000103 10.3205/000103 urn:nbn:de:0183-0001034 Review Article Übersichtsartikel 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)) Prävention, Diagnose, Therapie und Nachsorge der Sepsis 1. Revision der S-2k Leitlinien der Deutschen Sepsis-Gesellschaft e.V. (DSG) und der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI) Reinhart Reinhart K. K Prof. Dr. med.

German Sepsis Society, c/o University Hospital Jena, Clinic for Anaesthesiology and Intensive Care Therapy, Erlanger Allee 101, 07747 Jena, Deutschland, Tel.: +49 3641 932 3384University Hospital Jena, Clinic for Anaesthesiology and Intensive Care Therapy, Jena, Germany

Deutsche Sepsis-Gesellschaft e.V., c/o Universitätsklinikum Jena, Klinik für Anästhesiologie und Intensivtherapie, Erlanger Allee 101, 07747 Jena, Deutschland, Tel.: +49 3641 932 3384Universitätsklinikum Jena, Klinik für Anästhesiologie und Intensivtherapie, Jena, Deutschland

author Brunkhorst Brunkhorst F. M. FM Prof. Dr. med.

German Sepsis Society, c/o University Hospital Jena, Clinic for Anaesthesiology and Intensive Care Therapy, Erlanger Allee 101, 07747 Jena, Deutschland, Tel.: +49 3641 932 3381University Hospital Jena, Clinic for Anaesthesiology and Intensive Care Therapy, Jena, Germany

Deutsche Sepsis-Gesellschaft e.V., c/o Universitätsklinikum Jena, Klinik für Anästhesiologie und Intensivtherapie, Erlanger Allee 101, 07747 Jena, Deutschland, Tel.: +49 3641 932 3381Universitätsklinikum Jena, Klinik für Anästhesiologie und Intensivtherapie, Jena, Deutschland

frank.brunkhorst@med.uni-jena.de author Bone Bone H.-G. HG

Clinic for Anesthesiology and Operative Intensive Care Medicine, Knappschaftshospital Recklinghausen, Germany

Klinik für Anästhesiologie und operative Intensivmedizin, Knappschaftskrankenhaus Recklinghausen, Deutschland

author Bardutzky Bardutzky J. J

Clinic for Neurology, University Hospital Erlangen, Germany

Neurologische Klinik, Universitätsklinikum Erlangen, Deutschland

author Dempfle Dempfle C.-E. CE

I. Clinic for Medicine, University Hospital Mannheim, Germany

I. Medizinische Klinik, Universitätsklinikum Mannheim, Deutschland

author Forst Forst H. H

Clinic for Anesthesiology and Operative Intensive Care Medicine, Hospital Augsburg, Germany

Klinik für Anästhesiologie und operative Intensivmedizin, Klinikum Augsburg, Deutschland

author Gastmeier Gastmeier P. P

Institute for Hygiene and Environmental Medicine, Charité University Medicine, Berlin, Germany

Institut für Hygiene und Umweltmedizin, Charité – Universitätsmedizin, Berlin, Deutschland

author Gerlach Gerlach H. H

Clinic for Anaesthesia and Operative Intensive Care Medicine, Vivantes Hospital Neukölln, Berlin, Germany

Klinik für Anästhesie und operative Intensivmedizin, Vivantes Klinikum Neukölln, Berlin, Deutschland

author Gründling Gründling M. M

Clinic for Anaesthesia and Intensive Care Medicine, Ernst-Moritz-Arndt-University Greifswald, Germany

Klinik für Anästhesie und Intensivmedizin, Ernst-Moritz-Arndt-Universität Greifswald, Deutschland

author John John S. S

Clinic for Medicine 4, University Erlangen-Nürnberg, Germany

Medizinische Klinik 4, Universität Erlangen-Nürnberg, Deutschland

author Kern Kern W. W

Institute for Infectology, University Hospital Freiburg, Germany

Institut für Infektiologie, Universitätsklinikum Freiburg, Deutschland

author Kreymann Kreymann G. G

Clinic and Policlinic for Intensive Care Medicine, University Hospital Hamburg-Eppendorf, Germany

Klinik und Poliklinik für Intensivmedizin, Universitätsklinikum Hamburg-Eppendorf, Deutschland

author Krüger Krüger W. W

Clinic for Anaesthesiology and Operative Intensive Care Medicine, Hospital Konstanz, Germany

Klinik für Anästhesiologie und operative Intensivmedizin, Klinikum Konstanz, Deutschland

author Kujath Kujath P. P

Clinic for Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Germany

Klinik für Chirurgie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Deutschland

author Marggraf Marggraf G. G

Clinic for Thorax and Cardivascular Surgery, University Hospital Essen, Germany

Klinik für Thorax- und kardiovaskuläre Chirurgie, Universitätsklinikum Essen, Deutschland

author Martin Martin J. J

Clinic for Anaesthesiology, Klinik am Eichert, Göppingen, Germany

Klinik für Anästhesiologie, Klinik am Eichert, Göppingen, Deutschland

author Mayer Mayer K. K

Clinic of Medicine II, Justus-Liebig-University Gießen, Germany

Medizinische Klinik II, Justus-Liebig-Universität Gießen, Deutschland

author Meier-Hellmann Meier-Hellmann A. A

Clinic for Anesthesia, Intensive Care Medicine and Pain Therapy, HELIOS Hospital Erfurt GmbH, Germany

Klinik für Anästhesie, Intensivmedizin und Schmerztherapie, HELIOS Klinikum Erfurt GmbH, Deutschland

author Oppert Oppert M. M

Clinic for Nephrology and Internal Intensive Care Medicine, Charité University Medicine, Berlin, Germany

Klinik für Nephrologie und Internistische Intensivmedizin, Charité – Universitätsmedizin Berlin, Deutschland

author Putensen Putensen C. C

Clinic and Policlinic for Anesthesiology and Operative Intensive Care Medicine, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany

Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, Deutschland

author Quintel Quintel M. M

Anesthesiology, Rescue and Intensive Care Medicine, University Hospital Göttingen, Germany

Zentrum Anästhesiologie, Rettungs- und Intensivmedizin, Universitätsklinikum Göttingen, Deutschland

author Ragaller Ragaller M. M

Clinic for Anesthesiology and Intensive Care Therapy, University Hospital Carl Gustav Carus, Technical University Dresden, Germany

Klinik für Anästhesiologie und Intensivtherapie, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Deutschland

author Rossaint Rossaint R. R

Clinic for Anesthesiology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Germany

Klinik für Anästhesiologie, Universitätsklinikum der Rheinisch-Westfälische Technische Hochschule Aachen, Deutschland

author Seifert Seifert H. H

Institute for Medical Microbiology, Immunology and Hygiene, Hospital at the University of Köln, Germany

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Klinikum der Universität zu Köln, Deutschland

author Spies Spies C. C

Clinic for Anesthesiology and Operative Intensive Care Medicine, Charité University Medicine, Berlin, Germany

Klinik für Anästhesiologie und operative Intensivmedizin, Charité – Universitätsmedizin, Berlin, Deutschland

author Stüber Stüber F. F

University Hospital for Anesthesiology and Pain Therapy, Inselspital Bern, Switzerland

Universitätsklinik für Anästhesiologie und Schmerztherapie, Inselspital Bern, Schweiz

author Weiler Weiler N. N

Clinic for Anesthesiology and Operative Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany

Klinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Deutschland

author Weimann Weimann A. A

Clinic for General and Visceral Surgery, Hospital St. Georg gGmbH Leipzig, Germany

Klinik für Allgemein- und Viszeralchirurgie, Klinikum St. Georg gGmbH Leipzig, Deutschland

author Werdan Werdan K. K

Clinic and Policlinic for Internal Medicine III, Hospital of the Medical Faculty, Martin-Luther-University Halle-Wittenberg, Germany

Klinik und Poliklinik für Innere Medizin III, Klinikum der Medizinischen Fakultät der Martin-Luther-Universität Halle-Wittenberg, Deutschland

