intensive Care Units, Anesthesia, Artificial, medicine.symptom, Human, Artificial ventilation, Intensive Care Unit, NO, 03 medical and health sciences, Intensive care, Settore MED/41 - ANESTESIOLOGIA, Humans, business.industry, Research, Respiratory Distress Syndrome, Adult, lcsh:RC86-88.9, medicine.disease, Respiration, Artificial, respiratory tract diseases, Oxygen, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030228 respiratory system, business
Abstract: Background Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55–100 mmHg) patients (P = 0.47). Conclusions Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073
Published: 2020

18. Recombinant thrombomodulin attenuates hyper-inflammation and glycocalyx damage in a murine model of Streptococcus pneumoniae-induced sepsis

Author: Masaaki Ohmori, Masahiko Hatano, Naruhiko Ishiwada, Haruka Hishiki, Rintaro Nishimura, Chizuru Ito, Eizo Watanabe, Toshinobu Akamatsu, Lisa Fujimura, Noriko Takeuchi, and Mayu Kato
Subjects: Male, Endothelium, Thrombomodulin, Immunology, Inflammation, Systemic inflammation, Glycocalyx, Biochemistry, Pneumococcal Infections, Sepsis, Andrology, Mice, medicine, Immunology and Allergy, Animals, HMGB1 Protein, Molecular Biology, Lung, business.industry, Tumor Necrosis Factor-alpha, Endothelial Cells, Hematology, medicine.disease, Shock, Septic, Recombinant Proteins, Interleukin-10, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Streptococcus pneumoniae, Tumor necrosis factor alpha, medicine.symptom, Inflammation Mediators, business, Protein C, medicine.drug
Abstract: Purpose The anticoagulant agent recombinant thrombomodulin (rTM) activates protein C to prevent excessive coagulation and also possibly regulates hyper-inflammation via neutralization of high-mobility-group B1 (HMG-B1). The glycocalyx layer in endothelial cells also plays a pivotal role in preventing septic shock–associated hyperpermeability. The present study examined the effect of rTM in a murine model of Streptococcus pneumoniae–induced sepsis. Methods Male C57BL/6N mice were injected intratracheally via midline cervical incision with 2 × 107 CFU of S. pneumoniae (capsular subtype 19A). Control mice were sham-treated identically but injected with saline. rTM (10 mg/kg) was injected intraperitoneally 3 h after septic insult. Blood concentrations of soluble inflammatory mediators (interleukin [IL]-1β, IL-6, IL-10, and tumor necrosis factor [TNF]-α) were determined using a microarray immunoassay. Serum concentrations of HMG-B1 and syndecan-1, as a parameter of glycocalyx damage, were determined by enzyme-linked immunosorbent assay. The glycocalyx was also evaluated with electron microscopy. The lungs were removed, and digested to cells, which were then stained with a mixture of fluorophore-conjugated antibodies. Anti-mouse primary antibodies included PE-Cy7–conjugated anti-CD31, AlexaFluor 700–conjugated anti-CD45, PerCP-Cy5.5–conjugated anti-CD326, APC-conjugated anti–TNF-α, PE-conjugated anti–IL-6, and PE-conjugated anti–IL-10. A total of 1 × 106 cells per sample were analyzed, and 2 × 105 events were recorded by flow cytometry, and parameters were compared with/without rTM treatment. Results The blood concentration of TNF-α was significantly reduced 24 h after intratracheal injection in S. pneumoniae–challenged mice treated with rTM (P = 0.016). Levels of IL-10 in the lung endothelium of rTM-treated S. pneumoniae–challenged mice increased significantly 12 h after intratracheal injection (P = 0.03). Intriguingly, serum HMGB-1 and syndecan-1 levels decreased significantly (P = 0.010 and 0.015, respectively) in rTM-treated mice 24 h after intratracheal injection of S. pneumoniae. Electron microscopy indicated that rTM treatment preserved the morphology of the glycocalyx layer in septic mice. Conclusions These data suggest that rTM modulates local inflammation in the lung endothelium, thus diminishing systemic inflammation, i.e., hypercytokinemia. Furthermore, rTM treatment reduced serum syndecan-1 levels, thus preventing glycocalyx damage. The use of rTM to treat sepsis caused by bacterial pneumonia could therefore help prevent both excessive inflammation and glycocalyx injury in the lung endothelium.
Published: 2021

19. Blocking Liver Autophagy Accelerates Apoptosis and Mitochondrial Injury in Hepatocytes and Reduces Time to Mortality in a Murine Sepsis Model

Author: Takehiko Oami, Lisa Fujimura, Eizo Watanabe, Shigeto Oda, Paul E. Swanson, Kiyotaka Toshimori, Akemi Sakamoto, Youichi Teratake, Chizuru Ito, and Masahiko Hatano
Subjects: Male, 0301 basic medicine, Time Factors, Reactive oxygen species metabolism, Apoptosis, Punctures, Critical Care and Intensive Care Medicine, Sepsis, Mice, 03 medical and health sciences, 0302 clinical medicine, Autophagy, medicine, Animals, Cecum, Ligation, Liver injury, Reverse Transcriptase Polymerase Chain Reaction, business.industry, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Liver metabolism, Liver, 030220 oncology & carcinogenesis, Hepatocytes, Emergency Medicine, Cancer research, Cytokines, Reactive Oxygen Species, business, Liver pathology
Abstract: Autophagy plays an important role in cell survival, sequestering, and degrading a wide variety of substrates. Although an increase of autophagosomes in liver has been reported in sepsis patients as well as in septic mice, the influence of autophagy on liver injury, the interaction between autophagy, and other types of cell death in sepsis remain unclear. The aim of this study was to elucidate the contribution of liver autophagy to the pathophysiology of sepsis. We performed a cecal ligation and puncture on liver-specific autophagy-deficient (Alb-Cre/Atg5) mice (6-8-week-old male). When compared with controls (C57BL/6), we found a significant accumulation of p62 in the liver and demonstrated a greater number of cleaved caspase-3 immunoreactive hepatocytes in these knockout (KO) mice. Additionally, we confirmed a significant increase in autophagic vacuoles in the control mice relative to KO mice; in contrast, cell shrinkage and nuclear fragmentation (morphological characteristics of apoptosis) were preferentially seen in the KO mice by transmission electron microscopy. Severe mitochondrial damage was also prominent in KO mice, relative to controls, associated with an increase of reactive oxygen species in hepatocytes. Serum aspartate transaminase levels (P = 0.005) and serum interleukin-6 levels (P = 0.020) were significantly increased in the KO mice compared with controls. Deficiency of autophagy in liver significantly decreased survival in the murine sepsis model (P = 0.025). In conclusion, blocking liver autophagy accelerates time to mortality in the murine sepsis model, suggesting that liver autophagy plays a protective role for organ failure through degradation of damaged mitochondria, as well as prevention of apoptosis.
Published: 2018

20. Pharmacokinetics of recombinant human soluble thrombomodulin in disseminated intravascular coagulation patients with acute renal dysfunction

Author: Jun Tagawa, Eizo Watanabe, Mineji Hayakawa, Yasushi Suzuki, Fumiyo Komatsu, Satoshi Gando, Shigeki Kushimoto, Koji Goto, Tomoaki Yatabe, Toru Kotani, and Takeyuki Kiguchi
Subjects: Male, Thrombomodulin, 030204 cardiovascular system & hematology, Kidney, Severity of Illness Index, Gastroenterology, sepsis, 0302 clinical medicine, Japan, Prospective Studies, Plasma concentration, Aged, 80 and over, Disseminated intravascular coagulation, Anticoagulant, Hematology, Middle Aged, Recombinant Proteins, Treatment Outcome, Renal Elimination, medicine.anatomical_structure, Area Under Curve, Acute Disease, Female, Kidney Diseases, pharmacokinetics, Half-Life, Coagulation and Fibrinolysis, medicine.medical_specialty, Metabolic Clearance Rate, medicine.drug_class, Renal function, Hemorrhage, Models, Biological, 03 medical and health sciences, Pharmacokinetics, renal dysfunction, Internal medicine, medicine, Humans, Adverse effect, disseminated intravascular coagulation, Aged, business.industry, Anticoagulants, 030208 emergency & critical care medicine, medicine.disease, Surgery, business
Abstract: SummaryRecombinant human soluble thrombomodulin (ART-123) is a novel anticoagulant for patients with disseminated intravascular coagulation (DIC). It is widely used in clinical settings throughout Japan. Furthermore, a global Phase 3 study is currently being conducted. In healthy subjects, ART-123 is excreted mainly via the kidneys. Therefore, ART-123 dose decrease was recommended in DIC patients with severe renal dysfunction. However, the pharmacokinetics of ART-123 in DIC patients with severe acute renal dysfunction has not been elucidated. In an open-label, multicentre, prospective, clinical pharmacological study, we investigated the pharmacokinetics and safety of ART-123 upon repeated administration to DIC patients. ART-123 was administered to patients at a dose of 130 or 380 U/kg/day for six consecutive days. Plasma concentrations of ART-123 were measured at 21 time points until eight days after the final administration. Urinary excretion rates during the first 24 hours (h) were calculated. Patient renal functions were evaluated by measuring 24-h creatinine clearance (Ccr). Forty-three patients were enrolled in the present study. The urinary excretion rates of ART-123 correlated closely with 24-h Ccr. Total body clearance of ART-123 was also weakly related with 24-h Ccr. However, the plasma concentrations of ART-123 were not considerably different among patients with different renal function. Two patients had subcutaneous haemorrhage as an adverse event related to ART-123. In conclusion, plasma concentrations of ART-123 may not be different among patients with different renal functions. ART-123 was well tolerated in these patients.
Published: 2017

21. Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study

Author: Shigeto Oda, Tatsuaki Okamura, Motoi Odani, Tomohiro Harada, Yasuyuki Kakihana, Osamu Nishida, and Eizo Watanabe
Subjects: Male, AUC, average AUC from time 0 to infinity, medicine.medical_treatment, Lymphocyte, adverse event, Cmin, 030204 cardiovascular system & hematology, Pharmacology, Critical Care and Intensive Care Medicine, Clinical Science Aspects, end of infusion concentration, intensive care unit, time to maximum concentration, Sequential Organ Failure Assessment, 0302 clinical medicine, trough concentration, PD-1, SOFA, immunostimulation, concentration on day 14, apparent volume of distribution, volume of distribution under steady state conditions, Infusions, Intravenous, Immune Checkpoint Inhibitors, programmed death-1, immunosuppression, TSH, recombinant thrombomodulin, monocyte human leukocyte antigen-DR subtype, Immunosuppression, clinical trial, Vss, lymphopenia, AUCinf, medicine.anatomical_structure, Nivolumab, C28d, Emergency Medicine, CL, Cmax, Female, concentration on day 28, standard deviation, half-life, area under the curve, Sepsis, 03 medical and health sciences, Vd, Pharmacokinetics, Adjuvants, Immunologic, Ceoi, medicine, Humans, full analysis set, Trough Concentration, Adverse effect, Aged, SD, mAb, Tmax, mHLA-DR, business.industry, rTM, AE, CTCAE, 030208 emergency & critical care medicine, Q2W, Anti-programmed death-1 (PD-1), apparent total body clearance of the drug from serum, immune checkpoint blockade, FAS, thyroid stimulating hormone, medicine.disease, every 2 weeks, T1/2, maximum concentration, monoclonal antibody, Pharmacodynamics, C14d, ICU, business, Common Terminology Criteria for Adverse Events
Abstract: Background: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. Methods: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]). Results: Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 μg/mL) was similar to the predicted concentration at the end of infusion with 3 mg/kg Q2W (117 μg/mL). The concentration on Day 28 after 960 mg (33.1 μg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0–163 μg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 mg and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred. Conclusions: A single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 mg and 960 mg nivolumab seemed to improve immune system indices over time. Trial registration: JAPIC, JapicCTI-173600.
Published: 2019

22. Improvement of optical setup for microcirculation imaging and flow analysis in septic shock rats

Author: Shigeto Oda, Hideaki Haneishi, Mami Kawasaki, Ryohei Hashimoto, Takashi Ohnishi, Kazuya Nakano, Masashi Sekine, and Eizo Watanabe
Subjects: Flow (mathematics), business.industry, Septic shock, Medicine, business, medicine.disease, Biomedical engineering, Microcirculation
Published: 2019

23. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020)

Author: Kazuma Yamakawa, Takeshi Unoki, Yoh Sugawara, Hiroyuki Kawano, Ayaka Sakamoto, Kenji Uehara, Yasuyuki Kakihana, Eizo Watanabe, Hiromu Okano, Yukitoshi Toyoda, Goro Tajima, Ryuichi Yotsumoto, Hiroshi Ogura, Asako Matsushima, Motoshi Kainuma, Ryo Fujii, Takuya Mayumi, Tomonori Yamamoto, Masaaki Sakuraya, Yuuki Tanaka, Toshikazu Abe, Tomoko Fujii, Daisuke Kobashi, Naoki Yamada, Yoshiki Masuda, Satoru Hashimoto, Atsunori Sugita, Kazuaki Atagi, Yutaka Igarashi, Akira Shimoyama, Tomohisa Nomura, Tasuku Matsuyama, Jun Maki, Akemi Utsunomiya, Kazuya Kikutani, Kei Nishiyama, Joji Kotani, Megumi Moriyasu, Yasuhiro Kuroda, Hiromi Kato, Ryuta Itakura, Seitaro Fujishima, Yusuke Kawamura, Kazuyuki Oka, Hiroyuki Koami, Asuka Tsuchiya, Jun Okamoto, Yasuhiro Shiga, Hiroki Saito, Masaharu Nagae, Hiroyuki Ohbe, Kenji Sonota, Kentaro Tomita, Yutaka Kondo, Sho Kimura, Haruki Imura, Taiki Haga, Satoshi Ono, Tomoaki Yatabe, Yuki Enomoto, Yohei Hirano, Yuji Suzuki, Jun Takeshita, Kentaro Ide, Junji Hatakeyama, Kazuyuki Miyamoto, Naoki Tominaga, Masanori Tani, Hideo Tohira, Yuhta Oyama, Toru Hifumi, Yuji Miyatake, Kohei Yamada, Yoshimi Nakamura, Hiromu Naraba, Hideki Asai, Daisuke Kudo, Mitsunobu Toyosaki, Yuhei Yoshida, Takaki Naito, Hideaki Sakuramoto, Naoto Hosokawa, Takao Yano, Shutaro Isokawa, Hiroshi Yonekura, Masaki Nakane, Shusuke Sekine, Hiroshi Takahashi, Atsuki Hayamizu, Masami Ishikawa, Ryo Yamamoto, Tomoya Nishimura, Iwao Saiki, Hiromichi Naito, Go Haraguchi, Kenichi Tetsuhara, Hideki Hashimoto, Toru Yamada, Yosuke Matsumura, Yuko Egawa, Daisuke Hasegawa, Noritaka Ushio, Takanori Ohno, Teppei Murata, Mai Inada, Osamu Nishida, Motoki Fujita, Masahito Horiguchi, Jumpei Yoshimura, Nobunaga Okada, Hitoshi Kikuchi, Nana Furushima, Koji Endo, Yasuhiro Norisue, Yuya Miyazaki, Chikashi Takeda, Shinya Shimoyama, Takumi Taniguchi, Tadashi Kaneko, Takuya Hayashi, Kenji Kubo, Toshiaki Iba, Yutaka Umemura, Chihiro Narita, Tadashi Nagato, Hiroomi Tatsumi, Takeshi Yoshida, Satoshi Suzuki, Isao Nahara, Takashi Tagami, Akihito Tampo, Tatsuya Kawasaki, Kensuke Nakamura, Shuhei Takauji, Shin Nunomiya, Yujiro Matsuishi, Yusuke Tsutsumi, Kent Doi, Katsuhiko Hashimoto, Norihiro Nishioka, Shigeki Kushimoto, Keita Kanehata, Naoki Higashibeppu, Kohkichi Andoh, Go Ishimaru, Nozomi Takahashi, Takeshi Umegaki, Isao Nagata, Ryosuke Tsuruta, Keisuke Minami, Yoko Takahashi, Hirotaka Furusono, Yusuke Kawai, Naoya Iguchi, Takero Terayama, Hisashi Imahase, Akira Ouchi, Hiroshi Tanaka, Yoshihiro Tomioka, Motohiro Sekino, Yoshihiro Hagiwara, Takayuki Ogura, Hiraku Funakoshi, Tomoya Hirose, Hiroshi Okuda, Morihiro Katsura, Takeshi Wada, Shinya Miura, Sho Takahashi, Yu Inata, Sei Takahashi, Shigeaki Inoue, Hiroyuki Yamada, Takeshi Suzuki, Kiyoyasu Kurahashi, Yoshitaka Aoki, Yuki Nakamori, Moritoki Egi, Toshiaki Hamasaki, Minoru Hayashi, Naoki Hara, Ichiro Nagasawa, Naoyuki Fujimura, Shunsuke Taito, Tetsuro Nishimura, Shodai Yoshihiro, Yoshifumi Ohchi, Yu Onodera, Tomohiro Suhara, Machi Yanai, Naoyuki Matsuda, Masayuki Ozaki, Yohei Okada, Takeshi Hatachi, Tomohisa Shoko, Naohisa Masunaga, Masahiro Kashiura, Yoshitaka Hara, Ryoichi Miyashita, Matsuyuki Doi, Kentaro Tokunaga, Kenta Ito, Akihiro Kanaya, Eisuke Kako, Taichiro Tsunoyama, Tadashi Ishihara, Makoto Aoki, Nobuaki Shime, Tatsuma Fukuda, Kohei Ota, Kei Hayashida, Ken ichi Kano, Masahito Sakai, Takashi Irinoda, Taka-aki Nakada, Atsushi Kawaguchi, Takakuni Abe, Manabu Shimoto, Yuki Iida, Takahiro Kido, Tetsuya Sato, Yusuke Minematsu, Kohei Takashima, Yusuke Ito, Shinichiro Ohshimo, and Hideto Yasuda
Subjects: medicine.medical_specialty, Weakness, Acute medicine, Guideline, Critical Care and Intensive Care Medicine, Sepsis, sepsis, systematic review, Multidisciplinary approach, Medicine, guidelines, Intensive care medicine, Treatment system, evidence‐based medicine, RC86-88.9, business.industry, Septic shock, General Engineering, Medical emergencies. Critical care. Intensive care. First aid, Evidence-based medicine, medicine.disease, Clinical Practice, GRADE, septic shock, medicine.symptom, business, evidence-based medicine
Abstract: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines., other authors: Satoru Hashimoto,Daisuke Hasegawa,Junji Hatakeyama,Naoki Hara,Naoki Higashibeppu,Nana Furushima,Hirotaka Furusono,Yujiro Matsuishi,Tasuku Matsuyama,Yusuke Minematsu,Ryoichi Miyashita,Yuji Miyatake,Megumi Moriyasu,Toru Yamada,Hiroyuki Yamada,Ryo Yamamoto,Takeshi Yoshida,Yuhei Yoshida,Jumpei Yoshimura,Ryuichi Yotsumoto,Hiroshi Yonekura,Takeshi Wada,Eizo Watanabe,Makoto Aoki,Hideki Asai,Takakuni Abe,Yutaka Igarashi,Naoya Iguchi,Masami Ishikawa,Go Ishimaru,Shutaro Isokawa,Ryuta Itakura,Hisashi Imahase,Haruki Imura,Takashi Irinoda,Kenji Uehara,Noritaka Ushio,Takeshi Umegaki,Yuko Egawa,Yuki Enomoto,Kohei Ota,Yoshifumi Ohchi,Takanori Ohno,Hiroyuki Ohbe,Kazuyuki Oka,Nobunaga Okada,Yohei Okada,Hiromu Okano,Jun Okamoto,Hiroshi Okuda,Takayuki Ogura,Yu Onodera,Yuhta Oyama,Motoshi Kainuma,Eisuke Kako,Masahiro Kashiura,Hiromi Kato,Akihiro Kanaya,Tadashi Kaneko,Keita Kanehata,Ken-ichi Kano,Hiroyuki Kawano,Kazuya Kikutani,Hitoshi Kikuchi,Takahiro Kido,Sho Kimura,Hiroyuki Koami,Daisuke Kobashi,Iwao Saiki,Masahito Sakai,Ayaka Sakamoto,Tetsuya Sato,Yasuhiro Shiga,Manabu Shimoto,Shinya Shimoyama,Tomohisa Shoko,Yoh Sugawara,Atsunori Sugita,Satoshi Suzuki,Yuji Suzuki,Tomohiro Suhara,Kenji Sonota,Shuhei Takauji,Kohei Takashima,Sho Takahashi,Yoko Takahashi,Jun Takeshita,Yuuki Tanaka,Akihito Tampo,Taichiro Tsunoyama,Kenichi Tetsuhara,Kentaro Tokunaga,Yoshihiro Tomioka,Kentaro Tomita,Naoki Tominaga,Mitsunobu Toyosaki,Yukitoshi Toyoda,Hiromichi Naito,Isao Nagata,Tadashi Nagato,Yoshimi Nakamura,Yuki Nakamori,Isao Nahara,Hiromu Naraba,Chihiro Narita,Norihiro Nishioka,Tomoya Nishimura,Kei Nishiyama,Tomohisa Nomura,Taiki Haga,Yoshihiro Hagiwara,Katsuhiko Hashimoto,Takeshi Hatachi,Toshiaki Hamasaki,Takuya Hayashi,Minoru Hayashi,Atsuki Hayamizu,Go Haraguchi,Yohei Hirano,Ryo Fujii,Motoki Fujita,Naoyuki Fujimura,Hiraku Funakoshi,Masahito Horiguchi,Jun Maki,Naohisa Masunaga,Yosuke Matsumura,Takuya Mayumi,Keisuke Minami,Yuya Miyazaki,Kazuyuki Miyamoto,Teppei Murata,Machi Yanai,Takao Yano,Kohei Yamada,Naoki Yamada,Tomonori Yamamoto,Shodai Yoshihiro,Hiroshi Tanaka,Osamu Nishida, Guidelines
Published: 2021