author Welte Welte T. T

Department of Pneumology, Medical University Hannover, Germany

Abteilung Pneumologie, Medizinische Hochschule Hannover, Deutschland

author German Medical Science GMS Publishing House

Düsseldorf

610 guideline German Sepsis Society German Sepsis Aid severe sepsis septic shock prevention diagnosis treatment follow-up care Leitlinie Deutsche Sepsis-Gesellschaft Deutsche Sepsis-Hilfe schwere Sepsis septischer Schock Prävention Diagnose Therapie Nachsorge 20100421 20100628 engl germ 1612-3174 8 GMS German Medical Science GMS Ger Med Sci 14 Leitlinien sind systematisch entwickelte Darstellungen und Empfehlungen mit dem Zweck, Ärzte und Patienten bei der Entscheidung über angemessene Maßnahmen der Krankenversorgung unter spezifischen medizinischen Umständen und unter Berücksichtigung des spezifischen nationalen Gesundheitssystems zu unterstützen. Die erste Revision der S-2k-Leitlinie der Deutschen Sepsis-Gesellschaft in Kooperation mit 17 weiteren wissenschaftlichen medizinischen Fachgesellschaften und einer Selbsthilfegruppe gibt den Stand des Wissens (Ergebnisse von kontrollierten klinischen Studien und Wissen von Experten) über effektive und angemessene Krankenversorgung zum Zeitpunkt der „Drucklegung“ wieder. Die Leitlinienentwicklung erfolgte entsprechend des „Deutschen Instrumentes zur methodischen Leitlinien-Bewertung“ der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). In Anbetracht der unausbleiblichen Fortschritte wissenschaftlicher Erkenntnisse und der Technik müssen periodische Überarbeitungen, Erneuerungen und Korrekturen unternommen werden. Die Empfehlungen der Leitlinien können nicht unter allen Umständen angemessen genutzt werden. Die Entscheidung darüber, ob einer bestimmten Empfehlung gefolgt werden soll, muß vom Arzt unter Berücksichtigung der beim individuellen Patienten vorliegenden Gegebenheiten und der verfügbaren Ressourcen getroffen werden. Practice guidelines are systematically developed statements and recommendations that assist the physicians and patients in making decisions about appropriate health care measures for specific clinical circumstances taking into account specific national health care structures. The 1st revision of the S-2k guideline of the German Sepsis Society in collaboration with 17 German medical scientific societies and one self-help group provides state-of-the-art information (results of controlled clinical trials and expert knowledge) on the effective and appropriate medical care (prevention, diagnosis, therapy and follow-up care) of critically ill patients with severe sepsis or septic shock. The guideline had been developed according to the “German Instrument for Methodological Guideline Appraisal” of the Association of the Scientific Medical Societies (AWMF). In view of the inevitable advancements in scientific knowledge and technical expertise, revisions, updates and amendments must be periodically initiated. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources. Table of contentsDefinition and explanation of the term "guidelines"Recommendations in accordance with the provisions of S2k guidelinesDefinition and diagnosis of sepsisDiagnosis of infection Blood cultures Ventilator-associated pneumonia Catheter- and foreign body-related sepsis Surgical infections and intraabdominal focus of infection Invasive Candida infections Acute bacterial meningitisPrevention Infection prevention programs (ventilator-associated pneumonia, central venous catheter-associated bacteremia, urinary catheter-associated urinary tract infections) Manipulation of devices Body position Nutrition Immunonutrition Insulin therapy Selective bowel decontamination Oral antiseptics for mouth care Preemptive antifungal therapy Coated vascular catheters Staffing VaccinationsCausal treatment Infectious source control Antimicrobial therapySupportive therapy Hemodynamic stabilization Measures for initial hemodynamic stabilization Further measures for hemodynamic stabilization Volume therapy Therapy with inotropic agents and vasopressors Renal replacement therapy Airway management and ventilationAdjunctive therapy Recombinant activated protein C (rhAPC) Antithrombin Immunoglobulins Selenium Other therapeutic approachesOther supportive therapies Deep venous thrombosis (DVT) prophylaxis Nutrition and metabolic control Enteral vs. parenteral nutrition Parenteral nutrition Immunonutrition Glutamine Ulcer prophylaxis Use of bicarbonate in lactic acidosis Blood products Erythropoietin Fresh Frozen Plasma (FFP) Sedation, analgesia, delirium and neuromuscular blockadeFollow-up care and rehabilitation InhaltsverzeichnisDefinition und Erläuterung des Begriffs "Leitlinie"Empfehlungen gemäß den Regeln der S2k-LeitlinienSepsisdefinition und -diagnoseDiagnose der Infektion Blutkulturen Ventilator-assoziierte Pneumonien Katheter- und Fremdkörper-induzierte Sepsis Chirurgische Infektionen und intraabdomineller Fokus Invasive Candida-Infektionen Akute bakterielle MeningitisPrävention Programme zur Infektionsprävention (Ventilator-assoziierte Pneumonien, ZVK-assoziierte Bakteriämie, Harnwegkatheter-assoziierte Harnweginfektionen) Umgang mit „devices“ Körperposition Ernährung Immunonutrition Insulintherapie Selektive Darmdekontamination Orale Antiseptika zur Mundpflege Präemptive antimykotische Behandlung Imprägnierte Gefäßkatheter Personalausstattung ImpfungenKausale Therapie Fokussanierung Antimikrobielle TherapieSupportive Therapie Hämodynamische Stabilisierung Maßnahmen zur initialen hämodynamischen Stabilisierung Fortführende Maßnahmen zur hämodynamischen Stabilisierung Volumentherapie Therapie mit Inotropika und Vasopressoren Nierenersatzverfahren Airway-Management und BeatmungAdjunktive Therapie Rekombinantes aktiviertes Protein C (rhAPC) Antithrombin Immunglobuline Selen Andere TherapieansätzeAndere supportive Therapien Thromboseprophylaxe Ernährung und metabolische Kontrolle Ernährung enteral vs. parenteral Parenterale Ernährung Immunonutrition Glutamin Ulkusprophylaxe Bikarbonat bei Laktatazidose Blutprodukte Erythropoetin Fresh Frozen Plasma (FFP) Sedation, Analgesie, Delir und neuromuskuläre BlockadeNachsorge und Rehabilitation 1. Definition and explanation of the term "guidelines"(Based on the definition by the US Agency for Health Care Policy and Research for “Clinical Practice Guidelines”): “Practice guidelines are systematically developed statements and recommendations that assist the physicians and patients in making decisions about appropriate health care measures (prevention, diagnosis, therapy and follow-up care) for specific clinical circumstances.”The guidelines provide state-of-the-art information (results of controlled clinical trials and expert knowledge) on the effective and appropriate medical care at the time of “publication”. In view of the inevitable advancements in scientific knowledge and technical expertise, revisions, updates and amendments must be periodically initiated. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources. 1. Definition und Erläuterung des Begriffs "Leitlinie"(Orientiert an der Definition der Agency for Health Care Policy and Research für die „Clinical Practice Guidelines“ der USA): „Leitlinien sind systematisch entwickelte Darstellungen und Empfehlungen mit dem Zweck, Ärzte und Patienten bei der Entscheidung über angemessene Maßnahmen der Krankenversorgung (Prävention, Diagnostik, Therapie und Nachsorge) unter spezifischen medizinischen Umständen zu unterstützen.“Leitlinien geben den Stand des Wissens (Ergebnisse von kontrollierten klinischen Studien und Wissen von Experten) über effektive und angemessene Krankenversorgung zum Zeitpunkt der „Drucklegung“ wieder. In Anbetracht der unausbleiblichen Fortschritte wissenschaftlicher Erkenntnisse und der Technik müssen periodische Überarbeitungen, Erneuerungen und Korrekturen unternommen werden. Die Empfehlungen der Leitlinien können nicht unter allen Umständen angemessen genutzt werden. Die Entscheidung darüber, ob einer bestimmten Empfehlung gefolgt werden soll, muß vom Arzt unter Berücksichtigung der beim individuellen Patienten vorliegenden Gegebenheiten und der verfügbaren Ressourcen getroffen werden. 2. Recommendations in accordance with the provisions of S2k guidelinesIn devising these recommendations, the underlying studies were closely reviewed by the expert committee and classified into the following levels of evidence suggested by the Oxford Centre of Evidence Based Medicine:Ia – systematic overview of randomized clinical trials (RCT)Ib – one RCT (with a narrow confidence interval)Ic – all-or-none principleIIa – systematic overview of well-designed cohort studies IIb – one well-designed cohort study or one downgraded RCTIIc – outcomes research, ecological studiesIIIa – systematic overview of case-control studiesIIIb – one case-control studyIV – case series or downgraded cohort/ case-control studiesV – expert opinion without explicit critical appraisal or one that is based on physiological models/ lab researchThe “all-or-none principle” (level of evidence Ic) allows for the classification of medical interventions that make an integral part of routine medical care without the requirement of relevant studies on hand because they cannot be conducted for ethical reasons (e.g. oxygen insufflation for hypoxia). Despite growing acceptance of systematic reviews, they must also be critically reviewed. A recent meta-analysis of some trials with a small number of cases has shown a protective effect of a certain therapy regimen , only to be later disproved be a subsequent large prospective trial . It must also be noted that meta-analyses may involve a selection of studies with positive results (publication bias).Based on the levels of evidence, recommendations of the following level may be argued for a certain clinical issue :A – at least 2 studies with evidence level IB – one study with evidence level I or evidence level IcC – only studies with evidence level IID – at least 2 studies with evidence level IIIE – level IV or evidence level VThe evidence level of the study is named that leads to the corresponding recommendation level. The expert committee may vote to decide to upgrade or downgrade the level of recommendation by one level. This reassessment must be substantiated (please also see the detailed methodology report). 2. Empfehlungen gemäß den Regeln der S2k-LeitlinienBei der Erstellung dieser Empfehlungen wurden die zugrunde liegenden Studien von dem Expertenkommittee gesichtet und gemäß dem Oxford Centre of Evidence Based Medicine in folgende Evidenzgrade eingeteilt:Ia – Systematische Übersicht über randomisierte kontrollierte Studien (RCT)Ib – Ein RCT (mit engem Konfidenzintervall)Ic – Alle-oder-Keiner-Prinzip IIa – Systematische Übersicht gut geplanter KohortenstudienIIb – Eine gut geplante Kohortenstudie oder ein RCT minderer QualitätIIc – Outcome-Studien, Ökologische StudienIIIa – Systematische Übersicht über Fall-KontrollstudienIIIb – Eine Fall-Kontroll-StudieIV –Fallserien oder Kohorten-/Fall-Kontroll-Studien minderer QualitätV –Expertenmeinung ohne explizite Bewertung der Evidenz oder basierend auf physiologischen Modellen/LaborforschungDas „Alle-oder-Keiner“-Prinzip (Evidenzgrad Ic) erlaubt die Graduierung von medizinischen Maßnahmen, die fester Bestandteil der ärztlichen Routineversorgung sind, ohne dass entsprechende Studien vorliegen müssen, da diese aus ethischen Gründen nicht möglich sind (z.B. Sauerstoffinsufflation bei Hypoxie). Trotz der zunehmenden Akzeptanz von systematischen Übersichtsarbeiten müssen diese auch kritisch bewertet werden. So hatte eine kürzliche Metaanalyse einiger Studien mit kleinen Fallzahlen einen protektiven Effekt einer Therapie ergeben , der dann durch eine große prospektive Studie widerlegt wurde . Es muss auch bedacht werden, dass bei Metaanalysen eine Selektion von Studien mit positiven Ergebnissen vorliegen kann (Publikationsbias). Gemäß der Evidenzgrade können für eine bestimmte Fragestellung Empfehlungen mit folgendem Empfehlungsgrad ausgesprochen werden :A – Mind. 2 Studien mit Evidenzgrad IB – Eine Studie mit Evidenzgrad I oder Evidenzgrad IcC – Nur Studien mit Evidenzgrad IID –Mind. Zwei Studien mit Evidenzgrad IIIE –Level IV oder Evidenzgrad VEs wird der Evidenzgrad der Studie benannt, die zu dem entsprechenden Empfehlungsgrad geführt hat. Das Expertenkommittee kann per Abstimmung entscheiden, den Empfehlungsgrad um eine Stufe auf- bzw. abzuwerten. Die Umwertung muss begründet werden (s. auch ausführlichen Methodenreport). 3. Definition and diagnosis of sepsisPreliminary remarks: Sepsis is a complex systemic inflammatory reaction of the host to an infection. Currently, the diagnosis cannot be established based on any single parameter. Sepsis, severe sepsis and septic shock constitute a continuous spectrum of disease, characterized by a combination of vital parameters, laboratory parameters, hemodynamic data and organ functions. Depending on prior antibiotic therapy, bacteremia is found only in approximately 30% of patients with severe sepsis or septic shock , , , , . In approximately 30% of cases, no proof of infection backed by microbiological data can be furnished, although the clinical criteria make an infection likely , . Interpretation of microbiological findings in critically ill patients is often intricate because oftentimes microorganisms are identified that satisfy merely the definition of colonization. Critically ill patients often present with SIRS and multiple organ dysfunction; hence, an infectious cause-effect relationship often cannot be established with certainty. It is recommended to use the sepsis criteria provided by the German Sepsis Competence Network (SepNet) to establish a clinical diagnosis of severe sepsis or septic shock.→ Recommendation level E (evidence level V: expert opinion)Comment: Using the diagnostic criteria listed in Table 1 , a prevalence of severe sepsis and septic shock in German ICUs was determined to be 11% and the prevalence of hospital mortality 55% . These criteria differ substantially from the microbiology-driven criteria of the Centers of Disease Control (CDC) , but they have been used since 2005 in the German version of the International Classification of Diseases (ICD-10) and starting in 2011 they will be in use world-wide as well (http://www.dimdi.de/, see Appendix).Early determination of serum procalcitonin (PCT) levels is recommended to rule out severe sepsis and/or to confirm the diagnosis.→ Recommendation level C (evidence level IIb for )Comment: Severe sepsis or septic shock are unlikely in the presence of serum procalcitonin concentrations of <0.5 ng/ml, while it is highly likely at values above a threshold level of 2.0 ng/ml , , , . It must be noted that operative stress and other causes may result in a transitory increase in procalcitonin (PCT) levels . In order to shorten the duration of antimicrobial therapy, serial procalcitonin (PCT) measurements may be considered.→ Recommendation level C (evidence level IIb for )Comment: For the first time ever, a randomized trial demonstrated that as compared to a routine clinical decision-making process, the use of procalcitonin (PCT) allows for a safe reduction of the duration of antibiotic therapy in patients with severe sepsis by a median of 3.5 days. However, the study enrolled only 70 patients, which is indeed a low caseload . Studies on this subject with larger number of cases are currently underway with the results to be published in 2010. 3. Sepsisdefinition und -diagnoseVorbemerkung: Sepsis ist eine komplexe systemische inflammatorische Wirtsreaktion auf eine Infektion. Es gibt derzeit keinen Parameter, der allein zur Diagnose der Sepsis führen kann. Sepsis, schwere Sepsis und septischer Schock definieren ein Krankheitskontinuum, das über eine Kombination aus Vitalparametern, Laborwerten, hämodynamischen Daten und Organfunktionen definiert wird. Eine Bakteriämie findet sich in Abhängigkeit von einer antibiotischen Vorbehandlung nur bei durchschnittlich 30% von Patienten mit schwerer Sepsis oder septischem Schock , , , , . Insgesamt kann in ca. 30% kein mikrobiologisch gesicherter Infektionsnachweis geführt werden, obwohl eine Infektion nach klinischen Kriterien wahrscheinlich ist , . Die Interpretation mikrobiologischer Befunde ist bei kritisch kranken Patienten häufig problematisch, da häufig Mikroorganismen nachgewiesen werden, die lediglich einer Kolonisation entsprechen können. Kritisch kranke Patienten weisen häufig ein SIRS und multiple Organdysfunktionen auf, der kausale Zusammenhang mit einer Infektion ist daher oft nicht sicher nachzuweisen. Es wird empfohlen, die Sepsiskriterien des deutschen Kompetenznetzwerkes Sepsis (SepNet) für die klinische Diagnose der schweren Sepsis bzw. des septischen Schocks zu verwenden. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Unter Verwendung dieser diagnostischen Kriterien (Tabelle 1 ) wurde auf deutschen Intensivstationen eine Prävalenz der schweren Sepsis und des septischen Schocks von 11% und eine Krankenhaussterblichkeit von 55% beobachtet . Diese Kriterien weichen erheblich von den mikrobiologisch orientierten Kriterien der Centers of Disease Control (CDC) ab, werden jedoch seit 2005 in der deutschen Version der International Classification of Diseases (ICD-10) und ab 2011 auch weltweit verwendet (http://www.dimdi.de/, s. Appendix).Der frühzeitige Nachweis von Procalcitonin (PCT) im Serum zum Ausschluss einer schweren Sepsis bzw. zur Sicherung der Diagnose wird empfohlen. → Empfehlung Grad C (Evidenzgrad IIb für )Kommentar: Bei Procalcitoninkonzentrationen von <0,5 ng/ml im Serum ist eine schwere Sepsis oder ein septischer Schock unwahrscheinlich, ab einem Schwellenwert von 2,0 ng/ml hochwahrscheinlich , , , . Dabei ist zu beachten, dass operatives Trauma und andere Ursachen zu einer transitorischen Procalcitonin (PCT)-Erhöhung führen können . Um die Dauer einer antimikrobiellen Behandlung zu verkürzen, können Procalcitonin (PCT)-Verlaufsmessungen erwogen werden. → Empfehlung Grad C (Evidenzgrad IIb für )Kommentar: In einer randomisierten Studie konnte erstmalig nachgewiesen werden, dass die Dauer der Antibiotikatherapie bei Patienten mit schwerer Sepsis durch Verwendung von Procalcitonin (PCT) im Vergleich zu einer routinemässigen klinischen Entscheidungsfindung um 3,5 Tage (median) gefahrlos reduziert werden kann. Die Fallzahl war mit lediglich 70 Patienten allerdings gering . Studien mit größerer Fallzahl werden gegenwärtig hierzu durchgeführt bzw. werden in 2010 publiziert. 4. Diagnosis of infectionBlood culturesIt is recommended to collect blood cultures when sepsis is clinically suspected or when one or more of the following criteria are met: fever, chills/shivering, hypothermia, leukocytosis, left shift in differential blood count, increase in procalcitonin or C-reactive protein (CRP) levels, and/or neutropenia , , .→ Recommendation level C (evidence level IIb for )Comment: Compared with C-reactive protein, procalcitonin carries a higher diagnostic positive predictive value , , , and can be detected sooner in the course of infection .It is recommended to collect blood cultures (2–3 sets) as soon as possible before instituting antimicrobial therapy , . → Recommendation level B (evidence level Ic)In patients on antimicrobial therapy, it is recommended to collect blood cultures immediately before administration of the next dose , .→ Recommendation level E (evidence level V: expert opinion)Comment (also see Table 2 ): After appropriate skin disinfection, blood cultures should be collected via a peripheral venipuncture , . Because of the two-fold increase in the risk of contamination , blood cultures may be collected via a central venous catheter or an arterial access device only in exceptional circumstances. To fill the culture bottle (a minimum of 10 ml , ), a sterile needle must be used . 2 or 3 sets of blood cultures should be collected (always an aerobic and an anaerobic blood culture bottle, together comprising a blood culture set) from various body sites (for instance, the right and the left cubital vein) , ; a specified time interval between the collections need not be honored , . Identification of infectious agents using polymerase chain reaction (PCR) amplification protocols, such as the multiplex PCR (identification of a limited number of infectious agents) and the broad-range PCR (identification of all kinds of infectious agents) is a promising new approach which is currently being assessed in clinical trials. Clinical trials conducted to date suggest that this approach allows for a considerably more frequent and faster positive identification of infectious agents , , . Due to a lack of resistance testing, it currently still does not constitute a substitute for blood cultures. In addition, there are no data on cost-effectiveness. Clear-cut recommendations for clinical practice cannot yet be derived from the results collected to date .Ventilator-associated pneumoniasPreliminary remarks: Ventilator-associated pneumonia (diagnosis of pneumonia established after more than 48 hours of mechanical ventilation in previously pneumonia-free patients) must be differentiated from pneumonia that requires ventilation assistance. The latter may be community-acquired or hospital-acquired (nosocomial pneumonia); diagnostic principles for each disease entity apply , . The previously recommended stratification scheme dividing ventilator-associated pneumonias into “early onset” (days 1–4) and “late onset” (after day 4) VAP and the corresponding different empiric antimicrobial therapy regimens , have been judged no longer indicated in a recent study by the National Reference Center for the Surveillance of Nosocomial Infections because the pathogen spectrum does not differ between the two groups . Fresh infiltrates on chest X-ray, leukocytosis or leukopenia and purulent tracheal secretions are sensitive clinical signs of a VAP . It is recommended that the modified “clinical pulmonary infection score (CPIS)” (a score of >6) be used for initial screening (Table 3 ) , . → Recommendation level C (level of evidence IIb for )Comment: A combination of CPIS (cut-off ≥6) and procalcitonin (cut-off ≥2.99 ng/ml) can further increase the diagnostic positive predictive value .When pneumonia is suspected, it is recommended to obtain secretions from deep airway segments before initiating antimicrobial therapy .→ Recommendation level E (evidence level V: expert opinion)Comment: Sampling should in no event delay timely administration of a carefully-selected antimicrobial therapy in patients with severe sepsis or septic shock (see the section on antimicrobial therapy). To date, no diagnostic procedure (endotracheal aspiration, blind or bronchoscopic protected specimen brush (PSB), bronchoalveolar lavage (BAL)) has proven superior over another , , . Hence, the choice of technique should be guided by experiences of individual institutions.It is recommended that quantitative or semi-quantitative (≥100,000 CFU/ml) techniques be employed, if at all possible , .→ Recommendation level B (evidence level Ic)Comment: Processing should be done in accordance with the guidelines of the German Society for Hygiene and Microbiology (DGHM) by counting the number of polymorphonuclear granulocytes (>25 per high-power field) and epithelial cells (max. 25 per high-power field) , , . The use of routine serological tests is not recommended for diagnosis of a VAP , .→ Recommendation level E (evidence level V: expert opinion)Catheter- and foreign body-related sepsis A catheter-induced infection cannot be unequivocally confirmed without removing the catheter . If a central venous catheter (CVC) is deemed to be the likely source of sepsis, it is recommended that the catheter be removed to allow for the diagnosis to be established, and the catheter tip sent for microbiological analysis , . → Recommendation level E (evidence level V: expert opinion)Before removing the central venous catheter, it is recommended to collect blood cultures through the indwelling catheter and concomitantly via a peripheral vein to be able to compare the results of culture analysis , , . → Recommendation level C (evidence level IIb for , )In the presence of purulent secretions from the puncture site, it is recommended to take smears and perform a new catheter placement. The new puncture should be performed at a site away from the infected [original] puncture site.→ Recommendation level D (Evidence level IIb for )If a catheter-related infection is suspected, it is not recommended to use a guidewire to facilitate introduction of a new catheter , .→ Recommendation level C (evidence level IIa for )There is no evidence that a routine change of intravascular catheters reduces the risk of bacteremia , . Hence, it is recommended to change intravascular catheters only in the presence of signs of infection. → Recommendation level C (evidence level IIa for )Surgical infections and intraabdominal focus of infection When a surgical wound infection or an intraabdominal infection is suspected, it is recommended to obtain blood cultures (see the section on blood cultures). Furthermore, it is recommended to obtain fresh material (tissue) or wound smears and to perform Gram staining, as well as to collect anaerobic and aerobic blood cultures , , , .→ Recommendation level D (evidence level IIIb for , )Comment: It should be kept in mind that drainage secretions are plagued by a risk of contamination. Compared to wound smears, fresh material (tissue) has a higher microbiological detection rate. It is recommended to perform an abdominal ultrasound as a method of first choice when searching for an intraabdominal focus. If this method proves unsuccessful, it is recommended to perform a CT scan which may include the use of a contrast , . In the case of a full-blown unequivocal presentation of acute abdomen, it is recommended to resort to emergency laparotomy/laparoscopy. → Recommendation level B (evidence level Ic)It is recommended to perform radiologically- or ultrasound-guided aspirations of suspicious areas and send the specimens for microbiological analysis . → Recommendation level D (evidence level V: expert opinion)Invasive Candida infections In neutropenic and immunosuppressed patients, as well as in patients who have undergone abdominal surgical interventions or those who have received prolonged antibiotic therapy, it is recommended to obtain blood cultures to confirm a Candida infection . → Recommendation level E (evidence level V: expert opinion)Comment: The cumulative incidence of invasive Candida infections in ICU patients is approximately 1–2% , . The diagnostic gold standard of an invasive Candida infection is a histopathological or cytopathological evidence obtained from the analysis of the effected tissue or of normally sterile body fluids with the exception of urine . Routine screening to determine Candida colonizations is not recommended.→ Recommendation level E (evidence level V: expert opinion)Comment: Candida colonization is identified in approximately 16% of ICU patients , . However, it carries a low positive predictive value for a Candida infection .Acute bacterial meningitisPreliminary remarks: Bacterial meningitis occurs either primarily as a result of hematogenous or lymphogenic pathogen dissemination or secondarily by a direct entry of microorganisms into the CNS (most often a spreading infection, e.g. otitis, sinusitis, or iatrogenic, associated with medical procedures) . Of the 696 patients with community-acquired bacterial meningitis, almost all presented with at least 2 of the 4 typical symptoms such as headaches, nuchal rigidity, fever and impaired consciousness . The diagnosis of bacterial meningitis rests on a cytological/biochemical analysis of the cerebrospinal fluid (CSF) and is confirmed upon detection of pathogens in the CSF , . CSF analysis typically gives a profile of granulocytic pleocytosis (>1,000 cells/µl); protein of >120 mg/dL; glucose of <30 mg/dL or CSF: serum glucose ratio of <0.3; lactate of >3.5 mmol/L , , . In patients with suspected bacterial meningitis who present with one of the following criteria: impaired consciousness, a focal neurological deficit, immunosuppression, disease of the CNS, or de novo seizures, it is recommended to perform a CCT prior to performing a lumbar puncture (LP) in order to rule out increased intracranial pressure , , , . Furthermore, it is recommended to start the first course of antibiotic therapy in these patients without delay, immediately following the collection of blood cultures and before performing a CCT and LP. → Recommendation level B (evidence level Ic)In patients who do not present with signs of elevated intracranial pressure (see above), it is recommended to obtain blood cultures (see above) and perform a LP as soon as possible before initiating antimicrobial therapy and before performing the CCT , , .→ Recommendation level B (evidence level Ic)Subsequently, it is recommended to initiate a carefully-selected antibiotic therapy without delay .→ Recommendation level B (evidence level Ic)To confirm the diagnosis, it is recommended to promptly perform a Gram stain on the CSF sediment. → Recommendation level B (evidence level Ic)Comment: Microscopic analysis with Gram staining enables successful pathogen determination in 60–90% of cases (specificity ≥97%) , , , , . In patients who underwent prior treatment, or in the case of a negative Gram stain and negative blood cultures, the use of latex agglutination test and PCR may possibly increase the probability of successful pathogen identification , , , .It is recommended to institute early dexamethasone therapy prior to or concurrently with the initial antibiotic administration.→ Recommendation level A (evidence level Ia for )Comment: It is impossible to make a clear statement about the use of dexamethasone in patients concurrently presenting with bacterial meningitis and sepsis because of the lack of controlled trials with adequate number of cases. A large European placebo-controlled trial revealed that a significant reduction in mortality and frequency of witnessing unfavorable course of disease was achieved with adjuvant dexamethasone therapy administered prior to or concurrently with the initial course of antibiotics . A subgroup analysis showed that dexamethasone proved effective only in pneumococcal meningitis. These favorable effects of dexamethasone administration in adult patients with pneumococcal meningitis were confirmed in 2 meta-analyses of controlled trials , . However, both meta-analyses yielded only an insignificant reduction in mortality and frequency of residual permanent neurological deficits also in adult patients with meningococcal meningitis who were treated with dexamethasone. In contrast, dexamethasone seems not to confer any advantages over placebo under conditions prevailing in a developing country, particularly in children , , . Based on the results of the European trial and the data from meta-analyses , , the German Society of Neurology generally recommends intravenous administration of 10 mg of dexamethasone in adult patients with suspected bacterial meningitis immediately prior to the administration of antibiotics, followed by 10 mg every 6 hours over 4 days . 4. Diagnose der InfektionBlutkulturenEs wird empfohlen, bei klinischem Verdacht auf eine Sepsis bzw. eines oder mehrerer der folgenden Kriterien: Fieber, Schüttelfrost, Hypothermie, Leukozytose, Linksverschiebung im Differentialblutbild, Erhöhung von Procalcitonin oder C-reaktivem Protein bzw. einer Neutropenie Blutkulturen abzunehmen , , .→ Empfehlung Grad C (Evidenzgrad IIb für )Kommentar: Procalcitonin hat eine höhere diagnostische Präzision als C-reaktives Protein , , , und ist nach dem infektiösen Stimulus früher nachweisbar . Es wird empfohlen, Blutkulturen (2–3 Pärchen) schnellstmöglich vor Einleitung einer antimikrobiellen Therapie abzunehmen , . → Empfehlung Grad B (Evidenzgrad Ic)Es wird empfohlen, bei Patienten unter vorbestehender antimikrobieller Therapie Blutkulturen unmittelbar vor der nächsten Gabe abzunehmen , . → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar (Tabelle 2 ): Blutkulturen müssen nach adäquater Hautdesinfektion über eine periphere Venenpunktion erfolgen , . Aufgrund des zweifach höheren Kontaminationsrisikos sollten Blutkulturen nur in Ausnahmefällen über einen zentralen Venenkatheter bzw. einen arteriellen Zugang abgenommen werden. Für die Befüllung der Kulturflasche (mindestens 10 ml , ) muss eine sterile Nadel benutzt werden . Es sollten 2 bis 3 Blutkulturen (jeweils eine aerobe und eine anaerobe Blutkulturflasche, zusammen ein sogenanntes Blutkulturpaar oder Blutkultursets) von verschiedenen Entnahmeorten (z.B. rechte und linke Vena cubitalis) entnommen werden , , wobei auf ein definiertes zeitliches Intervall zwischen den Abnahmen verzichtet werden kann , .Eine Erregeridentifizierung mittels Methoden der Polymerase-Kettenreaktion (PCR), wie Multiplex-PCR (Identifizierung einer begrenzten Anzahl von Erregern) und Breitband-PCR (Identifizierung aller Erreger) ist ein vielversprechender neuer Ansatz und wird gegenwärtig in klinischen Studien untersucht. Die bisherigen klinischen Studien legen nahe, dass hiermit deutlich häufiger und schneller ein Erregernachweis geling , , . Wegen der weitgehend fehlenden Resistenztestung ist dies jedoch derzeit kein Ersatz für die Blutkultur. Ebenfalls fehlen Daten zur Kosteneffektivität. Klare Empfehlungen für die klinische Praxis können aus den bisherigen Ergebnissen noch nicht abgeleitet werden .Ventilator-assoziierte PneumonienVorbemerkung: Eine ventilatorassoziierte Pneumonie (Diagnose einer Pneumonie nach mehr als 48 Stunden Beatmungsdauer bei zuvor pneumoniefreien Patienten) ist von einer Pneumonie, welche eine Beatmung erforderlich macht, zu unterscheiden. Letztere kann ambulant erworben oder nosokomial sein, es gelten die diagnostischen Regeln für die jeweiligen Erkrankungsbilder , . Die früher empfohlene Stratifizierung in eine „early onset“ (zwischen Tag 1–4) und „late onset“ (nach Tag 4) VAP und damit verbundene unterschiedliche empirische antimikrobielle Therapieplanung ist nach einer jüngsten Erhebung des Nationalen Referenzzentrums für Surveillance von nosokomialen Infektionen nicht mehr sinnvoll, da sich das Erregerspektrum nicht unterscheidet .Neu aufgetretene Infiltrate im Röntgen-Thorax, eine Leukozytose oder Leukopenie und purulentes Trachealsekret sind sensitive klinische Hinweise auf eine VAP . Es wird empfohlen, den modifizierten „Klinische Pulmonale Infektions Score (CPIS)“ (Score >6) für das initiale Screening zu verwenden (Tabelle 3 ) , . → Empfehlung Grad C (Evidenzgrad IIb für )Kommentar: Eine Kombination von CPIS (cut-off ≥6) und Procalcitonin (cut-off ≥2,99 ng/ml) kann die diagnostische Präzision noch weiter erhöhen .Bei V. auf Pneumonie wird empfohlen, Sekrete aus den tiefen Atemwegen vor Einleitung einer antimikrobiellen Therapie zu gewinnen .→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Keinesfalls sollte hierdurch die Intitierung einer kalkulierten antimikrobiellen Therapie bei Patienten mit schwerer Sepsis oder septischem Schock verzögert werden (s. Abschnitt antimikrobielle Therapie). Bisher konnte für kein diagnostisches Verfahren (endotracheale Aspirate, blinde oder bronchoskopische PSB, BAL) ein signifikanter Vorteil bewiesen werden , , . Die Wahl der Technik sollte sich daher nach der Erfahrung der einzelnen Einrichtungen richten. Es wird empfohlen, quantitative oder semiquantitative (≥100.000 cfu/ml) Techniken zu bevorzugen , . → Empfehlung Grad B (Evidenzgrad Ic)Kommentar: Die Aufarbeitung sollte gemäß den Richtlinien der Deutschen Gesellschaft für Hygiene und Mikrobiologie (DGHM) mit Auszählung der polymorphkernigen Granulozyten (>25 pro Gesichtsfeld) und Epithelzellen (max. 25 pro Gesichtsfeld) erfolgen , , .Routinemäßige serologische Tests werden zur Diagnose einer VAP nicht empfohlen , . → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Katheter- und Fremdkörper-induzierte Sepsis Das Vorliegen einer Katheter-induzierten Infektion kann ohne Entfernung des Katheters nicht sicher festgestellt werden . Wenn ein zentraler Venenkatheter (ZVK) eine mögliche Sepsisquelle darstellt, wird empfohlen, den ZVK zur Diagnosesicherung zu entfernen und die Katheterspitze zur mikrobiologischen Diagnostik einzuschicken , . → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Es wird empfohlen, Blutkulturen vor Entfernung des ZVK über den liegenden Katheter und zeitgleich über eine periphere Vene abzunehmen und die Kulturergebnisse miteinander zu vergleichen , , .→ Empfehlung Grad C (Evidenzgrad IIb für , )Bei Vorliegen einer eitrigen Sekretion aus dem Stichkanal wird empfohlen, Abstriche und eine Katheterneuanlage durchzuführen, wobei die neue Punktion fern von der infizierten Punktionsstelle erfolgen sollte.→ Empfehlung Grad D (Evidenzgrad IIb für )Bei Verdacht auf eine Katheterinfektion wird ein Katheterwechsel über einen Führungsdraht nicht empfohlen , .→ Empfehlung Grad C (Evidenzgrad IIa für )Es gibt keinen Hinweis, dass ein routinemäßiger Wechsel intravasaler Katheter das Risiko einer Bakteriämie vermindert , . Daher wird empfohlen, intravasale Katheter nur bei Anzeichen einer Infektion zu wechseln.→ Empfehlung Grad C (Evidenzgrad IIa für )Chirurgische Infektionen und intraabdomineller Fokus Bei V. a. chirurgische Wundinfektionen oder intraabdominelle Infektionen wird empfohlen, Blutkulturen abzunehmen (s. Abschnitt Blutkulturen). Zusätzlich wird empfohlen, Nativmaterial (Gewebe) oder Wundabstriche und eine Gramfärbung sowie aerobe und anaerobe Kulturen zu veranlassen , , , .→ Empfehlung Grad D (Evidenzgrad IIIb für , )Kommentar: Bei Sekreten aus Drainagen sollte die Kontaminationsgefahr beachtet werden. Nativmaterial (Gewebe) hat gegenüber Wundabstrichen eine höhere mikrobiologische Nachweisrate.Es wird empfohlen, eine Sonografie als Mittel der ersten Wahl zur Suche eines intraabdominellen Fokus durchzuführen. Ist diese Methode erfolglos, wird empfohlen, eine Computertomographie, ggf. mit Kontrastmittel-Darstellung durchzuführen , . Bei Vollbild eines akuten Abdomens wird die notfallmäßige Laparotomie/Laparaskopie empfohlen.→ Empfehlung Grad B (Evidenzgrad Ic)Es wird empfohlen, verdächtige Areale unter sonographischer bzw. radiologischer Kontrolle zu punktieren und das Punktat zur mikrobiologischen Untersuchung einzuschicken . → Empfehlung Grad D (Evidenzgrad V: Expertenmeinung)Invasive Candida-Infektionen Bei neutropenischen, immunsupprimierten und bei Patienten nach abdominalchirurgischen Eingriffen und solchen nach prolongierter antibiotischer Vorbehandlung wird empfohlen, Blutkulturen zum Nachweis einer Candida-Infektion abzunehmen .→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Die Inzidenz von invasiven Candida-Infektionen bei Intensivpatienten liegt bei ca. 1–2% , . Der Goldstandard der Diagnose einer invasiven Candida-Infektion ist der histopathologische bzw. zytopathologische Nachweis in betroffenen Geweben oder in normalerweise sterilen Körperflüssigkeiten, jedoch nicht im Urin .Ein Routinescreening zum Nachweis von Candidakolonisierungen wird nicht empfohlen.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Candida-Kolonisierungen werden bei ca. 16% von Intensivpatienten nachgewiesen , . Diese haben jedoch einen geringen positiv prädiktiven Wert zur Vorhersage einer Candida-Infektion .Akute bakterielle MeningitisVorbemerkung: Eine bakterielle Meningitis entsteht entweder primär infolge einer hämatogenen oder lymphogenen Erregeraussaat oder sekundär durch direkten Eintritt von Mikroorganismen in das ZNS (meist fortgeleitete Infektion z.B. Otitis, Sinusitis oder iatrogen in Zusammenhang mit medizinischen Eingriffen) . Bei 696 Patienten mit ambulant erworbener bakterieller Meningitis hatten nahezu alle Patienten mindestens 2 der 4 charakteristischen Symptome Kopfschmerzen, Nackensteife, Fieber und Bewusstseinsstörung . Die Diagnose einer bakteriellen Meningitis stützt sich auf der zytologisch-biochemischen Untersuchung des Liquors und wird durch den Erregernachweis im Liquor gesichert , . Der Liqourbefund zeigt typischerweise eine granulozytäre Pleozytose >1000 Zellen/µl; Protein >120 mg/dl; Glukose <30 mg/dl, oder Liquor/Serum-Glukose-Quotient <0,3; Laktat >3,5 mmol/l , , . Bei Patienten mit V.a. bakterielle Meningitis, die eines der Kriterien: Bewusstseinsminderung, fokales neurologisches Defizit, Immunsuppression, ZNS-Erkrankung in der Anamnese, oder neu aufgetretene Krampfanfälle aufweisen, wird empfohlen, vor der Lumbalpunktion (LP) ein CCT durchzuführen, um einen erhöhten intrakraniellen Druck auszuschließen , , , . Es wird auch empfohlen, die erste Antibiose bei diesen Patienten ohne Zeitverlust unmittelbar nach Abnahme von Blutkulturen vor CCT und LP zu geben.→ Empfehlung Grad B (Evidenzgrad Ic)Bei Patienten ohne Hinweise auf eine intrakranielle Drucksteigerung (s.o.) wird empfohlen, schnellstmöglich vor Beginn der antimikrobiellen Therapie und vor CCT Blutkulturen (s. o.) und eine LP durchzuführen , , .→ Empfehlung Grad B (Evidenzgrad Ic)Danach wird empfohlen ohne Zeitverlust mit einer kalkulierten Antibiotikatherapie zu beginnen .→ Empfehlung Grad B (Evidenzgrad Ic)Zur Sicherung der Diagnose wird eine sofortige Gramfärbung im Liquor empfohlen.→ Empfehlung Grad B (Evidenzgrad Ic)Kommentar: Der Erregernachweis gelingt mikroskopisch mittels Gramfärbung in 60–90% (Spezifität ≥97%) , , , , . Bei vorbehandelten Patienten, negativem Ergebnis in der Gramfärbung und Kultur kann der Einsatz von Latexagglutionationstests und PCR die Chance des Erregernachweises möglicherweise erhöhen , , , . Eine frühzeitige Behandlung mit Dexamethason vor oder mit der ersten AB-Gabe wird empfohlen.→ Empfehlung Grad A (Evidenzgrad Ia für )Kommentar: Über den Einsatz von Dexamethason bei Patienten mit bakterieller Meningitis und gleichzeitiger Sepsis kann keine definitive Aussage gemacht werden, da kontrollierte Studien hierzu mit einer ausreichenden Anzahl an Patienten fehlen. In einer großen plazebo-kontrollierten europäischen Studie führte die adjunktive Therapie mit Dexamethason vor oder zeitgleich mit der ersten Antibiotikagabe zu einer signifikanten Reduktion der Letalität und der Häufigkeit ungünstiger klinischer Verläufe . Die Subgruppenanalyse zeigte, dass Dexamethason nur bei Pneumokokkenmeninigitis wirksam war. Diese günstigen Effekte von Dexamethason bei erwachsenen Patienten mit Pneumokokkenmeningitis konnten in 2 Metaanalysen kontrollierter Studien bestätigt werden , . Beide Metaanalysen zeigten aber auch bei Erwachsenen mit Meningokokkenmeningitis eine nichtsignifikante Reduktion der Letalität und Häufigkeit neurologischer Residuen unter Dexamethasonbehandlung. Dagegen scheint Dexamethason unter in einem Entwicklungsland herrschenden Bedingungen insbesondere bei Kindern keinen Vorteil gegenüber Placebo zu besitzen , , . Aufgrund der europäischen Therapiestudie und den Daten der Metaanalysen , empfiehlt die Deutsche Gesellschaft für Neurologie, grundsätzlich bei erwachsenen Patienten mit Verdacht auf bakterielle Meningitis Dexamethason 10 mg iv unmittelbar vor Gabe des Antibiotikums zu verabreichen, danach 10 mg alle 6 Stunden für insgesamt 4 Tage . 5. PreventionInfection prevention programs (ventilator-associated pneumonias, central venous catheter- associated bacteremia, urinary catheter-associated urinary tract infections)We recommend that training programs and universal precaution protocols be implemented for ICU staff because these measures significantly reduce the incidence of ventilator-associated pneumonias , , , , , , central venous catheter-associated bacteremia , , , , and catheter-associated urinary tract infections . → Recommendation level B (evidence level IIc for , ) It is recommended to regularly compile and analyze data on the incidence of ventilator-associated pneumonias and central venous catheter-associated bacteremia in order to record trends and assess the situation prevailing in the in-house ICU in comparison with other ICUs. To that effect, institutional definitions for the diagnosis of a VAP and central venous catheter-associated bacteremia should be employed , and institutional frequencies determined (i.e. the number of ventilator-associated pneumonia cases per 1,000 ventilation days and the number of bacteremia cases per 1,000 central venous catheter days) , , . In addition, it is recommended to regularly compile and evaluate data on the causative organisms and their antibiotic resistance profiles. → Recommendation level B (evidence level IIc for )Manipulation of devicesHygienic hand disinfection is recommended before and after each patient encounter , .→ Recommendation level A (evidence level Ia for )Comment: Hygienic hand disinfection before each patient encounter is the most important measure aimed at limiting the spread of pathogens to the patients. Regular hygienic hand disinfection following patient encounters primarily serves to protect the hospital staff and to prevent the spread of pathogens in the inanimate patient environment. In recent years, various studies indicated that the incidence of nosocomial MRSA infections could be significantly reduced by promoting hand disinfection compliance , . It is recommended to use aseptic techniques during the placement of central venous catheters and other comparable central intravascular catheters .→ Recommendation level A (evidence level Ib for )Comment: A randomized controlled trial indicated advantages from the combined use of sterile gloves, a sterile surgical gown, a face mask, surgical headgear and a large surgical drape over the use of sterile gloves and a small surgical drape during the placement of central venous catheters. No randomized controlled trial evaluated the contribution of each individual component. It is recommended to remove the intravascular and urinary catheters without delay as soon as they are no longer indicated . → Recommendation level A (evidence level Ic)A routine change of intravascular and urinary catheters is not recommended .→ Recommendation level B (evidence level Ib for )The use of endotracheal tubes enabling subglottic suction may be considered because it is associated with reduced incidence of pneumonia , .→ Recommendation level C (evidence level IIb for )Body positionUnless contraindicated, it is recommended to keep the head of bed elevated whenever possible in intubated patients in order to prevent ventilator-associated pneumonia (VAP). → Recommendation level B (evidence level IIb for )Comment: Aspiration of bacterially contaminated secretions from the upper GI tract and pharynx is generally considered a risk factor as well as a triggering factor for the development of nosocomial and ventilator-associated pneumonias (VAP). It follows that measures that lead to diminished gastroesophageal reflux and a smaller volume of oropharyngeal secretions are associated with a lower incidence of nosocomial pneumonias and VAP , , , . The effects of elevating the head of bed in order to prevent aspiration and pneumonia were researched in orotracheally intubated patients without known risk factors for gastroesophageal reflux, who have received a nasogastric tube and stress ulcer prophylaxis and in whom the endotracheal cuff pressure was controlled and maintained above 25 cm H2O. A proportion of enrolled patients received enteral nutrition. In these patients, a continuous maintenance of a 45° elevation of the head of bed resulted in a delayed gastroesophageal reflux and/or a reduction, but not a complete avoidance, of aspiration of pharyngeal secretions , and the incidence of VAP, when compared to a flat supine position (i.e. 0° head of bed elevation). A head of bed elevation of 30° in combination with a suction of subglottic secretions did not result in a diminished colonization of lower airways, when compared to a flat supine position with no head of bed elevation . A clinical trial attempted to maintain a head of bed elevation of 45° in the interventional group, yet the measurements indicated that despite trial conditions, a head of bed elevation of only 30° has actually been achieved. In comparison to the supine position with a 10° head of bed elevation , the 30° elevation did not result in a reduction of VAP incidence. NutritionAccording to a meta-analysis, early oral or enteral nutrition led to a reduction of infections and duration of inpatient stays in surgical patients who underwent surgical procedures involving the gastrointestinal tract. Hence, early oral or enteral nutrition is recommended in this patient population.→ Recommendation level B (evidence level Ia for )Comment: Early enteral or oral nutrition should be taken to mean the resumption of regular diet within 24 hours postoperatively. The amount of nutrition provided must be tailored according to the patient's individual tolerance level. Supplying even small amounts of nutrition and/or liquid is associated with an improved course of disease. Orogastric gavage is only required when the patient is not longer able to swallow unassisted . ImmunonutritionThe perioperative or postoperative use of immunomodulating enteral nutrition (arginine, omega-3 fatty acids, nucleotides) is recommended for use in elective surgical patients with gastrointestinal tumors or in multiple trauma patients who are in the position to receive enteral nutrition, because such nutrition is associated with a reduction of the duration of inpatient stay as well as a reduction in the number of nosocomial infection cases , .→ Recommendation level A (evidence level Ia for )Insulin therapyThe routine use of intensified intravenous insulin therapy with a target to reestablish normoglycemia (4.4–6.1 mmol/l (i.e. 80–110 mg/dl)) in ICU patients cannot be recommended except for clinical trial purposes.→ Recommendation level A (evidence level Ia for )Comment: Based on currently-available data, continuous intravenous administration of insulin with the purpose of restoring normoglycemia (4.4–6.1 mmol/l (80–110 mg/dl)) in ICU patients has so far been considered a measure having the potential to prevent septic complications in postoperative and mechanically ventilated predominantly cardiological surgical patients (severe sepsis prevention) and therefore help reduce mortality and morbidity , . However, this has been shown in only one single-center randomized trial; a confirmatory study is still pending. A further trial involving internal medicine ICU patients failed to confirm either a reduction in septic complications or a survival advantage; however, there was a concomitant 5- to 6-fold increase in the incidence of severe hypoglycemic episodes (<40 mg/dl; [2.2 mmol/l]). A meta-analysis published in 2008 , which analyzed the results of 29 randomized trials with a total of 8,432 enrolled patients, revealed no differences in hospital mortality between patients who were managed by a ‘tight glycemic control (TGC)’ protocol and those who were not, i.e. with either an IIT (target values of 80–110 mg/dl) or a moderate glycemic control regimen (target values of <150 mg/dl) (23% vs. 25.2%; RR, 0.90; 95% CI, 0.77–1.04; and 17.3% vs. 18.0%; RR, 0.99; 95% CI, 0.83–1.18). TGC failed to result in an increased survival either in the strictly surgical ICUs (8.8% vs. 10.8%, RR, 0.88; 95% CI, 0.63–1.22), or in the exclusively internal medicine ICUs (26.9% vs. 29.7%; RR, 0.92; 95% CI, 0.82–1.04) or medical-surgical ICUs (26.1% vs. 27.0%; RR, 0.95; 95% CI, 0.80–1.13). IIT did not reduce the frequency of acute kidney failure requiring renal replacement therapy (11.2% vs. 12.1%; RR, 0.96; 95% CI, 0.76–1.20), but it did reduce the “frequency of sepsis” (10.9% vs. 13.4%; RR, 0.76; 95% CI, 0.59–0.97). However, this difference was limited to surgical ICU patients. Moreover, compared to the patients with severe sepsis, these patients showed an unusually low mortality. TGC significantly increased the risk of severe hypoglycemic episodes (i.e. glucose of ≤40 mg/dl [2.2 mmol/l]) (13.7% vs. 2.5%; RR, 5.13; 95% CI, 4.09–6.43). The result of the NICE-SUGAR trial from the year 2009 and a subsequent more recent meta-analysis that included this study confirmed that an intensified intravenous insulin therapy aimed at restoring normoglycemia should not be applied to routine clinical practice. A moderate intravenous insulin therapy to lower the increased blood glucose levels (threshold value of >150 mg/dl (>8.3 mmol/l)) may be considered in ICU patients. (After reaching consensus on the present guidelines, the published results of the control arm of the NICE-SUGAR trial prompted the Surviving Sepsis Campaign to recently propose a threshold value of >180 mg/dl (i.e. 10.0 mmol/l)).→ Recommendation level E (evidence level V: expert opinion)Comment: Trials conducted to date have not established whether the moderate glycemic control protocol is advantageous. In the presence of increased blood glucose levels, the parenterally delivered glucose quantities should be reduced first and the indication for steroid therapy, if it is being administered, reviewed. Older patients (age >60), internal medicine patients and patients with generally more severe underlying diseases run a higher risk of hypoglycemia when the insulin therapy regimen is used in intensive care settings. Supposedly, the risk of severe hypoglycemic events is lower with the use of moderate intravenous insulin therapy. A closely monitored (every 1–2 hours) initial bedside glycemic control is imperative in this case as well. Determination of glucose concentrations in whole blood is one of the most complex laboratory tests in ICU patients because the values depend, among other things, on the current hematocrit concentration . Due to the lack of precision (variation coefficient of >20%) and lower sensitivity of the available measuring devices, used for determination of glucose in whole blood, in the hypoglycemic measurement range, only those devices which allow for a secure and early detection of hypoglycemia should be used .Selective bowel decontamination Preliminary remarks: Multiple studies have demonstrated that selective decontamination of the digestive tract (SDD) reduced the rate of nosocomial infections in ICU patients, especially pneumonias and bacteremia cases , , . Moreover, 4 independent prospective randomized clinical trials have shown that SDD reduced mortality in ventilated ICU patients. Selective bowel decontamination consists of a 2- to 4-day intravenous administration of antibiotics, usually cefotaxime (unless the patient is already receiving antibiotic therapy) and topical application of non-resorbable antibiotics in the oropharyngeal cavity, as well as via a gastric tube, during the entire intubation period. In selected studies, a reduction in the incidence of pneumonia could also be achieved by a sole selective oral decontamination (SOD, without intravenous or gastric administration) . One study demonstrated similar positive effects of both SOD and SDD on improved survival .It is recommended to use SDD or SOD as a prophylactic measure against infections in patients with anticipated longer intubation periods (>48 h).→ Recommendation level A (evidence level Ia for )Comment: One publication involving a total of 934 patients revealed that the use of SDD resulted in a reduced ICU (15 vs. 23%; p<0.002) and hospital mortality (24 vs. 31%, p<0.02) in critically ill patients. However, this study was a randomized trial based on hospital wards rather than patients . A bicentric, prospective, randomized, placebo-controlled double-blind trial involving 546 trauma surgery ICU patients revealed that the survival rate during the entire inpatient stay and after 60 days was significantly improved in the SDD-treated group of patients who presented with an initial APACHE-II score of 20–29 . In a further prospective, randomized, placebo-controlled double-blind trial involving a total of 107 patients with severe burns, ICU mortality was significantly reduced (9.4% vs. 27.8%, risk ratio 0.25, 95% confidence interval: 0.10–0.80) . Two long-term studies revealed no relevant antibiotic resistance issues after years of SDD use , . A prerequisite for the use of SBD should involve keeping a regular statistical record of resistance data to ensure timely recognition of increasing appearance of multiresistant pathogens. The advantage of SDD has not been proven in the presence of high prevalence of methicillin-resistant staphylococci .A 3-arm, prospective, open-label trial conducted in 13 ICUs with randomized, semiannual alternation between SDD, SOD or none of these measures (cluster randomized design) employed on over 6,000 patients has initially failed to reveal a benefit of the use of SDD or SOD with respect to the 28-day mortality . However, as far as the accompanying risk factors are concerned, the study groups were not randomized in a balanced manner which negatively affected both treatment arms. A logistic regression analysis revealed a significant survival advantage conferred upon the patients in the SDD group once the factors of age over 65 and APACHE score of over 20 had been statistically adjusted. Upon inclusion of further factors, a significant survival advantage was demonstrated for SOD as well. It comes as no surprise that the omission of gastric administration of antibiotics does not have a significant effect, because the necessity of this measure is the least documented in the scientific literature on SDD and because the orally administered antibiotics end up in the stomach anyway. It is impossible to state with certainty whether the administration of intravenous antibiotics is indeed unnecessary because in all SDD trials the majority of patients, including the control groups, received intravenous antibiotics and most trial protocols excluded the additional administration of cefotaxime in SDD groups when the patients were receiving antibiotics for clinical indication reasons. In a study by Smet et. al., the overall use of I.V. antibiotics was the lowest in the SDD group and the highest in the standard group, despite routine administration of cefotaxime (Table 4 ). (Upon reaching a consensus, further data on resistance relating to the above-mentioned 3-arm study were published online . In respiratory secretions, bacteria resistant to ceftazidime, tobramycin and/or ciprofloxacin were initially identified in 10%, 10% and 14% of patients, respectively. With the use of SDD or SOD, the numbers dropped significantly to 4%, 6% and 5%, respectively, but later again rose to the baseline levels (10%, 12% and 12%, respectively). Similarly, in rectal swabs, compared to the period prior to and after the use of SDD, a significant suppression of tobramycin- and ciprofloxacin-resistant bacteria were observed during SDD use; SOD, on the other hand, had no effect. On average, the prevalence of ceftazidime-resistant bacteria remained the same before and during SDD use (confirmed in 6% and 5% of patients, respectively), but it increased significantly to 15% following the use of SDD. The data confirm previous scientific publications where even fewer resistant bacteria were found during SDD use; the post-interventional increase in ceftazidime resistance in rectal swabs, however, re-emphasizes the need for keeping a statistical record of resistance data.)Oral antiseptics for mouth careIt is recommended to use oral antiseptics for infection prevention.→ Recommendation level A (evidence level Ia for )Comment: A number of clinical studies indicate that the incidence of VAP can be reduced by adding oral antiseptic agents (mainly 0.12%–0.2% chlorhexidine) to the oral rinse and tooth brushing protocols in ICU patients , , , . However, a meta-analysis on 1,650 patients showed that this conferred no survival advantage .Preemptive antifungal therapyThe effectiveness and safety of a preemptive antifungal therapy in intensive care patients have not been sufficiently studied , ; hence, an intervention of this kind is not recommended.→ Recommendation level E (evidence level V: expert opinion)Coated vascular cathetersWhen the frequency of infections remains high despite intensive control measures , , , , it is recommended to use antiseptic-coated catheters. → Recommendation level E (evidence level V: expert opinion)Comment: Antibiotic-coated catheters decrease the frequency of infections ; however, it remains to be elucidated how the effects of their routine use reflect on the incidence of antibiotic resistance.StaffingIt is recommended to ensure qualitatively and quantitatively adequate staffing in ICUs , , , , , , , .→ Recommendation level C (evidence level IIb for )Comment: In the past, it has repeatedly been demonstrated during periods of outbreaks that outbreak events were associated with staff shortages. As for endemic situations, it has recently also been demonstrated that staff shortages go hand in hand with a high incidence of sepsis .VaccinationsIt is recommended to administer a pneumococcal vaccine to patients with anatomical or functional asplenism, regardless of their underlying disease, prior to (if feasible) or during the inpatient stay after splenectomy. The polysaccharide vaccine is recommended for use in older children (over the age of 5) and adults; a booster dose (of polysaccharide vaccine) is to be administered every 5 to 6 years. → Recommendation level B (evidence level IIa for )Comment: Patients who undergo splenectomy due to an underlying hematological malignancy run a higher risk of displaying inadequate vaccination response as well as a higher risk of vaccination failure , . Briefing of patients, relatives and primary attending physicians, as well as issuing appropriate vaccination record cards are thus essential measures. Certain societies recommend long-term antibiotic prophylaxis (with oral penicillin or low-dose erythromycin) in addition to vaccination , . Measuring post-vaccination antibody titers for the purpose of assessing the indication for an early booster vaccination or antibiotic prophylaxis is controversial . Asplenic patients also run an increased risk of facing more severe courses of post-bite infections, malaria and babesiosis, and possibly also other diseases caused by infectious agents. The available pneumococcal conjugate vaccine (PCV) is currently approved only for use in pediatric patients.In previously unvaccinated patients with anatomical or functional asplenia, regardless of their underlying disease, it is recommended to administer a single vaccination shot against Hemophilus influenzae type B (HiB) as well as a vaccine against meningococci of serogroup C (conjugate vaccine), followed by (after a 6-month interval) a meningococcal polysaccharide 4-valent vaccine (MPSV4) before (if possible) or 2 weeks after splenectomy. As recommended for asplenic patients, vaccination against pneumococci and meningococci is also recommended in patients with pharmacologically-induced immunosuppression or in those with other types of immune defects who are assumed to possess residual T or B cell activity.→ Recommendation level E (evidence level V for , )In patients with chronic diseases (cardiovascular, pulmonary, diabetes mellitus, renal, CNS incl. CSF fistulas) as well as in patients (regardless of their underlying disease) aged 60 or older, pneumococcal vaccination is also recommended. In older children (aged 5 or older) and adults, a polysaccharide vaccine is recommended. The available pneumococcal conjugate vaccines are currently only approved for use in pediatric patients. Booster immunization with a pneumococcal polysaccharide vaccine is no longer recommended in this patient population (also see: ) (except in nephrotic syndrome).→ Recommendation level C (evidence level IIb for , )Comment: There are approximately 10,000 deaths caused by pneumococcal infections expected in Germany every year. The most commonly affected population is people over the age of 60. 90 different pneumococcal serotypes are recognized based on their polysaccharide capsules. The available 23-valent pneumococcal vaccines cover 90% of serotypes that are responsible for pneumococcal diseases. They reduce the risk of pneumococcal bacteremia by 40–50% and prevent deaths due to pneumonia. It is, however, unclear to what extent the patients in this age group, who have recently been treated for pneumonia as inpatients, benefit from vaccination . 5. PräventionProgramme zur Infektionsprävention (Ventilator-assoziierte Pneumonien, ZVK-assoziierte Bakteriämie, Harnwegkatheter-assoziierte Harnweginfektionen)An das Intensivpersonal gerichtete Schulungsprogramme und Präventionsprotokolle werden empfohlen, da diese nachweislich die Rate an Ventilator-assoziierten Pneumonien , , , , , ZVK-assoziierte Bakteriämien , , , , und Katheter-assoziierter Harnweginfektionen reduzieren . → Empfehlung Grad B (Evidenzgrad IIc für , )Es wird empfohlen, die Rate an Ventilator-assoziierten Pneumonien und ZVK-assoziierten Bakteriämien regelmäßig zu erfassen und zu analysieren, um Trends zu erfassen und die Situation der eigenen Intensivstation im Vergleich zu anderen zu beurteilen. Deshalb sollten einheitliche Definitionen zur Diagnose einer VAP und ZVK-assoziierter Bakteriämie Verwendung finden , und einheitliche Raten bestimmt werden (Anzahl Ventilator-assoziierte Pneumonien pro 1000 Beatmungstage und Anzahl von Bakteriämien pro 1000 ZVK-Tage) , , . Auch wird empfohlen, die verursachenden Erreger und deren Resistenzsituation regelmäßig zu erfassen und zu analysieren.→ Empfehlung Grad B (Evidenzgrad IIc für )Umgang mit „devices“Eine hygienische Händedesinfektion vor und nach Patientenkontakt wird empfohlen , . → Empfehlung Grad A (Evidenzgrad Ia für )Kommentar: Die hygienische Händedesinfektion vor Patientenkontakt ist die wichtigste Maßnahme zur Vermeidung der Erregerübertragung auf die Patienten. Die regelmäßige hygienische Händedesinfektion nach Patientenkontakt dient vor allem dem Personalschutz und der Vermeidung der Erregerausbreitung in der unbelebten Patientenumwelt. In den letzten Jahren wurde in verschiedenen Studien gezeigt, dass mit Steigerung der Compliance zur Händedesinfektion die Inzidenz der nosokomialen MRSA-Infektionen signifikant reduziert werden konnte , .Eine aseptische Technik bei der Anlage von zentralen Venenkathetern und anderen vergleichbaren zentralen intravasalen Kathetern wird empfohlen .→ Empfehlung Grad A (Evidenzgrad Ib für )Kommentar: In einer randomisierten kontrollierten Studie wurde der Vorteil der gemeinsamen Anwendung von sterilen Handschuhen, sterilem Kittel, Mund-Nasenschutz, Kopfhaube und großem Abdecktuch versus sterile Handschuhe und kleinem Abdecktuch bei der Anlage von zentralen Venenkathetern gezeigt. Es gibt keine randomisierten kontrollierten Studien, die den Beitrag der verschiedenen Einzelkomponenten untersucht haben.Sofern diese nicht mehr indiziert sind, wird die unverzügliche Entfernung von intravasalen- und Harnwegskathetern empfohlen .→ Empfehlung Grad A (Evidenzgrad Ic)Ein routinemässiger Wechsel von intravasalen- und Harnwegskathetern wird nicht empfohlen . → Empfehlung Grad B (Evidenzgrad Ib für )Der Einsatz von Endotrachealtuben mit der Möglichkeit zur subglottischen Absaugung kann erwogen werden, da diese mit geringeren Pneumonieraten assoziiert sind , . → Empfehlung Grad C (Evidenzgrad IIb für )KörperpositionEs wird empfohlen, eine Oberkörperhochlagerung so häufig wie möglich zur Vermeidung einer Ventilator-assoziierten Pneumonie (VAP) bei intubierten Patienten durchzuführen – sofern hierfür keine Kontraindikation besteht.→ Empfehlung Grad B (Evidenzgrad IIb für )Kommentar: Die Aspiration von bakteriell kontaminierten Sekreten des oberen Magen-Darm-Traktes und des Pharynx wird allgemein als Risikofaktor und Auslöser für die Entwicklung einer nosokomialen und Ventilator-assoziierten Pneumonie (VAP) angesehen. Daraus wird geschlossen, dass Maßnahmen, die zu einer Abnahme des gastro-ösophagealen Refluxes und einer Reduktion der oro-pharyngealen Sekretmenge führen, mit einer geringeren Inzidenz nosokomialer Pneumonien und VAP einhergehen , , , . Die Effekte der Oberkörperhochlagerung zur Prävention einer Aspiration und Pneumonie wurde bei orotracheal intubierten Patienten ohne bekannte Risikofaktoren für einen gastro-ösophagealen Reflux, mit einer nasogastralen Sonde versorgt waren, eine Stressulkusprophylaxe erhielten und bei denen der endotracheale Cuffdruck kontrolliert und über 25 cmH2O gehalten wurde, untersucht. Ein Teil der eingeschlossenen Patienten erhielt eine enterale Ernährung. Bei diesen Patienten führte eine kontinuierliche 45°-Oberkörperhochlagerung zu einer Verzögerung des gastro-ösophagealen Refluxes und/oder zu einer Abnahme, aber nicht vollständigen Vermeidung der pulmonalen Aspiration pharyngealer Sekrete , , und der Inzidenz der VAP verglichen mit einer flachen Rückenlagerung (0°-Oberkörperhochlagerung). Die 30°-Oberkörperhochlagerung in Kombination mit der Absaugung von subglotischen Sekreten führte nicht zu einer Reduktion Kolonisation der unteren Atemwege verglichen mit einer flachen Rückenlagerung mit 0°-Oberkörperhochlagerung . Obwohl die 45°- Oberkörperhochlagerung in einer klinischen Untersuchung in der Interventionsgruppe angestrebt wurde, zeigten Messungen, dass trotz Studienbedingungen nur eine Oberkörperhochlagerung von 30° erreicht wurde. Diese Oberkörperhochlagerung von 30° führte nicht zu einer Reduktion der Inzidenz der VAP verglichen mit einer flachen Rückenlagerung mit 10°-Oberkörperhochlagerung . ErnährungNach einer Metaanalyse führt eine frühe orale bzw. enterale Ernährung bei chirurgischen Patienten mit Operationen am Gastrointestinaltrakt zu einer Verminderung von Infektionen und der Aufenthaltdauer im Krankenhaus . Eine frühe orale bzw. enterale Ernährung wird bei solchen Patienten empfohlen.→ Empfehlung Grad B (Evidenzgrad Ia für )Kommentar: Unter früher enteraler bzw. oraler Ernährung ist der Ernährungsaufbau binnen 24 Stunden postoperativ zu verstehen. Die Menge der zugeführten Ernährung hat sich nach der Toleranz des Patienten zu richten. Auch geringe Mengen von Nahrungs- bzw. Flüssigkeitszufuhr sind bereits mit einer Verbesserung des Verlaufes verbunden. Eine Sondenernährung ist lediglich dann erforderlich, wenn der Patient nicht im Stande ist selbständig zu schlucken . ImmunonutritionDer perioperative bzw. postoperative Einsatz von immunmodulierenden Sondennahrungen (Arginin, ω3-Fettsäuren, Nukleotide) bei elektiven chirurgischen Patienten mit gastrointestinalen Tumoren oder Polytraumapatienten, die enteral ernährt werden können wird empfohlen, da derartige Sondennahrungen mit einer Verminderung der Aufenthaltsdauer im Krankenhaus und einer Reduktion von nosokomialen Infektionen assoziiert sind , .→ Empfehlung Grad A (Evidenzgrad Ia für )InsulintherapieDie routinemässige Anwendung einer intensivierten intravenösen Insulintherapie mit dem Ziel der Wiederherstellung einer Normoglykämie (4,4–6,1 mmol/l (80–110 mg/dl) kann bei Intensivpatienten ausserhalb klinischer Studien nicht empfohlen werden. → Empfehlung Grad A (Evidenzgrad Ia für )Kommentar: Eine kontinuierliche intravenöse Verabreichung von Insulin mit dem Ziel der Wiederherstellung einer Normoglykämie (4,4–6,1 mmol/l (80–110 mg/dl)) bei Intensivpatienten war nach der bisher vorliegenden Datenlage eine Massnahme, welche septische Komplikationen bei postoperativen und mechanisch beatmeten, überwiegend kardiochirurgischen Patienten verhindert (Prävention einer schweren Sepsis) und damit zu einer Senkung der Letalität und Morbidität beitragen könnte , . Dieses ist jedoch nur in einer monozentrischen randomisierten Studie gezeigt worden; eine konfirmative Studie stand bisher aus. In einer weiteren Studie konnte bei internistischen Intensivpatienten weder eine Reduktion septischer Komplikationen noch ein Überlebensvorteil nachgewiesen werden, bei einer gleichzeitigen Steigerung der Rate schwerer Hypoglykämien (<40 mg/dl; [2,2 mmol/l]) um den Faktor 5–6 . In einer 2008 publizierten Metaanalyse , in der die Ergebnisse von 29 randomisierten Studien mit insgesamt 8432 eingeschlossenen Patienten analysiert wurden, zeigte sich kein Unterschied in der Krankenhaussterblichkeit zwischen Patienten, welche mit oder ohne eine „tight glycemic control“ (TGC), d.h. mit einer IIT (Zielwerte 80–110 mg/dl) oder einer moderaten Kontrolle der Hyperglykämie (Zielwerte <150 mg/dl) behandelt wurden (23% vs 25,2%; RR, 0,90; 95% CI, 0,77–1,04; bzw. 17,3% vs 18,0%; RR, 0,99; 95% CI, 0,83–1,18). Weder auf rein chirurgischen Intensivstationen (8,8% vs 10,8%; RR, 0,88; 95% CI, 0,63–1,22), noch rein internistischen (26,9% vs 29,7%; RR, 0,92; 95% CI, 0,82–1,04) oder internistisch-chirurgischen Intensivstationen (26,1% vs 27,0%; RR, 0,95; 95% CI, 0,80–1,13) zeigte sich ein Überlebensvorteil durch TGC. IIT reduzierte nicht die Rate eines nierenersatzpflichtigen akuten Nierenversagens (11,2% vs 12,1%; RR, 0,96; 95% CI, 0,76–1,20), jedoch die „Sepsisrate“ (10,9% vs 13,4%; RR, 0,76; 95% CI, 0,59-0,97). Allerdings war dieser Unterschied auf chirurgische Intensivpatienten beschränkt. Zudem wiesen diese Patienten eine – im Vergleich zu Patienten mit schwerer Sepsis – ungewöhnlich geringe Sterblichkeit auf. Eine TGC erhöhte das Risiko schwerer Hypoglykämien (Glukose: ≤40 mg/dl; [2,2 mmol/l]) signifikant (13,7% vs 2,5%; RR, 5,13; 95% CI, 4,09–6,43). Die Ergebnisse der NICE-SUGAR Studie aus dem Jahre 2009 und eine nachfolgende neuere Meta-Analyse unter Einbeziehung dieser Studie haben bestätigt, dass eine intensivierte intravenösen Insulintherapie mit dem Ziel der Wiederherstellung einer Normoglykämie nicht in der klinischen Routine durchgeführt werden sollte.Eine intravenöse moderate Insulintherapie zur Senkung erhöhter Glukosespiegel (Schwellenwert von >150 mg/dl (>8,3 mmol/l)) kann bei Intensivpatienten erwogen werden. (Aufgrund der – nach Abschluss des Konsentierungsverfahrens der vorliegenden Leitlinie – publizierten Ergebnisse im Kontrollarm der NICE-SUGAR Studie hat die Surviving Sepsis Campaign vor kurzem einen Schwellenwert von >180 mg/dl (10,0 mmol/l) vorgeschlagen). → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Ob eine moderatere Einstellung der Blutglukose vorteilhaft ist, ist allerdings derzeit nicht durch Studien belegt. Bei erhöhten Blutzuckerwerten sollte zunächst die parenteral zugeführte Glukosemenge reduziert und die Indikation einer evtl. bestehenden Medikation mit Glukokortikosteroiden überprüft werden. Bei älteren Patienten (>60 Jahre), bei internistischen Patienten und bei Patienten mit ansonsten hoher Krankheitsschwere besteht ein erhöhtes Risiko für eine Hypoglykämie bei der Anwendung einer Insulintherapie in der Intensivmedizin. Vermutlich ist das Risiko schwerer Hypoglykämien durch eine moderate intravenöse Insulintherapie geringer. Eine engmaschige initial (1–2 stündliche) bettseitige Kontrolle der Blutglukose ist jedoch auch hier zwingend erforderlich. Die Messung der Glukosekonzentration im Vollblut gehört u.a. wegen ihrer Abhängigkeit vom aktuellen Hämatokrit zu den komplexesten Laborbestimmungen bei intensivmedizinischen Patienten . Aufgrund der mangelnden Präzision (Variationskoeffizient bis >20%) und geringen Sensitivität im hypoglykämischen Messbereich der gegenwärtig verfügbaren Messgeräte zur Bestimmung der Glukosekonzentration im Vollblut, sollten nur Geräte zur Anwendung kommen, welche die sichere und frühzeitige Detektion einer Hypoglykämie gewährleisten .Selektive DarmdekontaminationVorbemerkung: In zahlreichen Studien konnte nachgewiesen werden, dass durch eine selektive Darmdekontaminaton (SDD) die Rate an nosokomialen Infektionen – v.a. Pneumonien und Bakteriämien bei Intensivpatienten reduziert werden kann , , . Darüber hinaus zeigten 4 unabhängige prospektive, randomisierte klinische Studien, dass durch SDD die Letalität von beatmeten Intensivpatienten reduziert wird. Die selektive Darmdekontamination besteht aus einer 2–4-tägigen intravenösen Antibiotikagabe, meist Cefotaxim (sofern nicht ohnehin bereits Antibiotika gegeben werden) und der topischen Applikation von nicht-resorbierbaren Antibiotika in den Mund-Rachenraum und über eine Magensonde während der gesamten Intubationsdauer. In einzelnen Studien konnte eine Reduktion der Pneumonie-Inzidenz auch durch alleinige selektive orale Dekontamination (SOD, ohne intravenöse oder gastrale Gabe) erreicht werden . Eine Studie zeigte bezüglich der Letalitätsreduktion eine ähnlich gute Wirksamkeit von SOD im Vergleich zu SDD . Es wird empfohlen, SDD oder SOD bei Patienten mit voraussichtlich längerer Beatmungsdauer (>48 h) zur Prophylaxe von Infektionen anzuwenden. → Empfehlung Grad A (Evidenzgrad Ia für Kommentar: In einer Publikation wurde bei insgesamt 934 Patienten eine verringerte ITS-(15 vs. 23%; p<0,002) und Krankenhaussterblichkeit (24 vs. 31%, p<0,02) bei kritisch kranken Patienten durch Verwendung der SDD nachgewiesen. Allerdings handelte es sich bei dieser Studie nicht um eine patienten- sondern stationsbezogene randomisierte Studie . In einer bizentrischen, prospektiven, randomisierten, Placebo-kontrollierten Doppelblindstudie an 546 chirurgisch-traumatologischen Intensivpatienten war die Überlebensrate während des gesamten stationären Aufenthalts und nach 60 Tagen in der SDD-Gruppe mit initialem APACHE-II Score von 20–29 signifikant verbessert . In einer weiteren prospektiven, randomisierten, placebo-kontrollierten Doppelblindstudie an insgesamt 107 schwer brandverletzten Patienten war die intensivstationäre Letalität signifikant reduziert (9,4% vs. 27,8%, Risk Ratio 0,25, 95% Konfidenzintervall: 0,10–0,80) . Zwei Langzeitstudien zeigten keine relevanten Resistenzprobleme nach mehrjähriger Anwendung von SDD , . Voraussetzung für die Verwendung von SDD sollte das regelmäßige Führen von Resistenzstatistiken sein, um ein gehäuftes Auftreten von multiresistenten Erregern rechtzeitig zu erkennen. Der Vorteil von SDD bei hoher Prävalenz von Methicillin-resistenten Staphylokokken ist nicht bewiesen .In einer 3-armigen, prospektiven, offenen Studie in 13 Intensivstationen mit randomisiertem, halbjährlichen Wechsel zwischen SDD, SOD oder keiner dieser Maßnahmen (cluster randomised design) an über 6000 Patienten zeigte sich zunächst kein Benefit durch SDD oder SOD bezüglich der 28-Tage Letalität . Allerdings waren die Studiengruppen bezüglich begleitender Risikofaktoren nicht ausgewogen verteilt, zum Nachteil der beiden Behandlungsgruppen. Eine logistische Regressionsanalyse ergab einen signifikanten Überlebensvorteil für die Patienten der SDD-Gruppe, wenn die Faktoren Alter >65 Jahre und APACHE-Score >20 rechnerisch ausgeglichen wurden. Nach Einbeziehen weiterer Faktoren zeigte sich für SOD ebenfalls ein signifikanter Überlebensvorteil. Es überrascht nicht, dass das Weglassen der gastralen Antibiotika-Gabe keinen wesentlichen Einfluss hat, da die Notwendigkeit dieser Maßnahme in der gesamten SDD-Literatur am wenigsten belegt ist und die oral applizierten Antibiotika ohnehin in den Magen gelangen. Ob die intravenöse Antibiotikagabe tatsächlich entbehrlich ist, lässt sich nicht eindeutig beantworten, da in allen SDD-Studien die Mehrheit der Patienten – auch in den Kontrollgruppen – intravenöse Antibiotika bekamen und in den SDD-Gruppen in den meisten Studienprotokollen auf die zusätzliche Gabe von Cefotaxim verzichtet wurde, wenn die Patienten Antibiotika aus klinischer Indikation bekamen. In der Arbeit von de Smet et al. war trotz Routine-Gabe von Cefotaxim der Gesamtverbrauch an i.v.-Antibiotika in der SDD-Gruppe am niedrigsten und in der Standard-Gruppe am höchsten (Tabelle 4 ).(Nach Konsentierung sind weitere Daten zur Resistenz unter o.g. 3-armiger Studie online publiziert worden . In respiratorischem Sekret wurden anfänglich Ceftazidim- Tobramycin- bzw. Ciprofloxacin-resistente Bakterien bei 10%, 10% bzw. 14% der Patienten gefunden. Unter SDD oder SOD fiel der Nachweis signifikant auf 4%, 6% bzw. 5% und stieg danach wieder signifikant auf das Ausgangsniveau an (10%, 12% bzw. 12%). In Rektalabstrichen wurde gleichermaßen eine signifikante Suppression von Tobramycin- und Ciprofloxacin-resistenten Bakterien während SDD nachgewiesen, im Vergleich zum Zeitraum vor und nach Anwendung von SDD, während SOD keinen Einfluss hatte. Im Mittel blieb die Prävalenz Ceftazidim-resistenter Bakterien vor und während Anwendung von SDD gleich (Nachweis bei 6% bzw. 5% der Patienten), stieg aber nach Anwendung von SDD signifikant auf 15% an. Die Daten bestätigen frühere Publikationen, in denen während Anwendung von SDD sogar weniger resistente Bakterien nachgewiesen wurden, der postinterventionelle Anstieg der Ceftazidim-Resistenz in Rektalabstrichen unterstreicht aber nochmals die Notwendigkeit zum Führen von Resistenzstatistiken.)Orale Antiseptika zur Mundpflege Es wird empfohlen, orale Antiseptika zur Prophylaxe von Infektionen anzuwenden. → Empfehlung Grad A (Evidenzgrad Ia für )Kommentar: Mehrere Arbeiten zeigen, dass die VAP-Inzidenz reduziert werden kann, wenn orale Antiseptika (meist 0,12%–0,2% Chlorhexidin) zur Mundpflege-Lösung und zum Zähneputzen bei Intensivpatienten hinzugefügt werden , , , . In einer Meta-Analyse an 1650 Patienten zeichnete sich dadurch aber kein Überlebensvorteil ab .Präemptive antimykotische BehandlungEffektivität und Sicherheit einer präemptiven antimykotischen Behandlung bei Intensivpatienten sind nicht ausreichend untersucht , ; eine derartige Intervention wird daher nicht empfohlen. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Imprägnierte GefäßkatheterWenn die Infektionsraten trotz intensiver Kontrollanstrengungen hoch bleiben , , , wird die Anwendung von mit Antiseptika-imprägnierten Kathetern empfohlen. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Antibiotika-imprägnierte Katheter reduzieren die Infektionsraten , es ist aber ungeklärt, wie sich ihre routinemäßige Anwendung in Bezug auf die Resistenzrate auswirkt. PersonalausstattungEine qualitativ und quantitativ ausreichende Personalaustattung von Intensivstationen wird empfohlen , , , , , , , .→ Empfehlung Grad C (Evidenzgrad IIb für )Kommentar: In der Vergangenheit konnte im Rahmen von Ausbruchsepisoden wiederholt gezeigt werden, dass die Ausbruchsereignisse mit Personalmangelsituationen assoziiert waren. Kürzlich wurde auch für endemische Situationen gezeigt, dass Personalmangel mit einer hohen Sepsisinzidenz assoziiert war .Impfungen Bei Patienten mit anatomischer oder funktioneller Asplenie wird unabhängig von der Grunderkankung vor (falls möglich) oder während des stationären Aufenthaltes nach Splenektomie eine Impfung gegen Pneumokokken empfohlen. Bei älteren Kindern (ab 5 Jahre) und Erwachsenen wird die Polysaccharidvakzine empfohlen; eine Wiederimpfung (mit Polysaccharidvakzine) sollte alle 5 bis 6 Jahre erfolgen.→ Empfehlung: Grad B (Evidenzgrad IIa für )Kommentar: Patienten mit Splenektomie aufgrund einer hämatologischen Tumorerkrankung haben ein höheres Risiko einer unzureichenden Impfantwort und ein höheres Risiko für ein Impfversagen , . Aufklärung der Patienten, Angehörigen und primär betreuenden Ärzte, Aushändigen eines entsprechenden Ausweises und Dokumentation der Impfungen sind daher wesentlich. Eine dauerhafte Antibiotikaprophylaxe (mit Oralpenicillin oder niedrig dosiertem Erythromycin) wird von einigen Gesellschaften zusätzlich zur Impfung empfohlen , . Die Bestimmung von Antikörpertitern nach Impfung zur Indikationsstellung vorzeitige Wiederimpfung bzw. Antibiotikaprophylaxe ist umstritten . Patienten mit Asplenie haben auch ein höheres Risiko für schwerverlaufende Infektionen nach Bissverletzung, bei Malaria und Babesiose, möglicherweise auch bei anderen Erregern. Die verfügbaren Pneumokokken-Konjugatvakzine sind bislang nur im pädiatrischen Bereich zugelassen.Bei Patienten mit anatomischer oder funktioneller Asplenie, die bisher nicht geimpft sind, werden unabhängig von der Grunderkankung vor (falls möglich) oder 2 Wochen nach Splenektomie die einmalige Impfung gegen Haemophilus Typ B sowie die Impfung gegen Meningokokken Serogruppe C (Konjugatvakzine) und nachfolgend (Abstand 6 Monate) die Impfung mit 4-valentem Meningokokken-Polysaccharid-Impfung empfohlen. Die Impfungen gegen Pneumokokken und Meningokokken werden – analog zur Empfehlung bei Asplenie – auch empfohlen bei Patienten mit medikamentöser Immunsuppression bzw. mit andersartigen Immundefekten, bei denen von einer T- und/oder B-zellulären Restfunktion ausgegangen werden kann. → Empfehlung: Grad E (Evidenzgrad V für , )Bei Patienten mit chronischen Krankheiten (Herz-Kreislauf, Atmungsorgane, Diabetes mellitus, Niere, ZNS incl. Liquorfistel) sowie bei Patienten (unabhängig von einer Grunderkrankung), die 60 Jahre oder älter sind, wird ebenfalls eine Impfung gegen Pneumokokken empfohlen. Bei älteren Kindern (ab 5 Jahre) und Erwachsenen wird die Polysaccharid-Vakzine empfohlen. Die verfügbaren Pneumokokken-Konjugatvakzine sind bislang nur im pädiatrischen Bereich zugelassen Die Wiederimpfung mit Pneumokokken-Polysaccharid-Vakzine wird bei diesen Patienten inzwischen nicht mehr empfohlen (siehe auch ) (Ausnahme: nephrotisches Syndrom). → Empfehlung: Grad C (Evidenzgrad IIb für , ).Kommentar: Man rechnet in Deutschland jährlich mit ~10.000 Todesfällen durch Pneumokokkeninfektionen. Hauptbetroffene sind Menschen über 60 Jahre. Anhand der Kapselpolysaccharide werden 90 Pneumokokken-Serotypen unterschieden. Die verfügbaren 23-valenten Pneumokokken-Impfstoffe erfassen 90 Prozent der Serotypen, die für Pneumokokken-Erkrankungen ursächlich sind. Sie reduzieren das Pneumokken-Bakteriämierisiko um 40 bis 50% und verhindern Pneumonietodesfälle. Inwieweit Patienten in dieser Altersgruppe, die kürzlich wegen einer Pneumonie stationär behandelt werden, von einer Impfung profitieren, ist nicht klar . 6. Causal treatmentInfectious source control Preliminary remarks: Thorough control of the septic source of infection is the (main) prerequisite for successful treatment of severe sepsis and septic shock. Inadequate infectious source control goes hand in hand with increased mortality , . Correspondingly, it has been demonstrated for various disease entities that the interval between the onset of septic symptoms and the implementation of adequate measures to control the septic focus is an important determinant of patient outcome , . Surgical infectious source control may be accomplished by one or more measures: Removal of implants (catheter , vascular prostheses , osteosynthesis material , joint replacement )Incision or CT-guided drainage of abscesses Wound opening and necrectomy, amputation and fasciotomy Treatment of peritonitis, anastomotic insufficiency and ileus by peritoneal lavage, drainage or enterostomy , As for the value of different lavage techniques in the treatment of peritonitis, current study data do not favor a particular procedure over the others. We recommend that infectious source control measures be instituted early because they are associated with reduced mortality , .→ Recommendation level A (evidence level Ic)Comment: Randomized clinical trials on the issue of infectious source control do not exist due to difficulties in conducting studies sourcing on this clinical problem . Antimicrobial therapy Preliminary remarks: Despite a number of improved supportive and adjuvant therapeutic measures, not much has changed in the last 20 years in respect to high mortality and morbidity caused by severe sepsis and septic shock. The reasons for it primarily include recognized deficits in establishing a timely diagnosis, shortcomings in the surgical (whenever possible) infectious source control and/or in antimicrobial therapy of the infectious source. A worldwide increase in resistance of the most important infectious agents against all standard antibiotics is not being offset by a comparable development of novel anti-infectious substances. Especially in the area of problematic Gram-negative infections caused by non-fermenters such as Pseudomonas aeruginosa, no new substances are to be expected in the foreseeable future. Hence, preventive measures as well as optimization of antimicrobial diagnostic and therapeutic strategies must be emphasized in current clinical practice and research. A broad, high-dose, timely instituted initial therapy, a de-escalation strategy guided by clinical parameters and molecular markers as well as limitation of therapy duration to 7–10 days (with exceptions) are of utmost importance. In view of the fact that the field of infectious diseases is expected to be plagued with dramatic problems in the future, immense weight will be placed on close collaboration among the experts from the fields of microbiology, hygiene and clinical infectious disease. No data on antimicrobial therapy in patients with severe sepsis are available from prospective randomized controlled therapeutic trials. The reason is that due to high mortality, these patients have so far been excluded from the approval studies for new antimicrobial substances. Hence, answers to important questions concerning therapy of sepsis unfortunately cannot be obtained. Statistical records of international surveillance systems list catheter and wound infections, urogenital infections and pneumonias as primary potential nosocomial sources of sepsis , . Substantially increased mortality is primarily associated with sepsis caused by pneumonia, abdominal and skin and soft tissue infections because these infections more often result in organ dysfunction and hence a more severe course of sepsis. The significance of the site of infection for prognosis and assessment of pathogen epidemiology must be considered in devising a carefully selected antimicrobial therapy scheme. Epidemiological variability of infections, however, is high. Significant differences with regard to important infectious agents and resistance patterns are displayed not only between various countries and regions, but even between hospitals in the same city or between different ICUs of the same facility. Statistical data on pathogens and resistances should therefore be compiled separately for each individual hospital ward and reported at regular intervals. It is recommended to institute antimicrobial therapy after obtaining blood cultures (see the Diagnosis of Infection section), but in any case as soon as possible (within 1 hour) after recognition of sepsis .→ Recommendation level B (evidence level Ic)Comment: An early intravenously administered antimicrobial therapy that has been carefully chosen based on the patient's individual risk profile and the ICU-specific microbiological resistance pattern reduces mortality in patients with Gram-negative and Gram-positive bacteremia, fungemia and sepsis , , , , , , , , , , , , , , , , , , , , , .It is recommended to re-evaluate the selected antimicrobial regimen every 48–72 hours based on clinical and microbiological criteria in order to narrow the antimicrobial spectrum and thereby decrease the risk of resistance, toxicity and costs.→ Recommendation level E (evidence level V: expert opinion)If an infection cannot be confirmed using clinical and/or microbiological criteria, it is recommended to stop antimicrobial therapy.→ Recommendation level E (evidence level V: expert opinion)It is recommended to tailor the duration of antimicrobial therapy according to the clinical response; therapy continued for longer than 7–10 days is generally not required.→ Recommendation level C (evidence level IIb for )Depending on the local resistance patterns, it is recommended to use an antibiotic with Pseudomonas coverage (ureidopenicillin (piperacillin) or 3rd or 4th generation cephalosporins [ceftazidime or cefepime] or carbapenems (imipenem or meropenem))→ Recommendation level E (evidence level V: expert opinion)Comment: Superiority of a combination therapy with an aminoglycoside could not be proven , although it should be noted that there is insufficient data on Pseudomonas sepsis. Further yet, no solid data exist for beta-lactam antibiotics combined with a fluoroquinolone except for one negative trial on VAP patients . Fluoroquinolones should not be used as monotherapy in Enterobacteriaceae and Pseudomonas due to increasing evidence of resistance. Ceftazidime must be combined with a substance with Gram-positive coverage. In the presence of a high suspicion of a MRSA infection, it is recommended to initiate MRSA-effective therapy with linezolid or daptomycin (the latter in severe skin and soft tissue infections or in MRSA bacteremia of unknown origin)→ Recommendation level E (evidence level V: expert opinion)Comment: Clinical trial data in support of a combination therapy with fosfomycin or rifampicin unfortunately do not exist. Fusidic acid is not available in Germany. Also, no reliable data exist in support of a combination therapy with linezolid. Data on daptomycin exist for severe skin and soft tissue infections and MRSA bacteremia of unknown origin . Tigecyclin is approved for use in intraabdominal infections and severe skin and soft tissue infections. Case reports on septic patients, however, do exist .In pulmonary MRSA infections, it is not recommended to employ monotherapy with glycopeptides because glycopeptides display limited tissue penetration due to their molecular size , , .→ Recommendation level C (evidence level 2b for )Comment: From the clinical perspective, no substances tested in clinical trials other than glycopeptides and linezolid are available for the treatment of MRSA pneumonia. Linezolid proved slightly more beneficial in one trial , while in another study it did not prove superior to vancomycin with respect to the primary endpoint. Hence, only glycopeptides and linezolid are generally available for the treatment of MRSA pneumonia. In confirmed cases of pulmonary MRSA infections , as well as in skin and soft tissue infections, treatment with linezolid is recommended as it is superior to vancomycin monotherapy , , .→ Recommendation level C (evidence level IIb for , )Comment: Glycopeptides display limited penetration into tissues due to their molecular size . It has not been studied whether a recommendation for use of glycopeptide monotherapy may be made for other types of infections, e.g. intraabdominal MRSA infections. A small, non-randomized trial on burn patients revealed superior efficacy of a combination therapy with vancomycin and rifampicin over the use of vancomycin alone. For the combination of vancomycin and fosfomycin, only in vitro data are available . For the combination of teicoplanin and rifampicin only one case series exists which suggests efficacy and safety . In individual case series, the combination of rifampicin and fusidic acid has been used . However, fusidic acid has in the meantime become plagued with resistance problems.In sepsis secondary to community-acquired pneumonia, a combination therapy consisting of a beta-lactam antibiotic and a macrolide is recommended .→ Recommendation level B (evidence level Ib for )Antimycotic therapy is recommended in candidemia , .→ Recommendation level C (evidence level IIb for )Calculated empiric therapy with antimycotic agents is not recommended for routine use in patients with severe sepsis and septic shock who are neither neutropenic nor immunosuppressed . → Recommendation level E (evidence level V; expert opinion)Comment: The low incidence of invasive candidiasis in ICUs and the concomitant risk of resistance development do not justify the use of empiric antifungal therapy , . In neutropenic patients presenting with fever of unknown origin, antifungal therapy should only be administered when the calculated empiric antibiotic therapy fails to achieve the desired result after 72–96 hours and the patient's clinical condition worsens . See on therapy of neutropenic patients. 6. Kausale TherapieFokussanierungVorbemerkung: Die vollständige Sanierung der septischen Infektionsquelle ist (Grund-) Voraussetzung für eine erfolgreiche Behandlung der schweren Sepsis und des septischen Schocks. Unzureichende Fokussanierung ist mit einer erhöhten Letalität vergesellschaftet , . Entsprechend wurde für verschiedene Krankheitsentitäten gezeigt, dass die Zeitdauer zwischen Auftreten der septischen Symptomatik und der Einleitung suffizienter Maßnahmen zur Beherrschung des septischen Fokus maßgeblich das Outcome des Patienten bestimmt , . Eine operative Fokussanierung kann durch eine oder mehrere Maßnahmen erfolgen:Entfernung von Implantaten (Katheter , Gefäßprothesen , Osteosynthesematerial , Gelenkersatz )Inzision bzw. CT-gestützte Drainage von Abszessen Wunderöffnung und Nekrektomie, Amputation und Fasziotomie Behandlung von Peritonitis, Anastomoseninsuffizienz und Ileus durch Peritoneallavage, Drainage oder Enterostomie , .Hinsichtlich der Wertigkeit differenter Spülverfahren bei der Behandlung der Peritonitis zeigt die derzeitige Studienlage keine Vorteile für ein bestimmtes Verfahren.Wir empfehlen frühzeitige Massnahmen zur Fokussanierung, da diese mit einer Reduktion der Letalität verbunden sind , .→ Empfehlung Grad A (Evidenzgrad Ic)Kommentar: Randomisierte klinische Studien zur Fokussanierung liegen aufgrund der Schwierigkeit der Studiendurchführung zu diesen Fragestellungen nicht vor .Antimikrobielle Therapie Vorbemerkung: Trotz einer Vielzahl verbesserter supportiver und adjunktiver Therapiemaßnahmen hat sich an der hohen Letalität und Morbidität, welche der schweren Sepsis und des septischen Schocks geschuldet sind, innerhalb der letzten 20 Jahre wenig geändert. Grund hierfür sind vor allem Defizite in der frühzeitigen Diagnose, der – wenn immer möglichen – chirurgischen Herdsanierung und/oder der antimikrobiellen Therapie des Infektionsfokus. Einer weltweit steigenden Resistenzentwicklung der wichtigsten Infektionserreger gegenüber allen gängigen Antibiotika einerseits, steht andererseits keine vergleichbare Entwicklung neuer antiinfektiver Substanzen gegenüber. Vor allem im Bereich gram negativer Probleminfektionen mit Non-Fermentern wie Pseudomonas aeruginosa sind auf absehbare Zeit keine neuen Substanzen zu erwarten. Schwerpunkt der gegenwärtigen klinischen Versorgung und Forschung müssen daher präventive Massnahmen und die Optimierung der antimikrobiellen diagnostischen und therapeutischen Strategien darstellen. Von besonderer Bedeutung ist hierbei eine breite, hochdosierte, frühzeitig applizierte Initialtherapie, eine klinisch und an molekularen Markern orientierte Deeskalationsstrategie und eine – mit Ausnahmen – auf 7–10 Tagen begrenzte Therapiedauer. Einer engen Zusammenarbeit zwischen Mikrobiologie, Hygiene und klinischer Infektiologie kommt in Anbetracht der dramatischen infektiologischen Probleme der Zukunft eine entscheidende Bedeutung zu. Zur antimikrobiellen Therapie von Patienten mit schwerer Sepsis liegen keine Ergebnisse aus prospektiven randomisierten, kontrollierten Therapiestudien vor. Grund hierfür ist, dass diese Patienten aufgrund der hohen Letalität in den Zulassungsstudien neuer antimikrobieller Substanzen bisher ausgeschlossen wurden. Wichtige Fragen zur Sepsistherapie können dadurch leider nicht beantwortet werden. In den Statistiken internationaler Surveillancesysteme werden als potentielle nosokomiale Sepsisquellen vor allem Katheter – und Wundinfektionen, Urogenitalinfektionen und Pneumonien aufgeführt , . Mit einer substantiellen Steigerung der Letalität sind allerdings im wesentlichen die pneumonische, abdominelle und durch Haut-Weichteilinfektionen verursachte Sepsis assoziiert , da diese Infektionen häufiger mit Organdysfunktionen und damit schweren Verläufen der Sepsis einhergehen. Die Bedeutung des Infektionsortes für die Prognose und die Einschätzung der Erregerepidemiologie müssen bei der Planung einer kalkulierten antimikrobiellen Therapie berücksichtigt werden. Die infektionsepidemiologische Variabilität ist allerdings hoch. Nicht nur zwischen verschiedenen Ländern und Regionen, sondern sogar zwischen Krankenhäusern derselben Stadt oder verschiedenen Intensivstationen desselben Hauses kann es erhebliche Unterschiede hinsichtlich der wichtigsten Erreger und Resistenzen geben. Erreger- und Resistenzstatistiken sollten daher für jede Station eines Krankenhauses einzeln erfasst und in regelmäßigen Abständen kommuniziert werden.Es wird empfohlen, eine antimikrobielle Therapie nach Abnahme von Blutkulturen (siehe Kapitel Diagnose der Infektion), jedoch frühest möglich (innerhalb einer Stunde) nach Diagnosestellung der Sepsis zu verabreichen . → Empfehlung Grad B (Evidenzgrad Ic)Kommentar: Eine frühzeitige intravenös verabreichte kalkulierte, am individuellen Risikoprofil des Patienten und am ITS-spezifischen mikrobiologischen Resistenzmuster ausgerichtete antimikrobielle Therapie reduziert die Letalität bei Patienten mit gramnegativer und grampositiver Bakteriämie, Fungämie und Sepsis , , , , , , , , , , , , , , , , , , , , , .Es wird empfohlen, das gewählte antimikrobielle Regime alle 48–72 Stunden anhand klinischer und mikrobiologischer Kriterien neu zu evaluieren, um das antimikrobielle Spektrum zu verengen und damit das Risiko von Resistenzen, die Toxizität und die Kosten zu verringern. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Falls eine Infektion nach klinischen und/oder mikrobiologischen Kriterien nicht bestätigt werden kann, wird empfohlen, die antmikrobielle Behandlung einzustellen.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Es wird empfohlen, die Dauer der antimikrobiellen Therapie nach der klinischen Reaktion auszurichten, im allgemeinen ist eine Therapiedauer länger als 7–10 Tage nicht erforderlich.→ Empfehlung Grad C (Evidenzgrad IIb für )Es wird empfohlen, ein Pseudomonas-wirksames Antibiotikum anzuwenden (Ureidopenicilline (Piperacillin) oder Dritt- bzw. Viertgenerations-Cephalosporine [Ceftazidime oder Cefepime] oder Carbapeneme (Imipenem oder Meropenem) unter Berücksichtigung lokaler Resistenzmuster einzusetzen. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Die Überlegenheit einer Kombinationstherapie mit einem Aminoglykosid konnte nicht belegt werden , wobei die Datenlage zur Pseudomonassepsis nicht ausreicht und für die Kombination Beta-Laktam-Antibiotika plus Fluorchinolone ausser einer negativen Studie bei VAP-Patienten ebenfalls keine verlässlichen Daten vorliegen. Fluorchinolone sollten aufgrund der steigenden Resistenzlage bei Enterobacteriaceae und Pseudomonas als Monotherapie nicht verwendet werden. Ceftazidime muss mit einer Substanz im grampositiven Wirkungsbereich kombiniert werden.Bei dringendem Verdacht auf eine MRSA-Infektion wird empfohlen, eine MRSA-wirksame Therapie mit Linezoliden bzw. Daptomycin (letzteres bei schweren Haut-, Weichteilinfektionen bzw. MRSA-Bakteriämie unklarer Genese) einzuleiten.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Für eine Kombinationstherapie mit Fosfomycin oder Rifampicin fehlen leider klinische Studien. Fusidinsäure steht Deutschland nicht zur Verfügung. Auch zur Kombinationstherapien mit Linezolid gibt es keine verlässlichen Daten. Für schwere Haut- und Weichteilinfektionen und eine MRSA Bakteriämie unklarer Genese liegen Daten für Daptomycin vor . Tigecyclin ist für intraabdominelle Infektion und schwere Haut- und Weichteilinfektion zugelassen Es existieren aber Fallberichte zu septischen Patienten .Bei pulmonalen MRSA-Infektionen wird eine Glykopeptid-Monotherapie nicht empfohlen, da Glykopeptide aufgrund ihrer Molekülgröße schlecht in das Gewebe penetrieren , , .→ Empfehlung Grad C (Evidenzgrad 2b für )Kommentar: Aus klinischer Sicht stehen außer Glykopeptiden und Linezolid keine in klinisch Studien geprüften Substanzen für die MRSA Pneumonie zur Verfügung. Linezolid war in einer Studie zwar etwas vorteilhafter, in einer anderen im primären Endpunkt Vancomycin jedoch nicht überlegen. Grundsätzlich stehen daher zur Therapie der MRSA Pneumonie nur Glykopeptide und Linezolid zur Verfügung , . Bei gesicherten pulmonalen MRSA-Infektionen , sowie Haut- und Weichteilinfektionen wird eine Linezolidbehandlung empfohlen, welche einer Vancomycin-Monotherapie überlegen ist , , .→ Empfehlung Grad C (Evidenzgrad IIb für , )Kommentar: Glykopeptide penetrieren aufgrund ihrer Molekülgröße schlecht in das Gewebe . Ob bei anderen z.B. intraabdominellen Infektionen mit MRSA eine Glykopeptid-Monotherapie empfohlen werden kann, ist nicht untersucht. Die Kombinationstherapie von Vancomycin mit Rifampicin zeigte in einer kleinen, nicht randomisierten Studien bei Verbrennungspatienten eine gegenüber Vancomycin überlegene Wirkung. Zur Kombination von Vancomycin und Fosfomycin gibt es nur in vitro Daten . Für die Kombination Teicoplanin und Rifampicin gibt es nur eine Fallserie, die Wirksamkeit und Sicherheit nahe legt . In einzelnen Fallserien wurde die Kombination aus Rifampicin und Fusidinsäure angewendet . Fusidinsäure ist jedoch inzwischen ebenfalls durch Resistenzprobleme belastet. Bei Sepsis infolge einer ambulant erworbenen Pneumonie wird eine Kombination aus Betalaktam-Antibiotika und Makrolid empfohlen . → Empfehlung Grad B (Evidenzgrad Ib für )Eine antimykotische Therapie bei Candidämie wird empfohlen , .→ Empfehlung Grad C (Evidenzgrad IIb für )Es wird nicht empfohlen, Antimykotika bei nicht-neutropenischen, nicht-immunsupprimierten Patienten routinemäßig als kalkulierte Therapie bei Patienten mit schwerer Sepsis oder septischem Schock einzusetzen .→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Die niedrige Inzidenz von invasiven Candidainfektionen auf Intensivstationen bei gleichzeitiger Gefahr der Resistenzentwicklung rechtfertigt den kalkulierten Einsatz von Antimykotika nicht , . Bei neutropenischen Patienten sollten Antimykotika bei unklarem Fieber dann eingesetzt werden, wenn eine kalkulierte Antibiotikatherapie nach 72–96 Std. erfolglos war und der klinische Zustand des Patienten sich verschlechtert . Zur Behandlung neutropenischer Patienten siehe . 7. Supportive therapyHemodynamic stabilizationPreliminary remarks: The goal of hemodynamic stabilization is to achieve an adequate cellular oxygen supply immediately upon recognition of severe sepsis or septic shock . Although the benefit of an extended hemodynamic monitoring for increased survival and lower morbidity has not been established, we recommended carrying out extended hemodynamic monitoring in the case of increased need for vasopressor administration. → Recommendation level E (evidence level V: expert opinion)Comment: For the evaluation of myocardial preload, volumetric parameters (i.e. the transpulmonary indicator dilution, echocardiography) are superior to filling pressures , , , . Measures for initial hemodynamic stabilizationVolume replacement therapy is recommended as the initial hemodynamic stabilization measure. → Recommendation A (evidence level Ic)Comment: In patients with suspected hypovolemia, 500–1000 ml of crystalloids or 300–500 ml of colloids should be initially administered over 30 min. The volume requirements in patients with severe sepsis or septic shock are initially considerably higher. A possible repeat volume restitution is guided by the effects (increase in blood pressure, diuresis, ScvO2) and tolerance (signs of intravascular hypervolemia) .The target parameter is central venous oxygen saturation (ScvO2) of >70% . In order to attain a ScvO2 of >70%, intravascular volume administration as well as the administration of dobutamine and packed red blood cells (when hematocrit is <30%) is recommended. → Recommendation level B (evidence level Ib for )Comment: The effectiveness of this intervention has to date been unequivocally established only in patients with initially clearly increased blood lactate values. Patients with chronic heart failure may present with ScvO2 values of less than 70% in the absence of any signs of tissue hypoxia or impaired organ perfusion. Exactly which one of the above-mentioned measures used to increase the ScvO2 to >70% contributes to increased survival remains unresolved. It has also not yet been clarified whether intermittent measurements of ScvO2 are on a par with a continuous measurement.For the purpose of early hemodynamic stabilization, a set of the following hemodynamic target criteria is recommended: CVP ≥8 or ≥12 mmHg in mechanical ventilationMAP ≥65 mmHgDiuresis ≥0.5 ml/kg/hrCentral venous oxygen saturation (ScvO2) ≥70% Lactate ≤1.5 mmol/l or a decrease in [blood] lactate levels→ Recommendation level C (Evidence level IIc for )Comment: A number of current studies were able to demonstrate that a systematic implementation of these criteria is associated with a lower mortality due to sepsis , , , .Further measures for hemodynamic stabilization Although there are no reliable data, it is recommended that further therapy course rest on the above-mentioned measures as well. → Recommendation level E (evidence level V: expert opinion)Volume therapyAccording to current data, the administration of HAES solutions (200/0.5 and 200/0.62) in patients with severe sepsis or septic shock is not recommended.→ Recommendation level A (evidence level Ia for , , , )Comment: The randomized, multi-center VISEP trial showed that in patients with severe sepsis and septic shock, an almost identically rapid hemodynamic stabilization and optimization of oxygen transport can be achieved with the use of a modified lactated Ringer's solution as with a hyperoncotic hydroxyethyl starch solution (HAES 200/0.5). The required crystalloid volume was only 30–40% higher than the required colloidal volume. Similarly, the randomized, multi-center SAFE trial also showed that hypovolemic ICU patients required only 30–40% more of the 0.9% NaCl solution compared to the 4% human albumin solution to achieve the same hemodynamic endpoints. In a further randomized, multi-center trial which studied the effects of a hyperoncotic hydroxyethyl starch solution (HAES 200/0.6) on the development of acute kidney injury in patients with severe sepsis and septic shock, a 19% higher incidence of acute kidney injury was recorded for the use of HAES 200/0.6 compared to the use of a 3% gelatin solution . The VISEP trial revealed a 12% increase in the incidence of acute kidney injury and a 2-fold increase in the need for renal replacement therapy with the use of HAES 10% 200/0.5 in comparison with a modified lactated Ringer's solution. The negative effects on kidney function were dose-dependent, but they also appeared in patients in whom a daily dose of 22 ml/kg/BW had never been exceeded as well as in the case of cumulative doses of only 48 ml/kg/BW. In patients who received a higher cumulative dose of HAES (i.e. 136 ml/kg/BW), a 17% increase in the 90-day mortality was recorded. The SAFE trial recorded a trend of reduced 28-day mortality in a subgroup of 1,620 patients with sepsis who had received human albumin for volume restitution (788 patients; p=0.088) . Comparative studies comparing gelatin solutions with crystalloid solutions or with human albumin in patients with severe sepsis or septic shock are not available. Data on safety of “'more modern” low molecular weight HAES and gelatin solutions in severe sepsis or septic shock do not exist , , but in view of the cumulative dose (>50 ml/kg BW) they are of vital importance; see http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/NewDrugApplicationsNDAs/ucm081717.htmAccording to current data, the use of low molecular weight HAES solutions and other artificial colloidal solutions in patients with severe sepsis and septic shock is not recommended. → Recommendation level E (evidence level V: expert opinion)In patients with severe sepsis or septic shock, the administration of human albumin may be considered.→ Recommendation level E (evidence level V: expert opinion)For the purposes of hemodynamic stabilization we recommend volume restitution with the use of crystalloid solutions.→ Recommendation level B (evidence level Ib for )Therapy with inotropic agents and vasopressors If cardiac output remains decreased despite intravascular volume therapy, we recommend the use of dobutamine as the catecholamine of first choice .→ Recommendation level E (evidence level V: expert opinion)If left ventricular function remains impaired despite the administration of dobutamine, therapy with epinephrine, phosphodiesterase inhibitors or levosimendan may be considered.→ Recommendation level E (evidence level V: expert opinion)Comment: Phosphodiesterase inhibitors or levosimendan can further augment arterial vasodilatation characteristics of septic shock states and hence significantly increase the need for vasopressors.An increase in cardiac output to a predefined supranormal target value (the concept of “supramaximal oxygen supply”) is not recommended , , .→ Recommendation level C (evidence level IIb for )The use of dopexamine in the treatment of patients with severe sepsis or septic shock is not recommended , , , , . → Recommendation level E (evidence level V: expert opinion)If volume therapy fails to maintain the target mean arterial pressure (MAP) of >65 mmHg or adequate organ perfusion, it is recommended to use catecholamines with vasopressor effects.→ Recommendation level B (evidence level Ic)Comment: In certain patient populations, such as in patients with a history of arterial hypertension, a higher MAP target may be indicated.On the basis of currently available data, a clear-cut recommendation cannot be made for the use of a specific vasopressor agent . We recommend administration of noradrenalin as the substance of first-choice , .→ Recommendation level E (evidence level IIb)Comment: In life-threatening hypotension, short-term vasopressor therapy may also be required in the case where the potentials of volume therapy have not yet been completely exhausted. There are indications that epinephrine exerts negative effects on gastrointestinal perfusion , . However, a randomized, multi-center trial involving 330 patients revealed no differences with respect to the 28-day mortality between a combination therapy with dobutamine/epinephrine and epinephrine monotherapy . A combination of epinephrine and dobutamine is not recommended .The routine use of vasopressin is not recommended. → Recommendation level E (evidence level V: expert opinion)Comment: Vasopressin has the potential of causing an increase in arterial blood pressure in patients with septic shock , , , , but it leads to a significant reduction in cardiac output and a redistribution of regional blood flow. With dosages of >0.04 U/min, myocardial ischemia, a drop in cardiac output, cardiac arrest and ischemic skin lesions were reported , . According to the results of the VASST trial, vasopressin was beneficial in patients with a low noradrenalin delivery dose (<15 μg per minute), if at all . Moreover, in view of the diverse exclusion criteria, the patient population with septic shock that was studied in the VASST trial is not representative for clinical practice.The use of low-dose dopamine (5 µg·kg–1·min–1) for renal protection is not recommended because neither any positive effects on kidney function nor a survival benefit could be established; moreover, dopamine displays adverse endocrinological and immunological side effects , , , , , .→ Recommendation level A (evidence level Ia for )Renal replacement therapyPreliminary remarks: The appearance of acute kidney injury (AKI) (Table 5 ) in patients with severe sepsis and septic shock is an independent risk factor for mortality in this patient population . The optimization of the systemic hemodynamics is the most important measure used to positively affect the evolution and progression of AKI.Diuretics do not lead to an improvement in kidney function; in addition, there is no evidence that diuretics positively affect the outcome of AKI. The administration of diuretic agents may be considered in order to either test the kidney's reaction to adequate volume challenge or to facilitate intravascular volume management in the presence of maintained diuresis. → Recommendation level E (evidence level V: expert opinion)In the presence of inadequate diuresis or initiation of renal replacement therapy, it is not recommended to continue administering diuretic agents so as to prevent side effects such as ototoxicity. → Recommendation level E (evidence level V: expert opinion) In patients with AKI in the presence of severe sepsis or septic shock, continuous convection-based veno-venous hemofiltration (CVVH) is recommended as an equivalent to intermittent diffusion-based techniques (intermittent hemodialysis (IHD)).→ Recommendation level B (evidence level Ib for and IIa for , ) Comment: Two meta-analyses, which took into consideration non-randomized trials with small patient caseloads, showed no significant difference in mortality of patients who were treated with continuous renal replacement therapy versus those who were treated with intermittent renal replacement therapy , . Even when only randomized trials were considered in these analyses, no difference was revealed . To date, five prospective randomized trials have been published on this topic , , , , . Four of them showed no difference in mortality, and one study determined a significantly higher mortality in the continuous renal replacement therapy arm . However, patients in this trial were not evenly randomized; the patients treated with continuous renal replacement therapy presented with a more severe disease already at the enrollment stage of the study. The most recent and the largest trial enrolled 360 patients with AKI and multiple organ failure; sepsis as the underlying cause of AKI was determined in 69% of the patients in the IHD group and in 56% of patients in the CVVH group. There were no differences in mortality found between the two groups . CVVH is recommended in hemodynamically instable patients because this technique is better tolerated in comparison to conventional IHD and it facilitates easier fluid balancing , .→ Recommendation level C (evidence level IIb for , , )By modifying the IHD technique (e.g. longer dialysis periods, chilled dialysate, limited blood flow and dialysate flow), a hemodynamic stability comparable to the one of CVVH can be achieved , , .→ Recommendation level B (evidence level Ib for and II a for , )Comment: Currently, there are no clear indications confirming superiority of the continuous techniques over other renal replacement techniques with regard to hemodynamic tolerability. Two prospective trials, however, reported a better hemodynamic tolerability of CVVH , , yet without demonstrating an improvement in organ perfusion or in survival rates . Four further prospective trials recorded no significant differences in mean arterial pressure (MAP) values or decrease in the systolic blood pressure between the two methods , , , . Hemodynamic tolerance of intermittent techniques may be significantly improved by modifications such as longer dialysis periods, dialysate chilling, limitation of blood and dialysate flows; in this way, their tolerability becomes comparable to the hemodynamic tolerability of the continuous techniques , , . As for fluid balance management, two studies showed a significant improvement in balance targets with the use of continuous renal replacement therapy , .In order to avoid uremia, it is recommended that renal replacement therapy be instituted early in the course of oliguric acute kidney injury in patients with severe sepsis or septic shock.→ Recommendation level E (evidence level V: expert opinion)Comment: No clear-cut recommendations can be made on the issue of “early” or “late” therapy initiation because the data are less than authoritative. The appropriate start of therapy must oftentimes be determined on a case-by-case basis. In order to avoid metabolic crises and uremic complications, the start of renal replacement therapy should not be delayed in the most critically ill patients with a rapidly progressing AKI and persistent oliguria (<500 ml/per 24 hours over 6–24 hours despite therapy). In critically ill patients with AKI, adequately dose delivery of renal replacement therapy (CVVH or CVVHDF: at least >20 ml/kg/per hour ultrafiltration rate; IHD: at least 3 times per week; Kt/Vurea 1.2–1.4) is recommended. According to the results from current trials, dose delivery intensification (CVVHDF 35ml/kg/per hour, IHD daily) does not result in lower mortality in this patient population , .→ Recommendation level B (evidence level Ib for )Comment: Six randomized controlled trials have studied the issue of whether the rate of survival in critically ill patients with acute kidney injury depends on the magnitude of dose delivery in each renal replacement technique , , , , , . Three trials confirmed a reduction in mortality in patients who were treated with a higher dose of renal replacement therapy (CVVH 35 ml/kg/per hour ultrafiltration , , IHD daily ). Nevertheless, these studies did not reveal any survival benefits , , . None of these studies were conducted a priori in patients with severe sepsis or septic shock. Unlike in other studies, however, 63% of the patients in the largest and most recent trial presented with sepsis . In this study, dose intensification of renal replacement therapy (CVVHDF 35 ml/kg/per hour or daily IHD) in comparison with a standard dose (CVVHDF 20 ml/kg/per hour dialysis 3 time a week with Kt/Vurea > 1.2–1.4 per IHD session) was not associated with reduced mortality. Conventional renal replacement therapy (CVVH and IHD) is not capable of exerting a significant effect on plasma concentrations of inflammatory mediators in patients with severe sepsis or septic shock , , . Beyond a renal indication, its use in therefore not recommended. → Recommendation level C (evidence level IIb for )Comment: In contrast, newer extracorporeal methods with a goal of achieving increased elimination of inflammatory mediators, such as for instance the “high volume” hemofiltration (HVHF), “high cut-off” hemofiltration, or adsorption techniques (e.g. endotoxin adsorption, immunoadsorption), are generally able to affect the plasma concentrations of certain mediators;, but these methods must undergo evaluations in randomized outcome studies with respect to their risks and benefits for septic patients. Except for clinical research purposes, the use of these methods for treatment of severe sepsis or septic shock currently is not recommended. Airway management and ventilationIt is recommended to keep the oximetric oxygen saturation above 90% .→ Recommendation level B (evidence level Ic)It is recommended to initiate early mechanical ventilation in patients with severe sepsis or septic shock.→ Recommendation level E (evidence level V: expert opinion)Comment: Indications include severe tachypnea (respiratory rate >35/min), muscle fatigue (use of respiratory muscles), reduced alertness and a decrease in oxygen saturation to ≤90% despite oxygen insufflation. It is recommended to ventilate patients with severe sepsis or septic shock and ALI/ARDS (Table 6 ) with a low tidal volume (6 ml/kg standard body weight) and a plateau pressure of <30 cm H2O (Table 7) , .→ Recommendation level A (evidence level Ib for , )Comment: Standard body weight should be routinely measured in all ventilated patients (Table 7 ). In approximately 30% of patients with severe ARDS, even tidal volumes of 6 ml/kg may lead to hyperinflation. In such a state, ventilation should be performed with a low tidal volume . Even in the presence of a low plateau pressure, high tidal volume ventilation leads to increased mortality . It is recommended that mechanical ventilation always be performed with positive end-expiratory pressures (PEEP) . → Recommendation level B (evidence level Ic)Comment: No recommendation can currently be made about the level of PEEP. The values listed in Table 7 serve as guidelines.It is recommended to tolerate hypercapnia in ventilated patients with ALI/ARDS who display high pCO2 values in the presence of low tidal volumes , . → Recommendation level D (evidence level IIIb )Comment: Permissive hypercapnia should be tolerated only up to a pH value of 7.2 in the absence of buffering .In patients with increased intracranial pressure, permissive hypercapnia constitutes a relative contraindication. It is recommended to carry out the treatment only under intracranial pressure control and risk assessment.→ Recommendation level E (evidence level V: expert opinion)The prone body position or the 135-degree lateral decubitus position is recommended in severely impaired oxygenation (PaO2/FiO2≤88 mmHg).→ Recommendation level C (evidence level IIb for )Comment: A ventral- or 135-degree lateral decubitus position can significantly improve oxygenation. However, a survival advantage could only be demonstrated in patients with severe ARDS , .Routine therapy with inhalation nitrogen monoxide (NO) is not recommended. → Recommendation level A (evidence level Ib for , )Comment: A survival advantage was recorded in ICU patients with ALI/ARDS who received inhalation nitrogen monoxide (NO) therapy , , .It is recommended that patients who are hemodynamically stable, responsive and adequately oxygenated be subjected to a once-daily spontaneous breathing trial in order to determine whether they are ready for extubation , , (see Figure 1 as an example) → Recommendation level A (evidence level Ib for , ) 7. Supportive TherapieHämodynamische StabilisierungVorbemerkung: Ziel der hämodynamischen Stabilisierung ist das Erreichen eines adäquaten zellulären O2-Angebotes unmittelbar nach Diagnosestellung der schweren Sepsis bzw. des septischen Schocks . Obgleich der Nutzen eines erweiterten hämodynamischen Monitorings in Bezug auf die Überlebensrate und die Morbidität nicht belegt ist, empfehlen wir bei erhöhtem Vasopressorbedarf ein erweitertes hämodynamisches Monitoring. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Zur Abschätzung der myokardialen Vorlast sind volumetrische Parameter (transpulmonale Indikatordilution, Echokardiographie) den Füllungsdrücken überlegen , , , . Maßnahmen zur initialen hämodynamischen StabilisierungEine Volumensubstitution wird als erste Massnahme zur hämodynamischen Stabilisierung empfohlen. → Empfehlung Grad A (Evidenzgrad Ic)Kommentar: Bei Patienten mit vermuteter Hypovolämie sollten initial 500–1000 ml Kristalloide oder 300–500 ml Kolloide über 30 min verabreicht werden. In der Regel ist der Volumenbedarf von Patienten mit schwerer Sepsis oder septischem Schock initial erheblich höher. Eine Wiederholung der Volumengabe richtet sich nach Wirkung (Anstieg von Blutdruck, Diurese, ScvO2) und Toleranz (Hinweis auf intravasale Hypervolämie) .Zielparameter ist eine zentralvenöse Sauerstoffsättigung (ScvO2) >70% . Um eine ScvO2 >70% zu erzielen, wird die Gabe von Volumen, Dobutamin und Erythrozytenkonzentraten (bei Hkt <30%) empfohlen.→ Empfehlung Grad B (Evidenzgrad Ib für )Kommentar: Die Effektivität dieser Maßnahme ist jedoch bisher nur für Patienten mit initial deutlich erhöhten Laktatwerten eindeutig belegt. Bei Patienten mit chronischer Herzinsuffizienz können ScvO2-Werte <70% ohne Zeichen der Gewebehypoxie bzw. Organminderperfusion vorliegen. Welche der oben genannten Maßnahmen zur Anhebung der ScvO2 auf >70% im einzelnen zu dem Überlebensvorteil beitragen, ist nicht geklärt. Ob eine diskontinuierliche Messung der ScvO2 einer kontinuierlichen Messung gleichwertig ist, ist ebenfalls nicht geklärt.Zur frühen hämodynamischen Stabilisierung wird ein Bündel von folgenden hämodynamischen Zielkriterien empfohlen:ZVD ≥8 bzw. ≥12 mmHg unter mechanischer BeatmungMAP ≥65 mmHgDiurese ≥0,5 ml/kg/Stdzentralvenöse Sauerstoffsättigung (ScvO2) ≥70% Laktat ≤1,5 mmol/l bzw. Abfall des Laktats → Empfehlung Grad C (Evidenzgrad IIc für )Kommentar: Eine Reihe von aktuellen Studien haben zeigen können, dass ein konsequentes Umsetzen dieses Bündels mit einer geringeren Sepsissterblichkeit einhergeht , , .Fortführende Maßnahmen zur hämodynamischen Stabilisierung Obwohl keine gesicherten Daten vorliegen, wird auch im weiteren Verlauf eine Orientierung an den o.g. Maßnahmen empfohlen. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)VolumentherapieNach der gegenwärtigen Datenlage kann der Einsatz von HAES-Lösungen (200/0,5 und 200/0,62) bei Patienten mit schwerer Sepsis bzw. septischem Schock nicht empfohlen werden.→ Empfehlung Grad A (Evidenzgrad Ia für , , , )Kommentar: In der randomisierten, multizentrischen VISEP-Studie konnte bei Patienten mit schwerer Sepsis und septischem Schock gezeigt werden, dass mit einer modifizierten Ringerlaktatlösung eine nahezu gleich schnelle hämodynamische Stabilisierung und Optimierung des Sauerstofftransports zu erzielen ist wie mit einer hyperonkotischen Hydroxyäthylstärkelösung (HAES 200/0,5). Das hierzu erforderliche kristalloide Volumen war lediglich 30–40% höher als der Bedarf an kolloidalem Volumen. Auch in der randomisierten, multizentrischen SAFE Studie konnte gezeigt werden, dass bei hypovolämischen Intensivpatienten mit lediglich 30–40% mehr NaCl 0,9% Lösung die gleichen hämodynamischen Endpunkte erzielt werden können, wie mit einer 4%igen Humanalbuminlösung. In einer weiteren randomisierten multizentrischen Studie, in welcher der Einfluss einer hyperonkotischen Hydroxyäthylstärkelösung (HAES 200/0,6) im Vergleich zu einer 3%igen Gelatinelösung auf die Entwicklung eines akuten Nierenversagens bei Patienten mit schwerer Sepsis und septischem Schock untersucht wurde, zeigte sich eine um 19% höhere Inzidenz eines akuten Nierenversagens unter HAES 200/0,6 . In der VISEP Studie fand sich beim Vergleich einer modifizierten Ringerlaktatlösung mit HAES 10% 200/0,5 eine um 12% erhöhte Inzidenz von akutem Nierenversagen und eine Verdopplung der Notwendigkeit eines Nierenersatzverfahrens unter HAES 200/0,5. Die negativen Effekte auf die Nierenfunktion waren dosisabhängig, traten jedoch auch bei Patienten auf, bei denen eine Tagesdosis von 22 ml/kg KG pro Tag nie überschritten wurde sowie bei einer kumulativen Dosis von lediglich 48 ml/kg/KG. Patienten mit einer höheren kumulativen HAES Gabe (136 ml/kg KG) hatten eine um 17% höhere 90 Tage Sterblichkeit. In der SAFE-Studie zeigte sich in einer Subgruppe von 1620 Patienten mit Sepsis ein Trend zu einer reduzierten 28-Tage-Sterblichlichkeit unter Humanalbumintherapie als Volumenersatz (788 Patienten; p=0,088) . Vergleichende Untersuchungen von Gelatinelösungen mit kristalloiden Lösungen oder mit Humanalbumin liegen für Patienten mit schwerer Sepsis oder septischem Schock nicht vor. Daten zur Sicherheit von „moderneren“ niedermolekularen HAES Lösungen und Gelatinelösungen bei schwerer Sepsis bzw. septischem Schock fehlen , , sind aber vor allem in Hinsicht auf die kumulative Dosis (>50 ml/kg KG) dringend erforderlich, siehe http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/NewDrugApplicationsNDAs/ucm081717.htm. Nach der gegenwärtigen Datenlage kann der Einsatz von niedermolekularen HAES-Lösungen und anderen künstlichen kolloidalen Lösungen bei Patienten mit schwerer Sepsis bzw. septischem Schock nicht empfohlen werden. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Bei Patienten mit schwerer Sepsis bzw. septischem Schock kann eine Gabe von Humanalbumin erwogen werden.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Wir empfehlen zur hämodynamischen Stabilisierung einen Volumenersatz mit kristalloiden Lösungen.→ Empfehlung Grad B (Evidenzgrad Ib für )Therapie mit Inotropika und VasopressorenBesteht trotz Volumentherapie weiterhin ein eingeschränktes Herzzeitvolumen, empfehlen wir Dobutamin als Katecholamin der ersten Wahl . → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Besteht trotz einer Behandlung mit Dobutamin weiterhin eine linksventrikuläre Pumpfunktionstörung kann eine Therapie mit Adrenalin, Phosphodiesterasehemmern oder Levosimendan erwogen werden. → Empfehlung Grad E (Evidenzgrad V: ExpertenmeinungKommentar: Phosphodiesterasehemmer und Levosimendan können die im septischen Schock typische arterielle Vasodilatation noch verstärken und den Vasopressorbedarf erheblich steigern. Eine prinzipielle Anhebung des Herzzeitvolumens auf prädefinierte supranormale Zielgrößen (Konzept der „supramaximalen Sauerstoffversorgung“) kann nicht empfohlen werden , , .→ Empfehlung Grad C (Evidenzgrad IIb für )Die Verwendung von Dopexamin in der Therapie von Patienten mit schwerer Sepsis oder septischem Schock kann nicht empfohlen werden , , , , . → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Wenn die Volumentherapie nicht ausreicht, einen adäquaten arteriellen Mitteldruck (>65 mmHg) zu erzielen, bzw. die Organperfusion aufrecht zu erhalten, wird empfohlen, vasopressorische Katecholamine anzuwenden.→ Empfehlung Grad B (Evidenzgrad Ic)Kommentar: Bei einigen Patienten (z.B. bei vorbestehender arterieller Hypertonie) kann ein höherer Mitteldruck sinnvoll sein. Die momentane Datenlage erlaubt eine eindeutige Empfehlung eines bestimmten Vasopressors nicht . Wir empfehlen den Einsatz von Noradrenalin als Substanz der ersten Wahl , .→ Empfehlung Grad E (Evidenzgrad IIb)Kommentar: Eine Vasopressortherapie kann bei lebensbedrohlicher Hypotension kurzfristig auch dann notwendig sein, wenn die Volumentherapie noch nicht ausgeschöpft ist. Für Adrenalin gibt es Hinweise für negative Auswirkungen auf die gastrointestinale Perfusion , . Eine randomisierte multizentrische Studie an 330 Patienten hat jedoch keinen Unterschied zwischen einer Kombinationstherapie mit Dobutamin/Noradrenalin und einer Monotherapie mit Adrenalin bezgl. der 28-Tage-Sterblichkeit aufgezeigt . Eine Kombination von Adrenalin und Dobutamin ist nicht zu empfehlen .Die routinemäßige Anwendung von Vasopressin kann nicht empfohlen werden.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Vasopressin kann den arteriellen Blutdruck bei Patienten mit septischem Schock steigern , , , , führt aber zu einer deutlichen Reduktion des Herzzeitvolumens und einer Umverteilung regionaler Blutflüsse. Bei Dosierungen >0,04 U/min wurden Myokardischämien, Abfälle des Herzzeitvolumens, Herzstillstand und ischämische Hautläsionen beschrieben , . Nach Ergebnissen der VASST-Studie ist Vasopressin, wenn überhaupt bei Patienten mit einer niedrigen Noradrenalindosis (<15 µg pro Minute) vorteilhaft . Darüber hinaus ist das in der VASST-Studie untersuchte Patientengut mit septischem Schock aufgrund vielfältiger Ausschlusskriterien nicht repräsentativ für die klinische Praxis. Der Einsatz von niedrig dosiertem Dopamin (5 µg·kg–1·min–1) zur Nephroprotektion kann nicht empfohlen werden, da weder positive Effekte auf die Nierenfunktion noch auf das Überleben von Intensivpatienten nachgewiesen werden konnten und Dopamin unerwünschte endokrinologische und immunologische Nebenwirkungen hat , , , , , .→ Empfehlung Grad A (Evidenzgrad Ia für )Nierenersatzverfahren Vorbemerkungen: Der Eintritt eines akuten Nierenversagens (ANV) (Tabelle 5 ) bei Patienten mit schwerer Sepsis und septischem Schock ist ein unabhängiger Risikofaktor für die Letalität dieser Patienten . Eine Optimierung der systemischen Hämodynamik ist die wichtigste Maßnahme, um die Entwicklung und Progression eines ANV günstig zu beeinflussen. Diuretika führen zu keiner Verbesserung der Nierenfunktion, auch gibt es keine Evidenz, dass Diuretika das „outcome“ eines ANV günstig beeinflussen. Eine Diuretikagabe kann erwogen werden, um die Reaktion der Niere nach adäquater Volumentherapie zu testen, oder um bei erhaltener Diurese das Volumenmanagement zu erleichtern. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Bei nicht ausreichender Diurese oder Beginn eines Nierenersatzes wird nicht empfohlen, Diuretika weiter zu verabreichen, um Nebenwirkungen wie Ototoxizität zu vermeiden.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung) Bei Patienten mit ANV im Rahmen einer schweren Sepsis oder eines septischen Schocks ist ein kontinuierliches, konvektives venovenöses Nierenersatzverfahren (CVVH) einem intermittierendem diffusivem Verfahren (intermittierende Hämodialyse, IHD) als gleichwertig zu empfehlen.→ Empfehlung Grad B (Evidenzgrad Ib für und IIa für , ) Kommentar: Zwei Metaanalysen unter Berücksichtigung zahlreicher nicht-randomisierte Studien an kleinen Patientenzahlen zeigten keinen signifikanten Unterschied bzgl. der Letalität von Patienten, die mit kontinuierlichen vs. intermittierenden Nierenersatzverfahren behandelt wurden , . Auch wenn diese Analysen ausschliesslich randomisierte Studien berücksichtigten, zeigte sich kein Unterschied . Bisher wurden fünf prospektive, randomisierte Studien zu diesem Thema publiziert , , , , . Vier davon zeigten keinen Unterschied in der Letalität, eine Studie fand eine signifikant höhere Letalität in der Gruppe der Patienten die mit einem kontinuierlichem Nierenersatzverfahren behandelt wurden . Allerdings waren die Patienten in dieser Studie nicht balanziert randomisiert worden, so wiesen Patienten mit kontinuierlichem Nierenersatzverfahren bereits bei Studieneinschluss eine höheren Krankheitsschweregrad auf. Die neueste und größte Studie schloss 360 Patienten mit ANV und Multiorganversagen ein, davon hatten 69% in der IHD-Gruppe und 56% in der CVVH Gruppe eine Sepsis als Ursache für das ANV. Ein Unterschied bzgl. der Letalität fand sich zwischen den beiden Gruppen nicht .Bei hämodynamisch instabilen Patienten wird eine CVVH empfohlen, da dieses Verfahren Vergleich zu einer konventionellen IHD besser verträglich ist und die Flüssigkeitsbilanzierung erleichtert , . → Empfehlung Grad C (Evidenzgrad IIb für , , )Durch Modifikation einer IHD (z.B. längere Dialysezeiten, gekühltes Dialysat, reduzierter Blut und Dialysatfluss) kann eine einer CVVH gleichwertige hämodynamische Stabilität erreicht werden , , .→ Empfehlung Grad B (Evidenzgrad Ib für und II a für , )Kommentar: Bzgl. der hämodynamischen Toleranz der einzelnen Nierenersatzverfahren, gibt es derzeit keine eindeutigen Hinweise, welche eine Überlegenheit kontinuierlicher Verfahren belegen. Zwei prospektive Studien berichten allerdings über eine bessere hämodynamische Toleranz mit CVVH , , jedoch ohne eine Verbesserung der Organperfusion oder einen Überlebensvorteil aufzeigen zu können. Vier weitere prospektive Studien fanden keinen signifikanten Unterschied im mittleren arteriellen Blutdruck oder Abfall des systolischen Blutdruckes zwischen den beiden Methoden , , , . Die hämodynamische Toleranz intermittierender Verfahren lässt sich durch Modifikationen wie z.B. längere Dialysezeiten, gekühltes Dialysat, reduzierter Blut- und Dialysatfluss deutlich verbessern und damit der hämodynamischen Toleranz kontinuierlicher Verfahren angleichen , , . Bzgl. der Flüssigkeitsbilanzierung zeigten 2 Studien eine signifikante Verbesserung der Bilanzziele durch den Einsatz kontinuierlicher Nierenersatzverfahren , .Um eine urämische Stoffwechsellage zu vermeiden, wird empfohlen, bei Patienten mit schwerer Sepsis/septischem Schock und bestehendem oligurischem ANV frühzeitig ein Nierenersatzverfahren einzuleiten. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Zur Frage eines „frühen“ oder „späten“ Beginns kann aufgrund wenig robuster Daten keine klare Empfehlung gegeben werden. Der Beginn muss oft individuell entschieden werden. Um metabolische Entgleisungen und urämische Komplikationen zu vermeiden, sollte bei schwerst kranken Patienten mit einem sich rasch entwickelnden ANV und persistierender Oligurie (<500 ml/pro 24 Stunden über 6–24 Stunden trotz Therapie) der Beginn eines Nierenersatzverfahrens nicht verzögert werden. Bei kritisch kranken Patienten mit ANV wird eine ausreichend hohe Dosis eines Nierenersatzverfahrens (CVVH oder CVVHDF: mindestens >20 ml/kg/pro Stunde Ultrafiltrationsrate; IHD: mindestens 3 mal/proWoche; Kt/Vurea 1,2–1,4) empfohlen. Eine Intensivierung der Dosis (CVVHDF 35 ml/kg/pro Stunde, IHD täglich) ist nach aktuellen Studien nicht mit einer Reduktion der Sterblichkeit dieser Patienten verbunden , .→ Empfehlung Grad B (Evidenzgrad Ib für )Kommentar: Sechs randomisierte, kontrollierte Studien haben die Frage untersucht, ob die verwendete Dosis des jeweiligen Nierenersatzverfahrens die Letalität bei kritisch kranken Patienten mit akutem Nierenversagen günstig beeinflusst , , , , , . Drei Studien wiesen eine Letalitätsreduktion bei Patienten nach, welche mit einer höheren Dosis des Nierenersatzverfahrens (CVVH 35 ml/kg/pro Stunde Ultrafiltration , , (IHD täglich . Jedoch konnte in drei Studien diesbezgl. kein Überlebensvorteil nachgewiesen werden , , . Keine dieser Studien wurde a priori bei Patienten mit schwerer Sepsis bzw. septischem Schock durchgeführt. Im Gegensatz zu den anderen Studien, wiesen jedoch in der größten und aktuellsten Studie 63% der Patienten eine Sepsis auf . In dieser Studie war die Intensivierung der Dosis des Nierenersatzverfahren (CVVHDF 35 ml/kg/pro Stunde oder tägliche IHD) nicht mit einer Letalitätsreduktion – verglichen mit einer konventionellen Dosis (CVVHDF 20 ml/kg/pro Stunde Dialyse 3 mal/Woche mit Kt/Vurea >1,2–1,4 pro IHD Sitzung) – verbunden. Konventionelle Nierenersatzverfahren (CVVH und IHD) sind nicht geeignet, die Plasmakonzentrationen von Entzündungsmediatoren bei Patienten mit schwerer Sepsis bzw. septischem Schock signifikant zu beeinflussen , , . Über eine renale Indikation hinaus kann ihr Einsatz daher nicht empfohlen werden. → Empfehlung Grad C (Evidenzgrad IIb für )Kommentar: Dagegen sind neuere extrakorporale Verfahren mit dem Ziel einer gesteigerten Elimination von Entzündungsmediatoren wie z.B. „high volume“ Hämofiltration (HVHF), „high cut-off“ Hämofiltration, oder adsorptive Verfahren (z.B. Endotoxinadsorbtion, Immunadsorption), zwar prinzipiell geeignet, die Plasmakonzentrationen bestimmter Mediatoren zu beeinflussen. Nutzen und Gefahren dieser Methoden für den septischen Patienten, müssen jedoch in randomisierten „outcome“ Studien überprüft werden. Außerhalb von Studien kann der Einsatz dieser Verfahren zur Therapie der schweren Sepsis bzw. des septischen Schocks derzeit jedoch nicht empfohlen werden. Airway-Management und Beatmung Es wird empfohlen, die oximetrische Sauerstoffsättigung bei über 90% zu halten . → Empfehlung Grad B (Evidenzgrad Ic)Es wird empfohlen, Patienten mit schwerer Sepsis oder septischem Schock frühzeitig zu beatmen. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Zu den Indikationen gehören schwere Tachypnoe (Atemfrequenz >35/min), muskuläre Erschöpfung (Einsatz der Atemhilfsmuskulatur), eingeschränkte Vigilanz und ein Sättigungsabfall ≤90% trotz Sauerstoffinsufflation. Es wird empfohlen, Patienten mit schwerer Sepsis oder septischem Schock und ALI/ARDS (Tabelle 6 ) mit einem niedrigen Atemzugvolumen (von 6 ml/kg Standardkörpergewicht) und einem Plateaudruck von <30 cmH2O zu beatmen (Tabelle 7 ) , .→ Empfehlung Grad A (Evidenzgrad Ib für , )Kommentar: Bei allen beatmeten Patienten sollte das Standardkörpergewicht (Tabelle 7 ) routinemäßig bestimmt werden. Bei ca. 30% der Patienten mit schwerem ARDS können auch Atemzugvolumina von 6 ml/kg KG zu einer Überblähung führen. Diese sollte mit einem niedrigeren Tidalvolumen beatmet werden . Selbst bei niedrigem Plateaudruck führt eine Beatmung mit hohen Atemzugvolumina zu einer erhöhten Letalität . Es wird empfohlen, eine mechanische Beatmung immer mit positiv endexspiratorischen Drücken (PEEP) durchzuführen . → Empfehlung Grad B (Evidenzgrad Ic)Kommentar: Über die Höhe des PEEP kann zurzeit keine Empfehlung gegeben werden. Die in Tabelle 7 genannten Werte gelten als Orientierung.Es wird empfohlen, bei beatmeten Patienten mit ALI/ARDS, die bei niedrigen Tidalvolumina hohe pCO2-Werte aufweisen, eine Hyperkapnie zu tolerieren , . → Empfehlung Grad D (Evidenzgrad IIIb )Kommentar: Eine permissive Hyperkapnie sollte nur bis zu einem pH-Wert von 7,2 ohne Pufferung durchgeführt werden .Bei Patienten mit erhöhtem intrakraniellen Druck besteht eine relative Kontraindikation für eine permissive Hyperkapnie. Es wird empfohlen, eine Behandlung nur unter Kontrolle des intrakraniellen Drucks und Abwägen der Risiken durchzuführen.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Eine Bauchlagerung bzw. 135 Grad Seitenlage bei schweren Oxygenierungsstörungen (PaO2/FiO2 ≤88 mmHg) wird empfohlen.→ Empfehlung Grad C (Evidenzgrad IIb für )Kommentar: Eine Bauchlagerung bzw. 135 Grad Seitenlage kann die Oxygenierung signifikant verbessern. Allerdings konnte ein Überlebensvorteil von Patienten nur bei schwerem ARDS nachgewiesen werden , .Eine routinemäßige Therapie mit inhalativem Stickstoffmonoxid (NO) kann nicht empfohlen werden.→ Empfehlung Grad A (Evidenzgrad Ib für , )Kommentar: Durch die Gabe von inhalativem Stickstoffmonoxid (NO) konnte bei Intensivpatienten mit ALI/ARDS kein Überlebensvorteil nachgewiesen werden , , .Es wird empfohlen, alle Patienten, die hämodynamisch stabil, ansprechbar und ausreichend oxygeniert sind, einmal pro Tag einem Spontanatmungsversuch zu unterziehen, um die Möglichkeit zu einer Extubation zu überprüfen , , (Abbildung 1 ). → Empfehlung Grad A (Evidenzgrad Ib für , ) 8. Adjunctive therapyDefinitionAdjunctive therapy is treatment used together with and in addition to causal and supportive sepsis therapy. GlucocorticosteroidsThe use of high-dose glucocorticosteroids is not recommended in treatment of patients with severe sepsis or septic shock , . → Recommendation level A (evidence level Ib for , )According to current data, low-dose intravenous hydrocortisone, administered in a daily dose of 200–300 mg, is no longer recommended in the routine treatment of patients with septic shock.→ Recommendation level B (evidence level Ib for )Comment: The previous recommendation of hydrocortisone administration was largely based on the results of a randomized, multi-center placebo-controlled trial with a 7-day administration of intravenous hydrocortisone in an dose of 50 mg every 6 hours in combination with 50 mg of oral fludrocortisone every 24 hours, or placebo. Prior to therapy, an ACTH stimulation test was carried out with 250 μg of corticotropin in order to identify the patients with a “relative adrenal insufficiency” (“non-responders”: a ≤9 µg/dl increase in plasma cortisol after 30 or 60 min). A reduction in the 28-day mortality from 63% to 53% was reported in non-responders; however, it was established only after a complex adjustment of 6 variables in the Cox regression analysis (p=0.04). In responders, the effect was the opposite (61% vs. 53%), but it was insignificant due to a small number of cases. The entire patient group displayed no differences either. In the European multi-center CORTICUS trial which included 499 patients, an effect of hydrocortisone on the 28-day mortality (39.2% versus 36.1%) was recorded neither in non-responders nor in the entire patient group. Since hydrocortisone caused increased incidences of hyperglycemic events and hypernatremic states in addition to increased incidence of superinfections, the authors of this study recommend that hydrocortisone no longer be used in routine therapy of patients with septic shock. The use of low-dose hydrocortisone with a dosing scheme of 200–300 mg/day may be considered as a therapy of last resort in patients with septic shock that is refractory to therapy, meaning that the patients cannot be stabilized despite volume restitution and administration of high-dose vasopressors. → Recommendation level E (evidence level V: expert opinion)Comment: There is no information available regarding therapy lasting more than 7 days. Possible therapy side effects are: hyperglycemia (necessitating increased doses of insulin) and hypernatremia (due to intrinsic mineralocorticoid effects of hydrocortisone). Determination of plasma cortisol levels prior to the initiation of hydrocortisone therapy is currently no longer recommended because it is unclear which plasma cortisol threshold levels are valid for the diagnosis of relative adrenal insufficiency in patients with septic shock. The absence of an increase in plasma cortisol ≥9.0 μg/dl after a cortisol stimulation test with 250 μg corticotropin has no prognostic value . The inter-assay variance of cortisol determinations is significant . The only biologically active part is free cortisol (comprising 10% of the total plasma cortisol) . However, the available assays measure only the cortisol bound to globulin and albumin, which means that in patients with low levels of albumin, false negative cortisol level results may be obtained . A hydrocortisone dose of 200–300 mg daily may be given as a bolus 3–4 times a day or as a long-term infusion, preferably as a continuous infusion (serving to prevent the hyperglycemic events). After instituting hydrocortisone therapy, hemodynamic and immunological rebound phenomena were described . It is recommended that therapy be gradually tapered off according to clinical judgment.Insulin therapyAn intensified intravenous insulin therapy to reduce increased blood glucose levels (threshold level of >110 mg/dl [>6.1 mmol/l] is not recommended in patients with severe sepsis and septic shock.→ Recommendation level B (evidence level Ib for VISEP)Comment: The multi-center randomized VISEP trial demonstrated a lack of positive effects for intensified insulin therapy with respect to morbidity and mortality in patients with severe sepsis or septic shock. Moreover, a 6-fold increase in the incidence of severe hypoglycemic events was recorded with the use of intensified insulin therapy .Intravenous insulin therapy with the goal of lowering increased blood glucose levels (threshold level of >150 mg/dl [>8.3 mmol/l] may be considered in patients with severe sepsis and septic shock. (After reaching consensus on the present guidelines, the published results of the control arm of the NICE-SUGAR trial prompted the Surviving Sepsis Campaign to recently propose a threshold value of >180 mg/dl (i.e. 10.0 mmol/l)). → Recommendation level E (evidence level V: expert opinion)Comment: If there are increased blood sugar levels, parenterally delivered glucose amounts may possibly first have to be reduced and the indication for corticosteroid therapy reevaluated if it is being administered. Patients with an already manifest severe sepsis or septic shock, older patients (age >60), internal medicine patients and patients with a generally more severe underlying disease run a higher risk of developing hypoglycemia with the use of insulin therapy in intensive care settings. Moderate intravenous insulin therapy supposedly reduces the risk of severe hypoglycemic events. It is not known if moderate glycemic control is of benefit. Close initial bedside glycemic monitoring performed in 1–2 hour intervals is of vital importance here as well. Determination of glucose concentrations in whole blood is one of the most complex laboratory tests in ICU patients because the values depend, among other things, on current hematocrit concentration . Due to the lack of precision (coefficient of variation >20%) and lower sensitivity of the available measuring devices, used for determination of glucose in whole blood, in the hypoglycemic measurement range, only those devices which allow for a secure and early detection of hypoglycemia should be used. Data from current studies indicate that the degree of individual variation in blood glucose concentrations in critically ill patients has proven to be a more important prognostic index that the 24-hour arithmetic mean value . The necessity of timely and close monitoring of blood glucose levels emphasizes the possible future importance of continuous monitoring methods. These methods are currently already in an advanced stage of development. Recombinant activated protein C (rhAPC)In patients with severe sepsis or septic shock and high risk of mortality, it is recommended to use rhAPC in patients who do present with any contraindications for its use.→ Recommendation level C (evidence level 1c for )Comment: The risk of mortality is generally increased in patients with septic shock, multiple organ dysfunction syndrome (MODS) or an APACHE II score of >25 on admission.In patients with severe sepsis and low risk of mortality, it is not recommended to use rhAPC; this patient population constitute patients presenting with an admission APACHE II score of <25 points or failure of a single organ system.→ Recommendation level A (evidence level 1a for , )Comment: The rationale for the use of rhAPC rests on data from 2 controlled randomized trials , ], while further data on safety are based on post-approval non-randomized trials . The PROWESS trial, which was terminated early for efficacy reasons, revealed a 6.1% absolute reduction in 28-day mortality. Subgroup analysis revealed that patients with a high risk of mortality (i.e. an APACHE II score of >25 or multiple organ dysfunction syndrome) derive more benefits from the compound than do patients with a lower risk of mortality. In addition, subgroup analyses also suggest that patients with community-acquired pneumonia and high mortality risk benefit most highly from the compound, while the patients with surgical interventions and nosocomial pneumonia see a lower decrease in mortality with the use of rhAPC. Despite some issues underlying the interpretation of the subgroup analysis , the FDA issued approval of the substance for use in patients with a high risk of disease with a requirement that further data be provided on safety in patients with a low risk of disease. In Europe, the approval was issued for use in patients with multiple organ dysfunction syndromes. The European regulatory authorities issued a time-limited approval which must be reevaluated on a yearly basis with respect to new data. In the meantime, the ADDRESS trial yielded further data on patients with a low risk of mortality (In response to a request from the European Medicines Agency, the manufacturer of rhAPC is currently conducting a multicentric placebo-controlled trial in 1,200 patients with septic shock. The protocol has been published ahead of the start of the trial ). It is not recommended to discontinue a prophylactic heparin therapy for deep venous thrombosis (DVT) while the patient in on rhAPC therapy.