24. Septic shock due to infected giant venous malformation complicated by massive bleeding

Author: Yoshihisa Tateishi, Koichiro Shinozaki, Shigeto Oda, Eizo Watanabe, Naoki Rikihisa, Keisuke Tomita, and Tomohito Sadahiro
Subjects: Disseminated intravascular coagulation, Damage control, medicine.medical_specialty, Resuscitation, Septic shock, business.industry, 030232 urology & nephrology, General Engineering, 030204 cardiovascular system & hematology, medicine.disease, Intensive care unit, Surgery, law.invention, Hemangioma, 03 medical and health sciences, 0302 clinical medicine, law, Shock (circulatory), Anesthesia, medicine, medicine.symptom, business, Venous malformation
Abstract: Case A 19-year-old man with a hemangioma that extended from the left arm to the axillary region had deteriorated due to shock, and no improvement was observed after fluid resuscitation. His status on arrival led to complications of hemorrhagic and septic shock with his left arm swollen and deep purple in color. Left arm amputation to control the source of bleeding and infection was thought to be indicated, however, the coagulation system had collapsed. Therefore, initial reduction of the blood flow to the hemangioma with angiographic endovascular treatment was carried out. Thereafter, continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter against hypercytokinemia was introduced in the intensive care unit for damage control, which resulted in success. Outcome We completed the arm amputation, and subsequently carried out a latissimus dorsi muscle flap transfer on the amputated stump. The patient achieved an ambulatory discharge. Conclusions We successfully treated the very rare case of massive venous malformation with shock due to hemorrhage and infection by performing damage control.
Published: 2015

25. Immunoadjuvant therapy in sepsis: novel strategies for immunosuppressive sepsis coming down the pike

Author: Eizo Watanabe, Richard S. Hotchkiss, and Lukose K. Thampy
Subjects: 0301 basic medicine, Programmed cell death, autophagy, T cell, medicine.medical_treatment, Apoptosis, Immunoadjuvant, Sepsis, sepsis, 03 medical and health sciences, Mini Review Article, medicine, programmed cell death, immunosuppression, business.industry, General Engineering, Immunosuppression, clinical trial, Immunotherapy, medicine.disease, Acquired immune system, 030104 developmental biology, medicine.anatomical_structure, Immunology, Cytokine storm, business
Abstract: Recent efforts have focused on immunoadjuvant therapies for sepsis. The host inflammatory response consequent to initial exposure to pathogens is often followed by anti-inflammatory forces, resulting in increased morbidity and mortality in such critically ill patients. In the subacute stage of sepsis, apoptosis (type I programmed cell death) and subsequently autophagy (type II programmed cell death) have been attracting recent research interest. Although many patients may die during the initial cytokine storm, those who survive this phase might acquire defining characteristics of profound immunosuppression, including failure to clear the primary infection, development of secondary opportunistic infections, and reactivation of latent viruses. Both types of cell death are currently thought to be associated with this subacute immunosuppressive phase of sepsis, and acceleration of autophagy might alleviate immunosuppression through regulation of apoptosis of key immune effector cells. Programmed cell death 1 (PD-1) and its corresponding ligand play a major pathological role in immunosuppression not only in cancer but also in sepsis. Positive costimulatory pathways in T cells, such as CD28 signaling, permit the effector T cell to expand, persist, and effectively clear antigen. However, PD-1 is a negative costimulatory pathway on T cells that broadly enhances immunosuppressive signals across the innate and adaptive immune system. To counter this immunosuppression in sepsis, checkpoint blockade has garnered attention in an area of clinical research. In this review, we introduce some approaches of immunotherapy using anti-PD-1 antibody in infectious diseases and share our future perspectives.
Published: 2018

26. Influence of autophagy on acute kidney injury in a murine cecal ligation and puncture sepsis model

Author: Takehiko Oami, Satoshi Sunahara, Takashi Shimazui, Chiwei Lee, Paul E. Swanson, Lisa Fujimura, Youichi Teratake, Shigeto Oda, Masahiko Hatano, and Eizo Watanabe
Subjects: Male, 0301 basic medicine, lcsh:Medicine, Renal function, Kidney, Article, Andrology, Sepsis, Mice, 03 medical and health sciences, 0302 clinical medicine, Autophagy, Animals, Medicine, lcsh:Science, Multidisciplinary, LAMP1, business.industry, lcsh:R, Autophagosomes, Acute kidney injury, Kidney metabolism, Acute Kidney Injury, medicine.disease, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, lcsh:Q, biological phenomena, cell phenomena, and immunity, Lysosomes, business, Homeostasis
Abstract: The role of autophagy in the maintenance of renal homeostasis during sepsis is not well understood. We therefore aimed to determine the influence of autophagy on kidney during sepsis using a murine sepsis model, i.e. cecal ligation and puncture (CLP). In CLP treated animals, the number of autolysosomes observed by electron microscopy increased over time. The number of autophagosomes in CLP animals decreased relative sham operated controls at 24 hrs after CLP, indicating that autophagy flux is already diminishing by that time. Moreover, CLP induced an increase in LC3-II/LC3-I ratio at 6–8 hrs, demonstrated in western blots, as well as an increase in GFP-LC3 dots at 6–8 hrs and 24 hrs, using immunofluorescence and anti-LC3 and LAMP1 antibodies on tissue sections from GFP-LC3 transgenic mice. LC3-II/LC3-I ratio and the number of co-localized GFP-LC3 dots and LAMP1 signals (GFP LC3 + LAMP1 dots) in CLP mice at 24 hrs were significantly reduced compared with data obtained at 6–8 hrs. Notably, acceleration of autophagy by rapamycin resulted in improvement of renal function that was associated with improvement in the histologic severity of tubular epithelial injury in CLP treated animals. Autophagy in the kidney was significantly slowed in the kidney during the acute phase of sepsis; nonetheless, autophagy in kidney appears to play a protective role against sepsis.
Published: 2018

27. Thrombocytopenia in the ICU: disseminated intravascular coagulation and thrombotic microangiopathies-what intensivists need to know

Author: Manuel Praga, Beverley J. Hunt, Jose Rojas-Suarez, Eizo Watanabe, Pedro Castro, Achim Jörres, and Jean Louis Vincent
Subjects: medicine.medical_specialty, Thrombotic microangiopathy, Soins intensifs réanimation, MEDLINE, Thrombotic thrombocytopenic purpura, 030204 cardiovascular system & hematology, Disseminated intravascular coagulation, Critical Care and Intensive Care Medicine, law.invention, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, law, Medicine, Thrombotic Microangiopathies, Hemolytic uremic syndrome, Humans, Intensive care unit, Intensive care medicine, Unitats de cures intensives, Coagulació sanguínia, business.industry, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Blood coagulation, Disseminated Intravascular Coagulation, medicine.disease, Thrombocytopenia, Intensive Care Units, Editorial, Hemolytic-Uremic Syndrome, business
Abstract: SCOPUS: ed.j, info:eu-repo/semantics/published
Published: 2018

28. Pharmacokinetics of Standard- and Reduced-Dose Recombinant Human Soluble Thrombomodulin in Patients with Septic Disseminated Intravascular Coagulation during Continuous Hemodiafiltration

Author: Eizo Watanabe, Shingo Yamazaki, Yoshihisa Tateishi, Shigeto Oda, Daisuke Setoguchi, Tomohito Sadahiro, Tatsuya Suzuki, and Itsuko Ishii
Subjects: medicine.medical_specialty, medicine.medical_treatment, Urology, Cmax, 030204 cardiovascular system & hematology, law.invention, coagulopathy, Sepsis, sepsis, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, law, renal dysfunction, medicine, Coagulopathy, Renal replacement therapy, Original Research, Disseminated intravascular coagulation, business.industry, Acute kidney injury, 030208 emergency & critical care medicine, General Medicine, medicine.disease, Intensive care unit, Surgery, acute kidney injury, Medicine, business, renal replacement therapy
Abstract: Introduction: Recombinant human soluble thrombomodulin (rTM) is reportedly excreted by the kidneys; therefore, the recommended dose for patients with renal impairment is one-third of the standard dose. The aim of this study was to evaluate whether this reduced dose of rTM achieves effective drug concentrations that are comparable to those of the standard dose in treating sepsis-induced disseminated intravascular coagulation (DIC) during continuous hemodiafiltration (CHDF). Methods: Eight patients in an intensive care unit were randomized to receive either reduced-dose (0.02 mg/kg, n = 4) or standard-dose (0.06 mg/kg, n = 4) rTM. We evaluated the effect of standard dose in comparison to that of reduced dose on the pharmacokinetics of rTM for the sepsis-induced DIC patients receiving CHDF. Patients received rTM during a 30-min infusion for 6 consecutive days. Pharmacokinetic parameters of rTM were analyzed using the one-compartment model. Results: The elimination half-life, clearance (T1/2), and distribution volume (Vd) of soluble thrombomodulin (sTM) were similar between the reduced and standard doses. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) of sTM, were approximately 2.5 times higher with standard-dose daily infusions than that with reduced-dose drip infusions (p = 0.041 and 0.062, respectively). The time when the blood concentration of sTM was >500 ng/mL was significantly longer with standard-dose infusions than those with reduced dose (p = 0.039). Conclusions: rTM displayed dose-dependent pharmacokinetic behavior at clinically relevant doses. During CHDF, effective blood concentration of rTM was not achieved with the reduced dose, and rTM was found to not bioaccumulate. Therefore, this pilot study suggests that reducing the rTM dose is unnecessary, even in sepsis-induced DIC patients who require CHDF due to kidney injury. We however need to perform a definitive study to determine the dosage of rTM for the case.
Published: 2017
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29. Atypical Hemolytic Uremic Syndrome With the p.Ile1157Thr C3 Mutation Successfully Treated With Plasma Exchange and Eculizumab: A Case Report

Author: Daiki Saito, Eizo Watanabe, Yasufumi Ohtsuka, Toshiyuki Miyata, Noriyuki Hattori, Hideki Kato, Shigeto Oda, Akira Ashida, Yoko Yoshida, and Masaomi Nangaku
Subjects: medicine.medical_specialty, Case Report, Gastroenterology, chemistry.chemical_compound, plasma exchange, Internal medicine, Atypical hemolytic uremic syndrome, medicine, complement, genetics, Creatinine, Hematology, atypical hemolytic uremic syndrome, business.industry, Acute kidney injury, General Medicine, Eculizumab, medicine.disease, Hemolysis, Schistocyte, Acetaminophen, acute kidney injury, chemistry, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business, medicine.drug
Abstract: Supplemental Digital Content is available in the text., Objectives: To describe a case of atypical hemolytic uremic syndrome induced by influenza A infection with the p.Ile1157Thr C3 mutation. Data Sources: Clinical observations of a patient. Study Selection: Case reports. Data Extraction: Data extracted from medical records, after patient’s consent. Data Synthesis: Four days prior to presentation to our hospital, a 16-year-old adolescent had a fever and arthralgia with hematuria. He was found to be positive for type A influenza and prescribed oseltamivir and acetaminophen by a primary-care physician. A bleeding tendency and purpura in the extremities and on the trunk developed; therefore, he was transferred to Chiba University Hospital. Hematology revealed severe thrombocytopenia, hyperbilirubinemia, and acute kidney injury. Aspartate aminotransferase, lactate dehydrogenase, and potassium could not be determined because of severe hemolysis. Highly elevated blood urea nitrogen and creatinine levels indicated acute kidney injury. A platelet count of 24,000/μL indicated thrombocytopenia, with low hemoglobin level. Peripheral blood profiling identified schistocytes. Continuous hemodiafiltration and plasma infusion were initiated immediately; however, he became oliguric. Plasma exchange was initiated on ICU day 3, but decreased urine output, hemolysis, and thrombocytopenia persisted. IV eculizumab therapy was initiated on day 7 and resulted in recovery of these symptoms and also successful discontinuation of renal support. The patient showed a stable condition without recurrence of hemolytic findings and acute kidney injury and is currently on maintenance therapy of eculizumab (1,200 mg, every other week) without any relapse of atypical hemolytic uremic syndrome symptoms. A plasma sample collected prior to initiation of plasma exchange showed an disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13 activity level of 104.9%. The absence of both Shiga toxin-producing Escherichia coli in feces led to suspicion of atypical hemolytic uremic syndrome. Subsequent genetic analysis identified a mutation in C3 (p.Ile1157Thr), confirming the diagnosis of atypical hemolytic uremic syndrome. Conclusions: Although managing thrombocytopenia secondary to infection, inclusion of atypical hemolytic uremic syndrome in the differential diagnosis at an early stage is important in clinical practice.
Published: 2019

30. PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF NIVOLUMAB IN PATIENTS WITH SEPSIS-INDUCED IMMUNOSUPPRESSION: A MULTICENTER, OPEN-LABEL PHASE 1/2 STUDY.

Author: Eizo Watanabe, Osamu Nishida, Yasuyuki Kakihana, Motoi Odani, Tatsuaki Okamura, Tomohiro Harada, and Shigeto Oda
Published: 2020
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31. Improvement of optical setup for microcirculation imaging and flow analysis in septic shock rats.

Author: Mami Kawasaki, Ryohei Hashimoto, Kazuya Nakano, Takashi Ohnishi, Masashi Sekine, Eizo Watanabe, Shigeto Oda, and Hideaki Haneishi
Published: 2019
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32. Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Author: Deborah Janks, Brian Sato, R. Eliot Fagley, Osamu Takasu, Igor R. Efimov, Sam B. Bhayani, Richard S. Hotchkiss, Anil Srivastava, Anne M. Drewry, Steve Jarman, Eizo Watanabe, Kathleen To, Joseph P. Gaut, and Paul E. Swanson
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Programmed cell death, Pathology, medicine.medical_specialty, Necrosis, Adolescent, Critical Care and Intensive Care Medicine, Sepsis, medicine, Humans, Myocyte, Myocytes, Cardiac, Renal Insufficiency, Aged, Aged, 80 and over, Heart Failure, Kidney, Cell Death, business.industry, Middle Aged, medicine.disease, Immunohistochemistry, Microscopy, Electron, Kidney Tubules, medicine.anatomical_structure, Apoptosis, Case-Control Studies, Heart failure, Female, medicine.symptom, business
Abstract: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined.To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death.Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study.Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 ± 9.5% and 32.3 ± 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes.Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.
Published: 2013

33. Suppression of T Cell Autophagy Results in Decreased Viability and Function of T Cells Through Accelerated Apoptosis in a Murine Sepsis Model