→ Recommendation level B (evidence level Ib for )Comment: Contrary to the initial belief, concomitant administration of heparin does not increase the risk of hemorrhage .Antithrombin Antithrombin therapy is not recommended. → Recommendation level B (according to evidence level Ib for )Comment: High-dose antithrombin therapy did not result in a reduction of the 28-day mortality in a phase III trial in patients with severe sepsis or septic shock . The lack of efficacy of antithrombin in patients with severe sepsis may be caused by adjunctive heparin therapy . While on antithrombin therapy, patients also run an increased risk of hemorrhage. ImmunoglobulinsPreliminary remarks: A most recent meta-analysis included 27 trials on the use of immunoglobulins. This is the only analysis which ran separate evaluations of trials on adults and on newborns and which created additional subgroups for studies involving IgM-enriched immunoglobulins (ivIgGAM) and non-IgM-enriched immunoglobulins (ivIgG). In adults, eight trials conducted with ivIgGAM on 60 patients revealed a pooled relative risk of mortality of 0.64 (95% CI 0.54–0.84). In contrast, the pooled effect of seven studies conducted with ivIgG on 932 patients was 0.85 (95% CI 0.73–0.99). The use of ivIgGAM may be considered for treatment of adult patients with severe sepsis or septic shock.→ Recommendation level C (evidence level Ia for )Comment: The experts in the field are not in agreement about this recommendation. The recommendation rests on a meta-analysis from the year 2007 [322]. However, a further meta-analysis published in 2007 in the same volume of Crit Care Med , which employed a different trial quality evaluation methodology and produced different results, recommends that a high-quality, adequately powered and transparently presented study be conducted in order to determine the significance of I.V. immunoglobulin therapy. The use of ivIgG in the treatment of adult patients with severe sepsis or septic shock is not recommended. → Recommendation level B (evidence level Ia for , )Comment: The above-mentioned meta-analysis revealed poorer performance of IgG products in adult patients as well as in neonates as compared to IgGAM, and barely reached the significance threshold in adults. In contrast, the SBITS study conducted on 624 patients showed no improvement in the survival rate.SeleniumThe use of selenium in the treatment of patients with severe sepsis or septic shock may be considered. → Recommendation level C (evidence level Ia for )Comment: Ten trials with low numbers of cases and different indications studied the administration of selenium (alone or in combination with other anti-oxidants). A meta-analysis that included nine of these trials showed a significant difference in mortality with the use of selenium . However, a randomized trial with a small number of cases and high initial selenium administration doses to be published shortly showed no difference in mortality . A large, multi-center, randomized trial is needed for unequivocal determination of selenium's efficacy.Other therapeutic approachesIbuprofen , growth hormones , prostaglandins , , , , pentoxifyllin , , , high-dose N-acetylcysteine , granulocyte colony-stimulating factor , , , , , and protein C concentrates are not recommended for treatment of patients with severe sepsis or septic shock.→ Recommendation level E (evidence level V: expert opinion) 8. Adjunktive TherapieDefinitionEine adjunktive Therapie ist eine Behandlung gemeinsam mit und zusätzlich zur kausalen und supportiven Therapie der Sepsis GlukokortikosteroideEine Behandlung mit hochdosierten Glukokortikosteroiden wird in der Therapie von Patienten mit schwerer Sepsis bzw.septischem Schocks nicht empfohlen , . → Empfehlung Grad A (Evidenzgrad Ib für , )Niedrig dosiertes intravenös verabreichtes Hydrokortison in einer Dosierung von 200–300 mg/Tag kann nach der gegenwärtigen Datenlage in der Behandlung von Patienten mit septischem Schock nicht mehr empfohlen werden. → Empfehlung Grad B (Evidenzgrad Ib für )Kommentar: Die bisherige Empfehlung zur Gabe von Hydrokortison beruhte im wesentlichen auf den Ergebnissen einer randomisierten, multizentrischen, placebo-kontrollierten Studie, in der Hydrokortison in einer Dosierung von 50 mg i.v. 6 stdl. plus Fludrokortison 50 mg p.o. 24 stdl. oder Placebo über 7 Tage verabreicht wurde. Vorher wurde ein ACTH-Stimulationstest mit 250 μg Kortikotropin durchgeführt, um Pat. mit „relativer NNR-Insuffizienz“ zu identifizieren („Non-Responder“: ≤9 µg/dL Anstieg im Plasma-Cortisol nach 30 oder 60 min). Es wurde über eine Reduktion der 28-Tage Letalität von 63% auf 53% bei Non-Respondern berichtet, welche allerdings erst nach einer komplexen Cox-Adjustierung um 6 Variablen nachweisbar war (p=0,04). Bei den Respondern war der Effekt umgekehrt (61% vs 53%), aufgrund der kleinen Fallzahl jedoch nicht signifikant. Auch im Gesamtkollektiv war kein Unterschied nachweisbar. In der europäischen multizentrischen CORTICUS-Studie wurde auf der Basis von 499 Patienten weder ein Effekt von Hydrokortison auf die 28-Tage Letalität (39,2% versus 36,1%) bei Non-Respondern, noch im Gesamtkollektiv aufgezeigt. Da neben mehr Superinfektionen auch eine erhöhte Rate von Hyperglykämien und -natriämien durch Hydrokortison beobachtet wurde, empfehlen die Autoren dieser Studie, Hydrokortison nicht mehr in der Routinetherapie von Patienten mit septischem Schock zu verwenden. Der Einsatz von niedrig dosiertes Hydrokortison in einer Dosierung von 200–300 mg/Tag kann bei Patienten mit therapiefraktärem septischem Schock, die trotz Volumentherapie und Vasopressorentherapie in hoher Dosis nicht zu stabilisieren sind, als ultima ratio Therapie erwogen werden. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Bezgl. einer Therapiedauer von mehr als 7 Tagen liegen keine Erfahrungen vor. Potenzielle Nebenwirkungen der Therapie sind: Hyperglykämie (erhöhte Dosen von Insulin erforderlich) und Hypernatriämie (aufgrund der intrinsischen mineralokortikoiden Wirkung von Hydrokortison). Eine Kortisolbestimmung vor Einleitung einer Therapie mit Hydrocortison kann derzeit nicht mehr empfohlen werden, da unklar ist, welche Plasma-Cortisol-Schwellenwerte für die Diagnose einer relativen Nebenrindeninsuffizienz bei Patienten mit septischem Schock Gültigkeit haben. Ein nach einem Kortisol-Stimulationstest mit 250 μg Kortikotropin ausbleibender Anstieg des Plasma-Kortisols ≥9,0 μg/dl hat keine prognostische Bedeutung . Die Inter-Assay-Varianz der Kortisolbestimmungen variiert erheblich . Biologisch aktiv ist lediglich das freie Kortisol (10% des Gesamt-Kortisols) . Die verfügbaren Assays messen jedoch das an Globulin und Albumin gebundene Kortisol, wodurch bei hypalbuminämischen Patienten falsch niedrige Kortisolkonzentrationen gemessen werden können . Hydrokortison in einer Dosierung von 200–300 mg/Tag kann als Bolus 3–4 x täglich oder als Dauerinfusion verabreicht werden, wobei eine kontinuierliche Infusion bevorzugt werden sollte (z.B. Vermeidung von Hyperglykämien). Nach Einstellung der Hydrokortison-Behandlung wurden hämodynamische und immunologische rebound-Phänomene beschrieben . Eine ausschleichende Beendigung der Therapie nach klinischem Ermessen wird daher empfohlen.InsulintherapieEine intensivierte intravenöse Insulintherapie zur Senkung erhöhter Glukosespiegel (Schwellenwert von >110 mg/dl [>6,1 mmol/l]) wird bei Patienten mit schwerer Sepsis oder septischem Schock nicht empfohlen. → Empfehlung: Grad B (Evidenzgrad Ib für VISEP)Kommentar: In der multizentrischen randomisierten VISEP-Studie konnten weder günstige Effekte einer intensivierten Insulintherapie auf die Morbidität noch auf die Letalität von Patienten mit schwerer Sepsis bzw. septischem Schock aufgezeigt werden. Dagegen war die Rate an schweren Hypoglykämien unter einer intensivierte Insulintherapie um den Faktor 6 erhöht .Eine intravenöse Insulintherapie zur Senkung erhöhter Glukosespiegel (Schwellenwert von >150 mg/dl [>8,3 mmol/l]) kann bei Patienten mit schwerer Sepsis oder septischem Schock erwogen werden. (Aufgrund der – nach Abschluss des Konsentierungsverfahrens der vorliegenden Leitlinie – publizierten Ergebnisse im Kontrollarm der NICE-SUGAR Studie hat die Surviving Sepsis Campaign vor kurzem einen Schwellenwert von >180 mg/dl (10,0 mmol/l) vorgeschlagen).→ Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Bei erhöhten Blutzuckerwerten sollte zunächst die parenteral zugeführte Glukosemenge evtl. reduziert und die Indikation einer evtl. bestehenden Medikation mit Glukokortikosteroiden überprüft werden. Bei Patienten mit bereits manifester schwerer Sepsis bzw. septischen Schock, bei älteren Patienten (>60 Jahre), bei internistischen Patienten und bei Patienten mit ansonsten hoher Krankheitsschwere besteht ein erhöhtes Risiko für eine Hypoglykämie bei der Anwendung einer Insulintherapie in der Intensivmedizin. Vermutlich ist das Risiko schwerer Hypoglykämien durch eine moderate intravenöse Insulintherapie geringer. Ob eine moderatere Einstellung der Blutglukose vorteilhaft ist, ist derzeit nicht bekannt. Eine engmaschige initial (1–2 stündliche) bettseitige Kontrolle der Blutglukose ist jedoch auch hier zwingend erforderlich. Die Messung der Glukosekonzentration im Vollblut gehört u.a. wegen ihrer Abhängigkeit vom aktuellen Hämatokrit zu den komplexesten Laborbestimmungen bei intensivmedizinischen Patienten . Aufgrund der mangelnden Präzision (Variationskoeffizient bis >20%) und geringen Sensitivität im hypoglykämischen Messbereich der gegenwärtig verfügbaren Messgeräte zur Bestimmung der Glukosekonzentration im Vollblut, sollten nur Geräte zur Anwendung kommen, welche die sichere und frühzeitige Detektion einer Hypoglykämie gewährleisten. Nach aktuellen Studien ist das Ausmass der intraindividuellen Variabilität der Blutglukosekonzentration bei kritisch kranken Patienten offenbar ein wichtigerer prognostischer Index als das arrithmetische 24-Stundenmittel . Die Notwendigkeit möglichst engmaschig Informationen über die Glukosekonzentration zu erhalten, unterstreicht wie wichtig kontinuierliche Messverfahren in Zukunft sein könnten. Diese Verfahren befinden sich derzeit bereits in einem fortgeschrittenen Zustand der Entwicklung.Rekombinantes aktiviertes Protein C (rhAPC)Bei Patienten mit schwerer Sepsis bzw. septischem Schock und hohem Sterberisiko wird der Einsatz von rhAPC für solche Patienten empfohlen, welche keine Kontraindikationen für die Anwendung von rhAPC aufweisen. → Empfehlung Grad C (Evidenzgrad 1c für )Kommentar: Das Sterberisiko ist in der Regel bei Patienten mit septischem Schock, Mehrfachorganversagen bzw. einem APACHE II Score bei Aufnahme von >25 Punkten erhöht. Bei Patienten mit schwerer Sepsis und niedrigem Sterberisiko wird der Einsatz von rhAPC nicht empfohlen, dieses sind in der Regel Patienten mit einem APACHE II Score bei Aufnahme von <25 Punkten, oder mit Versagen eines einzigen Organsystems. → Empfehlung Grad A (Evidenzgrad 1a für , )Kommentar: Die Rationale für den Einsatz für rhAPC basiert auf 2 kontrollierten randomisierten Studien , , weitere Daten zur Sicherheit basieren auf nicht randomisierten Studien, die nach der Zulassung erfolgten . Die PROWESS Studie, welche frühzeitig wegen Wirksamkeit gestoppt wurde, zeigte eine 6,1%ige absolute Reduzierung der 28 Tage-Sterblichkeit. In der Subgruppenanalyse zeigte sich, dass Patienten mit höherem Sterberisiko (APACHE II Score >25 oder mit Mehrfachorganversagen) stärker von der Substanz profitieren als Patienten mit geringerem Sterberisiko. Subgruppenanalysen legen auch nahe, dass Patienten mit ambulant erworbener Pneumonie und hohem Sterberisiko am meisten von der Substanz profitieren, während bei Patienten mit chirurgischen Eingriffen und nosokomialen Pneumonien die Letalitätsreduktion durch rhAPC geringer ist. Trotz der Problematik, welche der Interpretation von Subgruppenanalysen zu Grunde liegt erfolgte die Zulassung der Substanz für die Patienten mit höherem Krankheitsrisiko durch die FDA mit der Auflage, weitere Daten zur Sicherheit bei Patienten mit niedrigerem Krankheitsrisiko zu generieren. In Europa erfolgte die Zulassung für Patienten mit Mehrfachorganversagen. Die europäischen Zulassungsbehörden begrenzten die Zulassung zeitlich und unterwarfen sie einem jährlichen Überprüfungsprozess hinsichtlich neuer Daten. Inzwischen liegen mit der ADDRESS Studie weitere Daten zu Patienten mit niedrigem Sterberisiko vor. (Der Auflage der Zulassungsbehörde EMEA folgend, führt der Hersteller gegenwärtig eine multizentrische, doppelblinde, placebo-kontrollierte Studie an 1.500 Patienten mit septischem Schock durch. Der Prüfplan zu dieser Studie wurde im Vorfeld veröffentlicht ). Ein Aussetzen einer Behandlung mit Heparin zur Thromboseprophylaxe unter einer Behandlung mit rhAPC wird nicht empfohlen.→ Empfehlung Grad B (Evidenzgrad Ib für )Kommentar: Entgegen ursprünglicher Annahmen ist durch die gleichzeitige Gabe von Heparin das Blutungsrisiko nicht erhöht .Antithrombin Eine Behandlung mit Antithrombin wird nicht empfohlen. → Empfehlung Grad B (gemäß Evidenzgrad Ib für )Kommentar: Eine hochdosierte Therapie mit Antithrombin führte in einer Phase-III Studie nicht zu einer Senkung der 28-Tage-Letalität bei Patienten mit schwerer Sepsis oder septischem Schock . Möglicherweise wird die fehlende Wirksamkeit von Antithrombin bei Patienten mit schwerer Sepsis durch eine Begleitbehandlung mit Heparin verursacht . Auch unter Antithrombin ist das Blutungsrisiko erhöht.ImmunglobulineVorbemerkung: In eine jüngste Metaanalyse wurden 27 Studien mit Immunglobulinen einbezogen. Sie ist die einzige, in der die Studien getrennt für Erwachsene und Neugeborene ausgewertet und zusätzlich Untergruppen für Studien mit IgM-angereicherten Immunglobulinen (ivIgGAM) und mit nicht IgM-angereicherten Immunglobulinen (ivIgG) gebildet wurden. Bei den Erwachsenen ergaben 8 Studien, die mit ivIgGAM an 560 Patienten durchgeführt wurden, ein gepooltes relatives Sterberisiko von 0,64 (95% CI 0,54–0,84). Dagegen betrug der gepoolte Effekt von 7 Studien, die mit ivIgG an 932 Patienten durchgeführt wurden, 0,85 (95% CI 0,73–0,99). Der Einsatz von ivIgGAM in der Behandlung von erwachsenen Patienten mit schwerer Sepsis oder septischem Schock kann erwogen werden.→ Empfehlung Grad C (Evidenzgrad Ia für )Kommentar: Die Experten sind bezgl. dieser Empfehlung unterschiedlicher Auffassung. Der Empfehlung liegt eine Metaanalyse aus dem Jahre 2007 zugrunde . Eine im gleichen Heft von Crit Care Med 2007 publizierte weitere Metaanalyse nimmt jedoch eine andere Qualitätsbewertung der Studien vor, kommt zu anderen Ergebnissen und empfiehlt eine qualitativ hochwertige, adäquat gepowerte und transparent dargelegte Studie zum Stellenwert einer Therapie mit ivIg durchzuführen. Der Einsatz von ivIgG in der Behandlung von erwachsenen Patienten mit schwerer Sepsis oder septischem Schock wird nicht empfohlen. → Empfehlung Grad B (Evidenzgrad Ia für , )Kommentar: In der genannten Metaanalyse fielen die Ergebnisse sowohl bei den Erwachsenen als auch bei den neugeborenen Patienten für die IgG Präparate jeweils schlechter aus als für IgGAM und erreichten bei den Erwachsenen gerade die Signifikanzgrenze. Darüber hinaus zeigte die SBITS Studie bei 624 Patienten keine Verbesserung der Überlebensrate. Selen Der Einsatz von Selen in der Behandlung von Patienten mit schwerer Sepsis oder septischem Schock kann erwogen werden.→ Empfehlung Grad C (Evidenzgrad Ia für )Kommentar: Zur Gabe von Selen (allein oder in Kombination mit anderen Antioxydantien) liegen zehn Studien mit kleiner Fallzahl und unterschiedlichen Indikationen vor. Eine Metaanalyse, die neun dieser Studien beinhaltete, zeigte einen signifikanten Letalitätsunterschied zugunsten von Selen . Eine kürzlich veröffentlichte randomisierte Studie mit kleiner Fallzahl und hoher initialer Selen-Gabe zeigte jedoch keinen Letalitätsunterschied auf . Zur endgültigen Klärung der Wirksamkeit von Selen ist eine große randomisierte multizentrische Studie erforderlich.Andere TherapieansätzeIbuprofen , Wachstumshormone , Prostaglandine , , , , Pentoxifyllin , , , hoch dosiertes N-Acetylcystein , Granulozyten-colony stimulating factor , , , , , Protein C-Konzentrate, werden in der Behandlung von Patienten mit schwerer Sepsis oder septischem Schock nicht empfohlen.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung) 9. Other supportive therapiesDeep venous thrombosis (DVT) prophylaxisCurrently, no randomized trials involving patients with severe sepsis or septic shock exist; nevertheless, DVT prophylaxis with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is recommended , , because this patient population possesses a very limited cardiopulmonary reserve for thromboembolic complications. → Recommendation level E (evidence level V: expert opinion)Comment: ICU patients run a high risk of developing deep venous thrombosis , but its incidence may be significantly reduced with the use of pharmacological DVT prophylaxis , . In the presence of an underlying kidney failure, the LMWH dose must be properly adjusted . Further details in s. S3-Guidelines for prevention of venous thromboembolism (see: http://www.uni-duesseldorf.de/AWMF/ll/003-001k.pdf).Nutrition and metabolic control In all patients who are not projected to be able to receive regular food within 3 days, artificial nutrition is recommended, especially in the presence of reduced nutritional condition. → Recommendation level E (evidence level V: expert opinion)In sepsis, decreased substrate utilization is an expression of disease severity. It is recommended that the level of calories delivered be based primarily on substrate tolerance, regardless of the estimated or measured caloric requirements. → Recommendation level E (evidence level V: expert opinion)Enteral vs. parenteral nutrition As a general rule, enteral nutrition is the preferred type of nutrition in critically ill patients. It is not recommended to administer parenteral nutrition when adequate oral and/or enteral nutrition is possible . → Recommendation level E (evidence level V: expert opinion)It is not recommended to institute total parenteral nutrition (TPN) in patients without signs of malnutrition who are expected not to be able to receive adequate enteral nutrition for less than 5 days . → Recommendation level E (evidence level V: expert opinion)Comment: Trials involving septic patients do not exist. One study compared the use of intravenous glucose with total parenteral nutrition in postoperative patients . In a subgroup of patients who were able to receive enteral nutrition after a few days, patients with parenteral nutrition saw more complications and displayed a trend of increased mortality. Hence, this group should not immediately receive total parenteral nutrition; rather, a basal daily glucose delivery (150–200 g) should be ensured.It is recommended to institute total parenteral nutrition regimens at the very beginning of intensive care treatment in patients who are expected not to be able to receive oral or enteral nutrition even after a period of 5–7 days .→ Recommendation level B (evidence level Ic)It is recommended to institute a combined enteral/parenteral nutrition regimen each time when there is an indication for artificial nutrition and when the caloric requirements cannot be met due to the limited enteral tolerance at a given substrate utilization level. This is especially true when the caloric supply lies under 60% of the calculated requirement and a central venous access has already been established . → Recommendation level E (evidence level V: expert opinion)Comment: In contrast to [the situation with] other critically ill patients, there are no trials specifically covering the issue of enteral vs. parenteral substrate delivery in patients with severe sepsis or septic shock. In critically ill patients who are able to receive enteral nutrition, several meta-analyses showed the advantage of early institution of enteral nutrition with a significantly lower rate of infectious complications and no effects on mortality , . The proportion of patients able to receive enteral nutrition increases with implementation of a protocol , . Sepsis may be characterized by a limited loading and transport capacity of the intestines; hence, enteral delivery must be increased only very gradually. A meta-analysis showed that in the presence of inadequate enteral nutrition, early parenteral nutrition showed clear advantages with regard to infectious complications and mortality. This speaks for an additive enteral/parenteral nutrition provided that enteral nutrition can only satisfy a small fraction of the caloric requirements.Parenteral nutritionIt is not recommended to institute parenteral nutrition when adequate oral or enteral nutrition are possible.→ Recommendation level E (evidence level V: expert opinion)In patients with a severe sepsis or septic shock, it is recommended to provide 30–50% of non-protein calories in the form of fats.→ Recommendation level E (evidence level V: expert opinion)It is not recommended to administer lipid emulsions containing only long-chain triglycerides (LCT). → Recommendation level E (evidence level V: expert opinion)Comment: Unlike glucose, lipids undergo increased oxidation in septic patients and are the physiological energy carriers under such conditions , . Adverse effects such as a high rate of complications, longer ventilation times as well as longer ICU stays and hospital inpatient stays have been observed with the use of exclusively LCT-containing fat emulsions . The long-chain triglycerides contain primarily unsaturated omega-6 fatty acids with a high inflammatory potential in the synthesis of prostaglandins and leukotrienes. Hence, the administration of such fat emulsions should be regarded as problematic for their role in systemic inflammatory reactions. In a parenteral nutrition of undefined duration, it is recommended to immediately institute the administration of a standard supplement together with the daily substitution of vitamins and trace elements. → Recommendation level E (evidence level V: expert opinion)Immunonutrition In patients with severe sepsis or septic shock, the use of immunonutritive formulations is associated with an increased risk of mortality and is therefore not recommended.→ Recommendation level B (evidence level Ib for )Comment: In a multi-center trial involving internal medicine ICU patients with sepsis, the use of immunomodulating diet showed a significant reduction in mortality. This effect was recorded primarily in patients with an APACHE-II score between 10 and 15, while in patients with higher APACHE II scores the control group displayed better survival . In a further trial in patients with severe sepsis, an enteral diet enriched with arginine, omega-3 fatty acids and antioxidants was associated with a significantly increased mortality compared to the patients in the control arm who received parenteral nutrition . These results were confirmed in a meta-analysis of the available trials . A randomized trial compared an early enteral immunonutrition with a parenteral nutrition in critically ill patients without severe sepsis . Patients who received enteral immunomodulating nutrition developed significantly fewer episodes of severe sepsis or a severe shock and recorded shorter ICU stays. However, the difference in the 28-day mortality was insignificant. Because this trial lacked a group receiving standard enteral nutrition, only a limited use of these results may be made in favor of the enteral immunonutrition.A continuous enteral nutrition with omega-3 fatty acids in combination with antioxidants may be considered. → Recommendation level C (evidence level Ib)Comment: A single-center trial involving 165 ventilated patients with severe sepsis and septic shock recorded a significant, 19.4% reduction in mortality in patients who received enteral nutrition, enriched by omega-3 fatty acids and antioxidants, in addition to improvements in the respiratory parameters and shortening of the inpatient ICU stays . Previous studies already indicated that this diet significantly reduced the duration of ventilation and shortened the ICU inpatient stays . However, in only 30% of patients ARDS was triggered by a severe sepsis. Significantly better ventilation parameters (the Horowitz index on days 4 and 7) were confirmed in patients with respiratory failure . GlutamineIt is recommended to supply critically ill patients who are receiving total parenteral nutrition with parenterally administered glutamine dipeptide in addition to parenteral amino acids.→ Recommendation level E (evidence level V: expert opinion)Comment: No studies examined the parenteral or enteral delivery of glutamine in septic patients. Eight trials studied the parenteral delivery of glutamine in ICU patients , . A meta-analysis of the data showed positive effects with respect to mortality and appearance of infections. In two of the studies, the effects of parenteral glutamine administration were best documented in patients who received parenteral nutrition for 9 to 10 days . The patients mostly received a dose of 0.3–0.4 g/kg/BW/day (corresponding to 0.2–0.26 g glutamine/kg BW/day). Most recently, it has been shown that parenteral administration of glutamine in critically ill patients leads to an improvement in glucose tolerance and sensitivity to insulin along with a significant reduction in the incidence of hyperglycemic events and complications , .Glutamine-enriched enteral nutrition is not recommended in septic patients.→ Recommendation level E (evidence level V: expert opinion)Comment: There are no data on septic patients. A meta-analysis showed that the enteral administration of glutamine-enriched diet was associated with a reduction in the number of infections only in trauma and burn patients . A multi-center 4-arm trial (REDOXS) researching the administration of glutamine and antioxidants alone and in combination versus placebo in critically ill patients was initiated in the USA and Canada in 2006. The results will be available at the end of year 2010 at the earliest .Ulcer prophylaxisIt is recommended that stress ulcer prophylaxis be administered in patients with severe sepsis/septic shock. → Recommendation level B (evidence level Ic)Comment: The effectiveness of pharmacological stress ulcer prophylaxis for prevention of gastrointestinal bleeding has been proven in intensive care patients , , , .Stress ulcer prophylaxis with histamine-2 receptor blockers or with proton pump inhibitors (PPIs) is recommended , , .→ Recommendation level B (evidence level Ib for , )Comment: Prophylaxis with PPI is associated with an increased risk of nosocomial infections with Clostridium difficile and is to be critically appraised especially in combination with antibiotic therapy , .It is recommended to carry out recurrence prophylaxis with proton pump inhibitors (PPIs). → Recommendation level A (evidence level Ia for )Enteral nutrition is recommended as a supporting additional measure for stress ulcer prophylaxis . → Recommendation level E (evidence level V: expert opinion)The use of bicarbonate in lactic acidosisBicarbonate treatment to correct for the hypoperfusion-induced lactic acidosis at a pH level of ≥7.15 is not recommended in patients with severe sepsis or septic shock. → Recommendation level D (evidence level IIIb for , )Comment: Hemodynamic improvements or a reduced need for vasopressors were not shown in two studies , . There are no available studies for bicarbonate use at a pH level of ≤7.15.Blood productsWith restored tissue perfusion and the absence of clinically-relevant coronary heart disease or bleeding, treatment with packed red blood cells is recommended if Hb drops below 7.0 g/dl (4.4 mmol/l). The Hb should then be increased to 7.0–9.0 g/dl (4.4–5.6 mmol/l).→ Recommendation level E (evidence level V: expert opinion) Comment: A transfusion trigger of 7.0 g/dl (4.4 mmol/l) does not lead to higher mortality in critically ill patients . In patients with severe sepsis, blood transfusion can lead to an increase in O2 availability, but not to an increase in O2-utilization , . On the use of RBC transfusion in severe sepsis or septic shock and impaired tissue perfusion, see the section on Hemodynamic stabilization .ErythropoietinErythropoietin is not recommended for treatment of sepsis-associated anemia.→ Recommendation level E (evidence level V: expert opinion)Comment: The administration of erythropoietin in intensive care patients does not lead to a significant reduction in the need for packed red blood cells , . To date, a reduction in mortality through the administration of erythropoietin has only been established in a subgroup of intensive care trauma patients , . Special studies on patients with severe sepsis or septic shock are currently unavailable.Fresh Frozen Plasma (FFP) The administration of FFP to correct the abnormal coagulation parameters in patients with severe sepsis or septic shock is not recommended. → Recommendation level E (evidence level V: expert opinion)Comment: Transfusion-related acute lung injury (TRALI) occurs in intensive care patients after the administration of fresh frozen plasma (FFP) with a frequency of up to 8% . Patients with sepsis have a higher risk of developing TRALI after FFP administration . At this time there is no indication for the use of fresh frozen plasma (FFP) in the absence of a clinically manifest bleeding tendency .Sedation, analgesia, delirium and neuromuscular blockadeMonitoring of sedation, analgesia and deliriumThe use of sedation and ventilation protocols with specific safety checks and failure criteria is recommended in patients with severe sepsis or septic shock. → Recommendation level A (evidence level Ib for ) Comment: Patient-oriented therapeutic concepts in analgesia, sedation and antipsychotic treatment for delirium in intensive medicine call for establishing individual patient-oriented treatment goals and adequate monitoring of treatment effects in relation to the desired effects as well as side effects. With the use of sedation, analgesia and ventilation protocols, the length of ventilation, the duration of inpatient stays and the frequency of tracheotomy procedures , , could be reduced. It is recommended to assess aim and extent of analgesia, sedation and delirium therapy at least every 8 hours and after every change of therapy .→ Recommendation level E (evidence level V: expert opinion)The use of validated scoring systems to control treatment and monitor sedation, analgesia and delirium is recommended.→ Recommendation Grade B (evidence level IIb for )Comment: At a minimum, one must use adequate scoring systems for respectively setting sedation, analgesia and delirium targets, whereby validated scoring systems are preferred. In patients with severe sepsis or septic shock who for the most part are not able to adequately communicate, physicians and nurses must use subjective factors and objective physiological parameters to judge analgesia, sedation and delirium as well as changes in these parameters under the relevant goal-oriented treatment. In order to objectively assess individual pains in ventilated patients who cannot communicate, the “Behavioral Pain Scale” (BPS) may be used. It allows for pain intensity quantification even in deeply sedated patients. Intensity is evaluated based on criteria such as facial expression, movement of the upper extremities and adaptation to the ventilation device.Sedation, analgesia and deliriumIt is recommended to administer adequate analgesia to critically ill ICU patients. → Recommendation level A (evidence level Ib for )It is recommended to limit the use of deep sedation only to a few specific indications.→ Recommendation level A (evidence level Ib for , )Comment: Modern sedation concepts are based on controlled suppression of consciousness and an effective switching off of pain sensation. A target value measured using a validated sedation score (e.g. Richmond Agitation Sedation Scale=RASS) should be set and adjusted for the current disease state in severe sepsis or septic shock. Sedation should be carried out up to predetermined endpoints (using sedation scales) with daily interruption of sedation to wake up the patient and undertake a spontaneous breathing attempt following a safety check with attention to the failure criteria . A better outcome marked by shorter ICU and inpatient treatment duration as well as lower one-year mortality was demonstrated in patients who underwent a daily spontaneous breathing trial following interruption of sedation to achieve full patient awakening .EtomidateIf there are alternatives, it is recommended not to use etomidate as an introductory hypnotic drug in septic patients.→ Recommendation: level E (evidence level V: expert opinion)Comment: Etomidate offers advantages as an introductory hypnotic agent for intubation of critically ill patients because, in addition to its fast onset of action, it displays good hemodynamic stability and only slight effects on respiratory depression. It does, however, cause a depression of adrenal steroid synthesis by inhibiting 11-beta- hydroxylase , possibly aggravating an existing adrenal insufficiency in septic shock . Already one intubation dose of etomidate may worsen the outcome of septic patients due to the suppression of steroid synthesis , . On the other hand, a study with 159 septic patients showed no association between the introductory hypnotic agent and the administration of vasopressors, as well as no evidence of clinical worsening or benefits of steroid administration after intubation with etomidate .Neuromuscular blockadeIt is recommended not to use muscle relaxants – when possible – in the treatment of patients with severe sepsis or septic shock.→ Recommendation level E (evidence level V: expert opinion)Comment: The use of muscle relaxants is associated with an increased risk of ICU-acquired paresis , , , , , . Should muscle relaxants nevertheless be required, monitoring of the depth of the blockade using Train-of-Four is obligatory . 9. Andere supportive TherapienThromboseprophylaxeObwohl zur Zeit keine randomisierte Studie bei Patienten mit schwerer Sepsis oder septischem Schock vorliegt, wird eine Thromboseprophylaxe mit unfraktionierten (UH) oder niedermolekularen Heparinen (LMWH) empfohlen , , da dieses Patientengut nur eine geringe kardiopulmonale Reserve für thromboembolische Komplikationen hat.→ Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Patienten auf Intensivstationen weisen ein hohes Risiko für eine tiefe Venenthrombose auf, deren Häufigkeit sich durch eine medikamentöse Thromboseprophylaxe signifikant reduzieren lässt , . Bei Vorliegen einer Niereninsuffizienz muss die Dosis von LMWH adaptiert werden . Näheres s. S3-Leitlinie zur Prophylaxe venöser Thromboembolien (siehe: http://www.uni-duesseldorf.de/AWMF/ll/003-001k.pdf).Ernährung und metabolische Kontrolle Für alle Patienten, die voraussichtlich nicht innerhalb von 3 Tagen vollständig mit normaler Kost ernährt werden können, wird eine künstliche Ernährung empfohlen. Dies gilt besonders bei Vorliegen eines reduzierten Ernährungsstatus. → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)In der Sepsis ist eine verminderte Substratutilisation Ausdruck der Schwere der Erkrankung. Es wird empfohlen, die Höhe der Energiezufuhr vor allem nach der Substrattoleranz ungeachtet des geschätzten oder gemessenen Energiebedarfs zu richten. → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Ernährung enteral vs. parenteral Grundsätzlich gilt, dass die enterale Ernährung die bevorzugte Form der Ernährung bei kritisch Kranken darstellt. Es wird nicht empfohlen, eine parenterale Ernährung durchzuführen, wenn eine ausreichende orale und/oder enterale Ernährung möglich ist . → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Es wird nicht empfohlen, Patienten ohne Zeichen der Mangelernährung, die voraussichtlich weniger als 5 Tage nicht ausreichend enteral ernährt werden können, vollständig parenteral zu ernähren . → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Studien an septischen Patienten existieren nicht. Eine Studie verglich den Einsatz von intravenöser Glukose mit vollständiger parenteraler Ernährung in post-operativen Patienten . In einer Subgruppe, die nach wenigen Tagen enteral ernährbar war, traten in Patienten mit parenteraler Ernährung mehr Komplikationen auf und zeigten einen Trend zu einer gesteigerten Letalität. Somit sollte diese Gruppe nicht sofort vollständig parenteral ernährt werden, sondern eine basale tägliche Glukosezufuhr (150–200 g) sollte sicher gestellt werden. Es wird empfohlen, Patienten von Anbeginn der Intensivtherapie parenteral zu ernähren, welche voraussichtlich auch nach einem Zeitraum von 5–7 Tagen nicht ausreichend oral oder enteral ernährt werden können .→ Empfehlung: Grad B (Evidenzgrad Ic)Es wird empfohlen, eine kombinierte enterale/parenterale Ernährung immer dann durchzuführen, wenn eine künstliche Ernährung indiziert ist und der Kalorienbedarf durch eingeschränkte enterale Toleranz bei bestehender Substratutilisation nicht ausreichend gedeckt werden kann. Dies gilt besonders, wenn die Kalorienzufuhr unter 60% des errechneten Bedarfs beträgt und ein zentralvenöser Zugang bereits vorhanden ist . → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Im Gegensatz zu anderen kritisch Kranken gibt es keine Studien, die spezifisch die Frage enterale versus parenterale Substratzufuhr bei Patienten mit schwerer Sepsis oder septischem Schock untersucht haben. Für kritisch Kranke, die enteral ernährbar sind, zeigen mehrere Metaanalysen den Vorteil der frühzeitigen enteralen Ernährung mit signifikant niedrigerer Rate infektiöser Komplikationen ohne Einfluß auf die Letalität , . Der Anteil enteral ernährbarer Patienten steigt mit Implementierung eines Protokolls , . In der Sepsis kann eine verminderte Belastbarkeit und Transportkapazität des Intestinums Teil der Erkrankung sein, so dass die enterale Zufuhr nur sehr vorsichtig gesteigert werden sollte. Eine Metaanalyse zeigte, dass bei unzureichender enteraler Ernährung eine frühzeitig begonnene parenterale Ernährung deutliche Vorteile in Bezug auf infektiöse Komplikationen und die Letalität aufweist. Dies spricht für eine additive enterale/parenterale Ernährung, sofern enteral nur ein geringer Teil des Bedarfs gedeckt werden kann.Parenterale ErnährungEs wird nicht empfohlen, eine parenterale Ernährung durchzuführen, wenn eine ausreichende orale oder enterale Ernährung möglich ist. → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Bei Patienten mit einer schweren Sepsis bzw. septischem Schock wird empfohlen, 30–50% der Non-Protein-Kalorien in Form von Fett zu verabreichen. → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Es wird nicht empfohlen, Lipidemulsionen mit ausschließlich langkettigen Triglyzeriden (LCT) zu verabreichen.→ Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Lipide werden im Gegensatz zur Glukose von septischen Patienten verstärkt oxidiert und sind unter diesen Bedingungen physiologische Energieträger , . Ungünstige Auswirkungen wie eine höhere Komplikationsrate, längere Beatmungs-, ICU- und Krankenhausverweildauer sind nur bei Verwendung ausschließlich LCT haltiger Fettemulsionen aufgetreten . Die langkettigen Triglyzeride enthalten vor allem mehrfach ungesättigte Omega-6 Fettsäuren mit hohem inflammatorischem Potential in der Synthese von Prostaglandinen und Leukotrienen. So ist die Gabe dieser Fettemulsionen im Rahmen der systemischen Entzündungsreaktion des kritisch Kranken als problematisch anzusehen. Bei einer parenteralen Ernährung unbestimmter Dauer wird empfohlen, unmittelbar mit der täglichen Substitution von Vitaminen und Spurenelementen mit einem Standardsupplement zu beginnen.→ Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Immunonutrition Für Patienten mit schwerer Sepsis oder septischem Schock ist der Einsatz von immunnutritiven Formeln mit einem erhöhten Letalitätsrisiko assoziiert und kann daher nicht empfohlen werden.→ Empfehlung: Grad B (Evidenzgrad Ib für )Kommentar: In einer Multicenterstudie an internistischen Intensivpatienten mit Sepsis zeigte sich bei Einsatz einer immunmodulierenden Diät eine signifikante Senkung der Letalität. Diese fand sich vor allem bei den Patienten mit einem APACHE-II Score zwischen 10–15, während bei Patienten mit höherem APACHE-II Score das Überleben in der Kontrollgruppe günstiger war . In einer weiteren Studie bei Patienten mit schwerer Sepsis war eine enteral mit Arginin, Omega-3-Fettsäuren und Antioxidanzien angereicherte Diät gegenüber der parenteral ernährten Kontrollgruppe mit einer signifikant höheren Letalität assoziiert . Diese Ergebnisse wurden in einer Metaanalyse der verfügbaren Studien bestätigt . In einer randomisierten Studie bei kritisch Kranken ohne schwere Sepsis ist die frühzeitige enterale Immunonutrition mit einer parenteralen Ernährung verglichen worden . Die enteral immunmodulierend ernährten Patienten entwickelten signifikant weniger Perioden einer schweren Sepsis oder eines schweren Schocks und hatten einen kürzeren Intensivaufenthalt. Die 28-Tage Letalität unterschied sich jedoch nicht signifikant. Da in dieser Studie eine standardenteral ernährte Gruppe fehlte, können diese Daten nur sehr eingeschränkt zugunsten der enteralen Immunonutrition interpretiert werden. Eine kontinuierliche enterale Ernährung mit Omega-3 Fettsäuren in Kombination mit Antioxidanzien kann erwogen werden. → Empfehlung: Grad C (Evidenzgrad Ib)Kommentar: In einer monozentrischen Studie an 165 beatmeten Patienten mit schwerer Sepsis und septischem Schock ist bei Gabe einer enteralen mit Omega-3-Fettsäuren und Antioxidanzien angereicherten Diät neben einer Verbesserung der respiratorischen Parameter und der Verkürzung der Intensivliegedauer eine signifkant 19,4% niedrigere Letalität der supplementiert ernährten Patienten gezeigt worden . Bereits früher war bei Patienten mit dieser Diät eine signifikant kürzere Beatmungs- und Intensivliegedauer gezeigt worden . Nur ca. 30% der Patienten hatten jedoch eines schwere Sepsis als Auslöser des ARDS. Die signifikant günstigeren Beatmungsparameter (Horowitzquotient an Tag 4 und 7) sind bei Patienten mit Lungenversagen bestätigt worden . GlutaminEs wird empfohlen, kritisch Kranken, welche ausschließlich parenteral ernährt werden, zusätzlich zur parenteralen Aminosäurenzufuhr parenteral Glutamindipeptid zuzuführen.→ Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Es existieren keine Studien, welche die parenterale oder enterale Zufuhr von Glutamin bei septischen Patienten untersucht haben. Acht Studien haben die parenterale Zufuhr von Glutamin bei Intensivpatienten untersucht , . Eine Metaanalyse der Daten zeigte einen positiven Effekt hinsichtlich der Letalität und des Auftretens von Infektionen. In zwei der Studien war der Effekt der parenteralen Glutamin-Gabe am besten bei Patienten zu dokumentieren, die 9–10 Tage parenteral ernährt wurden . Hierbei erhielten die Patienten zumeist eine Dosis von 0,3–0,4 g/kg/KG/Tag (entsprechend 0,2–0,26 g Glutamin/kg KG/Tag). Aktuell ist durch die parenterale Gabe von Glutamin bei kritisch Kranken eine Verbesserung der Glukosetoleranz und Insulinsensitivität mit signifikant niedrigerer Hyperglykämie- und Komplikationsrate gezeigt worden , . Eine enterale Supplementierung mit Glutamin wird bei septischen Patienten nicht empfohlen. → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Es fehlen Daten an septischen Patienten. Die enterale Gabe von glutaminsupplementierter Ernährung zeigte in der Metaanalyse eine Reduktion der Infektionen nur bei Trauma- und Verbrennungspatienten . In den USA und Kanada wurde bei kritisch Kranken 2006 eine multizentrische vierarmige Studie zur Gabe von Glutamin und Antioxidanzien allein und in Kombination versus einen Placebo (REDOXS) begonnen. Die Ergebnisse werden frühestens ab Ende 2010 zur Verfügung stehen .UlkusprophylaxeEs wird empfohlen, bei Patienten mit schwerer Sepsis/septischem Schock eine Stressulkusprophylaxe durchzuführen. → Empfehlung: Grad B (Evidenzgrad Ic)Kommentar: Die Effektivität einer medikamentösen Stressulkusprophylaxe zur Verhinderung gastrointestinaler Blutungen ist beim Intensivpatienten erwiesen , , , .Eine Stressulkusprophylaxe mit Histamin-2-Rezeptorblockern oder mit PPIs wird empfohlen , .→ Empfehlung: Grad B (Evidenzgrad Ib für , )Kommentar: Die Prophylaxe mit PPI ist mit einem erhöhten Risiko nosokomialer Infektionen mit Clostridium difficile assoziiert und ist insbesondere in Kombination mit einer Antibiotikatherapie kritisch abzuwägen , .Es wird empfohlen, eine Rezidivprophylaxe mit Protonenpumpeninhibitoren (PPIs) durchzuführen.→ Empfehlung: Grad A (Evidenzgrad Ia für )Enterale Ernährung kann als unterstützende zusätzliche Maßnahme zur Stressulkusprophylaxe empfohlen werden . → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Bikarbonat bei LaktatazidoseEine Bikarbonat-Therapie zum Ausgleich einer hypoperfusions-induzierten Laktatazidose bei einem pH ≥7,15 wird bei Patienten mit schwerer Sepsis oder septischem Schock nicht empfohlen. → Empfehlung Grad D (gemäß Evidenzgrad IIIb für , )Kommentar: Verbesserungen des hämodynamischen Status oder ein rückläufiger Vasopressorbedarf waren in zwei Studien nicht nachweisbar , . Studien zur Bikarbonat-Anwendung bei einem pH ≤7,15 liegen nicht vor.BlutprodukteBei normalisierter Gewebeperfusion und in Abwesenheit einer klinisch relevanten koronaren Herzerkrankung oder Blutung wird eine Behandlung mit Erythrozytenkonzentraten empfohlen, wenn der Hb unter 7,0 g/dl (4,4 mmol/l) fällt. Der Hb sollte dann auf 7,0–9,0 g/dl (4,4–5,6 mmol/l) angehoben werden.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Ein Transfusionstrigger von 7,0 g/dl (4,4 mmol/l) führt nicht zu einer erhöhten Letalität bei kritisch Kranken . Bei Patienten mit schwerer Sepsis führt eine Bluttransfusion zwar zu einem Anstieg des O2-Angebots, nicht aber zu einer Zunahme des O2-Verbrauchs , . Zu Erythrozytenersatz bei schwerer Sepsis oder septischem Schock und beeinträchtigter Gewebeperfusion: s. Abschnitt Hämodynamische Stabilisierung .ErythropoetinErythropoetin wird zur Therapie einer Sepsis-assoziierten Anämie nicht empfohlen.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Die Gabe von Erythropoetin bei Intensivpatienten führt zu keiner signifikanten Reduktion des Bedarfs an Erythrozytenkonzentraten , . Eine Sterblichkeitsreduktion durch die Gabe von Erythropoetin konnte bislang nur in einer Untergruppe von traumatologischen Intensivpatienten nachgewiesen warden , . Spezielle Studien an Patienten mit schwerer Sepsis bzw. septischem Schock liegen zurzeit nicht vor.Fresh Frozen Plasma (FFP) Die Gabe von FFP zur Korrektur von abnormen Gerinnungsparametern bei Patienten mit schwerer Sepsis oder septischem Schock wird nicht empfohlen. → Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Ein Transfusions-assoziiertes Lungenversagen (TRALI) tritt bei Intensivpatienten nach Gabe von Fresh Frozen Plasma (FFP) mit einer Häufigkeit von bis zu 8% auf . Patienten mit einer Sepsis haben ein höheres Risiko ein TRALI nach FFP-Gabe zu entwickeln . Es gibt daher keine Indikation für eine Anwendung von Fresh Frozen Plasma (FFP) in Abwesenheit einer klinisch manifesten Blutungsneigung .Sedation, Analgesie, Delir und neuromuskuläre BlockadeMonitoring von Sedation, Analgesie und DelirDer Einsatz von Sedierungs- und Beatmungsprotokollen mit spezifischen Sicherheitschecks und Versagenskriterien wird bei Patienten mit schwerer Sepsis oder septischem Schock empfohlen. → Empfehlung Grad A (Evidenzgrad Ib für ) Kommentar: Patientenorientierte Therapiekonzepte zur Analgesie, Sedierung und antideliranter Therapie in der Intensivmedizin setzen die individuelle patientenspezifische Festlegung von Therapiezielen und ein adäquates Monitoring der Therapieeffekte sowohl im Bezug auf gewünschte Wirkungen als auch Nebenwirkungen voraus. Unter Verwendung von Sedierungs-, Analgesie- und Beatmungsprotokollen können Beatmungsdauer, Liegedauer und die Tracheotomiehäufigkeit , , gesenkt werden. Es wird empfohlen, Ziel und Grad der Analgesie, Sedierung und antideliranten Therapie mindestens 8-stdl, sowie nach jeder Therapieänderung zu erfassen .→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Der Einsatz von validierten Scoringsystemen zur Therapiesteuerung und Überwachung der Sedierung, Analgesie und Delir wird empfohlen.