Author: Masahiko Hatano, Shigeto Oda, Eizo Watanabe, Lisa Fujimura, Akemi Sakamoto, Satoshi Sunahara, Takehiko Oami, Kiyotaka Toshimori, and Chizuru Ito
Subjects: 0301 basic medicine, Male, Programmed cell death, Cell Survival, T cell, T-Lymphocytes, Apoptosis, Mice, Transgenic, Biology, Mitochondrion, Critical Care and Intensive Care Medicine, B7-H1 Antigen, Article, Mice, 03 medical and health sciences, Online Laboratory Investigations, 0302 clinical medicine, Sepsis, medicine, Autophagy, Cannibalism, Cytotoxic T cell, Animals, Cecum, Mice, Knockout, immunosuppression, Bcl-2-Like Protein 11, cecal ligation and puncture, Cell biology, Interleukin-10, Mitochondria, critical care, Interleukin 10, Crosstalk (biology), Disease Models, Animal, cell death, 030104 developmental biology, medicine.anatomical_structure, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Spleen, 030215 immunology
Abstract: Supplemental Digital Content is available in the text., Objective: While type 1 programmed cell death (apoptosis) of T cells leads to immunosuppression in sepsis, a crosstalk between apoptosis and autophagy (type 2 programmed cell death) has not been shown. The aim of this study is to elucidate the details of the interaction between autophagy and immunosuppression. Design: Laboratory investigation in the murine sepsis model. Setting: University laboratory. Subjects: Six- to 8-week-old male mice. Interventions: We investigated the kinetics of autophagy in T cells from spleen in a cecal ligation and puncture model with green fluorescent protein-microtubule-associated protein light chain 3 transgenic mice. We analyzed apoptosis, mitochondrial homeostasis and cytokine production in T cells, and survival rate after cecal ligation and puncture using T cell–specific autophagy-deficient mice. Measurements and Main Results: We observed an increase of autophagosomes, which was assessed by flow cytometry. However, an autophagy process in CD4+ T cells during sepsis was insufficient including the accumulation of p62. On the other hand, a blockade of autophagy accelerated T cell apoptosis compared with the control mice, augmenting the gene expression of Bcl-2-like 11 and programmed cell death 1. Furthermore, mitochondrial accumulation in T cells occurred via a blockade of autophagy during sepsis. In addition, interleukin-10 production in CD4+ T cells from the cecal ligation and puncture–operated knockout mice was markedly increased. Consequently, deficiency of autophagy in T cells significantly decreased the survival rate in the murine sepsis model. Conclusions: We demonstrated that blocking autophagy accelerated apoptosis and increased mortality in concordance with the insufficient autophagy process in CD4+ T cells in the murine sepsis model, suggesting that T cell autophagy plays a protective role against apoptosis and immunosuppression in sepsis.
Published: 2016

34. Complete remission of thrombotic microangiopathy after treatment with eculizumab in a patient with non-Shiga toxin-associated bacterial enteritis

Author: Toshiyuki Miyata, Yoko Yoshida, Hideki Kato, Taku Omura, Masaomi Nangaku, Yasufumi Otsuka, Shigeto Oda, and Eizo Watanabe
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Thrombotic microangiopathy, abdominal infection, Surgical intensive care unit, Hemodiafiltration, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Gastroenterology, 03 medical and health sciences, Bacterial enteritis, 0302 clinical medicine, Internal medicine, medicine, Humans, Clinical Case Report, biology, Plasma Exchange, business.industry, atypical hemolytic uremic syndrome, Platelet Count, Thrombotic Microangiopathies, Complete remission, Shiga toxin, General Medicine, Eculizumab, Middle Aged, medicine.disease, 030104 developmental biology, acute kidney injury, Monoclonal, biology.protein, business, membrane cofactor protein, After treatment, medicine.drug, Research Article
Abstract: To describe a case of complete remission of thrombotic microangiopathy after treatment with eculizumab in a patient with non-Shiga toxin-associated bacterial enteritis. Case report: Medical/surgical intensive care unit (ICU) of a university teaching hospital. A 62-year-old man presented to a local hospital with mucous and bloody stool persisting for 1 month and worsening abdominal pain for 2 weeks. He had thrombocytopenia and renal dysfunction and was admitted with a diagnosis of sepsis due to intraabdominal infection. However, he did not respond to antimicrobial therapy, and after 7 days he was transferred to the Chiba University Hospital ICU. Antimicrobial therapy was continued, and continuous hemodiafiltration was initiated on ICU day 3, but the patient's condition deteriorated and he became anuric. Plasma exchange (PE) was initiated on ICU day 11, but anuria and thrombocytopenia persisted. Intravenous eculizumab therapy was initiated on day 26 and resulted in quick recovery of urine output and platelet count and successful discontinuation of renal support. The diagnosis of thrombotic microangiopathy was established by the presence of schistocytes on the peripheral blood smear on ICU day 9. A plasma sample collected prior to initiation of PE showed a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs member 13 (ADAMTS13) activity level of >10% (25.1%). The absence of both Shiga-toxin producing E coli in feces and anti-Shiga-toxin antibody in blood led to suspicion of atypical hemolytic uremic syndrome (aHUS). Genetic test identified a nonsynonymous mutation (p.Ala311Val) in the membrane cofactor protein gene (MCP). Although the pathological significance is currently unknown, this mutation may have been the cause of adult-onset aHUS in our patient. In this case, eculizumab was successfully introduced and discontinued, and the patient remained relapse-free after 1 year of follow-up. The duration of eculizumab therapy for patients with aHUS should be determined on a case-by-case basis and possibly according to the causative genetic mutation, even though discontinuation of eculizumab therapy once initiated is not generally recommended.
Published: 2016

35. A Case of Successful Extracorporeal Membrane Oxygenation Support for Cardiac Arrest Associated with Nonocclusive Mesenteric Ischemia

Author: Ryuzo Abe, Eizo Watanabe, Shigeto Oda, Koichiro Ogura, Takehiko Oami, Takayuki Toma, Tomoaki Hashida, and Noriyuki Hattori
Subjects: medicine.medical_specialty, Abdominal pain, business.industry, medicine.medical_treatment, Colostomy, Anastomosis, Intensive care unit, Surgery, law.invention, Abdominal wall, surgical procedures, operative, medicine.anatomical_structure, Respiratory failure, Damage control surgery, law, medicine, Extracorporeal membrane oxygenation, medicine.symptom, business
Abstract: Background: We report a case of successful extracorporeal membrane oxygenation (ECMO) support for cardiac arrest associated with nonocclusive mesenteric ischemia (NOMI). Case presentation: A 34-year-old previously healthy woman in the sixth week of her second pregnancy was carried to our hospital for abdominal pain and vomiting. She had apparent peritoneal irritation signs with marked hyperglycemia and metabolic acidosis and developed refractory shock. Since portal venous gas and intestinal dilatation without enhancement in contrast-enhanced computed tomography (CT) were observed, a subtotal resection of the small intestine and right hemicolectomy against widespread intestinal necrosis were performed as an emergency operation. The patient returned to the intensive care unit (ICU) with open abdominal management. Severe respiratory failure gradually developed during the operation, and veno-venous (V-V) ECMO was prepared to start in the ICU after the operation. However, cardiac arrest occurred abruptly during the cannulation for ECMO. Therefore, veno-arterial (V-A) ECMO was implemented and hemodynamic status gradually improved. V-A ECMO was switched to V-V ECMO on Day 4 because of persistent respiratory failure. Colostomy was performed on Day 5, abdominal wall was closed on Day 8, and ECMO was successfully weaned off on Day 9. Furthermore, several surgical interventions including gauze packing for retroperitoneal bleeding and operation for intestinal dehiscence, and right lower extremity amputation were needed. She was free from the ICU on Day 78. Finally, closure of the colostomy and anastomosis of the residual duodenum and colon were performed, and the patient was discharged from the hospital without any neurologic impairment on Day 262. Conclusion: Successful surgical interventions and appropriate ECMO support contributed to the patient’s survival.
Published: 2016

36. Duration of well-controlled core temperature correlates with neurological outcome in patients with post-cardiac arrest syndrome

Author: Yo Hirayama, Hiroyuki Hirasawa, Nobuya Kitamura, Eizo Watanabe, Kasuya Nakanishi, Tomohito Sadahiro, Shigeto Oda, Masataka Nakamura, Yoshihisa Tateishi, and Koichiro Shinozaki
Subjects: Male, medicine.medical_specialty, Optimal cutoff, Logistic regression, Body Temperature, Hypothermia, Induced, Humans, Medicine, In patient, Post cardiac arrest, Hypoxia, Brain, Aged, Retrospective Studies, Controlled core temperature, business.industry, General Medicine, Middle Aged, Hypothermia, Surgery, Treatment Outcome, Duration (music), Anesthesia, Emergency Medicine, Bystander cpr, Female, medicine.symptom, business, Out-of-Hospital Cardiac Arrest
Abstract: Purpose Detailed procedures for optimal therapeutic hypothermia (TH) have yet to be established. We examined how duration of well-controlled core temperature within the first 24 hours after cardiac arrests (CA) correlated with neurological outcomes of successfully resuscitated out-of-hospital CA (OHCA) patients. Methods OHCA patients who survived over 24 hours and treated with TH were included. Core temperature was measured every hour. Physicians intended to maintain temperature at 33°C ± 1°C for 24 hours. Cerebral performance categories (CPC) of patients at 6 months were recorded and patients were retrospectively divided into favorable (CPC1,2) and poor (CPC3-5) neurological outcome groups. Total time while the core temperature reached to 33°C ± 1°C within the first 24 hours after CA was measured and this duration was defined that of well-controlled temperature. receiver-operating characteristic analysis was performed on duration of well-controlled temperature to select the optimal cutoff value. Neurological outcome predictors were investigated by logistic regression analysis. Results Fifty-six patients were included. Optimal cutoff value of duration of well-controlled temperature was 18 hours. Ratio of male sex, witnessed by emergency medical service (EMS) personnel, first electrocardiogram as shockable, and duration of well-controlled core temperature ≥18 h of favorable neurological outcome group (n = 21) were significantly larger than that of poor neurological outcome group (n = 35). Logistic regression analysis identified “witnessed by EMS”, “performed bystander CPR,” and “the duration ≥18 h” as independent predictors of favorable neurological outcome. Conclusion TH maintained at target temperature of 33°C ± 1°C over 18 hours independently correlated with favorable neurological outcome. Therefore, stable core temperature control may improve neurological outcome of successfully resuscitated OHCA.
Published: 2012

37. Tumor necrosis factor −308 polymorphism (rs1800629) is associated with mortality and ventilator duration in 1057 Caucasian patients

Author: Eizo Watanabe, Barbara A. Zehnbauer, Hiroyuki Hirasawa, Timothy G. Buchman, Shigeto Oda, and Yasunori Sato
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, Adolescent, Genotype, Critical Illness, Immunology, Kaplan-Meier Estimate, Polymorphism, Single Nucleotide, Biochemistry, Article, White People, law.invention, Sepsis, Young Adult, Gene Frequency, law, Intensive care, Internal medicine, medicine, Genetic predisposition, Humans, Immunology and Allergy, Molecular Biology, Survival rate, Aged, Aged, 80 and over, Ventilators, Mechanical, Tumor Necrosis Factor-alpha, business.industry, Proportional hazards model, Hematology, Odds ratio, Middle Aged, Prognosis, medicine.disease, Intensive care unit, Surgery, Survival Rate, Intensive Care Units, Logistic Models, SAPS II, Multivariate Analysis, Female, business
Abstract: Purpose Management of sepsis in critically ill patients remains difficult and requires prolonged intensive care. Genetic testing has been proposed as a strategy to identify patients at risk for adverse outcome of critical illnesses. Therefore, we wished to determine the influence of heredity on predisposition to poor outcome and on duration of ventilator support of intensive care unit (ICU) patients. Methods A study was conducted from July 2001 to December 2005 in heterogeneous population of patients from 12 US ICUs represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive. In 1057 Caucasian critically ill patients with SAPS II probability of survival of >0.2 in the US, six functional single nucleotide polymorphisms in relation to inflammatory cytokines and innate immunity (rs1800629, rs16944, rs1800795, rs1800871, rs2569190, and rs909253) were evaluated in terms of mortality and ventilator free days. Results The AA homozygote of TNF (−308) (rs1800629) was most over-represented in the deceased patient group ( P = 0.015 with recessive model). The carriage of the TNF (−308)*AA genotype showed significantly higher odds ratio of 2.67(1.29–5.55) ( P = 0.008) after adjustment with the covariates. However, the presence of 1, 2, or 3 acute organ dysfunctions was larger prognostic factors for the adverse outcome (OR(95%CI) = 2.98(2.00–4.45), 4.01(2.07–7.77), or 19.95(4.99–79.72), P TNF (−308)*AA patient significantly diverged from that of TNF (−308)*(GG + GA) ((AA v GG + GA), Adjusted HR(95%CI) = 2.53(1.11–5.79) with Cox regression, P = 0.028). Conclusions TNF (−308)*AA is significantly associated with susceptibility to adverse outcome and to longer ventilator duration. Therefore, heredity likely affects both predisposition to ICU prognosis as well as the resource utilization.
Published: 2012

38. Treatment of Septic Shock with Continuous HDF Using 2 PMMA Hemofilters for Enhanced Intensity

Author: Eizo Watanabe, Taka-aki Nakada, Yo Hirayama, Koichiro Shinozaki, Yoshihisa Tateishi, Hiroyuki Hirasawa, Tomohito Sadahiro, Shigeto Oda, Yosuke Matsumura, Ryuzo Abe, Masataka Nakamura, and Taku Oshima
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, Critical Care, Polymethyl methacrylate, Lactic acid blood, Treatment outcome, Biomedical Engineering, Medicine (miscellaneous), Blood Pressure, Bioengineering, Hemodiafiltration, Biomaterials, Young Adult, Japan, Continuous hemodiafiltration, Internal medicine, medicine, Humans, Polymethyl Methacrylate, Lactic Acid, Severe sepsis, Aged, Retrospective Studies, Interleukin-6, Chemistry, Septic shock, Membranes, Artificial, Equipment Design, General Medicine, Middle Aged, medicine.disease, Shock, Septic, Survival Analysis, Intensity (physics), Survival Rate, Intensive Care Units, Treatment Outcome, Shock (circulatory), Cardiology, Female, medicine.symptom, Biomarkers
Abstract: Purpose Cytokines play pivotal roles in the pathophysiology of severe sepsis/septic shock, and continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF) removes cytokines efficiently and continuously, mainly through adsorption to a hemofilter membrane. The aim of this study was to investigate the clinical efficacy of enhanced intensity PMMA-CHDF in treating refractory septic shock. Methods Seventy-two septic shock patients admitted to the intensive care unit (ICU) underwent critical care including PMMA-CHDF. We employed enhanced intensity PMMA-CHDF to improve the cytokine removal rate by increasing the hemofilter membrane area in 10 refractory septic shock patients (enhanced intensity group, EI group; 2 extracorporeal CHDF circuits using the hemofilter with a larger membrane area of 2.1 m2). Other patients undergoing conventional PMMA-CHDF and matched for severity with the EI group, comprised a matched conventional group (MC group; using a PMMA membrane hemofilter with a membrane area of 1.0 m2; n=15). The case-control comparison was performed between the 2 groups. Results Enhanced intensity PMMA-CHDF significantly increased mean arterial pressure by 23.8% in 1 hour (p=0.037), decreased the blood lactate level by 28.6% in 12 hours (p=0.006), and reduced blood IL-6 level in 24 hours (p=0.005). The ICU survival rate in the EI group was significantly better than that in the MC group (60% vs. 13.3%, p=0.028). Conclusion Enhanced intensity PMMA-CHDF may improve hemodynamics and survival rate in patients with refractory septic shock.
Published: 2012

39. Continuous Hemodiafiltration with a Cytokine-Adsorbing Hemofilter for Sepsis

Author: Hidetoshi Shiga, Kenichi Matsuda, Hiroyuki Hirasawa, Masataka Nakamura, Shigeto Oda, and Eizo Watanabe
Subjects: medicine.medical_specialty, Polymethyl methacrylate, medicine.medical_treatment, Hemodiafiltration, Sepsis, Continuous hemodiafiltration, medicine, Humans, Polymethyl Methacrylate, Intensive care medicine, Polymyxin B, Septic shock, business.industry, Pathogen-associated molecular pattern, Hematology, General Medicine, medicine.disease, Hemoperfusion, Continuous hemofiltration, Cytokine, Nephrology, Immunology, Cytokines, Adsorption, business
Abstract: Since the introduction of the new pathophysiological concept of pathogen-associated molecular patterns (PAMPS) and alarmins, endotoxin has been recognized as only one of the PAMPS. It is widely accepted that hypercytokinemia plays a pivotal role in the pathophysiology of sepsis. Many kinds of blood purification modalities have been proposed as a therapeutic tool against sepsis, including high-volume continuous hemofiltration whose efficacy has recently been questioned. We report that continuous hemodiafiltration (CHDF) with a cytokine-adsorbing hemofilter (CAH), such as polymethyl methacrylate hemofilter and AN69ST hemofilter (CAH-CHDF), can remove many kinds of cytokines and has been very effective in the treatment of severe sepsis and septic shock. Based on the understanding of the recent pathophysiology, we suggest that CAH-CHDF is an alternate therapy to direct hemoperfusion with endotoxin-adsorbing column in the treatment of sepsis.
Published: 2012

40. Experimental examination of anti-inflammatory effects of a 5-HT3 receptor antagonist, tropisetron, and concomitant effects on autonomic nervous function in a rat sepsis model

Author: Masataka Nakamura, Yoshihisa Tateishi, Daisuke Setoguchi, Henry Yatsuki, Tomoyuki Kuwaki, Shigeto Oda, and Eizo Watanabe
Subjects: Male, Indoles, medicine.drug_class, medicine.medical_treatment, Tropisetron, Immunology, Tropisetron Hydrochloride, Pharmacology, Autonomic Nervous System, Rats, Sprague-Dawley, Sepsis, Electrocardiography, Catecholamines, 5-HT3 Receptor Antagonist, Heart Rate, medicine, Animals, Immunology and Allergy, business.industry, Septic shock, medicine.disease, Receptor antagonist, Rats, Disease Models, Animal, Treatment Outcome, Cytokine, Catecholamine, Cytokines, Serotonin Antagonists, business, medicine.drug
Abstract: A 5-HT(3) receptor antagonist, tropisetron, has been reported to exhibit an anti-inflammatory effect in chronic inflammatory diseases by antagonizing a particular subtype of serotonin receptors. We investigated whether overproduction of cytokines could be controlled by intervention with tropisetron in an animal model of sepsis and also examined the effects of tropisetron on autonomic nervous activity.Sixty-eight adult male Sprague-Dawley rats were used (28 for examination of cytokine production and autonomic nervous activity; 40 for survival analysis). Each part of the study involved 4 animal groups, including two control groups without drug administration. Sepsis was induced by cecal ligation and puncture (CLP). Tropisetron hydrochloride (1mg/kg) was administered immediately after surgery. Continuous electrocardiograms were recorded for 5 min before and 1, 2, 4, and 6h after surgery in CLP and sham-operated animals for heart rate variability (HRV) analysis. Blood samples were collected 6h after surgery for serum cytokine and catecholamine assay.HRV analysis demonstrated a significant increase in LF/(LF+HF) in the CLP animals compared with the sham-operated animals, regardless of tropisetron administration, indicating induction of sympathetic overstimulation. Tropisetron significantly inhibited IL-6 induction in the CLP animals (p0.01). Although it did not significantly change HRV parameters, tropisetron significantly inhibited increase in serum level of noradrenaline (p0.05). Tropisetron did not significantly improve CLP animal survival rate.Intervention with a 5-HT(3) receptor antagonist can control excess cytokine production involved in the pathogenesis of severe sepsis/septic shock.
Published: 2011