→ Empfehlung Grad B (Evidenzgrad IIb für )Kommentar: Als Minimalforderung gilt der Einsatz eines für die jeweilige Zielstellung adäquaten Scoringsystems für Sedierung, Analgesie und Delir, wobei validierte Scoringsysteme zu bevorzugen sind. Bei Patienten mit schwerer Sepsis oder septischem Schock, die in der Regel nicht in der Lage sind adäquat zu kommunizieren, müssen Ärzte und Pflegepersonal subjektive Faktoren und objektive physiologische Parameter zur Beurteilung der Analgesie, der Sedierung und des Delir sowie die Veränderung dieser Parameter unter der entsprechenden zielorientierten Therapie zur Beurteilung heranziehen. Zur objektiven Beurteilung der individuellen Schmerzen beim beatmeten, nicht-kommunikationsfähigen Patienten steht die „Behavioural Pain Scale“ (BPS) zur Verfügung , die es ermöglicht, auch bei tiefer sedierten Patienten eine Quantifizierung der Schmerzintensität vorzunehmen. Diese wird bewertet anhand der Kriterien Gesichtsausdruck, Bewegung der oberen Extremität und Adaptation an das Beatmungsgerät.Therapie von Sedation, Analgesie und DelirEs wird empfohlen, bei kritisch kranken Patienten auf Intensivstationen eine adäquate Analgesie durchzuführen. → Empfehlung Grad A (Evidenzgrad Ib für )Es wird empfohlen, eine tiefe Sedierung nur noch wenigen speziellen Indikationen vorzubehalten. → Empfehlung Grad A (Evidenzgrad Ib für , )Kommentar: Moderne Analgosedierungskonzepte basieren auf einer kontrollierten Dämpfung der Bewusstseinslage und einer effektiven Ausschaltung des Schmerzempfindens. Es sollte ein Zielwert gemessen anhand eines validierten Sedierungsscores (z.B. Richmond Agitation-Sedation-Scale = RASS) angestrebt werden, der dem aktuellen Krankheitsgeschehen in der schweren Sepsis oder dem septischen Schock begründet anzupassen ist. Die Sedierung sollte bis zu vorher festgelegten Endpunkten (anhand der Sedierungsskalen) erfolgen mit täglicher Unterbrechung der Sedierung bis zum Erwachen des Patienten mit nachfolgendem Spontanatmungsversuch bei vorher erfüllter Sicherheitscheckliste und unter Beachtung von Versagenskriterien erreicht werden. Es konnte für diese Patienten eine besseres Outcome mit kürzerer ITS- und Krankenhaus Behandlungsdauer und niedrigerer 1 Jahresletalität gezeigt werden, bei denen nach täglicher Unterbrechung der Sedierung bis zum Erwachen des Patienten, ein Spontanatmungsversuch durchgeführt wurde . EtomidateFalls Alternativen bestehen, wird empfohlen, Etomidate als Einleitungshypnotikum bei septischen Patienten nicht zu verwenden. → Empfehlung: Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Etomidate bietet als Einleitungshypnotikum Vorteile zur Intubation kritisch kranker Patienten, da es neben einem schnellen Wirkeintritt, eine gute hämodynamische Stabilität und eine geringe Atemdepression aufweist. Es bewirkt jedoch eine Depression der Nebennierenrinden-Steroidsynthese durch Inhibition der 11beta-Hydroxylase , möglicherweise wird dadurch eine bereits im Rahmen des septischen Schocks bestehende Nebennierenrindeninsuffizienz aggraviert . Bereits eine Intubationsdosis Etomidate könnte durch die Suppression der Steroidsynthese das Outcome septischer Patienten verschlechtern , . Dagegen fand eine andere Studie mit 159 septischen Patienten keinen Zusammenhang zwischen dem Einleitungshypnotikum und der Vasopressorgabe, sowie keinen Hinweis auf eine klinische Verschlechterung oder dem Nutzen einer Steroidgabe nach Intubation mit Etomidate .Neuromuskuläre BlockadeEs wird empfohlen, Muskelrelaxantien – wenn immer möglich – in der Behandlung von Patienten mit schwerer Sepsis oder septischem Schock nicht zu verwenden.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Die Anwendung von Muskelrelaxantien ist mit einem erhöhten Risiko ITS-erworbener Paresen assoziiert , , , , , . Sollten Muskelrelaxantien dennoch angewendet werden müssen, dann ist ein Monitoring der Blockadetiefe mittels Train-of-Four obligat . 10. Follow-up and rehabilitationIntroduction: In addition to the limitations to the health-related quality of life that have been compiled with validated test instruments (e.g. SF-36) , , a number of former sepsis patients suffer from functional impairments, which are categorized under the terms Critical Illness Polyneuropathy (CIP) or Critical Illness Myopathy (CIM), which have been in existence for over 20 years now . More than 70% of patients with septic shock and more than 60% of the ventilated patients as well as patients with severe sepsis show significant electrophysiological changes already three days after admission to intensive care . In addition to sepsis and mechanical ventilation, multiple organ dysfunction syndrome (MODS), ARDS, systemic inflammation, corticosteroids, impaired glucose metabolism as well as the duration of ICU inpatient stay also display associations with myopathic or neuropathic changes. In summary, in patients with CIP/CIM, difficulties with weaning from the ventilator (weaning failure) and prolonged post-hospitalization rehabilitation periods have been noted with increased frequency . The issues of delirium during intensive therapy and persistent residual neurocognitive impairments, post-traumatic distress disorder (PTSD) and states of depression , related to perihospital functional development have increasingly attracted notice. The degree of functional deficits resulting from sepsis and the actual quality of life of those affected may, however, be influenced by taking appropriate rehabilitation measures. However, currently there exist neither therapeutic rehabilitation standards nor any rehabilitation facilities tailored to the needs of these patients, as the long-term consequences of sepsis following ICU treatments are little known to the physicians responsible for further care of these patients. Before the introduction of DRGs, sepsis patients were treated in an acute hospital up to the point of 'safe discharge'; such settings generally do not have adequate rehabilitation resources. With the introduction of DRGs, these patients continue to be confronted with further problems. Due to the lack of future accounting principles, the acute care hospital is motivated to discharge the patients prematurely in order not to exceed the available per capita budget. Consequently, sepsis patients are now discharged even earlier from acute medical care settings. Targeted studies are needed to improve our understanding of the often long-term neurocognitive and motor/functional impairments in this patient population, and to identify possible preventive or therapeutic approaches . It is recommended that the typical consequences of sepsis – to the degree possible – already be identified in an acute medical setting and that physicians assuming further care of these patients, be it in post-acute inpatient settings or on an outpatient basis, be instructed regarding the existing or potentially occurring long-term functional deficits.→ Recommendation level E (evidence level V: Expert Opinion) Comment: In collaboration with the German Sepsis Aid support group (Deutsche Sepsis-Hilfe e.V.), the German Sepsis Society has created an informational brochure about the consequences of sepsis, to be distributed free of charge to the patients, family members and physicians responsible for their subsequent care. 10. Nachsorge und RehabilitationVorbemerkung: Neben den im Rahmen validierter Testinstrumente (z.B. SF-36) erfassten Einschränkungen der gesundheitsbezogenen Lebensqualität , , , leiden eine Vielzahl von ehemaligen Sepsispatienten unter funktionellen Einschränkungen, die unter den Begriffen Critical Illness Polyneuropathy (CIP) bzw. Critical Illness Myopathy (CIM) seit mehr als zwei Jahrzehnten bekannt sind . Mehr als 70% der Patienten mit septischem Schock und mehr als 60% der mechanisch beatmeten Patienten sowie der Patienten mit einer schweren Sepsis zeigen signifikante elektrophysiologische Veränderungen bereits drei Tage nach Aufnahme auf die Intensivstation . Assoziationen mit myopathischen oder neuropathischen Veränderungen zeigen neben der Sepsis und der Beatmung auch das Multiorganversagen, ARDS, systemische Inflammation, Kortikosteroide, Störungen des Glukosemetabolismus und die Liegedauer auf der Intensivstation. In der Summe werden bei Patienten mit CIP/CIM häufiger Schwierigkeiten bei der Entwöhnung vom Ventilator (weaning failure) und prolongierte Phasen der post-hospitalen Rehabilitation beobachtet . Zunehmend in den Blickpunkt geraten im Zusammenhang der perihospitalen funktionellen Entwicklung auch das Delirium während der Intensivtherapie sowie anhaltende neurokognitive Einschränkungen, post-traumatischer Distress (PTSD) und Depressionen , . Der Grad der durch eine Sepsis resultierenden Funktionsdefizite und somit die tatsächliche Lebensqualität der Betroffenen kann jedoch durch eine geeignete Rehabilitationsmaßnahme durchaus beeinflussbar sein. Allerdings gibt es bis heute weder therapeutische Rehabilitations-Standards noch auf diese Patienten ausgerichtete Rehabilitationseinrichtungen, da die Langzeitfolgen einer Sepsis nach intensivtherapeutischer Behandlung den nachbehandelnden Ärzten in der Regel wenig bekannt sind. Bis zur Einführung der DRGs wurden Sepsis-Patienten bis zu ihrer „Entlassungsfähigkeit“ in der Regel im Akut-Krankenhaus versorgt, welches jedoch im Allgemeinen nicht über entsprechende rehabilitationsmedizinische Ressourcen verfügt. Mit Einführung der DRGs sehen sich diese Patienten jedoch mit einem weiteren Problem konfrontiert. Aufgrund zukünftig fehlender Abrechnungsgrundlagen ist das Akut-Krankenhaus an einer vorzeitigen Entlassung des Patienten interessiert, um das pro Behandlungsfall zur Verfügung stehende Budget nicht über Gebühr zu überschreiten. Das Ergebnis ist, dass Sepsis-Patienten nun noch früher aus der akutmedizinischen Versorgung entlassen werden. Gezielte Untersuchungen sind notwendig, um unser Verständnis der häufig lang andauernden neurokognitiven und motorisch-funktionellen Beeinträchtigungen dieser Patientengruppe zu verbessern und mögliche Präventions- bzw. Therapieansätze aufzuzeigen .Es wird empfohlen, typische Sepsisfolgen – sofern möglich – bereits im akutmedizinischen Bereich zu erfassen und die nachbehandelnden Ärzte im Postakut- und ambulanten Bereich über diesbezgl. bestehende bzw. potentiell im Langzeitverlauf auftretende Funktionsdefizite hinzuweisen.→ Empfehlung Grad E (Evidenzgrad V: Expertenmeinung)Kommentar: Die Deutsche Sepsis-Gesellschaft e.V. hat gemeinsam mit der Selbsthilfegruppe Deutsche Sepsis-Hilfe e.V. eine Informationsbroschüre zu Sepsisfolgen herausgegeben, welche Patienten, Angehörigen und nachbehandelnden Ärzten kostenlos zur Verfügung gestellt wird. AppendixCoding for sepsis, severe sepsis and septic shock in ICD-10-GMFrom age 16 onwards, the following applies:Definition of sepsis (corresp. R65.0! in ICD-10-GM)For a diagnosis of SIRS of infectious etiology without organ complication(s), the following requirements must be met: Collection of at least 2 sets of blood cultures (always a set of an aerobic and an anaerobic bottle)The following two combinations are to be distinguished:Negative blood culture, however fulfillment of all four of the following criteria:Fever (≥38.0° C) or hypothermia (≤36.0°C) confirmed through a rectal, intravascular or intravesical determinationTachycardia with a heart rate of ≥90/minTachypnea (frequency ≥20/min) or hyperventilation (confirmed by ABG with PaCO2 ≤4.3 kPa)Leukocytosis (≥12,000/mm3) or leukopenia (≤4,000/mm3) or 10% or more immature neutrophils in the differential countPositive blood culture,and fulfillment of at least two of the following criteria:Fever (≥38.0° C) or hypothermia (≤36.0°C) confirmed through a rectal, intravascular or intravesical determinationTachycardia with a heart rate of ≥90/minTachypnea (frequency ≥20/min) or hyperventilation (confirmed by ABG with PaCO2 ≤4.3 kPa)Leukocytosis (≥12,000/mm3) or leukopenia (≤4,000/mm3) or 10% or more immature neutrophils in the differential countDefinition of severe sepsis (corresp. R65.1! in ICD-10-GM)For a diagnosis of SIRS of infectious etiology with organ complication(s)* as well as a SIRS of non-infectious etiology with or without organ complication(s), at least two of the following four criteria must be met: Fever (≥38.0°C) or hypothermia (≤36.0°C ) confirmed through a rectal, intravascular or intravesical determinationTachycardia with a heart rate of ≥90/minTachypnea (frequency ≥20/min) or hyperventilation (confirmed by ABG with PaCO2 ≤4.3 kPa)Leukocytosis (≥12,000/mm3) or leukopenia (≤4,000/mm3) or 10% or more immature neutrophils in the differential count* with respect to the specifications on organ complications, the definitions of the German Sepsis Society apply (see Table 1 ). AppendixKodierung der Sepsis, schweren Sepsis und des septischen Schocks im ICD-10-GMAb dem 16. Lebensjahr gilt:Definition der Sepsis (entspr. R65.0! im ICD-10-GM)Für das Vorliegen eines SIRS infektiöser Genese ohne Organkomplikation(en) müssen folgende Faktoren erfüllt sein:Abnahme von mindestens 2 Blutkulturen (jeweils aerobes und anaerobes Pärchen)Die beiden folgenden Konstellationen werden unterschieden:Negative Blutkultur, jedoch Erfüllung aller vier der folgenden KriterienFieber (≥38,0° C) oder Hypothermie (≤36,0°C) bestätigt durch eine rektale, intravasale oder intravesikale MessungTachykardie mit Herzfrequenz ≥90/minTachypnoe (≥20/min) oder Hyperventilation (bestätigt durch art. BGA mit PaCO2 ≤4,3 kPa)Leukozytose (≥12.000/mm3) oder Leukopenie (≤4.000/mm3) oder 10% oder mehr unreife Neutrophile im DifferentialblutbildPositive Blutkultur, und Erfüllung von mindestens zwei der folgenden Kriterien:Fieber (≥38,0° C) oder Hypothermie (≤36,0°C) bestätigt durch eine rektale, intravasale oder intravesikale MessungTachykardie mit Herzfrequenz ≥90/minTachypnoe (Frequenz ≥20/min) oder Hyperventilation (bestätigt durch art.BGA mit PaCO2 ≤4,3 kPa)Leukozytose (≥12.000/mm3) oder Leukopenie (≤4.000/mm3) oder 10% oder mehr unreife Neutrophile im DifferentialblutbildDefinition der schweren Sepsis (entspr. R65.1! im ICD-10-GM)Für das Vorliegen eines SIRS infektiöser Genese mit Organkomplikation(en)* sowie eines SIRS nicht-infektiöser Genese ohne oder mit Organkomplikation(en) müssen mindestens zwei der folgenden vier Kriterien erfüllt sein: Fieber (≥38,0°C) oder Hypothermie (≤36,0°C ) bestätigt durch eine rektale, intravasale oder intravesikale MessungTachykardie mit Herzfrequenz ≥90/minTachypnoe (Frequenz ≥20/min) oder Hyperventilation (bestätigt durch art. BGA mit PaCO2 ≤4,3 kPa)Leukozytose (≥12000/mm3) oder Leukopenie (≤4000/mm3) oder ≥10% unreife Neutrophile im Differentialblutbild* bezüglich der Angabe von Organkomplikationen gelten die Definitionen der Deutschen Sepsis-Gesellschaft (siehe Tabelle 1 ) NotesCollaborationThe guidelines have been developed in collaboration with the following medical scientific professional societies:Deutsche Gesellschaft für Chirurgie (DGCH; [P.K.]), Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI; [R.R.]), Deutsche Gesellschaft für Herz-,</PlainText></TextGroup> Thorax- und Gef&#228;&#223;chirurgie (DGHTG; &#91;G.M.&#93;), Deutsche Gesellschaft f&#252;r Internistische Intensivmedizin und Notfallmedizin (DGIIN; &#91;T.W.&#93;), Deutsche Gesellschaft f&#252;r Pneumologie und Beatmungsmedizin (DGP; &#91;T.W.&#93;), Deutsche Gesellschaft f&#252;r Ern&#228;hrungsmedizin (DGEM; &#91;A.W.&#93;), Deutsche Gesellschaft f&#252;r Neurologie (DGN; &#91;J.B.&#93;), Deutsche Gesellschaft f&#252;r Kardiologie (DGK; &#91;K.W&#93;), Deutsche Gesellschaft f&#252;r Innere Medizin (DGIM; &#91;K.W.&#93;), Deutsche Gesellschaft f&#252;r Infektiologie (DGI; &#91;W.K.&#93;), Nationales Referenzzentrum f&#252;r Surveillance von nosokomialen Infektionen (NRZ; &#91;P.G.&#93;), Deutsche Gesellschaft f&#252;r Nephrologie (DGfN; &#91;S.J., M.O.&#93;), Deutsche Gesellschaft f&#252;r Hygiene und Mikrobiologie e.V. (DGHM; &#91;H.S.&#93;), Deutsche Gesellschaft f&#252;r Klinische Chemie und Laboratoriumsmedizin (DGKL), Deutsche Gesellschaft f&#252;r Neurochirurgie (DGNC), Paul-Ehrlich-Gesellschaft f&#252;r Chemotherapie e.V. (PEG),</Pgraph><Pgraph>and support groups:</Pgraph><Pgraph>Deutsche Sepsis-Hilfe e.V. (DSH; &#91;F.M.B.&#93;)</Pgraph><Pgraph>Approved by the directors of the involved medical scientific societies on February 15<Superscript>th</Superscript> 2010.</Pgraph><SubHeadline>Remark</SubHeadline><Pgraph>The guidelines apply to standard situations and take into account current scientific knowledge. They should not limit the physician&#8217;s therapeutic autonomy. These guidelines were developed by the authors with great care; however, no responsibility can be assumed for accuracy &#8211; particularly as related to dosing information.</Pgraph><SubHeadline>AWMF guideline register</SubHeadline><Pgraph>The guidelines are registered in the AWMF register with the no. 079&#47;001 (<Hyperlink href="http:&#47;&#47;leitlinien.net&#47;079-001.htm">http:&#47;&#47;leitlinien.net&#47;079-001.htm</Hyperlink>).</Pgraph><SubHeadline>Conflicts of interest</SubHeadline><Pgraph>The declarations of conflict of interest of all authors can be viewed on request.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Anmerkungen"> <MainHeadline>Anmerkungen</MainHeadline><SubHeadline>Mitwirkung</SubHeadline><Pgraph>Die Leitlinien wurden unter Mitwirkung der folgenden Medzinisch-Wissenschaftlichen Fachgesellschaften erarbeitet:</Pgraph><Pgraph>Deutsche Gesellschaft f&#252;r Chirurgie (DGCH; &#91;P.K.&#93;), Deutsche Gesellschaft f&#252;r An&#228;sthesiologie und Intensivmedizin (DGAI; &#91;R.R.&#93;), Deutsche Gesellschaft f&#252;r Herz-, Thorax- und Gef&#228;&#223;chirurgie (DGHTG; &#91;G.M.&#93;), Deutsche Gesellschaft f&#252;r Internistische Intensivmedizin und Notfallmedizin (DGIIN; &#91;T.W.9), Deutsche Gesellschaft f&#252;r Pneumologie und Beatmungsmedizin (DGP; &#91;T.W.&#93;), Deutsche Gesellschaft f&#252;r Ern&#228;hrungsmedizin (DGEM; &#91;A.W.&#93;), Deutsche Gesellschaft f&#252;r Neurologie (DGN; &#91;J.B.&#93;), Deutsche Gesellschaft f&#252;r Kardiologie (DGK; &#91;K.W&#93;), Deutsche Gesellschaft f&#252;r Innere Medizin (DGIM; &#91;K.W.&#93;), Deutsche Gesellschaft f&#252;r Infektiologie (DGI; &#91;W.K.&#93;), Nationales Referenzzentrum f&#252;r Surveillance von nosokomialen Infektionen (NRZ; &#91;P.G.&#93;), Deutsche Gesellschaft f&#252;r Nephrologie (DGfN); &#91;S.J., M.O.&#93;), Deutsche Gesellschaft f&#252;r Hygiene und Mikrobiologie e.V. (DGHM; &#91;H.S.&#93;), Deutsche Gesellschaft f&#252;r Klinische Chemie und Laboratoriumsmedizin (DGKL), Deutsche Gesellschaft f&#252;r Neurochirurgie (DGNC), Paul-Ehrlich-Gesellschaft f&#252;r Chemotherapie e.V. (PEG),</Pgraph><Pgraph>und Selbsthilfegruppen:</Pgraph><Pgraph>Deutsche Sepsis-Hilfe e.V. (DSH; &#91;F.M.B.&#93;)</Pgraph><Pgraph>Verabschiedet von den Vorst&#228;nden der beteiligten Fachgesellschaften am 15. Februar 2010</Pgraph><SubHeadline>Hinweis</SubHeadline><Pgraph>Leitlinien gelten f&#252;r Standardsituationen und ber&#252;cksichtigen die aktuellen wissenschaftlichen Erkenntnisse. Durch die Leitlinien soll die Methodenfreiheit des Arztes nicht eingeschr&#228;nkt werden. Die Leitlinien wurden von den Autoren mit gr&#246;&#223;ter Sorgfalt erarbeitet, dennoch kann f&#252;r die Richtigkeit &#8211; insbesondere von Dosierungsangaben &#8211; keine Verantwortung &#252;bernommen werden.</Pgraph><SubHeadline>AWMF Leitlinienregister</SubHeadline><Pgraph>Die Leitlinie ist im AWMF-Register unter der Nummer 079&#47;001 registriert (<Hyperlink href="http:&#47;&#47;leitlinien.net&#47;079-001.htm">http:&#47;&#47;leitlinien.net&#47;079-001.htm</Hyperlink>). </Pgraph><SubHeadline>Interessenkonflikte</SubHeadline><Pgraph>Die Erkl&#228;rungen zu Interessenkonflikten der Autoren k&#246;nnen auf Wunsch eingesehen werden.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>Yusuf S</RefAuthor> <RefAuthor>Teo K</RefAuthor> <RefAuthor>Woods K</RefAuthor> <RefTitle>Intravenous magnesium in acute myocardial infarction: An effective, safe, simple, and inexpensive intervention</RefTitle> <RefYear>1993</RefYear> <RefJournal>Circulation</RefJournal> <RefPage>2043-6</RefPage> <RefTotal>Yusuf S, Teo K, Woods K. Intravenous magnesium in acute myocardial infarction: An effective, safe, simple, and inexpensive intervention. Circulation. 1993;87(6):2043-6.</RefTotal> </Reference> <Reference refNo="2"> <RefAuthor>ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group</RefAuthor> <RefTitle>ISIS-4:a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction</RefTitle> <RefYear>1995</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>669-85</RefPage> <RefTotal>ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4:a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345(8951):669-85. DOI: 10.1016&#47;S0140-6736(95)90865-X</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(95)90865-X</RefLink> </Reference> <Reference refNo="3"> <RefAuthor>Sackett DL</RefAuthor> <RefTitle>Rules of evidence and clinical recommendations on the use of antithrombotic agents</RefTitle> <RefYear>1989</RefYear> <RefJournal>Chest</RefJournal> <RefPage>2S-4S</RefPage> <RefTotal>Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1989;95(2 Suppl):2S-4S.</RefTotal> </Reference> <Reference refNo="4"> <RefAuthor>Martin GS</RefAuthor> <RefAuthor>Mannino DM</RefAuthor> <RefAuthor>Eaton S</RefAuthor> <RefAuthor>Moss M</RefAuthor> <RefTitle>The epidemiology of sepsis in the United States from 1979 through 2000</RefTitle> <RefYear>2003</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1546-54</RefPage> <RefTotal>Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546-54. DOI: 10.1056&#47;NEJMoa022139</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa022139</RefLink> </Reference> <Reference refNo="5"> <RefAuthor>Bates DW</RefAuthor> <RefAuthor>Cook EF</RefAuthor> <RefAuthor>Goldman L</RefAuthor> <RefAuthor>Lee TH</RefAuthor> <RefTitle>Predicting bacteremia in hospitalized patients: A prospectively validated model</RefTitle> <RefYear>1990</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>495-500</RefPage> <RefTotal>Bates DW, Cook EF, Goldman L, Lee TH. Predicting bacteremia in hospitalized patients: A prospectively validated model. Ann Intern Med. 1990;113(7):495-500.</RefTotal> </Reference> <Reference refNo="6"> <RefAuthor>Bates DW</RefAuthor> <RefAuthor>Sands K</RefAuthor> <RefAuthor>Miller E</RefAuthor> <RefAuthor>Lanken PN</RefAuthor> <RefAuthor>Hibberd PL</RefAuthor> <RefAuthor>Graman PS</RefAuthor> <RefAuthor>Schwartz JS</RefAuthor> <RefAuthor>Kahn K</RefAuthor> <RefAuthor>Snydman DR</RefAuthor> <RefAuthor>Parsonnet J</RefAuthor> <RefAuthor>Moore R</RefAuthor> <RefAuthor>Black E</RefAuthor> <RefAuthor>Johnson BL</RefAuthor> <RefAuthor>Jha A</RefAuthor> <RefAuthor>Platt R</RefAuthor> <RefAuthor> Academic Medical Center Consortium Sepsis Project Working Group</RefAuthor> <RefTitle>Predicting bacteremia in patients with sepsis syndrome</RefTitle> <RefYear>1997</RefYear> <RefJournal>J Infect Dis</RefJournal> <RefPage>1538-51</RefPage> <RefTotal>Bates DW, Sands K, Miller E, Lanken PN, Hibberd PL, Graman PS, Schwartz JS, Kahn K, Snydman DR, Parsonnet J, Moore R, Black E, Johnson BL, Jha A, Platt R; Academic Medical Center Consortium Sepsis Project Working Group. Predicting bacteremia in patients with sepsis syndrome. J Infect Dis. 1997;176(6):1538-51. DOI: 10.1086&#47;514153</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;514153</RefLink> </Reference> <Reference refNo="7"> <RefAuthor>Crowe M</RefAuthor> <RefAuthor>Ispahani P</RefAuthor> <RefAuthor>Humphreys H</RefAuthor> <RefAuthor>Kelley T</RefAuthor> <RefAuthor>Winter R</RefAuthor> <RefTitle>Bacteraemia in the adult intensive care unit of a teaching hospital in Nottingham, UK, 1985-1996</RefTitle> <RefYear>1998</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>377-84</RefPage> <RefTotal>Crowe M, Ispahani P, Humphreys H, Kelley T, Winter R. Bacteraemia in the adult intensive care unit of a teaching hospital in Nottingham, UK, 1985-1996. Eur J Clin Microbiol Infect Dis. 1998;17(6):377-84.</RefTotal> </Reference> <Reference refNo="8"> <RefAuthor>Leibovici L</RefAuthor> <RefAuthor>Greenshtain S</RefAuthor> <RefAuthor>Cohen O</RefAuthor> <RefAuthor>Mor F</RefAuthor> <RefAuthor>Wysenbeek AJ</RefAuthor> <RefTitle>Bacteremia in febrile patients: A clinical model for diagnosis</RefTitle> <RefYear>1991</RefYear> <RefJournal>Arch Intern Med</RefJournal> <RefPage>1801-6</RefPage> <RefTotal>Leibovici L, Greenshtain S, Cohen O, Mor F, Wysenbeek AJ. Bacteremia in febrile patients: A clinical model for diagnosis. Arch Intern Med. 1991;151(9):1801-6.</RefTotal> </Reference> <Reference refNo="9"> <RefAuthor>Vincent JL</RefAuthor> <RefAuthor>Bihari DJ</RefAuthor> <RefAuthor>Suter PM</RefAuthor> <RefAuthor>Bruining HA</RefAuthor> <RefAuthor>White J</RefAuthor> <RefAuthor>Nicolas-Chanoin MH</RefAuthor> <RefAuthor>Wolff M</RefAuthor> <RefAuthor>Spencer RC</RefAuthor> <RefAuthor>Hemmer M</RefAuthor> <RefAuthor> EPIC International Advisory Committee</RefAuthor> <RefTitle>The prevalence of nosocomial infection in intensive care units in Europe: Results of the European Prevalence of Infection in Intensive Care (EPIC) Study</RefTitle> <RefYear>1995</RefYear> <RefJournal>Jama</RefJournal> <RefPage>639-44</RefPage> <RefTotal>Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas-Chanoin MH, Wolff M, Spencer RC, Hemmer M; EPIC International Advisory Committee. The prevalence of nosocomial infection in intensive care units in Europe: Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. Jama. 1995;274(8):639-44.</RefTotal> </Reference> <Reference refNo="10"> <RefAuthor>Alberti C</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefAuthor>Burchardi H</RefAuthor> <RefAuthor>Martin C</RefAuthor> <RefAuthor>Goodman S</RefAuthor> <RefAuthor>Artigas A</RefAuthor> <RefAuthor>Sicignano A</RefAuthor> <RefAuthor>Palazzo M</RefAuthor> <RefAuthor>Moreno R</RefAuthor> <RefAuthor>Boulm&#233; R</RefAuthor> <RefAuthor>Lepage E</RefAuthor> <RefAuthor>Le Gall R</RefAuthor> <RefTitle>Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study</RefTitle> <RefYear>2002</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>108-21</RefPage> <RefTotal>Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulm&#233; R, Lepage E, Le Gall R. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med. 2002;28(2):108-21. DOI: 10.1007&#47;s00134-001-1143-z</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-001-1143-z</RefLink> </Reference> <Reference refNo="11"> <RefAuthor>American College of Chest Physicians</RefAuthor> <RefAuthor> Society of Critical Care Medicine Consensus Conference</RefAuthor> <RefTitle>Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis</RefTitle> <RefYear>1992</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>864-74</RefPage> <RefTotal>American College of Chest Physicians; Society of Critical Care Medicine Consensus Conference. Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864-74.</RefTotal> </Reference> <Reference refNo="12"> <RefAuthor>Garner JS</RefAuthor> <RefAuthor>Jarvis WR</RefAuthor> <RefAuthor>Emori TG</RefAuthor> <RefAuthor>Horan TC</RefAuthor> <RefAuthor>Hughes JM</RefAuthor> <RefTitle>CDC definitions for nosocomial infections</RefTitle> <RefYear>1996</RefYear> <RefBookTitle>PIC Infection Control and Applied Epidemiology: Principles and Practice</RefBookTitle> <RefPage>A1-A20</RefPage> <RefTotal>Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections. In: Olmsted RN, editor. PIC Infection Control and Applied Epidemiology: Principles and Practice. St. Louis: Mosby, 1996. p. A1-A20.</RefTotal> </Reference> <Reference refNo="13"> <RefAuthor>Clec&#39;h C</RefAuthor> <RefAuthor>Ferriere F</RefAuthor> <RefAuthor>Karoubi P</RefAuthor> <RefAuthor>Fosse JP</RefAuthor> <RefAuthor>Cupa M</RefAuthor> <RefAuthor>Hoang P</RefAuthor> <RefAuthor>Cohen Y</RefAuthor> <RefTitle>Diagnostic and prognostic value of procalcitonin in patients with septic shock</RefTitle> <RefYear>2004</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1166-9</RefPage> <RefTotal>Clec&#39;h C, Ferriere F, Karoubi P, Fosse JP, Cupa M, Hoang P, Cohen Y. Diagnostic and prognostic value of procalcitonin in patients with septic shock. Crit Care Med. 2004;32(5):1166-9. DOI: 10.1097&#47;01.CCM.0000126263.00551.06</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000126263.00551.06</RefLink> </Reference> <Reference refNo="14"> <RefAuthor>Harbarth S</RefAuthor> <RefAuthor>Holeckova K</RefAuthor> <RefAuthor>Froidevaux C</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefAuthor>Ricou B</RefAuthor> <RefAuthor>Grau GE</RefAuthor> <RefAuthor>Vadas L</RefAuthor> <RefAuthor>Pugin J</RefAuthor> <RefAuthor> Geneva Sepsis Network</RefAuthor> <RefTitle>Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>396-402</RefPage> <RefTotal>Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, Vadas L, Pugin J; Geneva Sepsis Network. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001;164(3):396-402.</RefTotal> </Reference> <Reference refNo="15"> <RefAuthor>M&#252;ller B</RefAuthor> <RefAuthor>Becker KL</RefAuthor> <RefAuthor>Sch&#228;chinger H</RefAuthor> <RefAuthor>Rickenbacher PR</RefAuthor> <RefAuthor>Huber PR</RefAuthor> <RefAuthor>Zimmerli W</RefAuthor> <RefAuthor>Ritz R</RefAuthor> <RefTitle>Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit</RefTitle> <RefYear>2000</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>977-83</RefPage> <RefTotal>M&#252;ller B, Becker KL, Sch&#228;chinger H, Rickenbacher PR, Huber PR, Zimmerli W, Ritz R. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28(4):977-83. DOI: 10.1097&#47;00003246-200004000-00011</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200004000-00011</RefLink> </Reference> <Reference refNo="16"> <RefAuthor>Brunkhorst FM</RefAuthor> <RefAuthor>Wegscheider K</RefAuthor> <RefAuthor>Forycki ZF</RefAuthor> <RefAuthor>Brunkhorst R</RefAuthor> <RefTitle>Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock</RefTitle> <RefYear>2000</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>S148-S152</RefPage> <RefTotal>Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med. 2000;26(Suppl. 2):S148-S152. DOI: 10.1007&#47;s001340051134</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s001340051134</RefLink> </Reference> <Reference refNo="17"> <RefAuthor>Meisner M</RefAuthor> <RefAuthor>Tschaikowsky K</RefAuthor> <RefAuthor>Hutzler A</RefAuthor> <RefAuthor>Schick C</RefAuthor> <RefAuthor>Sch&#252;ttler J</RefAuthor> <RefTitle>Postoperative plasma concentrations of procalcitonin after different types of surgery</RefTitle> <RefYear>1998</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>680-4</RefPage> <RefTotal>Meisner M, Tschaikowsky K, Hutzler A, Schick C, Sch&#252;ttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med. 1998;24(7):680-4. DOI: 10.1007&#47;s001340050644</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s001340050644</RefLink> </Reference> <Reference refNo="18"> <RefAuthor>Nobre V</RefAuthor> <RefAuthor>Harbarth S</RefAuthor> <RefAuthor>Graf JD</RefAuthor> <RefAuthor>Rohner P</RefAuthor> <RefAuthor>Pugin J</RefAuthor> <RefTitle>Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial</RefTitle> <RefYear>2008</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>498-505</RefPage> <RefTotal>Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med. 2008;177(5):498-505. DOI: 10.1164&#47;rccm.200708-1238OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200708-1238OC</RefLink> </Reference> <Reference refNo="411"> <RefAuthor>Gramm HJ</RefAuthor> <RefAuthor>Hannemann L</RefAuthor> <RefAuthor>Reinhart K</RefAuthor> <RefAuthor>Lode H</RefAuthor> <RefTitle>Sepsis: ein Begriff im Wandel: M&#246;glichkeiten und Grenzen der Diagnose anhand klinischer Kriterien</RefTitle> <RefYear>1995</RefYear> <RefJournal>Dtsch Med Wochenschr</RefJournal> <RefPage>498-502</RefPage> <RefTotal>Gramm HJ, Hannemann L, Reinhart K, Lode H. Sepsis: ein Begriff im Wandel: M&#246;glichkeiten und Grenzen der Diagnose anhand klinischer Kriterien &#91;Sepsis: a conception in change: Possibilities and limitations of diagnosis based on clinical criteria&#93;. Dtsch Med Wochenschr. 1995;120(14):498-502.</RefTotal> </Reference> <Reference refNo="19"> <RefAuthor>Smith-Elekes S</RefAuthor> <RefAuthor>Weinstein MP</RefAuthor> <RefTitle>Blood cultures</RefTitle> <RefYear>1993</RefYear> <RefJournal>Infect Dis Clin North Am</RefJournal> <RefPage>221-34</RefPage> <RefTotal>Smith-Elekes S, Weinstein MP. Blood cultures. Infect Dis Clin North Am. 1993;7(2):221-34.</RefTotal> </Reference> <Reference refNo="20"> <RefAuthor>Dandona P</RefAuthor> <RefAuthor>Nix D</RefAuthor> <RefAuthor>Wilson MF</RefAuthor> <RefAuthor>Aljada A</RefAuthor> <RefAuthor>Love J</RefAuthor> <RefAuthor>Assicot M</RefAuthor> <RefAuthor>Bohuon C</RefAuthor> <RefTitle>Procalcitonin increase after endotoxin injection in normal subjects</RefTitle> <RefYear>1994</RefYear> <RefJournal>J Clin Endocrinol Metab</RefJournal> <RefPage>1605-8</RefPage> <RefTotal>Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M, Bohuon C. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab. 1994;79(6):1605-8. DOI: 10.1210&#47;jc.79.6.1605</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1210&#47;jc.79.6.1605</RefLink> </Reference> <Reference refNo="21"> <RefAuthor>Reimer LG</RefAuthor> <RefAuthor>Wilson ML</RefAuthor> <RefAuthor>Weinstein MP</RefAuthor> <RefTitle>Update on detection of bacteremia and fungemia</RefTitle> <RefYear>1997</RefYear> <RefJournal>Clin Microbiol Rev</RefJournal> <RefPage>444-65</RefPage> <RefTotal>Reimer LG, Wilson ML, Weinstein MP. Update on detection of bacteremia and fungemia. Clin Microbiol Rev. 1997;10(3):444-65.</RefTotal> </Reference> <Reference refNo="22"> <RefAuthor>Dellinger RP</RefAuthor> <RefAuthor>Carlet J</RefAuthor> <RefAuthor>Masur H</RefAuthor> <RefAuthor>Gerlach H</RefAuthor> <RefAuthor>Calandra T</RefAuthor> <RefAuthor>Cohen J</RefAuthor> <RefAuthor>Gea-Banacloche J</RefAuthor> <RefAuthor>Keh D</RefAuthor> <RefAuthor>Marshall JC</RefAuthor> <RefAuthor>Parker MM</RefAuthor> <RefAuthor>Ramsay G</RefAuthor> <RefAuthor>Zimmerman JL</RefAuthor> <RefAuthor>Vincent JL</RefAuthor> <RefAuthor>Levy MM</RefAuthor> <RefAuthor> Surviving Sepsis Campaign Management Guidelines Committee</RefAuthor> <RefTitle>Surviving Sepsis Campaign for management of severe sepsis and septic shock</RefTitle> <RefYear>2004</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>858-73</RefPage> <RefTotal>Dellinger RP, Carlet J, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign for management of severe sepsis and septic shock. Crit Care Med. 2004;32(3):858-73. DOI: 10.1097&#47;01.CCM.0000117317.18092.E4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000117317.18092.E4</RefLink> </Reference> <Reference refNo="23"> <RefAuthor>Shafazand S</RefAuthor> <RefAuthor>Weinacker AB</RefAuthor> <RefTitle>Blood cultures in the critical care unit: improving utilization and yield</RefTitle> <RefYear>2002</RefYear> <RefJournal>Chest</RefJournal> <RefPage>1727-36</RefPage> <RefTotal>Shafazand S, Weinacker AB. Blood cultures in the critical care unit: improving utilization and yield. Chest. 2002;122(5):1727-36. DOI: 10.1378&#47;chest.122.5.1727</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.122.5.1727</RefLink> </Reference> <Reference refNo="24"> <RefAuthor>Darby JM</RefAuthor> <RefAuthor>Linden P</RefAuthor> <RefAuthor>Pasculle W</RefAuthor> <RefAuthor>Saul M</RefAuthor> <RefTitle>Utilization and diagnostic yield of blood cultures in a surgical intensive care unit</RefTitle> <RefYear>1997</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>989-94</RefPage> <RefTotal>Darby JM, Linden P, Pasculle W, Saul M. Utilization and diagnostic yield of blood cultures in a surgical intensive care unit. Crit Care Med. 1997;25(6):989-94. DOI: 10.1097&#47;00003246-199706000-00016</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199706000-00016</RefLink> </Reference> <Reference refNo="25"> <RefAuthor>Shahar E</RefAuthor> <RefAuthor>Wohl-Gottesman BS</RefAuthor> <RefAuthor>Shenkman L</RefAuthor> <RefTitle>Contamination of blood cultures during venepuncture: fact or myth&#63;</RefTitle> <RefYear>1990</RefYear> <RefJournal>Postgrad Med J</RefJournal> <RefPage>1053-8</RefPage> <RefTotal>Shahar E, Wohl-Gottesman BS, Shenkman L. Contamination of blood cultures during venepuncture: fact or myth&#63; Postgrad Med J. 1990;66(782):1053-8. DOI: 10.1136&#47;pgmj.66.782.1053</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1136&#47;pgmj.66.782.1053</RefLink> </Reference> <Reference refNo="26"> <RefAuthor>Souvenir D</RefAuthor> <RefAuthor>Anderson DE Jr</RefAuthor> <RefAuthor>Palpant S</RefAuthor> <RefAuthor>Mroch H</RefAuthor> <RefAuthor>Askin S</RefAuthor> <RefAuthor>Anderson J</RefAuthor> <RefAuthor>Claridge J</RefAuthor> <RefAuthor>Eiland J</RefAuthor> <RefAuthor>Malone C</RefAuthor> <RefAuthor>Garrison MW</RefAuthor> <RefAuthor>Watson P</RefAuthor> <RefAuthor>Campbell DM</RefAuthor> <RefTitle>Blood cultures positive for coagulase-negative staphylococci: antisepsis, pseudobacteremia, and therapy of patients</RefTitle> <RefYear>1998</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>1923-6</RefPage> <RefTotal>Souvenir D, Anderson DE Jr, Palpant S, Mroch H, Askin S, Anderson J, Claridge J, Eiland J, Malone C, Garrison MW, Watson P, Campbell DM. Blood cultures positive for coagulase-negative staphylococci: antisepsis, pseudobacteremia, and therapy of patients. J Clin Microbiol. 1998;36(7):1923-6.</RefTotal> </Reference> <Reference refNo="27"> <RefAuthor>Martinez JA</RefAuthor> <RefAuthor>DesJardin JA</RefAuthor> <RefAuthor>Aronoff M</RefAuthor> <RefAuthor>Supran S</RefAuthor> <RefAuthor>Nasraway SA</RefAuthor> <RefAuthor>Snydman DR</RefAuthor> <RefTitle>Clinical utility of blood cultures drawn from central venous or arterial catheters in critically ill surgical patients</RefTitle> <RefYear>2002</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>7-13</RefPage> <RefTotal>Martinez JA, DesJardin JA, Aronoff M, Supran S, Nasraway SA, Snydman DR. Clinical utility of blood cultures drawn from central venous or arterial catheters in critically ill surgical patients. Crit Care Med. 2002;30(1):7-13. DOI: 10.1097&#47;00003246-200201000-00002</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200201000-00002</RefLink> </Reference> <Reference refNo="28"> <RefAuthor>Wilson ML</RefAuthor> <RefTitle>General principles of specimen collection and transport</RefTitle> <RefYear>1996</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>766-77</RefPage> <RefTotal>Wilson ML. General principles of specimen collection and transport. Clin Infect Dis. 1996;22(5):766-77.</RefTotal> </Reference> <Reference refNo="29"> <RefAuthor>Spitalnic SJ</RefAuthor> <RefAuthor>Woolard RH</RefAuthor> <RefAuthor>Mermel LA</RefAuthor> <RefTitle>The significance of changing needles when inoculating blood cultures: a meta-analysis</RefTitle> <RefYear>1995</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1103-6</RefPage> <RefTotal>Spitalnic SJ, Woolard RH, Mermel LA. The significance of changing needles when inoculating blood cultures: a meta-analysis. Clin Infect Dis. 1995;21(5):1103-6.</RefTotal> </Reference> <Reference refNo="30"> <RefAuthor>Weinstein MP</RefAuthor> <RefAuthor>Towns ML</RefAuthor> <RefAuthor>Quartey SM</RefAuthor> <RefAuthor>Mirrett S</RefAuthor> <RefAuthor>Reimer LG</RefAuthor> <RefAuthor>Parmigiani G</RefAuthor> <RefAuthor>Reller LB</RefAuthor> <RefTitle>The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults</RefTitle> <RefYear>1997</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>584-602</RefPage> <RefTotal>Weinstein MP, Towns ML, Quartey SM, Mirrett S, Reimer LG, Parmigiani G, Reller LB. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24(4):584-602.</RefTotal> </Reference> <Reference refNo="31"> <RefAuthor>Washington JA 2nd</RefAuthor> <RefTitle>Blood cultures: principles and techniques</RefTitle> <RefYear>1975</RefYear> <RefJournal>Mayo Clin Proc</RefJournal> <RefPage>91-8</RefPage> <RefTotal>Washington JA 2nd. Blood cultures: principles and techniques. Mayo Clin Proc. 1975;50(2):91-8.</RefTotal> </Reference> <Reference refNo="32"> <RefAuthor>Li J</RefAuthor> <RefAuthor>Plorde JJ</RefAuthor> <RefAuthor>Carlson LG</RefAuthor> <RefTitle>Effects of volume and periodicity on blood cultures</RefTitle> <RefYear>1994</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>2829-31</RefPage> <RefTotal>Li J, Plorde JJ, Carlson LG. Effects of volume and periodicity on blood cultures. J Clin Microbiol. 1994;32(11):2829-31.</RefTotal> </Reference> <Reference refNo="33"> <RefAuthor>Seifert H</RefAuthor> <RefAuthor>Abele-Horn M</RefAuthor> <RefAuthor>F&#228;tkenheuer G</RefAuthor> <RefAuthor>Gl&#252;ck T</RefAuthor> <RefAuthor>Jansen B</RefAuthor> <RefAuthor>Kern WV</RefAuthor> <RefAuthor>Mack D</RefAuthor> <RefAuthor>Plum G</RefAuthor> <RefAuthor>Reinert RR</RefAuthor> <RefAuthor>Roos R</RefAuthor> <RefAuthor>Salzberger B</RefAuthor> <RefAuthor>Shah PM</RefAuthor> <RefAuthor>Ullmann U</RefAuthor> <RefAuthor>Wei&#223; M</RefAuthor> <RefAuthor>Welte T</RefAuthor> <RefAuthor>Wisplinghoff H</RefAuthor> <RefTitle></RefTitle> <RefYear>2007</RefYear> <RefBookTitle>MiQ 3a: Blutkulturdiagnostik Sepsis, Endokarditis, Katheterinfektionen, Teil I</RefBookTitle> <RefPage></RefPage> <RefTotal>Seifert H, Abele-Horn M, F&#228;tkenheuer G, Gl&#252;ck T, Jansen B, Kern WV, Mack D, Plum G, Reinert RR, Roos R, Salzberger B, Shah PM, Ullmann U, Wei&#223; M, Welte T, Wisplinghoff H. MiQ 3a: Blutkulturdiagnostik Sepsis, Endokarditis, Katheterinfektionen, Teil I. M&#252;nchen: Urban &#38; Fischer; 2007. Available from: http:&#47;&#47;www.dgho-infektionen.de&#47;agiho&#47;content&#47;e2735&#47;e15963&#47;e15977&#47;index&#95;ger.html</RefTotal> <RefLink>http:&#47;&#47;www.dgho-infektionen.de&#47;agiho&#47;content&#47;e2735&#47;e15963&#47;e15977&#47;index&#95;ger.html</RefLink> </Reference> <Reference refNo="34"> <RefAuthor>Bloos F</RefAuthor> <RefAuthor>Hinder F</RefAuthor> <RefAuthor>Becker K</RefAuthor> <RefAuthor>Sachse S</RefAuthor> <RefAuthor>Mekontso Dessap A</RefAuthor> <RefAuthor>Straube E</RefAuthor> <RefAuthor>Cattoir V</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefAuthor>Reinhart K</RefAuthor> <RefAuthor>Peters G</RefAuthor> <RefAuthor>Bauer M</RefAuthor> <RefTitle>A multicenter trial to compare blood culture with polymerase chain reaction in severe human sepsis</RefTitle> <RefYear>2010</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>241-7</RefPage> <RefTotal>Bloos F, Hinder F, Becker K, Sachse S, Mekontso Dessap A, Straube E, Cattoir V, Brun-Buisson C, Reinhart K, Peters G, Bauer M. A multicenter trial to compare blood culture with polymerase chain reaction in severe human sepsis. Intensive Care Med. 2010;36(2):241-7. DOI: 10.1007&#47;s00134-009-1705-z</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-009-1705-z</RefLink> </Reference> <Reference refNo="35"> <RefAuthor>Lehmann LE</RefAuthor> <RefAuthor>Alvarez J</RefAuthor> <RefAuthor>Hunfeld KP</RefAuthor> <RefAuthor>Goglio A</RefAuthor> <RefAuthor>Kost GJ</RefAuthor> <RefAuthor>Louie RF</RefAuthor> <RefAuthor>Raglio A</RefAuthor> <RefAuthor>Regueiro BJ</RefAuthor> <RefAuthor>Wissing H</RefAuthor> <RefAuthor>St&#252;ber F</RefAuthor> <RefTitle>Potential clinical utility of polymerase chain reaction in microbiological testing for sepsis</RefTitle> <RefYear>2009</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>3085-90</RefPage> <RefTotal>Lehmann LE, Alvarez J, Hunfeld KP, Goglio A, Kost GJ, Louie RF, Raglio A, Regueiro BJ, Wissing H, St&#252;ber F. Potential clinical utility of polymerase chain reaction in microbiological testing for sepsis. Crit Care Med. 2009;37(12):3085-90. DOI: 10.1097&#47;CCM.0b013e3181b033d7</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;CCM.0b013e3181b033d7</RefLink> </Reference> <Reference refNo="36"> <RefAuthor>Louie RF</RefAuthor> <RefAuthor>Tang Z</RefAuthor> <RefAuthor>Albertson TE</RefAuthor> <RefAuthor>Cohen S</RefAuthor> <RefAuthor>Tran NK</RefAuthor> <RefAuthor>Kost GJ</RefAuthor> <RefTitle>Multiplex polymerase chain reaction detection enhancement of bacteremia and fungemia</RefTitle> <RefYear>2008</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1487-92</RefPage> <RefTotal>Louie RF, Tang Z, Albertson TE, Cohen S, Tran NK, Kost GJ. Multiplex polymerase chain reaction detection enhancement of bacteremia and fungemia. Crit Care Med. 2008;36(5):1487-92. DOI: 10.1097&#47;CCM.0b013e31816f487c</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;CCM.0b013e31816f487c</RefLink> </Reference> <Reference refNo="37"> <RefAuthor>Schrenzel J</RefAuthor> <RefTitle>Clinical relevance of new diagnostic methods for bloodstream infections</RefTitle> <RefYear>2007</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>S2-6</RefPage> <RefTotal>Schrenzel J. Clinical relevance of new diagnostic methods for bloodstream infections. Int J Antimicrob Agents. 2007;30(Suppl 1):S2-6. DOI: 10.1016&#47;j.ijantimicag.2007.06.030</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.ijantimicag.2007.06.030</RefLink> </Reference> <Reference refNo="38"> <RefAuthor>American Thoracic Society</RefAuthor> <RefAuthor> Infectious Diseases Society</RefAuthor> <RefTitle>Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia</RefTitle> <RefYear>2005</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>388-416</RefPage> <RefTotal>American Thoracic Society; Infectious Diseases Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416. DOI: 10.1164&#47;rccm.200405-644ST</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200405-644ST</RefLink> </Reference> <Reference refNo="39"> <RefAuthor>Hoffken G</RefAuthor> <RefAuthor>Lorenz J</RefAuthor> <RefAuthor>Kern W</RefAuthor> <RefAuthor>Welte T</RefAuthor> <RefAuthor>Bauer T</RefAuthor> <RefAuthor>Dalhoff K</RefAuthor> <RefAuthor>Dietrich E</RefAuthor> <RefAuthor>Ewig S</RefAuthor> <RefAuthor>Gastmeier P</RefAuthor> <RefAuthor>Grabein B</RefAuthor> <RefAuthor>Halle E</RefAuthor> <RefAuthor>Kolditz M</RefAuthor> <RefAuthor>Marre R</RefAuthor> <RefAuthor>Sitter H</RefAuthor> <RefTitle>S3-Leitlinie zu ambulant erworbener Pneumonie und tiefen Atemwegsinfektionen</RefTitle> <RefYear>2005</RefYear> <RefJournal>Pneumologie</RefJournal> <RefPage>612-64</RefPage> <RefTotal>Hoffken G, Lorenz J, Kern W, Welte T, Bauer T, Dalhoff K, Dietrich E, Ewig S, Gastmeier P, Grabein B, Halle E, Kolditz M, Marre R, Sitter H. S3-Leitlinie zu ambulant erworbener Pneumonie und tiefen Atemwegsinfektionen &#91;S3-guideline on ambulant acquired pneumonia and deep airway infections&#93;. Pneumologie. 2005;59(9):612-64.</RefTotal> </Reference> <Reference refNo="40"> <RefAuthor>Langer M</RefAuthor> <RefAuthor>Cigada M</RefAuthor> <RefAuthor>Mandelli M</RefAuthor> <RefAuthor>Mosconi P</RefAuthor> <RefAuthor>Tognoni G</RefAuthor> <RefTitle>Early onset pneumonia: a multicenter study in intensive care units</RefTitle> <RefYear>1987</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>342-6</RefPage> <RefTotal>Langer M, Cigada M, Mandelli M, Mosconi P, Tognoni G. Early onset pneumonia: a multicenter study in intensive care units. Intensive Care Med. 1987;13(5):342-6. DOI: 10.1007&#47;BF00255791</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;BF00255791</RefLink> </Reference> <Reference refNo="41"> <RefAuthor>Gastmeier P</RefAuthor> <RefAuthor>Sohr D</RefAuthor> <RefAuthor>Geffers C</RefAuthor> <RefAuthor>Ruden H</RefAuthor> <RefAuthor>Vonberg RP</RefAuthor> <RefAuthor>Welte T</RefAuthor> <RefTitle>Early- and late-onset pneumonia: is this still a useful classification&#63;</RefTitle> <RefYear>2009</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2714-8</RefPage> <RefTotal>Gastmeier P, Sohr D, Geffers C, Ruden H, Vonberg RP, Welte T. Early- and late-onset pneumonia: is this still a useful classification&#63; Antimicrob Agents Chemother. 2009;53(7):2714-8. DOI: 10.1128&#47;AAC.01070-08</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1128&#47;AAC.01070-08</RefLink> </Reference> <Reference refNo="42"> <RefAuthor>Wunderink RG</RefAuthor> <RefTitle>Clinical criteria in the diagnosis of ventilator-associated pneumonia</RefTitle> <RefYear>2000</RefYear> <RefJournal>Chest</RefJournal> <RefPage>191S-194S</RefPage> <RefTotal>Wunderink RG. Clinical criteria in the diagnosis of ventilator-associated pneumonia. Chest. 2000;117(4 Suppl 2):191S-194S. DOI: 10.1378&#47;chest.117.4&#95;suppl&#95;2.191S</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.117.4&#95;suppl&#95;2.191S</RefLink> </Reference> <Reference refNo="43"> <RefAuthor>Singh N</RefAuthor> <RefAuthor>Rogers P</RefAuthor> <RefAuthor>Atwood CW</RefAuthor> <RefAuthor>Wagener MM</RefAuthor> <RefAuthor>Yu VL</RefAuthor> <RefTitle>Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription</RefTitle> <RefYear>2000</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>505-11</RefPage> <RefTotal>Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162(2 Pt 1):505-11.</RefTotal> </Reference> <Reference refNo="44"> <RefAuthor>Fartoukh M</RefAuthor> <RefAuthor>Maitre B</RefAuthor> <RefAuthor>Honore S</RefAuthor> <RefAuthor>Cerf C</RefAuthor> <RefAuthor>Zahar JR</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefTitle>Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited</RefTitle> <RefYear>2003</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>173-9</RefPage> <RefTotal>Fartoukh M, Maitre B, Honore S, Cerf C, Zahar JR, Brun-Buisson C. Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited. Am J Respir Crit Care Med. 2003;168(2):173-9. DOI: 10.1164&#47;rccm.200212-1449OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200212-1449OC</RefLink> </Reference> <Reference refNo="45"> <RefAuthor>Ramirez P</RefAuthor> <RefAuthor>Garcia MA</RefAuthor> <RefAuthor>Ferrer M</RefAuthor> <RefAuthor>Aznar J</RefAuthor> <RefAuthor>Valencia M</RefAuthor> <RefAuthor>Sahuquillo JM</RefAuthor> <RefAuthor>Men&#233;ndez R</RefAuthor> <RefAuthor>Asenjo MA</RefAuthor> <RefAuthor>Torres A</RefAuthor> <RefTitle>Sequential measurements of procalcitonin levels in diagnosing ventilator-associated pneumonia</RefTitle> <RefYear>2008</RefYear> <RefJournal>Eur Respir J</RefJournal> <RefPage>356-62</RefPage> <RefTotal>Ramirez P, Garcia MA, Ferrer M, Aznar J, Valencia M, Sahuquillo JM, Men&#233;ndez R, Asenjo MA, Torres A. Sequential measurements of procalcitonin levels in diagnosing ventilator-associated pneumonia. Eur Respir J. 2008;31(2):356-62. DOI: 10.1183&#47;09031936.00086707</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1183&#47;09031936.00086707</RefLink> </Reference> <Reference refNo="46"> <RefAuthor>Michel F</RefAuthor> <RefAuthor>Franceschini B</RefAuthor> <RefAuthor>Berger P</RefAuthor> <RefAuthor>Arnal JM</RefAuthor> <RefAuthor>Gainnier M</RefAuthor> <RefAuthor>Sainty JM</RefAuthor> <RefAuthor>Papazian L</RefAuthor> <RefTitle>Early antibiotic treatment for BAL-confirmed ventilator-associated pneumonia: a role for routine endotracheal aspirate cultures</RefTitle> <RefYear>2005</RefYear> <RefJournal>Chest</RefJournal> <RefPage>589-97</RefPage> <RefTotal>Michel F, Franceschini B, Berger P, Arnal JM, Gainnier M, Sainty JM, Papazian L. Early antibiotic treatment for BAL-confirmed ventilator-associated pneumonia: a role for routine endotracheal aspirate cultures. Chest. 2005;127(2):589-97. DOI: 10.1378&#47;chest.127.2.589</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.127.2.589</RefLink> </Reference> <Reference refNo="47"> <RefAuthor>Luyt CE</RefAuthor> <RefAuthor>Chastre J</RefAuthor> <RefAuthor>Fagon JY</RefAuthor> <RefAuthor> VAP Trial Group</RefAuthor> <RefTitle>Value of the clinical pulmonary infection score for the identification and management of ventilator-associated pneumonia</RefTitle> <RefYear>2004</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>844-52</RefPage> <RefTotal>Luyt CE, Chastre J, Fagon JY; VAP Trial Group. Value of the clinical pulmonary infection score for the identification and management of ventilator-associated pneumonia. Intensive Care Med. 2004;30(5):844-52. DOI: 10.1007&#47;s00134-003-2125-0</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-003-2125-0</RefLink> </Reference> <Reference refNo="48"> <RefAuthor>Canadian Critical Care Trials Group</RefAuthor> <RefTitle>A randomized trial of diagnostic techniques for ventilator-associated pneumonia</RefTitle> <RefYear>2006</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>2619-30</RefPage> <RefTotal>Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med. 2006;355(25):2619-30. DOI: 10.1056&#47;NEJMoa052904</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa052904</RefLink> </Reference> <Reference refNo="49"> <RefAuthor>Torres A</RefAuthor> <RefAuthor>El-Ebiary M</RefAuthor> <RefTitle>Bronchoscopic BAL in the diagnosis of ventilator-associated pneumonia</RefTitle> <RefYear>2000</RefYear> <RefJournal>Chest</RefJournal> <RefPage>198S-202S</RefPage> <RefTotal>Torres A, El-Ebiary M. Bronchoscopic BAL in the diagnosis of ventilator-associated pneumonia. Chest. 