41. Outcome prediction in sepsis combined use of genetic polymorphisms – A study in Japanese population

Author: Tadanaga Shimada, Hiroyuki Hirasawa, Yoshihisa Tateishi, Masataka Nakamura, Shunsuke Otani, Tomohito Sadahiro, Yoh Hirayama, Taka-aki Nakada, Shigeto Oda, Takeshi Tokuhisa, Ryuzo Abe, Hajime Uno, and Eizo Watanabe
Subjects: Male, medicine.medical_specialty, Immunology, Combined use, Logistic regression, Biochemistry, Sepsis, Japan, Disease severity, Internal medicine, medicine, Humans, Immunology and Allergy, Intensive care medicine, Molecular Biology, APACHE, Aged, Past medical history, Polymorphism, Genetic, Models, Genetic, Icu mortality, Interleukin-6, business.industry, Hematology, Middle Aged, Japanese population, medicine.disease, Intensive Care Units, Treatment Outcome, ROC Curve, Area Under Curve, Female, Outcome prediction, business
Abstract: Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n = 123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF −308GA, IL1β −31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC–AUC = 0.68), use of APACHE II score and two genetic parameters (TNF −308 and IL1β −31) enabled more accurate prediction of ICU mortality (ROC–AUC = 0.80). Significant association of two genetic polymorphisms, TNF −308 and IL1β −31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients.
Published: 2011

42. Blood ammonia and lactate levels on hospital arrival as a predictive biomarker in patients with out-of-hospital cardiac arrest

Author: Koichiro Shinozaki, Yoshihisa Tateishi, Tomohito Sadahiro, Hiroyuki Hirasawa, Shigeto Oda, Yasunori Sato, Nobuya Kitamura, Eizo Watanabe, Yo Hirayama, Kazuya Nakanishi, and Masataka Nakamura
Subjects: Adult, Male, Emergency Medical Services, Resuscitation, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Emergency Nursing, Return of spontaneous circulation, Severity of Illness Index, Young Adult, Ammonia, Intensive care, Acute care, Internal medicine, Severity of illness, medicine, Humans, Prospective Studies, Cardiopulmonary resuscitation, Intensive care medicine, Prospective cohort study, Aged, Aged, 80 and over, business.industry, Middle Aged, Prognosis, Cardiopulmonary Resuscitation, Hospitalization, ROC Curve, Lactates, Emergency Medicine, Biomarker (medicine), Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Out-of-Hospital Cardiac Arrest, Follow-Up Studies
Abstract: No reliable predictor for the prognosis of out-of-hospital cardiac arrest (OHCA) on arrival at hospital has been identified so far. We speculate that ammonia and lactate may predict patient outcome.This is a prospective observational study. Non-traumatic OHCA patients who gained sustained return of spontaneous circulation and were admitted to acute care unit were included. Blood ammonia and lactate levels were measured on arrival at hospital. The patients were classified into two groups: 'favourable outcome' group (Cerebral Performance Category CPC1-2 at 6-months' follow-up) and 'poor outcome' group (CPC3-5). Basal characteristics obtained from the Utstein template and biomarker levels were compared between these two outcome groups. Independent predictors were selected from all candidates using logistic regression analysis.A total of 98 patients were included. Ammonia and lactate levels in the favourable outcome group (n=10) were significantly lower than those in poor outcome group (n=88) (p0.05, respectively). On receiver operating characteristic analysis, the optimal cut-off value for predicting favourable outcome was determined as 170 μg dl(-1) of ammonia and 12.0 mmol l(-1) of lactate (area under the curve; 0.714 and 0.735, respectively). Logistic regression analysis identified ammonia (≤170 μg dl(-1)), therapeutic hypothermia and witnessed by emergency medical service personnel as independent predictors of favourable outcome. When both these biomarker levels were over threshold, positive predictive value (PPV) for poor outcome was calculated as 100%.Blood ammonia and lactate levels on arrival are independent prognostic factors for OHCA. PPV with the combination of these biomarkers predicting poor outcome is high enough to be useful in clinical settings.
Published: 2011

43. Diagnosis and treatment of hemophagocytic syndrome

Author: Eizo Watanabe
Subjects: business.industry, Medicine, business
Published: 2011

44. Comparison of Interleukin-6 Removal Properties among Hemofilters Consisting of Varying Membrane Materials and Surface Areas: An in vitro Study

Author: Yoshihisa Tateishi, Kiyohito Wakabayashi, Yo Hirayama, Shigeto Oda, Masataka Nakamura, Tomohito Sadahiro, and Eizo Watanabe
Subjects: Polymethyl methacrylate, Polymers, law.invention, chemistry.chemical_compound, Adsorption, law, Humans, Polymethyl Methacrylate, Sulfones, Polysulfone, Cellulose, Filtration, chemistry.chemical_classification, Chromatography, Interleukin-6, Membranes, Artificial, Equipment Design, Hematology, General Medicine, Polymer, Kinetics, Cellulose triacetate, Membrane, chemistry, Nephrology, Hemofiltration
Abstract: Background/Aims: We sought to identify the most relevant hemofilter for cytokine removal based on the mechanisms of filtration and adsorption. Methods: Ascites were filtered using four types of hemofilters composed of different membrane materials (polymethyl methacrylate, PMMA, cellulose triacetate, CTA, or polysulfone, PS) and different surface areas (1.0 or 2.1 m2) to investigate the rate of interleukin-6 (IL-6) filtration. Next, ascites were perfused through each hemofilter without obtaining a filtrate to study each filter’s adsorptive capability. Results: The PMMA hemofilters resulted in a marginal observed IL-6 filtration rates, whereas the CTA and PS hemofilters resulted in highly effective IL-6 filtration. Regarding the IL-6 adsorptive capabilities of the filters, the PMMA hemofilter with a large surface area showed the highest level of IL-6 clearance. Conclusion: The present findings suggest that when cytokine removal based on filtration is desired, CTA or PS hemofilters should be selected. When IL-6 removal based on adsorption is desired, a PMMA hemofilter with a large surface area should be selected.
Published: 2010

45. IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis

Author: Johannes Tschoep, Jacqueline Unsinger, Margaret McGlynn, David A. Hildeman, Michel Morre, Andrew S. Hoekzema, Richard S. Hotchkiss, Eizo Watanabe, Jacquelyn S. McDonough, Jared T. Muenzer, Charles C. Caldwell, Kevin R. Kasten, Jonathan E. McDunn, and Thomas A. Ferguson
Subjects: Lymphocyte, medicine.medical_treatment, T cell, Immunology, Biology, medicine.disease, biology.organism_classification, Article, Sepsis, medicine.anatomical_structure, Immune system, Cytokine, Puma, medicine, Immunology and Allergy, Cytotoxic T cell, CD8
Abstract: Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-γ production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-γ– and T cell-dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis-induced PUMA, a heretofore unreported effect of IL-7. If additional animal studies support its efficacy in sepsis and if current clinical trials continue to confirm its safety in diverse settings, rhIL-7 should be strongly considered for clinical trials in sepsis.
Published: 2010

46. Association between lymphotoxin-α (tumor necrosis factor-β) intron polymorphism and predisposition to severe sepsis is modified by gender and age

Author: Timothy G. Buchman, Eizo Watanabe, Hiroyuki Hirasawa, and Barbara A. Zehnbauer
Subjects: Adult, Genetic Markers, Male, Lymphotoxin alpha, Critical Illness, medicine.medical_treatment, Single-nucleotide polymorphism, Critical Care and Intensive Care Medicine, Risk Assessment, Article, Genetic determinism, Sepsis, Age Distribution, Reference Values, Polymorphism (computer science), Intensive care, medicine, Humans, Genetic Predisposition to Disease, Sex Distribution, Lymphotoxin-alpha, Aged, Probability, Retrospective Studies, Aged, 80 and over, Polymorphism, Genetic, business.industry, Bayes Theorem, Gene Expression Regulation, Bacterial, Middle Aged, respiratory system, medicine.disease, Survival Analysis, Intensive Care Units, Cytokine, Case-Control Studies, Immunology, Regression Analysis, Female, Tumor necrosis factor alpha, business, human activities, Follow-Up Studies
Abstract: To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice.: Collaborative case-control study conducted from July 2001 to December 2005.A heterogeneous population of patients from 12 U.S. intensive care units represented by the Genetic Predisposition to Severe Sepsis archive.A total of 854 patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the intensive care unit without evidence of any infection (matched nonseptic controls).We developed assays for six functional single nucleotide polymorphisms present before the first codon of tumor necrosis factor at -308, IL1B at -511, IL6 at -174, IL10 at -819, and CD14 at -159, and in the first intron of LTA (also known as tumor necrosis factor-B) at +252 (LTA[+252]). The Project IMPACT critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high-throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3% and 6.4% of Caucasian and African American racial types, respectively. Overall mortality was 35.1% in both severe sepsis and matched nonseptic control patients group. Average ages (standard deviation) of the severe sepsis and matched nonseptic control patients were 63.0 (16.05) and 65.0 (15.58) yrs old, respectively. Among the six single nucleotide polymorphisms, LTA (+252) was most overrepresented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, p = .005). Furthermore, the genetic risk effect was most pronounced in males, age60 yrs (p = .005).LTA(+252) may influence predisposition to severe sepsis, a predisposition that is modulated by gender and age. Although the genetic influences can be overwhelmed by both comorbid factors and acute illness in individual cases, population studies suggest that this is an influential biological pathway modulating risk of critical illnesses.
Published: 2010

47. Clinical application of cytokine-related gene polymorphism analysis using a newly developed DNA chip in critically ill patients

Author: Eizo Watanabe, Masataka Nakamura, Hiroyuki Hirasawa, Tomohito Sadahiro, Shunsuke Otani, Shigeto Oda, Taka-aki Nakada, Ryuzo Abe, and Takeshi Tokuhisa
Subjects: Genotype, Critical Illness, DNA Mutational Analysis, Interleukin-1beta, Clinical Biochemistry, Single-nucleotide polymorphism, Biology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Gene Frequency, TaqMan, Humans, SNP, Genetic Predisposition to Disease, Genotyping, Gene, Interleukin-6, Tumor Necrosis Factor-alpha, Nucleic Acid Hybridization, Reproducibility of Results, General Medicine, Microarray Analysis, Single-base extension, Molecular biology, Intensive Care Units, chemistry, DNA microarray, DNA
Abstract: Objectives To investigate the usefulness of analysis of single nucleotide polymorphism (SNP) using a newly developed DNA chip assay involving single base extension(SBE) and subsequent hybridization in cytokine-related genes in critical care patients. Design and methods Genotyping was performed in 76 ICU patients admitted to the ICU. First, the DNA samples from 58 patients were subjected to PCR and SBE conditioning for DNA. Second, another 18 patients were subjected to genotyping for SNPs in IL-6 −596G/A, −572C/G, −174G/C, TNF-α −308G/A, −238G/A, IL-1β −511C/T and −31T/C by both TaqMan and DNA chip method, and by DNA direct sequencing prospectively. Results First, PCR and SBE condition were established with initial sample sets, which were consistent with results by TaqMan method. Second, no difference was observed between two assay methods in prospective validation set. Conclusions The genotyping assay using the new chip was developed and its usefulness was confirmed.
Published: 2009

48. Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study

Author: Jonathan E. McDunn, David Dixon, Eizo Watanabe, Megan R. Lerner, Paul E. Swanson, Christopher G. Davis, Jared T. Muenzer, Daniel J. Brackett, William G. Hawkins, and Richard S. Hotchkiss
Subjects: Adult, CD4-Positive T-Lymphocytes, Male, Pathology, medicine.medical_specialty, Programmed cell death, medicine.medical_treatment, Inflammation, Vacuole, Biology, Article, Pathology and Forensic Medicine, Sepsis, Mice, 03 medical and health sciences, 0302 clinical medicine, Autophagy, medicine, Animals, Humans, Molecular Biology, Aged, 030304 developmental biology, 0303 health sciences, electron microscopy, Reverse Transcriptase Polymerase Chain Reaction, Cell Biology, Middle Aged, medicine.disease, cytokines, Mitochondria, Mice, Inbred C57BL, Disease Models, Animal, cell death, medicine.anatomical_structure, Cytokine, Liver, Vacuolization, inflammation, 030220 oncology & carcinogenesis, Hepatocyte, Hepatocytes, gene expression, Female, medicine.symptom, Biomarkers, Spleen
Abstract: Autophagy is the regulated process cells use to recycle non-essential, redundant, or inefficient components and is an adaptive response during times of stress. In addition to its role in enabling the cell to gain vital nutrients in times of stress, autophagy can also be involved in elimination of intracellular microorganisms, tumor suppression, and antigen presentation. Because of difficulty in diagnosing autophagy, few clinical studies have been performed. This study examined whether autophagy occurs in hepatocytes during sepsis. Electron microscopy (EM) was performed on liver samples obtained from both an observational clinical cohort of 6 septic patients and 4 control patients as well as liver specimens from mice with surgical sepsis (via cecal ligation and puncture (CLP)) or sham operation. EM demonstrated increased autophagic vacuoles in septic versus non-septic patients. Randomly selected fields (3,000 square microns) from control and septic patients contained 1.2 ± 1.5 versus 5.3 ± 3.3 (mean ± SD) complex lysosomal/autophagolysosomal structures per image respectively (P
Published: 2009

49. Paracoccidioidomicose – acometimento encefálico e medular: relato de caso

Author: Maria Raquel Ramos Jubé, Caroline Campelo Feres, Gabriela Henrique de Souza Lima, Leonardo Eizo Watanabe, Renato da Silva Faria, Élbio Cândido de Paula, and Ana Cristina Ferreira Garcia
Subjects: General Medicine
Abstract: A paracoccidioidomicose (PCM) é uma micose sistêmica, tipo granulomatosa, sendo o Brasil responsável por 80% dos casos relatados no mundo. Mesmo em zonas endêmicas, sua incidência é baixa (3-4 novos casos/milhão até 1-3 novos casos/100mil habitantes ao ano). Relatamos um caso do sexo feminino, 54 anos, procedente do meio rural, região norte do estado de Goiás, centrooeste do Brasil. Durante investigação para síndrome compressiva medular foi identificada lesão tumoral em nível torácico, submetida à ressecção e firmado o diagnóstico de neuroparacoccidioidomicose no anatomopatológico. Foi admitida para reabilitação com diagnóstico de Paraplegia T9 Asia B. Durante a internação foram realizados exames (tomografia computadorizada (TC) de crânio e tórax) para investigação de acometimento de outros órgãos. A TC de tórax demonstrou aspecto sugestivo de PCM com micronódulos de localização centro-lobular e algumas opacidades em “árvore em brotamento” com discreta distorção da arquitetura pulmonar, além de focos de atenuação em “vidro fosco” de distribuição não homogênea. A TC crânio também se mostrou sugestiva de acometimento da PCM em fase ativa: áreas nodulares em cápsulonuclear à esquerda e tálamo correspondente, com edema reacional e importante realce periférico. A doença é um problema de saúde pública no Brasil devido ao seu potencial incapacitante, sendo o diagnóstico difícil especialmente quando acomete SNC, por ser uma manifestação pouco comum (maior acometimento pulmonar).
Published: 2009

50. Up-Regulation of Interleukin-10 mRNA Expression in Peripheral Leukocytes Predicts Poor Outcome and Diminished Human Leukocyte Antigen-DR Expression on Monocytes in Septic Patients

Author: Hiroyuki Hirasawa, Masataka Nakamura, Masahiko Hatano, Takeshi Tokuhisa, Tomohito Sadahiro, Shigeto Oda, Taka-aki Nakada, Eizo Watanabe, and Ryuzo Abe
Subjects: Adult, Male, medicine.medical_treatment, Human leukocyte antigen, Monocytes, Sepsis, Antigen, Gene expression, Leukocytes, Humans, Medicine, RNA, Messenger, Aged, Interleukin-6, business.industry, Monocyte, HLA-DR Antigens, Middle Aged, medicine.disease, Interleukin-10, Up-Regulation, Interleukin 10, Cytokine, medicine.anatomical_structure, Gene Expression Regulation, Bacteremia, Immunology, Female, Surgery, business
Abstract: None of the parameters can predict the deterioration of sepsis early enough. A new predictor allowing earlier detection of changes in septic patients' condition is indispensable.We examined whether cytokine-related mRNA expression in peripheral leukocytes, cytokine blood level, and monocyte human leukocyte antigen (HLA)-DR expression rate could be useful predictors of deterioration of sepsis. Twenty septic patients were enrolled. mRNA expression levels were quantified using real-time reverse transcriptase-polymerase chain reaction and assessed by percent changes during the first 24 h. Cytokine blood levels on admission and day 3 and monocyte HLA-DR expression rate on day 3 were also measured. Correlations between each of these parameters, and between these parameters and outcome were analyzed.Among seven kinds of cytokines studied, only IL-10 mRNA level showed significant difference between survivors and non-survivors (P0.05). Mortality rate of interleukin (IL)-10 mRNA level up-regulated group was significantly higher than that of IL-10 mRNA level down-regulated group (P0.05). HLA-DR expression rate in non-survivors were significantly lower than that in survivors (P0.05). Although IL-10 blood level on day 3 significantly correlated with HLA-DR expression on day 3(r = 0.54, P0.05), IL-10 blood level on admission did not correlate with it. Contrarily, the degree of up-regulation of IL-10 mRNA expression during the first 24 h significantly correlated with the degree of diminished HLA-DR expression on day 3 (r = 0.78, P0.001).Up-regulated IL-10 mRNA expression and diminished HLA-DR expression could be indicators of poor outcome. Furthermore, IL-10 mRNA expression measurement could predict the onset of immunoparalysis indicated by diminished HLA-DR expression earlier than IL-10 blood level measurement, leading to earlier commencement of the treatment.
Published: 2008

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