2000;117(4 Suppl 2):198S-202S. DOI: 10.1378&#47;chest.117.4&#95;suppl&#95;2.198S</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.117.4&#95;suppl&#95;2.198S</RefLink> </Reference> <Reference refNo="50"> <RefAuthor>Cook D</RefAuthor> <RefAuthor>Mandell L</RefAuthor> <RefTitle>Endotracheal aspiration in the diagnosis of ventilator-associated pneumonia</RefTitle> <RefYear>2000</RefYear> <RefJournal>Chest</RefJournal> <RefPage>195S-197S</RefPage> <RefTotal>Cook D, Mandell L. Endotracheal aspiration in the diagnosis of ventilator-associated pneumonia. Chest. 2000;117(4 Suppl 2):195S-197S. DOI: 10.1378&#47;chest.117.4&#95;suppl&#95;2.195S</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.117.4&#95;suppl&#95;2.195S</RefLink> </Reference> <Reference refNo="51"> <RefAuthor>Mauch H</RefAuthor> <RefAuthor>Wagner J</RefAuthor> <RefTitle>Heft 7: Infektionen der tiefen Atemwege, Teil 1</RefTitle> <RefYear>1999</RefYear> <RefBookTitle>MIQ &#8211; Qualit&#228;tsstandards in der mikrobiologisch-infektiologischen Diagnostik</RefBookTitle> <RefPage></RefPage> <RefTotal>Mauch H, Wagner J. Heft 7: Infektionen der tiefen Atemwege, Teil 1. In: Podbielski A, Herrmann M, Kniehl E, Mauch H, editors. MIQ &#8211; Qualit&#228;tsstandards in der mikrobiologisch-infektiologischen Diagnostik. M&#252;nchen: Urban &#38; Fischer; 1999.</RefTotal> </Reference> <Reference refNo="52"> <RefAuthor>Gerbeaux P</RefAuthor> <RefAuthor>Ledoray V</RefAuthor> <RefAuthor>Boussuges A</RefAuthor> <RefAuthor>Molenat F</RefAuthor> <RefAuthor>Jean P</RefAuthor> <RefAuthor>Sainty JM</RefAuthor> <RefTitle>Diagnosis of nosocomial pneumonia in mechanically ventilated patients: repeatability of the bronchoalveolar lavage</RefTitle> <RefYear>1998</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>76-80</RefPage> <RefTotal>Gerbeaux P, Ledoray V, Boussuges A, Molenat F, Jean P, Sainty JM. Diagnosis of nosocomial pneumonia in mechanically ventilated patients: repeatability of the bronchoalveolar lavage. Am J Respir Crit Care Med. 1998;157(1):76-80.</RefTotal> </Reference> <Reference refNo="53"> <RefAuthor>Llewelyn M</RefAuthor> <RefAuthor>Cohen J</RefAuthor> <RefTitle>Diagnosis of infection in sepsis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>S10-32</RefPage> <RefTotal>Llewelyn M, Cohen J. Diagnosis of infection in sepsis. Intensive Care Med. 2001;27 Suppl 1:S10-32.</RefTotal> </Reference> <Reference refNo="54"> <RefAuthor>Carratala J</RefAuthor> <RefAuthor>Gudiol F</RefAuthor> <RefAuthor>Pallares R</RefAuthor> <RefAuthor>Dorca J</RefAuthor> <RefAuthor>Verdaguer R</RefAuthor> <RefAuthor>Ariza J</RefAuthor> <RefAuthor>Manresa F</RefAuthor> <RefTitle>Risk factors for nosocomial Legionella pneumophila pneumonia</RefTitle> <RefYear>1994</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>625-9</RefPage> <RefTotal>Carratala J, Gudiol F, Pallares R, Dorca J, Verdaguer R, Ariza J, Manresa F. Risk factors for nosocomial Legionella pneumophila pneumonia. Am J Respir Crit Care Med. 1994;149(3 Pt 1):625-9.</RefTotal> </Reference> <Reference refNo="55"> <RefAuthor>Dobbins BM</RefAuthor> <RefAuthor>Kite P</RefAuthor> <RefAuthor>Wilcox MH</RefAuthor> <RefTitle>Diagnosis of central venous catheter related sepsis &#8211; a critical look inside</RefTitle> <RefYear>1999</RefYear> <RefJournal>J Clin Pathol</RefJournal> <RefPage>165-72</RefPage> <RefTotal>Dobbins BM, Kite P, Wilcox MH. Diagnosis of central venous catheter related sepsis &#8211; a critical look inside. J Clin Pathol. 1999;52(3):165-72. DOI: 10.1136&#47;jcp.52.3.165</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1136&#47;jcp.52.3.165</RefLink> </Reference> <Reference refNo="56"> <RefAuthor>Sherertz RJ</RefAuthor> <RefTitle>Surveillance for infections associated with vascular catheters</RefTitle> <RefYear>1996</RefYear> <RefJournal>Infect Control Hosp Epidemiol</RefJournal> <RefPage>746-52</RefPage> <RefTotal>Sherertz RJ. Surveillance for infections associated with vascular catheters. Infect Control Hosp Epidemiol. 1996;17(11):746-52. DOI: 10.1086&#47;647222</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;647222</RefLink> </Reference> <Reference refNo="57"> <RefAuthor>Blot F</RefAuthor> <RefAuthor>Nitenberg G</RefAuthor> <RefAuthor>Chachaty E</RefAuthor> <RefAuthor>Raynard B</RefAuthor> <RefAuthor>Germann N</RefAuthor> <RefAuthor>Antoun S</RefAuthor> <RefAuthor>Laplanche A</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefAuthor>Tancr&#232;de C</RefAuthor> <RefTitle>Diagnosis of catheter-related bacteraemia: a prospective comparison of the time to positivity of hub-blood versus peripheral-blood cultures</RefTitle> <RefYear>1999</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>1071-7</RefPage> <RefTotal>Blot F, Nitenberg G, Chachaty E, Raynard B, Germann N, Antoun S, Laplanche A, Brun-Buisson C, Tancr&#232;de C. Diagnosis of catheter-related bacteraemia: a prospective comparison of the time to positivity of hub-blood versus peripheral-blood cultures. Lancet. 1999;354(9184):1071-7. DOI: 10.1016&#47;S0140-6736(98)11134-0</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(98)11134-0</RefLink> </Reference> <Reference refNo="58"> <RefAuthor>Tanguy M</RefAuthor> <RefAuthor>Seguin P</RefAuthor> <RefAuthor>Laviolle B</RefAuthor> <RefAuthor>Desbordes L</RefAuthor> <RefAuthor>Malledant Y</RefAuthor> <RefTitle>Hub qualitative blood culture is useful for diagnosis of catheter-related infections in critically ill patients</RefTitle> <RefYear>2005</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>645-8</RefPage> <RefTotal>Tanguy M, Seguin P, Laviolle B, Desbordes L, Malledant Y. Hub qualitative blood culture is useful for diagnosis of catheter-related infections in critically ill patients. Intensive Care Med. 2005;31(5):645-8. DOI: 10.1007&#47;s00134-005-2600-x</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-005-2600-x</RefLink> </Reference> <Reference refNo="59"> <RefAuthor>Catton JA</RefAuthor> <RefAuthor>Dobbins BM</RefAuthor> <RefAuthor>Kite P</RefAuthor> <RefAuthor>Wood JM</RefAuthor> <RefAuthor>Eastwood K</RefAuthor> <RefAuthor>Sugden S</RefAuthor> <RefAuthor>Sandoe JA</RefAuthor> <RefAuthor>Burke D</RefAuthor> <RefAuthor>McMahon MJ</RefAuthor> <RefAuthor>Wilcox MH</RefAuthor> <RefTitle>In situ diagnosis of intravascular catheter-related bloodstream infection: a comparison of quantitative culture, differential time to positivity, and endoluminal brushing</RefTitle> <RefYear>2005</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>787-91</RefPage> <RefTotal>Catton JA, Dobbins BM, Kite P, Wood JM, Eastwood K, Sugden S, Sandoe JA, Burke D, McMahon MJ, Wilcox MH. In situ diagnosis of intravascular catheter-related bloodstream infection: a comparison of quantitative culture, differential time to positivity, and endoluminal brushing. Crit Care Med. 2005;33(4):787-91. DOI: 10.1097&#47;01.CCM.0000157968.98476.F3</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000157968.98476.F3</RefLink> </Reference> <Reference refNo="60"> <RefAuthor>Raad II</RefAuthor> <RefAuthor>Baba M</RefAuthor> <RefAuthor>Bodey GP</RefAuthor> <RefTitle>Diagnosis of catheter-related infections: the role of surveillance and targeted quantitative skin cultures</RefTitle> <RefYear>1995</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>593-7</RefPage> <RefTotal>Raad II, Baba M, Bodey GP. Diagnosis of catheter-related infections: the role of surveillance and targeted quantitative skin cultures. Clin Infect Dis. 1995;20(3):593-7.</RefTotal> </Reference> <Reference refNo="61"> <RefAuthor>Cobb DK</RefAuthor> <RefAuthor>High KP</RefAuthor> <RefAuthor>Sawyer RG</RefAuthor> <RefAuthor>Sable CA</RefAuthor> <RefAuthor>Adams RB</RefAuthor> <RefAuthor>Lindley DA</RefAuthor> <RefAuthor>Pruett TL</RefAuthor> <RefAuthor>Schwenzer KJ</RefAuthor> <RefAuthor>Farr BM</RefAuthor> <RefTitle>A controlled trial of scheduled replacement of central venous and pulmonary-artery catheters</RefTitle> <RefYear>1992</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1062-8</RefPage> <RefTotal>Cobb DK, High KP, Sawyer RG, Sable CA, Adams RB, Lindley DA, Pruett TL, Schwenzer KJ, Farr BM. A controlled trial of scheduled replacement of central venous and pulmonary-artery catheters. N Engl J Med. 1992;327(15):1062-8.</RefTotal> </Reference> <Reference refNo="62"> <RefAuthor>Cook D</RefAuthor> <RefAuthor>Randolph A</RefAuthor> <RefAuthor>Kernerman P</RefAuthor> <RefAuthor>Cupido C</RefAuthor> <RefAuthor>King D</RefAuthor> <RefAuthor>Soukup C</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefTitle>Central venous catheter replacement strategies: a systematic review of the literature</RefTitle> <RefYear>1997</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1417-24</RefPage> <RefTotal>Cook D, Randolph A, Kernerman P, Cupido C, King D, Soukup C, Brun-Buisson C. Central venous catheter replacement strategies: a systematic review of the literature. Crit Care Med. 1997;25(8):1417-24. DOI: 10.1097&#47;00003246-199708000-00033</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199708000-00033</RefLink> </Reference> <Reference refNo="63"> <RefAuthor>Eyer S</RefAuthor> <RefAuthor>Brummitt C</RefAuthor> <RefAuthor>Crossley K</RefAuthor> <RefAuthor>Siegel R</RefAuthor> <RefAuthor>Cerra F</RefAuthor> <RefTitle>Catheter-related sepsis: prospective, randomized study of three methods of long-term catheter maintenance</RefTitle> <RefYear>1990</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1073-9</RefPage> <RefTotal>Eyer S, Brummitt C, Crossley K, Siegel R, Cerra F. Catheter-related sepsis: prospective, randomized study of three methods of long-term catheter maintenance. Crit Care Med. 1990;18(10):1073-9.</RefTotal> </Reference> <Reference refNo="64"> <RefAuthor>Brook I</RefAuthor> <RefAuthor>Frazier EH</RefAuthor> <RefTitle>Aerobic and anaerobic microbiology of retroperitoneal abscesses</RefTitle> <RefYear>1998</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>938-41</RefPage> <RefTotal>Brook I, Frazier EH. Aerobic and anaerobic microbiology of retroperitoneal abscesses. Clin Infect Dis. 1998;26(4):938-41. DOI: 10.1086&#47;513947</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;513947</RefLink> </Reference> <Reference refNo="65"> <RefAuthor>Nichols RL</RefAuthor> <RefAuthor>Smith JW</RefAuthor> <RefTitle>Wound and intraabdominal infections: microbiological considerations and approaches to treatment</RefTitle> <RefYear>1993</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>S266-72</RefPage> <RefTotal>Nichols RL, Smith JW. Wound and intraabdominal infections: microbiological considerations and approaches to treatment. Clin Infect Dis. 1993;16 Suppl 4:S266-72.</RefTotal> </Reference> <Reference refNo="66"> <RefAuthor>Brook I</RefAuthor> <RefAuthor>Frazier EH</RefAuthor> <RefTitle>Microbiology of subphrenic abscesses: a 14-year experience</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am Surg</RefJournal> <RefPage>1049-53</RefPage> <RefTotal>Brook I, Frazier EH. Microbiology of subphrenic abscesses: a 14-year experience. Am Surg. 1999;65(11):1049-53.</RefTotal> </Reference> <Reference refNo="67"> <RefAuthor>Marshall JC</RefAuthor> <RefAuthor>Innes M</RefAuthor> <RefTitle>Intensive care unit management of intra-abdominal infection</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2228-37</RefPage> <RefTotal>Marshall JC, Innes M. Intensive care unit management of intra-abdominal infection. Crit Care Med. 2003;31(8):2228-37. DOI: 10.1097&#47;01.CCM.0000087326.59341.51</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000087326.59341.51</RefLink> </Reference> <Reference refNo="68"> <RefAuthor>B&#252;chner T</RefAuthor> <RefAuthor>Fegeler W</RefAuthor> <RefAuthor>Bernhardt H</RefAuthor> <RefAuthor>Brockmeyer N</RefAuthor> <RefAuthor>Duswald KH</RefAuthor> <RefAuthor>Herrmann M</RefAuthor> <RefAuthor>Heuser D</RefAuthor> <RefAuthor>Jehn U</RefAuthor> <RefAuthor>Just-N&#252;bling G</RefAuthor> <RefAuthor>Karthaus M</RefAuthor> <RefAuthor>Maschmeyer G</RefAuthor> <RefAuthor>M&#252;ller FM</RefAuthor> <RefAuthor>M&#252;ller J</RefAuthor> <RefAuthor>Ritter J</RefAuthor> <RefAuthor>Roos N</RefAuthor> <RefAuthor>Ruhnke M</RefAuthor> <RefAuthor>Schmalreck A</RefAuthor> <RefAuthor>Schwarze R</RefAuthor> <RefAuthor>Schwesinger G</RefAuthor> <RefAuthor>Silling G</RefAuthor> <RefAuthor> Panel of Interdisciplinary Investigators</RefAuthor> <RefTitle>Treatment of severe Candida infections in high-risk patients in Germany: consensus formed by a panel of interdisciplinary investigators</RefTitle> <RefYear>2002</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>337-52</RefPage> <RefTotal>B&#252;chner T, Fegeler W, Bernhardt H, Brockmeyer N, Duswald KH, Herrmann M, Heuser D, Jehn U, Just-N&#252;bling G, Karthaus M, Maschmeyer G, M&#252;ller FM, M&#252;ller J, Ritter J, Roos N, Ruhnke M, Schmalreck A, Schwarze R, Schwesinger G, Silling G; Panel of Interdisciplinary Investigators. Treatment of severe Candida infections in high-risk patients in Germany: consensus formed by a panel of interdisciplinary investigators. Eur J Clin Microbiol Infect Dis. 2002;21(5):337-52. DOI: 10.1007&#47;s10096-002-0730-4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s10096-002-0730-4</RefLink> </Reference> <Reference refNo="69"> <RefAuthor>Blumberg HM</RefAuthor> <RefAuthor>Jarvis WR</RefAuthor> <RefAuthor>Soucie JM</RefAuthor> <RefAuthor>Edwards JE</RefAuthor> <RefAuthor>Patterson JE</RefAuthor> <RefAuthor>Pfaller MA</RefAuthor> <RefAuthor>Rangel-Frausto MS</RefAuthor> <RefAuthor>Rinaldi MG</RefAuthor> <RefAuthor>Saiman L</RefAuthor> <RefAuthor>Wiblin RT</RefAuthor> <RefAuthor>Wenzel RP</RefAuthor> <RefAuthor> National Epidemiology of Mycoses Survey(NEMIS) Study Group</RefAuthor> <RefTitle>Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey</RefTitle> <RefYear>2001</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>177-86</RefPage> <RefTotal>Blumberg HM, Jarvis WR, Soucie JM, Edwards JE, Patterson JE, Pfaller MA, Rangel-Frausto MS, Rinaldi MG, Saiman L, Wiblin RT, Wenzel RP; National Epidemiology of Mycoses Survey(NEMIS) Study Group. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis. 2001;33(2):177-86. DOI: 10.1086&#47;321811</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;321811</RefLink> </Reference> <Reference refNo="70"> <RefAuthor>Petri MG</RefAuthor> <RefAuthor>Konig J</RefAuthor> <RefAuthor>Moecke HP</RefAuthor> <RefAuthor>Gramm HJ</RefAuthor> <RefAuthor>Barkow H</RefAuthor> <RefAuthor>Kujath P</RefAuthor> <RefAuthor>Dennhart R</RefAuthor> <RefAuthor>Sch&#228;fer H</RefAuthor> <RefAuthor>Meyer N</RefAuthor> <RefAuthor>Kalmar P</RefAuthor> <RefAuthor>Th&#252;lig P</RefAuthor> <RefAuthor>M&#252;ller J</RefAuthor> <RefAuthor>Lode H</RefAuthor> <RefAuthor> Paul-Ehrlich Society for Chemotherapy</RefAuthor> <RefAuthor>Divisions of Mycology and Pneumonia Research</RefAuthor> <RefTitle>Epidemiology of invasive mycosis in ICU patients: a prospective multicenter study in 435 non-neutropenic patients</RefTitle> <RefYear>1997</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>317-25</RefPage> <RefTotal>Petri MG, Konig J, Moecke HP, Gramm HJ, Barkow H, Kujath P, Dennhart R, Sch&#228;fer H, Meyer N, Kalmar P, Th&#252;lig P, M&#252;ller J, Lode H; Paul-Ehrlich Society for Chemotherapy, Divisions of Mycology and Pneumonia Research. Epidemiology of invasive mycosis in ICU patients: a prospective multicenter study in 435 non-neutropenic patients. Intensive Care Med. 1997;23(3):317-25. DOI: 10.1007&#47;s001340050334</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s001340050334</RefLink> </Reference> <Reference refNo="71"> <RefAuthor>Pappas PG</RefAuthor> <RefAuthor>Rex JH</RefAuthor> <RefAuthor>Sobel JD</RefAuthor> <RefAuthor>Filler SG</RefAuthor> <RefAuthor>Dismukes WE</RefAuthor> <RefAuthor>Walsh TJ</RefAuthor> <RefAuthor>Edwards JE</RefAuthor> <RefAuthor> Infectious Diseases Society of America</RefAuthor> <RefTitle>Guidelines for treatment of candidiasis</RefTitle> <RefYear>2004</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>161-89</RefPage> <RefTotal>Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, Edwards JE; Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38(2):161-89. DOI: 10.1086&#47;380796</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;380796</RefLink> </Reference> <Reference refNo="72"> <RefAuthor>Richards M</RefAuthor> <RefAuthor>Thursky K</RefAuthor> <RefAuthor>Buising K</RefAuthor> <RefTitle>Epidemiology, Prevalence, and Sites of Infections in Intensive Care Units</RefTitle> <RefYear>2003</RefYear> <RefJournal>Semin Respir Crit Care Med</RefJournal> <RefPage>3-22</RefPage> <RefTotal>Richards M, Thursky K, Buising K. Epidemiology, Prevalence, and Sites of Infections in Intensive Care Units. Semin Respir Crit Care Med. 2003;24(1):3-22. DOI: 10.1055&#47;s-2003-37913</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1055&#47;s-2003-37913</RefLink> </Reference> <Reference refNo="73"> <RefAuthor>Wildemann B</RefAuthor> <RefTitle>Meningitis</RefTitle> <RefYear>2005</RefYear> <RefJournal>Fortschr Neurol Psychiatr</RefJournal> <RefPage>102-17; quiz 118-9</RefPage> <RefTotal>Wildemann B. Meningitis. Fortschr Neurol Psychiatr. 2005;73(2):102-17; quiz 118-9. DOI: 10.1055&#47;s-2004-818425</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1055&#47;s-2004-818425</RefLink> </Reference> <Reference refNo="74"> <RefAuthor>van de Beek D</RefAuthor> <RefAuthor>de Gans J</RefAuthor> <RefAuthor>Spanjaard L</RefAuthor> <RefAuthor>Weisfelt M</RefAuthor> <RefAuthor>Reitsma JB</RefAuthor> <RefAuthor>Vermeulen M</RefAuthor> <RefTitle>Clinical features and prognostic factors in adults with bacterial meningitis</RefTitle> <RefYear>2004</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1849-59</RefPage> <RefTotal>van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351(18):1849-59. DOI: 10.1056&#47;NEJMoa040845</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa040845</RefLink> </Reference> <Reference refNo="75"> <RefAuthor>Tunkel AR</RefAuthor> <RefAuthor>Hartman BJ</RefAuthor> <RefAuthor>Kaplan SL</RefAuthor> <RefAuthor>Kaufman BA</RefAuthor> <RefAuthor>Roos KL</RefAuthor> <RefAuthor>Scheld WM</RefAuthor> <RefAuthor>Whitley RJ</RefAuthor> <RefTitle>Practice guidelines for the management of bacterial meningitis</RefTitle> <RefYear>2004</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1267-84</RefPage> <RefTotal>Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-84. DOI: 10.1086&#47;425368</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;425368</RefLink> </Reference> <Reference refNo="76"> <RefAuthor>Diener HC</RefAuthor> <RefAuthor>Ackermann H</RefAuthor> <RefTitle></RefTitle> <RefYear>2005</RefYear> <RefBookTitle>Leitlinien f&#252;r Diagnostik und Therapie in der Neurologie</RefBookTitle> <RefPage></RefPage> <RefTotal>Diener HC, Ackermann H. Leitlinien f&#252;r Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme; 2005.</RefTotal> </Reference> <Reference refNo="77"> <RefAuthor>Beckham JD</RefAuthor> <RefAuthor>Tyler KL</RefAuthor> <RefAuthor> IDSA</RefAuthor> <RefTitle>Initial management of acute bacterial meningitis in adults: summary of IDSA guidelines</RefTitle> <RefYear>2006</RefYear> <RefJournal>Rev Neurol Dis</RefJournal> <RefPage>57-60</RefPage> <RefTotal>Beckham JD, Tyler KL; IDSA. Initial management of acute bacterial meningitis in adults: summary of IDSA guidelines. Rev Neurol Dis. 2006;3(2):57-60.</RefTotal> </Reference> <Reference refNo="78"> <RefAuthor>Hasbun R</RefAuthor> <RefAuthor>Abrahams J</RefAuthor> <RefAuthor>Jekel J</RefAuthor> <RefAuthor>Quagliarello VJ</RefAuthor> <RefTitle>Computed tomography of the head before lumbar puncture in adults with suspected meningitis</RefTitle> <RefYear>2001</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1727-33</RefPage> <RefTotal>Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med. 2001;345(24):1727-33. DOI: 10.1056&#47;NEJMoa010399</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa010399</RefLink> </Reference> <Reference refNo="79"> <RefAuthor>Begg N</RefAuthor> <RefAuthor>Cartwright KA</RefAuthor> <RefAuthor>Cohen J</RefAuthor> <RefAuthor>Kaczmarski EB</RefAuthor> <RefAuthor>Innes JA</RefAuthor> <RefAuthor>Leen CL</RefAuthor> <RefAuthor>Nathwani D</RefAuthor> <RefAuthor>Singer M</RefAuthor> <RefAuthor>Southgate L</RefAuthor> <RefAuthor>Todd WT</RefAuthor> <RefAuthor>Welsby PD</RefAuthor> <RefAuthor>Wood MJ</RefAuthor> <RefAuthor> British Infection Society Working Party</RefAuthor> <RefTitle>Consensus statement on diagnosis, investigation, treatment and prevention of acute bacterial meningitis in immunocompetent adults</RefTitle> <RefYear>1999</RefYear> <RefJournal>J Infect</RefJournal> <RefPage>1-15</RefPage> <RefTotal>Begg N, Cartwright KA, Cohen J, Kaczmarski EB, Innes JA, Leen CL, Nathwani D, Singer M, Southgate L, Todd WT, Welsby PD, Wood MJ; British Infection Society Working Party. Consensus statement on diagnosis, investigation, treatment and prevention of acute bacterial meningitis in immunocompetent adults. J Infect. 1999;39(1):1-15. DOI: 10.1016&#47;S0163-4453(99)90095-6</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0163-4453(99)90095-6</RefLink> </Reference> <Reference refNo="80"> <RefAuthor>Aronin SI</RefAuthor> <RefAuthor>Peduzzi P</RefAuthor> <RefAuthor>Quagliarello VJ</RefAuthor> <RefTitle>Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing</RefTitle> <RefYear>1998</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>862-9</RefPage> <RefTotal>Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med. 1998;129(11):862-9.</RefTotal> </Reference> <Reference refNo="81"> <RefAuthor>Dunbar SA</RefAuthor> <RefAuthor>Eason RA</RefAuthor> <RefAuthor>Musher DM</RefAuthor> <RefAuthor>Clarridge JE 3rd</RefAuthor> <RefTitle>Microscopic examination and broth culture of cerebrospinal fluid in diagnosis of meningitis</RefTitle> <RefYear>1998</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>1617-20</RefPage> <RefTotal>Dunbar SA, Eason RA, Musher DM, Clarridge JE 3rd. Microscopic examination and broth culture of cerebrospinal fluid in diagnosis of meningitis. J Clin Microbiol. 1998;36(6):1617-20.</RefTotal> </Reference> <Reference refNo="82"> <RefAuthor>Karandanis D</RefAuthor> <RefAuthor>Shulman JA</RefAuthor> <RefTitle>Recent survey of infectious meningitis in adults: review of laboratory findings in bacterial, tuberculous, and aseptic meningitis</RefTitle> <RefYear>1976</RefYear> <RefJournal>South Med J</RefJournal> <RefPage>449-57</RefPage> <RefTotal>Karandanis D, Shulman JA. Recent survey of infectious meningitis in adults: review of laboratory findings in bacterial, tuberculous, and aseptic meningitis. South Med J. 1976;69(4):449-57.</RefTotal> </Reference> <Reference refNo="83"> <RefAuthor>La Scolea LJ Jr</RefAuthor> <RefAuthor>Dryja D</RefAuthor> <RefTitle>Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance</RefTitle> <RefYear>1984</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>187-90</RefPage> <RefTotal>La Scolea LJ Jr, Dryja D. Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance. J Clin Microbiol. 1984;19(2):187-90. Available from: http:&#47;&#47;jcm.asm.org&#47;cgi&#47;reprint&#47;19&#47;2&#47;187</RefTotal> <RefLink>http:&#47;&#47;jcm.asm.org&#47;cgi&#47;reprint&#47;19&#47;2&#47;187</RefLink> </Reference> <Reference refNo="84"> <RefAuthor>Poppert S</RefAuthor> <RefAuthor>Essig A</RefAuthor> <RefAuthor>Stoehr B</RefAuthor> <RefAuthor>Steingruber A</RefAuthor> <RefAuthor>Wirths B</RefAuthor> <RefAuthor>Juretschko S</RefAuthor> <RefAuthor>Reischl U</RefAuthor> <RefAuthor>Wellinghausen N</RefAuthor> <RefTitle>Rapid diagnosis of bacterial meningitis by real-time PCR and fluorescence in situ hybridization</RefTitle> <RefYear>2005</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>3390-7</RefPage> <RefTotal>Poppert S, Essig A, Stoehr B, Steingruber A, Wirths B, Juretschko S, Reischl U, Wellinghausen N. Rapid diagnosis of bacterial meningitis by real-time PCR and fluorescence in situ hybridization. J Clin Microbiol. 2005;43(7):3390-7. DOI: 10.1128&#47;JCM.43.7.3390-3397.2005</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1128&#47;JCM.43.7.3390-3397.2005</RefLink> </Reference> <Reference refNo="85"> <RefAuthor>Tarafdar K</RefAuthor> <RefAuthor>Rao S</RefAuthor> <RefAuthor>Recco RA</RefAuthor> <RefAuthor>Zaman MM</RefAuthor> <RefTitle>Lack of sensitivity of the latex agglutination test to detect bacterial antigen in the cerebrospinal fluid of patients with culture-negative meningitis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>406-8</RefPage> <RefTotal>Tarafdar K, Rao S, Recco RA, Zaman MM. Lack of sensitivity of the latex agglutination test to detect bacterial antigen in the cerebrospinal fluid of patients with culture-negative meningitis. Clin Infect Dis. 2001;33(3):406-8. DOI: 10.1086&#47;321885</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;321885</RefLink> </Reference> <Reference refNo="86"> <RefAuthor>de Gans J</RefAuthor> <RefAuthor>van de Beek D</RefAuthor> <RefTitle>Dexamethasone in adults with bacterial meningitis</RefTitle> <RefYear>2002</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1549-56</RefPage> <RefTotal>de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347(20):1549-56. DOI: 10.1056&#47;NEJMoa021334</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa021334</RefLink> </Reference> <Reference refNo="87"> <RefAuthor>van de Beek D</RefAuthor> <RefAuthor>de Gans J</RefAuthor> <RefAuthor>McIntyre P</RefAuthor> <RefAuthor>Prasad K</RefAuthor> <RefTitle>Steroids in adults with acute bacterial meningitis: a systematic review</RefTitle> <RefYear>2004</RefYear> <RefJournal>Lancet Infect Dis</RefJournal> <RefPage>139-43</RefPage> <RefTotal>van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis. 2004;4(3):139-43. DOI: 10.1016&#47;S1473-3099(04)00937-5</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S1473-3099(04)00937-5</RefLink> </Reference> <Reference refNo="88"> <RefAuthor>van de Beek D</RefAuthor> <RefAuthor>de Gans J</RefAuthor> <RefAuthor>McIntyre P</RefAuthor> <RefAuthor>Prasad K</RefAuthor> <RefTitle>Corticosteroids for acute bacterial meningitis</RefTitle> <RefYear>2007</RefYear> <RefJournal>Cochrane Database Syst Rev</RefJournal> <RefPage>CD004405</RefPage> <RefTotal>van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2007;(1):CD004405. DOI: 10.1002&#47;14651858.CD004405.pub2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1002&#47;14651858.CD004405.pub2</RefLink> </Reference> <Reference refNo="89"> <RefAuthor>Molyneux EM</RefAuthor> <RefAuthor>Walsh AL</RefAuthor> <RefAuthor>Forsyth H</RefAuthor> <RefAuthor>Tembo M</RefAuthor> <RefAuthor>Mwenechanya J</RefAuthor> <RefAuthor>Kayira K</RefAuthor> <RefAuthor>Bwanaisa L</RefAuthor> <RefAuthor>Njobvu A</RefAuthor> <RefAuthor>Rogerson S</RefAuthor> <RefAuthor>Malenga G</RefAuthor> <RefTitle>Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial</RefTitle> <RefYear>2002</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>211-8</RefPage> <RefTotal>Molyneux EM, Walsh AL, Forsyth H, Tembo M, Mwenechanya J, Kayira K, Bwanaisa L, Njobvu A, Rogerson S, Malenga G. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet. 2002;360(9328):211-8. DOI: 10.1016&#47;S0140-6736(02)09458-8</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(02)09458-8</RefLink> </Reference> <Reference refNo="90"> <RefAuthor>Scarborough M</RefAuthor> <RefAuthor>Gordon SB</RefAuthor> <RefAuthor>Whitty CJ</RefAuthor> <RefAuthor>French N</RefAuthor> <RefAuthor>Njalale Y</RefAuthor> <RefAuthor>Chitani A</RefAuthor> <RefAuthor>Peto TE</RefAuthor> <RefAuthor>Lalloo DG</RefAuthor> <RefAuthor>Zijlstra EE</RefAuthor> <RefTitle>Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa</RefTitle> <RefYear>2007</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>2441-50</RefPage> <RefTotal>Scarborough M, Gordon SB, Whitty CJ, French N, Njalale Y, Chitani A, Peto TE, Lalloo DG, Zijlstra EE. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med. 2007;357(24):2441-50. DOI: 10.1056&#47;NEJMoa065711</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa065711</RefLink> </Reference> <Reference refNo="91"> <RefAuthor>Joiner GA</RefAuthor> <RefAuthor>Salisbury D</RefAuthor> <RefAuthor>Bollin GE</RefAuthor> <RefTitle>Utilizing quality assurance as a tool for reducing the risk of ventilator-associated pneumonia</RefTitle> <RefYear>1996</RefYear> <RefJournal>Am J Med Qual</RefJournal> <RefPage>100-3</RefPage> <RefTotal>Joiner GA, Salisbury D, Bollin GE. Utilizing quality assurance as a tool for reducing the risk of ventilator-associated pneumonia. Am J Med Qual. 1996;11(2):100-3. DOI: 10.1177&#47;0885713X9601100208</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1177&#47;0885713X9601100208</RefLink> </Reference> <Reference refNo="92"> <RefAuthor>Zack JE</RefAuthor> <RefAuthor>Garrison T</RefAuthor> <RefAuthor>Trovillion E</RefAuthor> <RefAuthor>Clinkscale D</RefAuthor> <RefAuthor>Coopersmith CM</RefAuthor> <RefAuthor>Fraser VJ</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Effect of an education program aimed at reducing the occurence of ventilator-associated pneumonia</RefTitle> <RefYear>2002</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2407-12</RefPage> <RefTotal>Zack JE, Garrison T, Trovillion E, Clinkscale D, Coopersmith CM, Fraser VJ, Kollef MH. Effect of an education program aimed at reducing the occurence of ventilator-associated pneumonia. Crit Care Med. 2002;30(11):2407-12. DOI: 10.1097&#47;00003246-200211000-00001</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200211000-00001</RefLink> </Reference> <Reference refNo="93"> <RefAuthor>Salahuddin N</RefAuthor> <RefAuthor>Zafar A</RefAuthor> <RefAuthor>Sukhyani L</RefAuthor> <RefAuthor>Rahim S</RefAuthor> <RefAuthor>Noor MF</RefAuthor> <RefAuthor>Hussain K</RefAuthor> <RefAuthor>Siddiqui S</RefAuthor> <RefAuthor>Islam M</RefAuthor> <RefAuthor>Husain SJ</RefAuthor> <RefTitle>Reducing ventilator-associated pneumonia rates through a staff education porgramme</RefTitle> <RefYear>2004</RefYear> <RefJournal>J Hosp Infect</RefJournal> <RefPage>223-7</RefPage> <RefTotal>Salahuddin N, Zafar A, Sukhyani L, Rahim S, Noor MF, Hussain K, Siddiqui S, Islam M, Husain SJ. Reducing ventilator-associated pneumonia rates through a staff education porgramme. J Hosp Infect. 2004;57(3):223-7. DOI: 10.1016&#47;j.jhin.2004.03.002</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.jhin.2004.03.002</RefLink> </Reference> <Reference refNo="94"> <RefAuthor>Babcock HM</RefAuthor> <RefAuthor>Zack JE</RefAuthor> <RefAuthor>Garrison T</RefAuthor> <RefAuthor>Trovillion E</RefAuthor> <RefAuthor>Jones M</RefAuthor> <RefAuthor>Fraser VJ</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>An educational intervention to reduce ventilator-associated pneumonia in an integrated health system: a comparison of effects</RefTitle> <RefYear>2004</RefYear> <RefJournal>Chest</RefJournal> <RefPage>2224-31</RefPage> <RefTotal>Babcock HM, Zack JE, Garrison T, Trovillion E, Jones M, Fraser VJ, Kollef MH. An educational intervention to reduce ventilator-associated pneumonia in an integrated health system: a comparison of effects. Chest. 2004;125(6):2224-31. DOI: 10.1378&#47;chest.125.6.2224</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.125.6.2224</RefLink> </Reference> <Reference refNo="95"> <RefAuthor>Cocanour CS</RefAuthor> <RefAuthor>Peninger M</RefAuthor> <RefAuthor>Domonoske BD</RefAuthor> <RefAuthor>Li T</RefAuthor> <RefAuthor>Wright B</RefAuthor> <RefAuthor>Valdivia A</RefAuthor> <RefAuthor>Luther KM</RefAuthor> <RefTitle>Decreasing ventilator-associated pneumonia in a trauma ICU</RefTitle> <RefYear>2006</RefYear> <RefJournal>J Trauma</RefJournal> <RefPage>122-9</RefPage> <RefTotal>Cocanour CS, Peninger M, Domonoske BD, Li T, Wright B, Valdivia A, Luther KM. Decreasing ventilator-associated pneumonia in a trauma ICU. J Trauma. 2006;61(1):122-9. DOI: 10.1097&#47;01.ta.0000223971.25845.b3</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.ta.0000223971.25845.b3</RefLink> </Reference> <Reference refNo="96"> <RefAuthor>Jain M</RefAuthor> <RefAuthor>Miller L</RefAuthor> <RefAuthor>Belt D</RefAuthor> <RefAuthor>King D</RefAuthor> <RefAuthor>Berwick DM</RefAuthor> <RefTitle>Decline in ICU adverse events, nosocomial infections ans cost through a quality improvemnt initiative focusing on teamwork and culture change</RefTitle> <RefYear>2006</RefYear> <RefJournal>Qual Saf Health Care</RefJournal> <RefPage>235-9</RefPage> <RefTotal>Jain M, Miller L, Belt D, King D, Berwick DM. Decline in ICU adverse events, nosocomial infections ans cost through a quality improvemnt initiative focusing on teamwork and culture change. Qual Saf Health Care. 2006;15(4):235-9. DOI: 10.1136&#47;qshc.2005.016576</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1136&#47;qshc.2005.016576</RefLink> </Reference> <Reference refNo="97"> <RefAuthor>Warren DK</RefAuthor> <RefAuthor>Zack JE</RefAuthor> <RefAuthor>Cox MJ</RefAuthor> <RefAuthor>Cohen MM</RefAuthor> <RefAuthor>Fraser VJ</RefAuthor> <RefTitle>An educational intervention to prevent catheter-associated bloodstream infections in a nonteaching, community medical center</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1959-63</RefPage> <RefTotal>Warren DK, Zack JE, Cox MJ, Cohen MM, Fraser VJ. An educational intervention to prevent catheter-associated bloodstream infections in a nonteaching, community medical center. Crit Care Med. 2003;31(7):1959-63. DOI: 10.1097&#47;01.CCM.0000069513.15417.1C</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000069513.15417.1C</RefLink> </Reference> <Reference refNo="98"> <RefAuthor>Warren DK</RefAuthor> <RefAuthor>Zack JE</RefAuthor> <RefAuthor>Mayfield JL</RefAuthor> <RefAuthor>Chen A</RefAuthor> <RefAuthor>Prentice D</RefAuthor> <RefAuthor>Fraser VJ</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>The effect of an education program on the incidence of central venous catheter-associated bloodstream infection in a medical ICU</RefTitle> <RefYear>2004</RefYear> <RefJournal>Chest</RefJournal> <RefPage>1612-8</RefPage> <RefTotal>Warren DK, Zack JE, Mayfield JL, Chen A, Prentice D, Fraser VJ, Kollef MH. The effect of an education program on the incidence of central venous catheter-associated bloodstream infection in a medical ICU. Chest. 2004;126(5):1612-8. DOI: 10.1378&#47;chest.126.5.1612</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.126.5.1612</RefLink> </Reference> <Reference refNo="99"> <RefAuthor>Berenholtz SM</RefAuthor> <RefAuthor>Pronovost PJ</RefAuthor> <RefAuthor>Lipsett PA</RefAuthor> <RefAuthor>Hobson D</RefAuthor> <RefAuthor>Earsing K</RefAuthor> <RefAuthor>Farley JE</RefAuthor> <RefAuthor>Milanovich S</RefAuthor> <RefAuthor>Garrett-Mayer E</RefAuthor> <RefAuthor>Winters BD</RefAuthor> <RefAuthor>Rubin HR</RefAuthor> <RefAuthor>Dorman T</RefAuthor> <RefAuthor>Perl TM</RefAuthor> <RefTitle>Eliminating catheter-related bloodstream infections in the intensive care unit</RefTitle> <RefYear>2004</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2014-20</RefPage> <RefTotal>Berenholtz SM, Pronovost PJ, Lipsett PA, Hobson D, Earsing K, Farley JE, Milanovich S, Garrett-Mayer E, Winters BD, Rubin HR, Dorman T, Perl TM. Eliminating catheter-related bloodstream infections in the intensive care unit. Crit Care Med. 2004;32(10):2014-20. DOI: 10.1097&#47;01.CCM.0000142399.70913.2F</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000142399.70913.2F</RefLink> </Reference> <Reference refNo="100"> <RefAuthor>Pronovost P</RefAuthor> <RefAuthor>Needham D</RefAuthor> <RefAuthor>Berenholtz S</RefAuthor> <RefAuthor>Sinopoli D</RefAuthor> <RefAuthor>Chu H</RefAuthor> <RefAuthor>Cosgrove S</RefAuthor> <RefAuthor>Sexton B</RefAuthor> <RefAuthor>Hyzy R</RefAuthor> <RefAuthor>Welsh R</RefAuthor> <RefAuthor>Roth G</RefAuthor> <RefAuthor>Bander J</RefAuthor> <RefAuthor>Kepros J</RefAuthor> <RefAuthor>Goeschel C</RefAuthor> <RefTitle>An intervention to decrease catheter-related bloodstream infections in the ICU</RefTitle> <RefYear>2006</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>2725-32</RefPage> <RefTotal>Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S, Sexton B, Hyzy R, Welsh R, Roth G, Bander J, Kepros J, Goeschel C. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006;355(26):2725-32. DOI: 10.1056&#47;NEJMoa061115</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa061115</RefLink> </Reference> <Reference refNo="101"> <RefAuthor>Stephan F</RefAuthor> <RefAuthor>Sax H</RefAuthor> <RefAuthor>Wachsmuth M</RefAuthor> <RefAuthor>Hoffmeyer P</RefAuthor> <RefAuthor>Clerque F</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefTitle>Reduction of urinary tract infection and antibiotic use after surgery: A controlled, prospective, before-after intervention study</RefTitle> <RefYear>2006</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1544-51</RefPage> <RefTotal>Stephan F, Sax H, Wachsmuth M, Hoffmeyer P, Clerque F, Pittet D. Reduction of urinary tract infection and antibiotic use after surgery: A controlled, prospective, before-after intervention study. Clin Infect Dis. 2006;42(11):1544-51. DOI: 10.1086&#47;503837</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;503837</RefLink> </Reference> <Reference refNo="102"> <RefAuthor>Centers for Disease Control and Prevention</RefAuthor> <RefTitle></RefTitle> <RefYear>2008</RefYear> <RefBookTitle>CDC definitions</RefBookTitle> <RefPage></RefPage> <RefTotal>Centers for Disease Control and Prevention. CDC definitions. 2008. Available from: http:&#47;&#47;www.cdc.gov&#47;ncidod&#47;dhqp&#47;nhsn.html</RefTotal> <RefLink>http:&#47;&#47;www.cdc.gov&#47;ncidod&#47;dhqp&#47;nhsn.html</RefLink> </Reference> <Reference refNo="103"> <RefAuthor>Anonym</RefAuthor> <RefTitle></RefTitle> <RefYear>2005</RefYear> <RefBookTitle>Nationales Referenzzentrum f&#252;r die Surveillance von nosokomialen Infektionen</RefBookTitle> <RefPage></RefPage> <RefTotal>Nationales Referenzzentrum f&#252;r die Surveillance von nosokomialen Infektionen &#91;homepage on the Internet&#93;. Berlin: NRZ; c2005. Available from: http:&#47;&#47;www.nrz-hygiene.de</RefTotal> <RefLink>http:&#47;&#47;www.nrz-hygiene.de</RefLink> </Reference> <Reference refNo="104"> <RefAuthor>Gastmeier P</RefAuthor> <RefAuthor>Geffers C</RefAuthor> <RefAuthor>Brandt C</RefAuthor> <RefAuthor>Zuschneid I</RefAuthor> <RefAuthor>Sohr D</RefAuthor> <RefAuthor>Schwab F</RefAuthor> <RefAuthor>Behnke M</RefAuthor> <RefAuthor>Daschner F</RefAuthor> <RefAuthor>R&#252;den H</RefAuthor> <RefTitle>Effectiveness of a nationwide nosocomial infection surveillance system for reducing nosocomial infections</RefTitle> <RefYear>2006</RefYear> <RefJournal>J Hosp Infect</RefJournal> <RefPage>16-22</RefPage> <RefTotal>Gastmeier P, Geffers C, Brandt C, Zuschneid I, Sohr D, Schwab F, Behnke M, Daschner F, R&#252;den H. Effectiveness of a nationwide nosocomial infection surveillance system for reducing nosocomial infections. J Hosp Infect. 2006;64(1):16-22. DOI: 10.1016&#47;j.jhin.2006.04.017</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.jhin.2006.04.017</RefLink> </Reference> <Reference refNo="105"> <RefAuthor>Boyce JM</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefAuthor> Healthcare Infection Control Practices Advisory Committee</RefAuthor> <RefAuthor> HICPAC&#47;SHEA&#47;APIC&#47;IDSA Hand Hygiene Task Force</RefAuthor> <RefTitle>Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC&#47;SHEA&#47;APIC&#47;IDSA Hand Hygiene Task Force; Society for Healthcare Epidemiology of America&#47;Association for Professionals in Infection Control&#47;Infectious Diseases Society of America</RefTitle> <RefYear>2002</RefYear> <RefJournal>MMWR Recomm Rep</RefJournal> <RefPage>1-45, quiz CE1-4</RefPage> <RefTotal>Boyce JM, Pittet D; Healthcare Infection Control Practices Advisory Committee; HICPAC&#47;SHEA&#47;APIC&#47;IDSA Hand Hygiene Task Force. Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC&#47;SHEA&#47;APIC&#47;IDSA Hand Hygiene Task Force; Society for Healthcare Epidemiology of America&#47;Association for Professionals in Infection Control&#47;Infectious Diseases Society of America. MMWR Recomm Rep. 2002;51(RR-16):1-45, quiz CE1-4.</RefTotal> </Reference> <Reference refNo="106"> <RefAuthor>Pittet D</RefAuthor> <RefAuthor>Hugonnet S</RefAuthor> <RefAuthor>Harbarth S</RefAuthor> <RefAuthor>Mourouga P</RefAuthor> <RefAuthor>Sauvan V</RefAuthor> <RefAuthor>Touveneau S</RefAuthor> <RefAuthor>Perneger TV</RefAuthor> <RefTitle>Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Infection Control Programme</RefTitle> <RefYear>2000</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>1307-12</RefPage> <RefTotal>Pittet D, Hugonnet S, Harbarth S, Mourouga P, Sauvan V, Touveneau S, Perneger TV. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Infection Control Programme. Lancet. 2000;356(9238):1307-12. DOI: 10.1016&#47;S0140-6736(00)02814-2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(00)02814-2</RefLink> </Reference> <Reference refNo="107"> <RefAuthor>Vernaz N</RefAuthor> <RefAuthor>Sax H</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefAuthor>Bonnabry P</RefAuthor> <RefAuthor>Schrenzel J</RefAuthor> <RefAuthor>Harbarth S</RefAuthor> <RefTitle>Temporal effects of antibiotic use and hand rub consumption on the incidence of MRSA and Clostridium difficile</RefTitle> <RefYear>2008</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>601-7</RefPage> <RefTotal>Vernaz N, Sax H, Pittet D, Bonnabry P, Schrenzel J, Harbarth S. Temporal effects of antibiotic use and hand rub consumption on the incidence of MRSA and Clostridium difficile. J Antimicrob Chemother. 2008;62(3):601-7. DOI: 10.1093&#47;jac&#47;dkn199</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;jac&#47;dkn199</RefLink> </Reference> <Reference refNo="108"> <RefAuthor>Raad II</RefAuthor> <RefAuthor>Hohn DC</RefAuthor> <RefAuthor>Gilbreath BJ</RefAuthor> <RefAuthor>Suleiman N</RefAuthor> <RefAuthor>Hill LA</RefAuthor> <RefAuthor>Bruso PA</RefAuthor> <RefAuthor>Marts K</RefAuthor> <RefAuthor>Mansfield PF</RefAuthor> <RefAuthor>Bodey GP</RefAuthor> <RefTitle>Prevention of central venous catheter-related infections by using maximal sterile barrier precautions during insertion</RefTitle> <RefYear>1994</RefYear> <RefJournal>Infect Control Hosp Epidemiol</RefJournal> <RefPage>231-8</RefPage> <RefTotal>Raad II, Hohn DC, Gilbreath BJ, Suleiman N, Hill LA, Bruso PA, Marts K, Mansfield PF, Bodey GP. Prevention of central venous catheter-related infections by using maximal sterile barrier precautions during insertion. Infect Control Hosp Epidemiol. 1994;15(4 Pt 1):231-8. DOI: 10.1086&#47;646902</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;646902</RefLink> </Reference> <Reference refNo="109"> <RefAuthor>Parienti C</RefAuthor> <RefAuthor>Lederle F</RefAuthor> <RefAuthor>Impola C</RefAuthor> <RefAuthor>Peterson L</RefAuthor> <RefTitle>Reduction of unnecessary intravenous catheter use: internal medicine house staffparticipate in a successful quality improvement project</RefTitle> <RefYear>1994</RefYear> <RefJournal>Arch Intern Med</RefJournal> <RefPage>1829-32</RefPage> <RefTotal>Parienti C, Lederle F, Impola C, Peterson L. Reduction of unnecessary intravenous catheter use: internal medicine house staffparticipate in a successful quality improvement project. Arch Intern Med. 1994;154(16):1829-32.</RefTotal> </Reference> <Reference refNo="110"> <RefAuthor>Dezfulian C</RefAuthor> <RefAuthor>Shojania K</RefAuthor> <RefAuthor>Collard H</RefAuthor> <RefAuthor>Kim H</RefAuthor> <RefAuthor>Matthay M</RefAuthor> <RefAuthor>Saint S</RefAuthor> <RefTitle>Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis</RefTitle> <RefYear>2005</RefYear> <RefJournal>Am J Med</RefJournal> <RefPage>11-8</RefPage> <RefTotal>Dezfulian C, Shojania K, Collard H, Kim H, Matthay M, Saint S. Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis. Am J Med. 2005;118(1):11-8. DOI: 10.1016&#47;j.amjmed.2004.07.051</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.amjmed.2004.07.051</RefLink> </Reference> <Reference refNo="111"> <RefAuthor>Lorente L</RefAuthor> <RefAuthor>Lecuona M</RefAuthor> <RefAuthor>Jimenez A</RefAuthor> <RefAuthor>Mora ML</RefAuthor> <RefAuthor>Sierra A</RefAuthor> <RefTitle>Influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia</RefTitle> <RefYear>2007</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>1079-83</RefPage> <RefTotal>Lorente L, Lecuona M, Jimenez A, Mora ML, Sierra A. Influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia. Am J Respir Crit Care Med. 2007;176(11):1079-83. DOI: 10.1164&#47;rccm.200705-761OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200705-761OC</RefLink> </Reference> <Reference refNo="112"> <RefAuthor>Drakulovic MB</RefAuthor> <RefAuthor>Torres A</RefAuthor> <RefAuthor>Bauer TT</RefAuthor> <RefAuthor>Nicolas JM</RefAuthor> <RefAuthor>Nogue S</RefAuthor> <RefAuthor>Ferrer M</RefAuthor> <RefTitle>Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial</RefTitle> <RefYear>1999</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>1851-8</RefPage> <RefTotal>Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogue S, Ferrer M. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354(9193):1851-8. DOI: 10.1016&#47;S0140-6736(98)12251-1</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(98)12251-1</RefLink> </Reference> <Reference refNo="113"> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Ventilator-associated pneumonia: A multivariate analysis</RefTitle> <RefYear>1993</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>1965-70</RefPage> <RefTotal>Kollef MH. Ventilator-associated pneumonia: A multivariate analysis. JAMA. 1993;270(16):1965-70.</RefTotal> </Reference> <Reference refNo="114"> <RefAuthor>Cook D</RefAuthor> <RefAuthor>De Jonghe B</RefAuthor> <RefAuthor>Brochard L</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefTitle>Influence of airway management on ventilator-associated pneumonia: evidence from randomized trials</RefTitle> <RefYear>1998</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>781-7</RefPage> <RefTotal>Cook D, De Jonghe B, Brochard L, Brun-Buisson C. Influence of airway management on ventilator-associated pneumonia: evidence from randomized trials. JAMA. 1998;279(10):781-7. DOI: 10.1001&#47;jama.279.10.781</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.279.10.781</RefLink> </Reference> <Reference refNo="115"> <RefAuthor>Ib&#225;nez J</RefAuthor> <RefAuthor>Penafiel A</RefAuthor> <RefAuthor>Raurich JM</RefAuthor> <RefAuthor>Marse P</RefAuthor> <RefAuthor>Jord&#225; R</RefAuthor> <RefAuthor>Mata F</RefAuthor> <RefTitle>Gastroesophageal reflux in intubated patients receiving enteral nutrition: effect of supine and semirecumbent positions</RefTitle> <RefYear>1992</RefYear> <RefJournal>JPEN J Parenter Enteral Nutr</RefJournal> <RefPage>419-22</RefPage> <RefTotal>Ib&#225;nez J, Penafiel A, Raurich JM, Marse P, Jord&#225; R, Mata F. Gastroesophageal reflux in intubated patients receiving enteral nutrition: effect of supine and semirecumbent positions. JPEN J Parenter Enteral Nutr. 1992;16(5):419-22. DOI: 10.1177&#47;0148607192016005419</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1177&#47;0148607192016005419</RefLink> </Reference> <Reference refNo="116"> <RefAuthor>Iregui MG</RefAuthor> <RefAuthor>Vaughan WM</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Nonpharmacological prevention of hospital-acquired pneumonia</RefTitle> <RefYear>2002</RefYear> <RefJournal>Semin Respir Crit Care Med</RefJournal> <RefPage>489-96</RefPage> <RefTotal>Iregui MG, Vaughan WM, Kollef MH. Nonpharmacological prevention of hospital-acquired pneumonia. Semin Respir Crit Care Med. 2002;23(5):489-96. DOI: 10.1055&#47;s-2002-35720</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1055&#47;s-2002-35720</RefLink> </Reference> <Reference refNo="117"> <RefAuthor>Orozco-Levi M</RefAuthor> <RefAuthor>Torres A</RefAuthor> <RefAuthor>Ferrer M</RefAuthor> <RefAuthor>Piera C</RefAuthor> <RefAuthor>el-Ebiary M</RefAuthor> <RefAuthor>de la Bellacasa JP</RefAuthor> <RefAuthor>Rodriguez-Roisin R</RefAuthor> <RefTitle>Semirecumbent position protects from pulmonary aspiration but not completely from gastroesophageal reflux in mechanically ventilated patients</RefTitle> <RefYear>1995</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>1387-90</RefPage> <RefTotal>Orozco-Levi M, Torres A, Ferrer M, Piera C, el-Ebiary M, de la Bellacasa JP, Rodriguez-Roisin R. Semirecumbent position protects from pulmonary aspiration but not completely from gastroesophageal reflux in mechanically ventilated patients. Am J Respir Crit Care Med. 1995;152(4 Pt 1):1387-90.</RefTotal> </Reference> <Reference refNo="118"> <RefAuthor>Torres A</RefAuthor> <RefAuthor>Serra-Batlles J</RefAuthor> <RefAuthor>Ros E</RefAuthor> <RefAuthor>Piera C</RefAuthor> <RefAuthor>Puig de la Bellacasa J</RefAuthor> <RefAuthor>Cobos A</RefAuthor> <RefAuthor>Lome&#241;a F</RefAuthor> <RefAuthor>Rodr&#237;guez-Roisin R</RefAuthor> <RefTitle>Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position</RefTitle> <RefYear>1992</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>540-3</RefPage> <RefTotal>Torres A, Serra-Batlles J, Ros E, Piera C, Puig de la Bellacasa J, Cobos A, Lome&#241;a F, Rodr&#237;guez-Roisin R. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position. Ann Intern Med. 1992;116(7):540-3.</RefTotal> </Reference> <Reference refNo="119"> <RefAuthor>Girou E</RefAuthor> <RefAuthor>Buu-Hoi A</RefAuthor> <RefAuthor>Stephan F</RefAuthor> <RefAuthor>Novara A</RefAuthor> <RefAuthor>Gutmann L</RefAuthor> <RefAuthor>Safar M</RefAuthor> <RefAuthor>Fagon JY</RefAuthor> <RefTitle>Airway colonisation in long-term mechanically ventilated patients. Effect of semi-recumbent position and continuous subglottic suctioning</RefTitle> <RefYear>2004</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>225-33</RefPage> <RefTotal>Girou E, Buu-Hoi A, Stephan F, Novara A, Gutmann L, Safar M, Fagon JY. Airway colonisation in long-term mechanically ventilated patients. Effect of semi-recumbent position and continuous subglottic suctioning. Intensive Care Med. 2004;30(2):225-33. DOI: 10.1007&#47;s00134-003-2077-4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-003-2077-4</RefLink> </Reference> <Reference refNo="120"> <RefAuthor>van Nieuwenhoven CA</RefAuthor> <RefAuthor>Vandenbroucke-Grauls C</RefAuthor> <RefAuthor>van Tiel FH</RefAuthor> <RefAuthor>Joore HC</RefAuthor> <RefAuthor>van Schijndel RJ</RefAuthor> <RefAuthor>van der Tweel I</RefAuthor> <RefAuthor>Ramsay G</RefAuthor> <RefAuthor>Bonten MJ</RefAuthor> <RefTitle>Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>396-402</RefPage> <RefTotal>van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, Joore HC, van Schijndel RJ, van der Tweel I, Ramsay G, Bonten MJ. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med. 2006;34(2):396-402. DOI: 10.1097&#47;01.CCM.0000198529.76602.5E</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000198529.76602.5E</RefLink> </Reference> <Reference refNo="121"> <RefAuthor>Lewis S</RefAuthor> <RefAuthor>Egger M</RefAuthor> <RefAuthor>Sylvester P</RefAuthor> <RefAuthor>Thomas S</RefAuthor> <RefTitle>Early enteral feeding versus &#34;nil by mouth&#34; after gastrointestinal surgery: systematic review and meta-analysis of controlled trails</RefTitle> <RefYear>2001</RefYear> <RefJournal>BMJ</RefJournal> <RefPage>773-6</RefPage> <RefTotal>Lewis S, Egger M, Sylvester P, Thomas S. Early enteral feeding versus &#34;nil by mouth&#34; after gastrointestinal surgery: systematic review and meta-analysis of controlled trails. BMJ. 2001;323(7316):773-6. DOI: 10.1136&#47;bmj.323.7316.773</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1136&#47;bmj.323.7316.773</RefLink> </Reference> <Reference refNo="122"> <RefAuthor>Weimann A</RefAuthor> <RefAuthor>Braga M</RefAuthor> <RefAuthor>Harsanyi L</RefAuthor> <RefAuthor>Laviano A</RefAuthor> <RefAuthor>Ljungqvist O</RefAuthor> <RefAuthor>Soeters P</RefAuthor> <RefAuthor> DGEM (German Society for Nutritional Medicine)</RefAuthor> <RefAuthor>Jauch KW</RefAuthor> <RefAuthor>Kemen M</RefAuthor> <RefAuthor>Hiesmayr JM</RefAuthor> <RefAuthor>Horbach T</RefAuthor> <RefAuthor>Kuse ER</RefAuthor> <RefAuthor>Vestweber KH</RefAuthor> <RefAuthor> ESPEN (European Society for Parenteral and Enteral Nutrition)</RefAuthor> <RefTitle>ESPEN Guidelines on Enteral Nutrition: Surgery including organ transplantation</RefTitle> <RefYear>2006</RefYear> <RefJournal>Clin Nutr</RefJournal> <RefPage>224-44</RefPage> <RefTotal>Weimann A, Braga M, Harsanyi L, Laviano A, Ljungqvist O, Soeters P; DGEM (German Society for Nutritional Medicine), Jauch KW, Kemen M, Hiesmayr JM, Horbach T, Kuse ER, Vestweber KH; ESPEN (European Society for Parenteral and Enteral Nutrition). ESPEN Guidelines on Enteral Nutrition: Surgery including organ transplantation. Clin Nutr. 2006;25(2):224-44. DOI: 10.1016&#47;j.clnu.2006.01.015</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.clnu.2006.01.015</RefLink> </Reference> <Reference refNo="123"> <RefAuthor>Heyland D</RefAuthor> <RefAuthor>Novak F</RefAuthor> <RefAuthor>Drover J</RefAuthor> <RefAuthor>Jain M</RefAuthor> <RefAuthor>Su X</RefAuthor> <RefAuthor>Suchner U</RefAuthor> <RefTitle>Should immunonutrition become routine in critically ill patients&#63; A systematic review of the evidence</RefTitle> <RefYear>2001</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>944-53</RefPage> <RefTotal>Heyland D, Novak F, Drover J, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients&#63; A systematic review of the evidence. JAMA. 2001;286(8):944-53. DOI: 10.1001&#47;jama.286.8.944</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.286.8.944</RefLink> </Reference> <Reference refNo="124"> <RefAuthor>Heys S</RefAuthor> <RefAuthor>walker L</RefAuthor> <RefAuthor>Smith I</RefAuthor> <RefAuthor>Eremin O</RefAuthor> <RefTitle>Enteral nutritional supplementation with key nutritiens in patients with critiacal illness and cancer: a meta-analysis of randomized controlled clinical trials</RefTitle> <RefYear>1999</RefYear> <RefJournal>Ann Surg</RefJournal> <RefPage>467-77</RefPage> <RefTotal>Heys S, walker L, Smith I, Eremin O. Enteral nutritional supplementation with key nutritiens in patients with critiacal illness and cancer: a meta-analysis of randomized controlled clinical trials. Ann Surg. 1999;229(4):467-77. DOI: 10.1097&#47;00000658-199904000-00004</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00000658-199904000-00004</RefLink> </Reference> <Reference refNo="125"> <RefAuthor>Wiener RS</RefAuthor> <RefAuthor>Wiener DC</RefAuthor> <RefAuthor>Larson RJ</RefAuthor> <RefTitle>Benefits and risks of tight glucose control in critically ill adults: a meta-analysis</RefTitle> <RefYear>2008</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>933-44</RefPage> <RefTotal>Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA. 2008;300(8):933-44. DOI: 10.1001&#47;jama.300.8.933</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.300.8.933</RefLink> </Reference> <Reference refNo="126"> <RefAuthor>van den Berghe G</RefAuthor> <RefAuthor>Wouters P</RefAuthor> <RefAuthor>Weekers F</RefAuthor> <RefAuthor>Verwaest C</RefAuthor> <RefAuthor>Bruyninckx F</RefAuthor> <RefAuthor>Schetz M</RefAuthor> <RefAuthor>Vlasselaers D</RefAuthor> <RefAuthor>Ferdinande P</RefAuthor> <RefAuthor>Lauwers P</RefAuthor> <RefAuthor>Bouillon R</RefAuthor> <RefTitle>Intensive insulin therapy in the critically ill patients</RefTitle> <RefYear>2001</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1359-67</RefPage> <RefTotal>van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-67. DOI: 10.1056&#47;NEJMoa011300</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa011300</RefLink> </Reference> <Reference refNo="127"> <RefAuthor>Krinsley JS</RefAuthor> <RefTitle>Effect of an intensive glucose management protocol on the mortality of critically ill adult patients</RefTitle> <RefYear>2004</RefYear> <RefJournal>Mayo Clin Proc</RefJournal> <RefPage>992-1000</RefPage> <RefTotal>Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc. 2004;79(8):992-1000. DOI: 10.4065&#47;79.8.992</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.4065&#47;79.8.992</RefLink> </Reference> <Reference refNo="128"> <RefAuthor>van den Berghe G</RefAuthor> <RefAuthor></RefAuthor> <RefTitle></RefTitle> <RefYear>2005</RefYear> <RefBookTitle>Intensive Insulin Therapy Study in Medical Intensive Care Patients</RefBookTitle> <RefPage></RefPage> <RefTotal>van den Berghe G, et al. Intensive Insulin Therapy Study in Medical Intensive Care Patients. ESICM. Amsterdam; September 2005.</RefTotal> </Reference> <Reference refNo="129"> <RefAuthor>Finfer S</RefAuthor> <RefAuthor>Chittock DR</RefAuthor> <RefAuthor>Su SY</RefAuthor> <RefAuthor>Blair D</RefAuthor> <RefAuthor>Foster D</RefAuthor> <RefAuthor>Dhingra V</RefAuthor> <RefAuthor>Bellomo R</RefAuthor> <RefAuthor>Cook D</RefAuthor> <RefAuthor>Dodek P</RefAuthor> <RefAuthor>Henderson WR</RefAuthor> <RefAuthor>H&#233;bert PC</RefAuthor> <RefAuthor>Heritier S</RefAuthor> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>McArthur C</RefAuthor> <RefAuthor>McDonald E</RefAuthor> <RefAuthor>Mitchell I</RefAuthor> <RefAuthor>Myburgh JA</RefAuthor> <RefAuthor>Norton R</RefAuthor> <RefAuthor>Potter J</RefAuthor> <RefAuthor>Robinson BG</RefAuthor> <RefAuthor>Ronco JJ</RefAuthor> <RefTitle>Intensive versus conventional glucose control in critically ill patients</RefTitle> <RefYear>2009</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1283-97</RefPage> <RefTotal>Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, H&#233;bert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-97. DOI: 10.1056&#47;NEJMoa0810625</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa0810625</RefLink> </Reference> <Reference refNo="130"> <RefAuthor>Griesdale DE</RefAuthor> <RefAuthor>de Souza RJ</RefAuthor> <RefAuthor>van Dam RM</RefAuthor> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>Cook DJ</RefAuthor> <RefAuthor>Malhotra A</RefAuthor> <RefAuthor>Dhaliwal R</RefAuthor> <RefAuthor>Henderson WR</RefAuthor> <RefAuthor>Chittock DR</RefAuthor> <RefAuthor>Finfer S</RefAuthor> <RefAuthor>Talmor D</RefAuthor> <RefTitle>Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data</RefTitle> <RefYear>2009</RefYear> <RefJournal>CMAJ</RefJournal> <RefPage>821-7</RefPage> <RefTotal>Griesdale DE, de Souza RJ, van Dam RM, Heyland DK, Cook DJ, Malhotra A, Dhaliwal R, Henderson WR, Chittock DR, Finfer S, Talmor D. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009;180(8):821-7. DOI: 10.1503&#47;cmaj.090206</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1503&#47;cmaj.090206</RefLink> </Reference> <Reference refNo="131"> <RefAuthor>Brunkhorst FM</RefAuthor> <RefAuthor>Wahl HG</RefAuthor> <RefTitle>Blood glucose measurements in the critically ill: more than just a blood draw</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>178</RefPage> <RefTotal>Brunkhorst FM, Wahl HG. Blood glucose measurements in the critically ill: more than just a blood draw. Crit Care. 2006;10(6):178. DOI: 10.1186&#47;cc5110</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc5110</RefLink> </Reference> <Reference refNo="132"> <RefAuthor>Clement S</RefAuthor> <RefAuthor>Braithwaite SS</RefAuthor> <RefAuthor>Magee MF</RefAuthor> <RefAuthor>Ahmann A</RefAuthor> <RefAuthor>Smith EP</RefAuthor> <RefAuthor>Schafer RG</RefAuthor> <RefAuthor>Hirsch IB</RefAuthor> <RefAuthor> American Diabetes Association Diabetes in Hospitals Writing Committee</RefAuthor> <RefTitle>Management of diabetes and hyperglycemia in hospitals</RefTitle> <RefYear>2004</RefYear> <RefJournal>Diabetes Care</RefJournal> <RefPage>553-91</RefPage> <RefTotal>Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, Hirsch IB; American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27(2):553-91. DOI: 10.2337&#47;diacare.27.2.553</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.2337&#47;diacare.27.2.553</RefLink> </Reference> <Reference refNo="133"> <RefAuthor>Nathens AB</RefAuthor> <RefAuthor>Marshall JC</RefAuthor> <RefTitle>Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence</RefTitle> <RefYear>1999</RefYear> <RefJournal>Arch Surg</RefJournal> <RefPage>170-6</RefPage> <RefTotal>Nathens AB, Marshall JC. Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence. Arch Surg. 1999;134(2):170-6. DOI: 10.1001&#47;archsurg.134.2.170</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;archsurg.134.2.170</RefLink> </Reference> <Reference refNo="134"> <RefAuthor>Silvestri L</RefAuthor> <RefAuthor>van Saene HK</RefAuthor> <RefAuthor>Milanese M</RefAuthor> <RefAuthor>Gregori D</RefAuthor> <RefAuthor>Gullo A</RefAuthor> <RefTitle>Selective decontamination of the digestive tract reduces bacterial bloodstream infection and mortality in critically ill patients: Systematic review of randomized, controlled trials</RefTitle> <RefYear>2007</RefYear> <RefJournal>J Hosp Infect</RefJournal> <RefPage>187-203</RefPage> <RefTotal>Silvestri L, van Saene HK, Milanese M, Gregori D, Gullo A. Selective decontamination of the digestive tract reduces bacterial bloodstream infection and mortality in critically ill patients: Systematic review of randomized, controlled trials. J Hosp Infect. 2007;65(3):187-203. DOI: 10.1016&#47;j.jhin.2006.10.014</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.jhin.2006.10.014</RefLink> </Reference> <Reference refNo="135"> <RefAuthor>Krueger WA</RefAuthor> <RefAuthor>Lenhart FP</RefAuthor> <RefAuthor>Neeser G</RefAuthor> <RefAuthor>Ruckdeschel G</RefAuthor> <RefAuthor>Schreckhase H</RefAuthor> <RefAuthor>Eissner HJ</RefAuthor> <RefAuthor>Forst H</RefAuthor> <RefAuthor>Eckart J</RefAuthor> <RefAuthor>Peter K</RefAuthor> <RefAuthor>Unertl KE</RefAuthor> <RefTitle>Influence of combined intravenous and topical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortality in critically ill surgical patients: a prospective, stratified, randomized, double-blind, placebo-controlled clinical trial</RefTitle> <RefYear>2002</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>1029-37</RefPage> <RefTotal>Krueger WA, Lenhart FP, Neeser G, Ruckdeschel G, Schreckhase H, Eissner HJ, Forst H, Eckart J, Peter K, Unertl KE. Influence of combined intravenous and topical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortality in critically ill surgical patients: a prospective, stratified, randomized, double-blind, placebo-controlled clinical trial. Am J Respir Crit Care Med. 2002;166(8):1029-37. DOI: 10.1164&#47;rccm.2105141</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.2105141</RefLink> </Reference> <Reference refNo="136"> <RefAuthor>Bergmans DC</RefAuthor> <RefAuthor>Bonten MJ</RefAuthor> <RefAuthor>Gaillard CA</RefAuthor> <RefAuthor>Paling JC</RefAuthor> <RefAuthor>van der Geest S</RefAuthor> <RefAuthor>van Tiel FH</RefAuthor> <RefAuthor>Beysens AJ</RefAuthor> <RefAuthor>de Leeuw PW</RefAuthor> <RefAuthor>Stobberingh EE</RefAuthor> <RefTitle>Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study</RefTitle> <RefYear>2001</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>382-8</RefPage> <RefTotal>Bergmans DC, Bonten MJ, Gaillard CA, Paling JC, van der Geest S, van Tiel FH, Beysens AJ, de Leeuw PW, Stobberingh EE. Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2001;164(3):382-8.</RefTotal> </Reference> <Reference refNo="137"> <RefAuthor>de Smet AM</RefAuthor> <RefAuthor>Kluytmans JA</RefAuthor> <RefAuthor>Cooper BS</RefAuthor> <RefAuthor>Mascini EM</RefAuthor> <RefAuthor>Benus RF</RefAuthor> <RefAuthor>van der Werf TS</RefAuthor> <RefAuthor>van der Hoeven JG</RefAuthor> <RefAuthor>Pickkers P</RefAuthor> <RefAuthor>Bogaers-Hofman D</RefAuthor> <RefAuthor>van der Meer NJ</RefAuthor> <RefAuthor>Bernards AT</RefAuthor> <RefAuthor>Kuijper EJ</RefAuthor> <RefAuthor>Joore JC</RefAuthor> <RefAuthor>Leverstein-van Hall MA</RefAuthor> <RefAuthor>Bindels AJ</RefAuthor> <RefAuthor>Jansz AR</RefAuthor> <RefAuthor>Wesselink RM</RefAuthor> <RefAuthor>de Jongh BM</RefAuthor> <RefAuthor>Dennesen PJ</RefAuthor> <RefAuthor>van Asselt GJ</RefAuthor> <RefAuthor>te Velde LF</RefAuthor> <RefAuthor>Frenay IH</RefAuthor> <RefAuthor>Kaasjager K</RefAuthor> <RefAuthor>Bosch FH</RefAuthor> <RefAuthor>van Iterson M</RefAuthor> <RefAuthor>Thijsen SF</RefAuthor> <RefAuthor>Kluge GH</RefAuthor> <RefAuthor>Pauw W</RefAuthor> <RefAuthor>de Vries JW</RefAuthor> <RefAuthor>Kaan JA</RefAuthor> <RefAuthor>Arends JP</RefAuthor> <RefAuthor>Aarts LP</RefAuthor> <RefAuthor>Sturm PD</RefAuthor> <RefAuthor>Harinck HI</RefAuthor> <RefAuthor>Voss A</RefAuthor> <RefAuthor>Uijtendaal EV</RefAuthor> <RefAuthor>Blok HE</RefAuthor> <RefAuthor>Thieme Groen ES</RefAuthor> <RefAuthor>Pouw ME</RefAuthor> <RefAuthor>Kalkman CJ</RefAuthor> <RefAuthor>Bonten MJ</RefAuthor> <RefTitle>Decontamination of the digestive tract and oropharynx in ICU patients</RefTitle> <RefYear>2009</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>20-31</RefPage> <RefTotal>de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS, van der Hoeven JG, Pickkers P, Bogaers-Hofman D, van der Meer NJ, Bernards AT, Kuijper EJ, Joore JC, Leverstein-van Hall MA, Bindels AJ, Jansz AR, Wesselink RM, de Jongh BM, Dennesen PJ, van Asselt GJ, te Velde LF, Frenay IH, Kaasjager K, Bosch FH, van Iterson M, Thijsen SF, Kluge GH, Pauw W, de Vries JW, Kaan JA, Arends JP, Aarts LP, Sturm PD, Harinck HI, Voss A, Uijtendaal EV, Blok HE, Thieme Groen ES, Pouw ME, Kalkman CJ, Bonten MJ. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med. 2009;360(1):20-31. DOI: 10.1056&#47;NEJMoa0800394</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa0800394</RefLink> </Reference> <Reference refNo="138"> <RefAuthor>de Jonge E</RefAuthor> <RefAuthor>Schultz MJ</RefAuthor> <RefAuthor>Spanjaard L</RefAuthor> <RefAuthor>Bossuyt PM</RefAuthor> <RefAuthor>Vroom MB</RefAuthor> <RefAuthor>Dankert J</RefAuthor> <RefAuthor>Kesecioglu J</RefAuthor> <RefTitle>Effects of selective decontamination of digestive tract on mortality and acquistition of resistant bacteria in intensive care: a randomized controlled trial</RefTitle> <RefYear>2003</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>1011-6</RefPage> <RefTotal>de Jonge E, Schultz MJ, Spanjaard L, Bossuyt PM, Vroom MB, Dankert J, Kesecioglu J. Effects of selective decontamination of digestive tract on mortality and acquistition of resistant bacteria in intensive care: a randomized controlled trial. Lancet. 2003;362(9389):1011-6. DOI: 10.1016&#47;S0140-6736(03)14409-1</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(03)14409-1</RefLink> </Reference> <Reference refNo="139"> <RefAuthor>de Jonge E</RefAuthor> <RefAuthor>Schultz MJ</RefAuthor> <RefAuthor>Spanjaard L</RefAuthor> <RefAuthor>Bossuyt PM</RefAuthor> <RefAuthor>Vroom MB</RefAuthor> <RefAuthor>Dankert J</RefAuthor> <RefAuthor>Kesecioglu J</RefAuthor> <RefTitle>Effects of selective decontamination of digestive tract on mortality and acquistition of resistant bacteria in intensive care: a randomized controlled trial</RefTitle> <RefYear>2003</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>1011-6</RefPage> <RefTotal>de Jonge E, Schultz MJ, Spanjaard L, Bossuyt PM, Vroom MB, Dankert J, Kesecioglu J. Effects of selective decontamination of digestive tract on mortality and acquistition of resistant bacteria in intensive care: a randomized controlled trial. Lancet. 2003;362(9389):1011-6. DOI: 10.1016&#47;S0140-6736(03)14409-1</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(03)14409-1</RefLink> </Reference> <Reference refNo="140"> <RefAuthor>Heininger A</RefAuthor> <RefAuthor>Meyer E</RefAuthor> <RefAuthor>Schwab F</RefAuthor> <RefAuthor>Marschal M</RefAuthor> <RefAuthor>Unertl K</RefAuthor> <RefAuthor>Krueger WA</RefAuthor> <RefTitle>Effects of long-term routine use of selective digestive decontamination on antimicrobial resistance</RefTitle> <RefYear>2006</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1569-76</RefPage> <RefTotal>Heininger A, Meyer E, Schwab F, Marschal M, Unertl K, Krueger WA. Effects of long-term routine use of selective digestive decontamination on antimicrobial resistance. Intensive Care Med. 2006;32(10):1569-76. DOI: 10.1007&#47;s00134-006-0304-5</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-006-0304-5</RefLink> </Reference> <Reference refNo="141"> <RefAuthor>Leone M</RefAuthor> <RefAuthor>Albanese J</RefAuthor> <RefAuthor>Antonini F</RefAuthor> <RefAuthor>Nguyen-Michel A</RefAuthor> <RefAuthor>Martin C</RefAuthor> <RefTitle>Long-term (6-year) effect of selective digestive decontamination on antimicrobial resistance in intensive care, multiple-trauma patients</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2090-5</RefPage> <RefTotal>Leone M, Albanese J, Antonini F, Nguyen-Michel A, Martin C. Long-term (6-year) effect of selective digestive decontamination on antimicrobial resistance in intensive care, multiple-trauma patients. Crit Care Med. 2003;31(8):2090-5. DOI: 10.1097&#47;01.CCM.0000079606.16776.C5</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000079606.16776.C5</RefLink> </Reference> <Reference refNo="143"> <RefAuthor>Chlebicki MP</RefAuthor> <RefAuthor>Safdar N</RefAuthor> <RefTitle>Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>595-602</RefPage> <RefTotal>Chlebicki MP, Safdar N. Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med. 2007;35(2):595-602. DOI: 10.1097&#47;01.CCM.0000253395.70708.AC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000253395.70708.AC</RefLink> </Reference> <Reference refNo="144"> <RefAuthor>Segers P</RefAuthor> <RefAuthor>Speekenbrink RG</RefAuthor> <RefAuthor>Ubbink DT</RefAuthor> <RefAuthor>van Ogtrop ML</RefAuthor> <RefAuthor>de Mol BA</RefAuthor> <RefTitle>Prevention of nosocomial infection in cardiac surgery by decontamination of the nasopharynx and oropharynx with chlorhexidine gluconate: a randomized controlled trial</RefTitle> <RefYear>2006</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>2460-6</RefPage> <RefTotal>Segers P, Speekenbrink RG, Ubbink DT, van Ogtrop ML, de Mol BA. Prevention of nosocomial infection in cardiac surgery by decontamination of the nasopharynx and oropharynx with chlorhexidine gluconate: a randomized controlled trial. JAMA. 2006;296(20):2460-6. DOI: 10.1001&#47;jama.296.20.2460</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.296.20.2460</RefLink> </Reference> <Reference refNo="145"> <RefAuthor>Kola A</RefAuthor> <RefAuthor>Gastmeier P</RefAuthor> <RefTitle>Efficacy of oral chlorhexidine in preventing lower respiratory tract infections: Meta-analysis of randomized controlled trials</RefTitle> <RefYear>2007</RefYear> <RefJournal>J Hosp Infect</RefJournal> <RefPage>207-16</RefPage> <RefTotal>Kola A, Gastmeier P. Efficacy of oral chlorhexidine in preventing lower respiratory tract infections: Meta-analysis of randomized controlled trials. J Hosp Infect. 2007;66(3):207-16. DOI: 10.1016&#47;j.jhin.2007.03.025</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.jhin.2007.03.025</RefLink> </Reference> <Reference refNo="146"> <RefAuthor>Chan EY</RefAuthor> <RefAuthor>Ruest A</RefAuthor> <RefAuthor>Meade MO</RefAuthor> <RefAuthor>Cook DJ</RefAuthor> <RefTitle>Oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis</RefTitle> <RefYear>2007</RefYear> <RefJournal>BMJ</RefJournal> <RefPage>889</RefPage> <RefTotal>Chan EY, Ruest A, Meade MO, Cook DJ. Oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis. BMJ. 2007;334(7599):889. DOI: 10.1136&#47;bmj.39136.528160.BE</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1136&#47;bmj.39136.528160.BE</RefLink> </Reference> <Reference refNo="147"> <RefAuthor>Piarroux R</RefAuthor> <RefAuthor>Grenouillet F</RefAuthor> <RefAuthor>Balvay P</RefAuthor> <RefAuthor>Tran V</RefAuthor> <RefAuthor>Blasco G</RefAuthor> <RefAuthor>Millon L</RefAuthor> <RefAuthor>Boillot A</RefAuthor> <RefTitle>Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients</RefTitle> <RefYear>2004</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2443-9</RefPage> <RefTotal>Piarroux R, Grenouillet F, Balvay P, Tran V, Blasco G, Millon L, Boillot A. Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med. 2004;32(12):2443-9. DOI: 10.1097&#47;01.CCM.0000147726.62304.7F</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000147726.62304.7F</RefLink> </Reference> <Reference refNo="148"> <RefAuthor>Ho K</RefAuthor> <RefAuthor>Rochford S</RefAuthor> <RefAuthor>John G</RefAuthor> <RefTitle>The use of topical nonabsorabable gastrointestinal antifungal prophylaxis to prevent fungal infections in critically ill immunocompetent patients: a meta-analysis</RefTitle> <RefYear>2005</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2383-92</RefPage> <RefTotal>Ho K, Rochford S, John G. The use of topical nonabsorabable gastrointestinal antifungal prophylaxis to prevent fungal infections in critically ill immunocompetent patients: a meta-analysis. Crit Care Med. 2005;33(10):2383-92. DOI: 10.1097&#47;01.CCM.0000181726.32675.37</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000181726.32675.37</RefLink> </Reference> <Reference refNo="149"> <RefAuthor>Veenstra DL</RefAuthor> <RefAuthor>Saint S</RefAuthor> <RefAuthor>Saha S</RefAuthor> <RefAuthor>Lumley T</RefAuthor> <RefAuthor>Sullivan SD</RefAuthor> <RefTitle>Efficacy of antiseptic-impregnated central venous catheters in preventing catheter-related bloodstream infection</RefTitle> <RefYear>1999</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>261-7</RefPage> <RefTotal>Veenstra DL, Saint S, Saha S, Lumley T, Sullivan SD. Efficacy of antiseptic-impregnated central venous catheters in preventing catheter-related bloodstream infection. JAMA. 1999;281(3):261-7. DOI: 10.1001&#47;jama.281.3.261</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.281.3.261</RefLink> </Reference> <Reference refNo="150"> <RefAuthor>Geffers C</RefAuthor> <RefAuthor>Zuschneid I</RefAuthor> <RefAuthor>Eckmanns T</RefAuthor> <RefAuthor>R&#252;den H</RefAuthor> <RefAuthor>Gastmeier P</RefAuthor> <RefTitle>The relationship between methodological trial quality and the effects of impregnated central venous catheters</RefTitle> <RefYear>2003</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>403-9</RefPage> <RefTotal>Geffers C, Zuschneid I, Eckmanns T, R&#252;den H, Gastmeier P. The relationship between methodological trial quality and the effects of impregnated central venous catheters. Intensive Care Med. 2003;29(3):403-9.</RefTotal> </Reference> <Reference refNo="151"> <RefAuthor>Walder B</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefAuthor>Tram&#232;r M</RefAuthor> <RefTitle>Prevention of bloodstream infections with central venous catheters treated with anti-infective agents depends on catheter type and insertion time: Evidence from a meta-analysis</RefTitle> <RefYear>2002</RefYear> <RefJournal>Infect Control Hosp Epidemiol</RefJournal> <RefPage>748-56</RefPage> <RefTotal>Walder B, Pittet D, Tram&#232;r M. Prevention of bloodstream infections with central venous catheters treated with anti-infective agents depends on catheter type and insertion time: Evidence from a meta-analysis. Infect Control Hosp Epidemiol. 2002;23(12):748-56. DOI: 10.1086&#47;502005</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;502005</RefLink> </Reference> <Reference refNo="152"> <RefAuthor>Johnson J</RefAuthor> <RefAuthor>Kuskowski M</RefAuthor> <RefAuthor>Wilt T</RefAuthor> <RefTitle>Systematic review: antimicrobial urinary cathetrs to prevent catheter-associated urinary tract infection in hospitalized patients</RefTitle> <RefYear>2006</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>116-26</RefPage> <RefTotal>Johnson J, Kuskowski M, Wilt T. Systematic review: antimicrobial urinary cathetrs to prevent catheter-associated urinary tract infection in hospitalized patients. Ann Intern Med. 2006;144(2):116-26.</RefTotal> </Reference> <Reference refNo="153"> <RefAuthor>Falagas M</RefAuthor> <RefAuthor>Fragoulis K</RefAuthor> <RefAuthor>Bliziotis I</RefAuthor> <RefAuthor>Chatzinikolaou I</RefAuthor> <RefTitle>Rifampicin-impregnated central venous catheters: a meta-analysis of randomized controlled trials</RefTitle> <RefYear>2007</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>359-69</RefPage> <RefTotal>Falagas M, Fragoulis K, Bliziotis I, Chatzinikolaou I. Rifampicin-impregnated central venous catheters: a meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2007;59(3):359-69. DOI: 10.1093&#47;jac&#47;dkl522</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;jac&#47;dkl522</RefLink> </Reference> <Reference refNo="154"> <RefAuthor>Fridkin SK</RefAuthor> <RefAuthor>Pear SM</RefAuthor> <RefAuthor>Williamson TH</RefAuthor> <RefAuthor>Galgiani JN</RefAuthor> <RefAuthor>Jarvis WR</RefAuthor> <RefTitle>The role of understaffing in central venous catheter-associated bloodstream infection</RefTitle> <RefYear>1996</RefYear> <RefJournal>Infect Control Hosp Epidemiol</RefJournal> <RefPage>150-8</RefPage> <RefTotal>Fridkin SK, Pear SM, Williamson TH, Galgiani JN, Jarvis WR. The role of understaffing in central venous catheter-associated bloodstream infection. Infect Control Hosp Epidemiol. 1996;17(3):150-8. DOI: 10.1086&#47;647262</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;647262</RefLink> </Reference> <Reference refNo="155"> <RefAuthor>Archibald LK</RefAuthor> <RefAuthor>Manning ML</RefAuthor> <RefAuthor>Bell LM</RefAuthor> <RefAuthor>Banerjee S</RefAuthor> <RefAuthor>Jarvis WR</RefAuthor> <RefTitle>Patient density, nurse-to-patient ratio and nosocomial infection risk in a pediatric cardiac intensive care unit</RefTitle> <RefYear>1997</RefYear> <RefJournal>Pediatr Infect Dis J</RefJournal> <RefPage>1045-8</RefPage> <RefTotal>Archibald LK, Manning ML, Bell LM, Banerjee S, Jarvis WR. Patient density, nurse-to-patient ratio and nosocomial infection risk in a pediatric cardiac intensive care unit. Pediatr Infect Dis J. 1997;16(11):1045-8. DOI: 10.1097&#47;00006454-199711000-00008</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00006454-199711000-00008</RefLink> </Reference> <Reference refNo="156"> <RefAuthor>Dorsey G</RefAuthor> <RefAuthor>Borneo HT</RefAuthor> <RefAuthor>Sun SJ</RefAuthor> <RefAuthor>Wells J</RefAuthor> <RefAuthor>Steele L</RefAuthor> <RefAuthor>Howland K</RefAuthor> <RefAuthor>Perdreau-Remington F</RefAuthor> <RefAuthor>Bangsberg DR</RefAuthor> <RefTitle>A heterogeneous outbreak of Enterobacter cloacae and Serratia marcescens infections in a surgical intensive care unit</RefTitle> <RefYear>2000</RefYear> <RefJournal>Infect Control Hosp Epidemiol</RefJournal> <RefPage>465-9</RefPage> <RefTotal>Dorsey G, Borneo HT, Sun SJ, Wells J, Steele L, Howland K, Perdreau-Remington F, Bangsberg DR. A heterogeneous outbreak of Enterobacter cloacae and Serratia marcescens infections in a surgical intensive care unit. Infect Control Hosp Epidemiol. 2000;21(7):465-9. DOI: 10.1086&#47;501789</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;501789</RefLink> </Reference> <Reference refNo="157"> <RefAuthor>Pessoa-Silva CL</RefAuthor> <RefAuthor>Toscano CM</RefAuthor> <RefAuthor>Moreira BM</RefAuthor> <RefAuthor>Santos AL</RefAuthor> <RefAuthor>Frota AC</RefAuthor> <RefAuthor>Solari CA</RefAuthor> <RefAuthor>Amorim EL</RefAuthor> <RefAuthor>Carvalho Mda G</RefAuthor> <RefAuthor>Teixeira LM</RefAuthor> <RefAuthor>Jarvis WR</RefAuthor> <RefTitle>Infection due to extended-spectrum beta-lactamase-producing Salmonella enterica subs. enterica serotype infantis in aneonatal unit</RefTitle> <RefYear>2002</RefYear> <RefJournal>J Pediatr</RefJournal> <RefPage>381-7</RefPage> <RefTotal>Pessoa-Silva CL, Toscano CM, Moreira BM, Santos AL, Frota AC, Solari CA, Amorim EL, Carvalho Mda G, Teixeira LM, Jarvis WR. Infection due to extended-spectrum beta-lactamase-producing Salmonella enterica subs. enterica serotype infantis in aneonatal unit. J Pediatr. 2002;141(3):381-7. DOI: 10.1067&#47;mpd.2002.127279</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1067&#47;mpd.2002.127279</RefLink> </Reference> <Reference refNo="158"> <RefAuthor>Robert J</RefAuthor> <RefAuthor>Fridkin SK</RefAuthor> <RefAuthor>Blumberg HM</RefAuthor> <RefAuthor>Anderson B</RefAuthor> <RefAuthor>White N</RefAuthor> <RefAuthor>Ray SM</RefAuthor> <RefAuthor>Chan J</RefAuthor> <RefAuthor>Jarvis WR</RefAuthor> <RefTitle>The influence of the composition of the nursing staff on primary bloodstream infection rates in a surgical intensive care unit</RefTitle> <RefYear>2000</RefYear> <RefJournal>Infect Control Hosp Epidemiol</RefJournal> <RefPage>12-7</RefPage> <RefTotal>Robert J, Fridkin SK, Blumberg HM, Anderson B, White N, Ray SM, Chan J, Jarvis WR. The influence of the composition of the nursing staff on primary bloodstream infection rates in a surgical intensive care unit. Infect Control Hosp Epidemiol. 2000;21(1):12-7. DOI: 10.1086&#47;501690</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;501690</RefLink> </Reference> <Reference refNo="159"> <RefAuthor>Harbarth S</RefAuthor> <RefAuthor>Sudre P</RefAuthor> <RefAuthor>Dharan S</RefAuthor> <RefAuthor>Cadenas M</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefTitle>Outbreak of Enterobacter cloacae related to understaffing, overcrowding, and poor hygiene practices</RefTitle> <RefYear>1999</RefYear> <RefJournal>Infect Control Hosp Epidemiol</RefJournal> <RefPage>598-603</RefPage> <RefTotal>Harbarth S, Sudre P, Dharan S, Cadenas M, Pittet D. Outbreak of Enterobacter cloacae related to understaffing, overcrowding, and poor hygiene practices. Infect Control Hosp Epidemiol. 1999;20(9):598-603. DOI: 10.1086&#47;501677</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;501677</RefLink> </Reference> <Reference refNo="160"> <RefAuthor>Halwani M</RefAuthor> <RefAuthor>Solaymani-Dodaran M</RefAuthor> <RefAuthor>Grundmann H</RefAuthor> <RefAuthor>Coupland C</RefAuthor> <RefAuthor>Slack R</RefAuthor> <RefTitle>Cross-transmission of nosocomial pathogens in an adult intensive care unit: incidence and risk factors</RefTitle> <RefYear>2006</RefYear> <RefJournal>J Hosp Infect</RefJournal> <RefPage>39-46</RefPage> <RefTotal>Halwani M, Solaymani-Dodaran M, Grundmann H, Coupland C, Slack R. Cross-transmission of nosocomial pathogens in an adult intensive care unit: incidence and risk factors. J Hosp Infect. 2006;63(1):39-46. DOI: 10.1016&#47;j.jhin.2005.10.012</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.jhin.2005.10.012</RefLink> </Reference> <Reference refNo="161"> <RefAuthor>Hugonnet S</RefAuthor> <RefAuthor>Chevrolet JC</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefTitle>The effect of workload on infection risk in critically ill patients</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>76-81</RefPage> <RefTotal>Hugonnet S, Chevrolet JC, Pittet D. The effect of workload on infection risk in critically ill patients. Crit Care Med. 2007;35(1):76-81. DOI: 10.1097&#47;01.CCM.0000251125.08629.3F</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000251125.08629.3F</RefLink> </Reference> <Reference refNo="162"> <RefAuthor>William BM</RefAuthor> <RefAuthor>Thawani N</RefAuthor> <RefAuthor>Sae-Tia S</RefAuthor> <RefAuthor>Corazza GR</RefAuthor> <RefTitle>Hyposplenism: a comprehensive review. Part II: clinical manifestations, diagnosis, and management</RefTitle> <RefYear>2007</RefYear> <RefJournal>Hematology</RefJournal> <RefPage>89-98</RefPage> <RefTotal>William BM, Thawani N, Sae-Tia S, Corazza GR. Hyposplenism: a comprehensive review. Part II: clinical manifestations, diagnosis, and management. Hematology. 2007;12(2):89-98. DOI: 10.1080&#47;10245330600938463</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1080&#47;10245330600938463</RefLink> </Reference> <Reference refNo="163"> <RefAuthor>Landgren O</RefAuthor> <RefAuthor>Bj&#246;rkholm M</RefAuthor> <RefAuthor>Konradsen HB</RefAuthor> <RefAuthor>S&#246;derqvist M</RefAuthor> <RefAuthor>Nilsson B</RefAuthor> <RefAuthor>Gustavsson A</RefAuthor> <RefAuthor>Axdorph U</RefAuthor> <RefAuthor>Kalin M</RefAuthor> <RefAuthor>Grimfors G</RefAuthor> <RefTitle>A prospective study on antibody response to repeated vaccinations with pneumococcal capsular polysaccharide in splenectomized individuals with special reference to Hodgkin&#39;s lymphoma</RefTitle> <RefYear>2004</RefYear> <RefJournal>J Intern Med</RefJournal> <RefPage>664-73</RefPage> <RefTotal>Landgren O, Bj&#246;rkholm M, Konradsen HB, S&#246;derqvist M, Nilsson B, Gustavsson A, Axdorph U, Kalin M, Grimfors G. A prospective study on antibody response to repeated vaccinations with pneumococcal capsular polysaccharide in splenectomized individuals with special reference to Hodgkin&#39;s lymphoma. J Intern Med. 2004;255(6):664-73. DOI: 10.1111&#47;j.1365-2796.2004.01312.x</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1111&#47;j.1365-2796.2004.01312.x</RefLink> </Reference> <Reference refNo="164"> <RefAuthor>Cherif H</RefAuthor> <RefAuthor>Landgren O</RefAuthor> <RefAuthor>Konradsen HB</RefAuthor> <RefAuthor>Kalin M</RefAuthor> <RefAuthor>Bj&#246;rkholm M</RefAuthor> <RefTitle>Poor antibody response to pneumococcal polysaccharide vaccination suggests increased susceptibility to pneumococcal infection in splenectomized patients with hematological diseases</RefTitle> <RefYear>2006</RefYear> <RefJournal>Vaccine</RefJournal> <RefPage>75-81</RefPage> <RefTotal>Cherif H, Landgren O, Konradsen HB, Kalin M, Bj&#246;rkholm M. Poor antibody response to pneumococcal polysaccharide vaccination suggests increased susceptibility to pneumococcal infection in splenectomized patients with hematological diseases. Vaccine. 2006;24(1):75-81. DOI: 10.1016&#47;j.vaccine.2005.07.054</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.vaccine.2005.07.054</RefLink> </Reference> <Reference refNo="165"> <RefAuthor>Davies JM</RefAuthor> <RefAuthor>Barnes R</RefAuthor> <RefAuthor>Milligan D</RefAuthor> <RefAuthor> British Committee for Standards in Haematology</RefAuthor> <RefTitle>Working Party of the Haematology&#47;Oncology Task Force. Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen</RefTitle> <RefYear>2002</RefYear> <RefJournal>Clin Med</RefJournal> <RefPage>440-3</RefPage> <RefTotal>Davies JM, Barnes R, Milligan D; British Committee for Standards in Haematology. Working Party of the Haematology&#47;Oncology Task Force. Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med. 2002;2(5):440-3.</RefTotal> </Reference> <Reference refNo="167"> <RefAuthor>Jackson LA</RefAuthor> <RefAuthor>Neuzil KM</RefAuthor> <RefAuthor>Yu O</RefAuthor> <RefAuthor>Benson P</RefAuthor> <RefAuthor>Barlow WE</RefAuthor> <RefAuthor>Adams AL</RefAuthor> <RefAuthor>Hanson CA</RefAuthor> <RefAuthor>Mahoney LD</RefAuthor> <RefAuthor>Shay DK</RefAuthor> <RefAuthor>Thompson WW</RefAuthor> <RefAuthor> Vaccine Safety Datalink</RefAuthor> <RefTitle>Effectiveness of pneumococcal polysaccharide vaccine in older adults</RefTitle> <RefYear>2003</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1747-55</RefPage> <RefTotal>Jackson LA, Neuzil KM, Yu O, Benson P, Barlow WE, Adams AL, Hanson CA, Mahoney LD, Shay DK, Thompson WW; Vaccine Safety Datalink. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med. 2003;348(18):1747-55. DOI: 10.1056&#47;NEJMoa022678</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa022678</RefLink> </Reference> <Reference refNo="168"> <RefAuthor>Vila-C&#243;rcoles A</RefAuthor> <RefAuthor>Ochoa-Gondar O</RefAuthor> <RefAuthor>Hospital I</RefAuthor> <RefAuthor>Ansa X</RefAuthor> <RefAuthor>Vilanova A</RefAuthor> <RefAuthor>Rodr&#237;guez T</RefAuthor> <RefAuthor>Llor C</RefAuthor> <RefAuthor> EVAN Study Group</RefAuthor> <RefTitle>Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population: the EVAN-65 study</RefTitle> <RefYear>2006</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>860-8</RefPage> <RefTotal>Vila-C&#243;rcoles A, Ochoa-Gondar O, Hospital I, Ansa X, Vilanova A, Rodr&#237;guez T, Llor C; EVAN Study Group. Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population: the EVAN-65 study. Clin Infect Dis. 2006;43(7):860-8. DOI: 10.1086&#47;507340</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;507340</RefLink> </Reference> <Reference refNo="169"> <RefAuthor>Ortqvist A</RefAuthor> <RefAuthor>Hedlund J</RefAuthor> <RefAuthor>Burman LA</RefAuthor> <RefAuthor>Elbel E</RefAuthor> <RefAuthor>H&#246;fer M</RefAuthor> <RefAuthor>Leinonen M</RefAuthor> <RefAuthor>Lindblad I</RefAuthor> <RefAuthor>Sundel&#246;f B</RefAuthor> <RefAuthor>Kalin M</RefAuthor> <RefTitle>Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group</RefTitle> <RefYear>1998</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>399-403</RefPage> <RefTotal>Ortqvist A, Hedlund J, Burman LA, Elbel E, H&#246;fer M, Leinonen M, Lindblad I, Sundel&#246;f B, Kalin M. Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet. 1998;351(9100):399-403. DOI: 10.1016&#47;S0140-6736(97)07358-3</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(97)07358-3</RefLink> </Reference> <Reference refNo="170"> <RefAuthor>Wacha H</RefAuthor> <RefAuthor>Hau T</RefAuthor> <RefAuthor>Dittmer R</RefAuthor> <RefAuthor>Ohmann C</RefAuthor> <RefTitle>Risk factors associated with intraabdominal infections: a prospective multicenter study. Peritonitis Study Group</RefTitle> <RefYear>1999</RefYear> <RefJournal>Langenbecks Arch Surg</RefJournal> <RefPage>24-32</RefPage> <RefTotal>Wacha H, Hau T, Dittmer R, Ohmann C. Risk factors associated with intraabdominal infections: a prospective multicenter study. Peritonitis Study Group. Langenbecks Arch Surg. 1999;384(1):24-32. DOI: 10.1007&#47;s004230050169</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s004230050169</RefLink> </Reference> <Reference refNo="171"> <RefAuthor>Barie PS</RefAuthor> <RefAuthor>Williams MD</RefAuthor> <RefAuthor>McCollam JS</RefAuthor> <RefAuthor>Bates BM</RefAuthor> <RefAuthor>Qualy RL</RefAuthor> <RefAuthor>Lowry SF</RefAuthor> <RefAuthor>Fry DE</RefAuthor> <RefAuthor> PROWESS Surgical Evaluation Committee</RefAuthor> <RefTitle>Benefit&#47;risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis</RefTitle> <RefYear>2004</RefYear> <RefJournal>Am J Surg</RefJournal> <RefPage>212-20</RefPage> <RefTotal>Barie PS, Williams MD, McCollam JS, Bates BM, Qualy RL, Lowry SF, Fry DE; PROWESS Surgical Evaluation Committee. Benefit&#47;risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis. Am J Surg. 2004;188(3):212-20. DOI: 10.1016&#47;j.amjsurg.2004.06.008</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.amjsurg.2004.06.008</RefLink> </Reference> <Reference refNo="172"> <RefAuthor>Koperna T</RefAuthor> <RefAuthor>Schulz F</RefAuthor> <RefTitle>Relaparotomy in peritonitis: prognosis and treatment of patients with persisting intraabdominal infection</RefTitle> <RefYear>2000</RefYear> <RefJournal>World J Surg</RefJournal> <RefPage>32-7</RefPage> <RefTotal>Koperna T, Schulz F. Relaparotomy in peritonitis: prognosis and treatment of patients with persisting intraabdominal infection. World J Surg. 2000;24(1):32-7. DOI: 10.1007&#47;s002689910007</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s002689910007</RefLink> </Reference> <Reference refNo="173"> <RefAuthor>Kaiser RE</RefAuthor> <RefAuthor>Cerra FB</RefAuthor> <RefTitle>Progressive necrotizing surgical infections--a unified approach</RefTitle> <RefYear>1981</RefYear> <RefJournal>J Trauma</RefJournal> <RefPage>349-55</RefPage> <RefTotal>Kaiser RE, Cerra FB. Progressive necrotizing surgical infections--a unified approach. J Trauma. 1981;21(5):349-55. DOI: 10.1097&#47;00005373-198105000-00003</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00005373-198105000-00003</RefLink> </Reference> <Reference refNo="174"> <RefAuthor>Byrnes MC</RefAuthor> <RefAuthor>Coopersmith CM</RefAuthor> <RefTitle>Prevention of catheter-related blood stream infection</RefTitle> <RefYear>2007</RefYear> <RefJournal>Curr Opin Crit Care</RefJournal> <RefPage>411-5</RefPage> <RefTotal>Byrnes MC, Coopersmith CM. Prevention of catheter-related blood stream infection. Curr Opin Crit Care. 2007;13(4):411-5. DOI: 10.1097&#47;MCC.0b013e3281f8d279</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;MCC.0b013e3281f8d279</RefLink> </Reference> <Reference refNo="175"> <RefAuthor>Z&#252;hlke H</RefAuthor> <RefTitle>Autologe Verfahren zur Therapie von Gef&#228;&#223;infektionen</RefTitle> <RefYear>2006</RefYear> <RefJournal>Gef&#228;&#223;chirurgie</RefJournal> <RefPage>409-422</RefPage> <RefTotal>Z&#252;hlke H. Autologe Verfahren zur Therapie von Gef&#228;&#223;infektionen &#91;Autologous procedure for the treatment of vascular infections&#93;. Gef&#228;&#223;chirurgie. 2006;11(6):409-422. DOI: 10.1007&#47;s00772-006-0491-y</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00772-006-0491-y</RefLink> </Reference> <Reference refNo="176"> <RefAuthor>Arens S</RefAuthor> <RefAuthor>Hansis M</RefAuthor> <RefTitle>Implantate in der Unfallchirurgie: Osteosynthese mit Titan</RefTitle> <RefYear>1998</RefYear> <RefJournal>Dtsch Arztebl</RefJournal> <RefPage>1516-1518</RefPage> <RefTotal>Arens S, Hansis M. Implantate in der Unfallchirurgie: Osteosynthese mit Titan. Dtsch Arztebl. 1998;95(24):1516-1518.</RefTotal> </Reference> <Reference refNo="177"> <RefAuthor>Sia IG</RefAuthor> <RefAuthor>Berbari EF</RefAuthor> <RefAuthor>Karchmer AW</RefAuthor> <RefTitle>Prosthetic joint infections</RefTitle> <RefYear>2005</RefYear> <RefJournal>Infect Dis Clin North Am</RefJournal> <RefPage>885-914</RefPage> <RefTotal>Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections. Infect Dis Clin North Am. 2005;19(4):885-914. DOI: 10.1016&#47;j.idc.2005.07.010</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.idc.2005.07.010</RefLink> </Reference> <Reference refNo="178"> <RefAuthor>Mehendiratta V</RefAuthor> <RefAuthor>McCarty BC</RefAuthor> <RefAuthor>Gomez L</RefAuthor> <RefAuthor>Graviss EA</RefAuthor> <RefAuthor>Musher DM</RefAuthor> <RefTitle>Computerized tomography (CT)-guided aspiration of abscesses: outcome of therapy at a tertiary care hospital</RefTitle> <RefYear>2007</RefYear> <RefJournal>J Infect</RefJournal> <RefPage>122-8</RefPage> <RefTotal>Mehendiratta V, McCarty BC, Gomez L, Graviss EA, Musher DM. Computerized tomography (CT)-guided aspiration of abscesses: outcome of therapy at a tertiary care hospital. J Infect. 2007;54(2):122-8. DOI: 10.1016&#47;j.jinf.2006.03.004</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.jinf.2006.03.004</RefLink> </Reference> <Reference refNo="179"> <RefAuthor>Schneider JI</RefAuthor> <RefTitle>Rapid infectious killers</RefTitle> <RefYear>2004</RefYear> <RefJournal>Emerg Med Clin North Am</RefJournal> <RefPage>1099-115</RefPage> <RefTotal>Schneider JI. Rapid infectious killers. Emerg Med Clin North Am. 2004;22(4):1099-115. DOI: 10.1016&#47;j.emc.2004.05.007</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.emc.2004.05.007</RefLink> </Reference> <Reference refNo="180"> <RefAuthor>van Ruler O</RefAuthor> <RefAuthor>Lamme B</RefAuthor> <RefAuthor>Gouma DJ</RefAuthor> <RefAuthor>Reitsma JB</RefAuthor> <RefAuthor>Boermeester MA</RefAuthor> <RefTitle>Variables associated with positive findings at relaparotomy in patients with secondary peritonitis</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>468-76</RefPage> <RefTotal>van Ruler O, Lamme B, Gouma DJ, Reitsma JB, Boermeester MA. Variables associated with positive findings at relaparotomy in patients with secondary peritonitis. Crit Care Med. 2007;35(2):468-76. DOI: 10.1097&#47;01.CCM.0000253399.03545.2D</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000253399.03545.2D</RefLink> </Reference> <Reference refNo="181"> <RefAuthor>Pieracci FM</RefAuthor> <RefAuthor>Barie PS</RefAuthor> <RefTitle>Intra-abdominal infections</RefTitle> <RefYear>2007</RefYear> <RefJournal>Curr Opin Crit Care</RefJournal> <RefPage>440-9</RefPage> <RefTotal>Pieracci FM, Barie PS. Intra-abdominal infections. Curr Opin Crit Care. 2007;13(4):440-9. DOI: 10.1097&#47;MCC.0b013e32825a6720</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;MCC.0b013e32825a6720</RefLink> </Reference> <Reference refNo="182"> <RefAuthor>Klompas M</RefAuthor> <RefAuthor>Yokoe DS</RefAuthor> <RefTitle>Automated surveillance of health care-associated infections</RefTitle> <RefYear>2009</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1268-75</RefPage> <RefTotal>Klompas M, Yokoe DS. Automated surveillance of health care-associated infections. Clin Infect Dis. 2009;48(9):1268-75. DOI: 10.1086&#47;597591</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;597591</RefLink> </Reference> <Reference refNo="183"> <RefAuthor>Anonym</RefAuthor> <RefTitle>Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Surveillance Report, data summary from January 1996 through December 1997: A report from the National Nosocomial Infections Surveillance (NNIS) System</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Infect Control</RefJournal> <RefPage>279-84</RefPage> <RefTotal>Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Surveillance Report, data summary from January 1996 through December 1997: A report from the National Nosocomial Infections Surveillance (NNIS) System. Am J Infect Control. 1999;27(3):279-84. DOI: 10.1053&#47;ic.1999.v27.a98878</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1053&#47;ic.1999.v27.a98878</RefLink> </Reference> <Reference refNo="184"> <RefAuthor>Engel C</RefAuthor> <RefAuthor>Brunkhorst FM</RefAuthor> <RefAuthor>Bone HG</RefAuthor> <RefAuthor>Brunkhorst R</RefAuthor> <RefAuthor>Gerlach H</RefAuthor> <RefAuthor>Grond S</RefAuthor> <RefAuthor>Gruendling M</RefAuthor> <RefAuthor>Huhle G</RefAuthor> <RefAuthor>Jaschinski U</RefAuthor> <RefAuthor>John S</RefAuthor> <RefAuthor>Mayer K</RefAuthor> <RefAuthor>Oppert M</RefAuthor> <RefAuthor>Olthoff D</RefAuthor> <RefAuthor>Quintel M</RefAuthor> <RefAuthor>Ragaller M</RefAuthor> <RefAuthor>Rossaint R</RefAuthor> <RefAuthor>Stuber F</RefAuthor> <RefAuthor>Weiler N</RefAuthor> <RefAuthor>Welte T</RefAuthor> <RefAuthor>Bogatsch H</RefAuthor> <RefAuthor>Hartog C</RefAuthor> <RefAuthor>Loeffler M</RefAuthor> <RefAuthor>Reinhart K</RefAuthor> <RefTitle>Epidemiology of sepsis in Germany: results from a national prospective multicenter study</RefTitle> <RefYear>2007</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>606-18</RefPage> <RefTotal>Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007;33(4):606-18. DOI: 10.1007&#47;s00134-006-0517-7</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-006-0517-7</RefLink> </Reference> <Reference refNo="185"> <RefAuthor>Freid MA</RefAuthor> <RefAuthor>Vosti KL</RefAuthor> <RefTitle>The importance of underlying disease in patients with gram-negative bacteremia</RefTitle> <RefYear>1968</RefYear> <RefJournal>Arch Intern Med</RefJournal> <RefPage>418-23</RefPage> <RefTotal>Freid MA, Vosti KL. The importance of underlying disease in patients with gram-negative bacteremia. Arch Intern Med. 1968;121(5):418-23.</RefTotal> </Reference> <Reference refNo="186"> <RefAuthor>McCabe WR</RefAuthor> <RefAuthor>Jackson GG</RefAuthor> <RefTitle>Gram negative bacteremia: I. Etiology and Ecology</RefTitle> <RefYear>1962</RefYear> <RefJournal>Arch Intern Med</RefJournal> <RefPage>847-855</RefPage> <RefTotal>McCabe WR, Jackson GG. Gram negative bacteremia: I. Etiology and Ecology. Arch Intern Med. 1962;110(6):847-855.</RefTotal> </Reference> <Reference refNo="187"> <RefAuthor>Bryant RE</RefAuthor> <RefAuthor>Hood AF</RefAuthor> <RefAuthor>Hood CE</RefAuthor> <RefAuthor>Koenig MG</RefAuthor> <RefTitle>Factors affecting mortality of gram-negative rod bacteremia</RefTitle> <RefYear>1971</RefYear> <RefJournal>Arch Intern Med</RefJournal> <RefPage>120-8</RefPage> <RefTotal>Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Arch Intern Med. 1971;127(1):120-8.</RefTotal> </Reference> <Reference refNo="188"> <RefAuthor>Young LS</RefAuthor> <RefAuthor>Martin WJ</RefAuthor> <RefAuthor>Meyer RD</RefAuthor> <RefAuthor>Weinstein RJ</RefAuthor> <RefAuthor>Anderson ET</RefAuthor> <RefTitle>Gram-negative rod bacteremia: microbiologic, immunologic, and therapeutic considerations</RefTitle> <RefYear>1977</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>456-71</RefPage> <RefTotal>Young LS, Martin WJ, Meyer RD, Weinstein RJ, Anderson ET. Gram-negative rod bacteremia: microbiologic, immunologic, and therapeutic considerations. Ann Intern Med. 1977;86(4):456-71.</RefTotal> </Reference> <Reference refNo="189"> <RefAuthor>Kreger BE</RefAuthor> <RefAuthor>Craven DE</RefAuthor> <RefAuthor>McCabe WR</RefAuthor> <RefTitle>Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients</RefTitle> <RefYear>1980</RefYear> <RefJournal>Am J Med</RefJournal> <RefPage>344-55</RefPage> <RefTotal>Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med. 1980;68(3):344-55. DOI: 10.1016&#47;0002-9343(80)90102-3</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;0002-9343(80)90102-3</RefLink> </Reference> <Reference refNo="190"> <RefAuthor>Leibovici L</RefAuthor> <RefAuthor>Paul M</RefAuthor> <RefAuthor>Poznanski O</RefAuthor> <RefAuthor>Drucker M</RefAuthor> <RefAuthor>Samra Z</RefAuthor> <RefAuthor>Konigsberger H</RefAuthor> <RefAuthor>Pitlik SD</RefAuthor> <RefTitle>Monotherapy versus beta-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study</RefTitle> <RefYear>1997</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>1127-33</RefPage> <RefTotal>Leibovici L, Paul M, Poznanski O, Drucker M, Samra Z, Konigsberger H, Pitlik SD. Monotherapy versus beta-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrob Agents Chemother. 1997;41(5):1127-33.</RefTotal> </Reference> <Reference refNo="191"> <RefAuthor>Chow JW</RefAuthor> <RefAuthor>Fine MJ</RefAuthor> <RefAuthor>Shlaes DM</RefAuthor> <RefAuthor>Quinn JP</RefAuthor> <RefAuthor>Hooper DC</RefAuthor> <RefAuthor>Johnson MP</RefAuthor> <RefAuthor>Ramphal R</RefAuthor> <RefAuthor>Wagener MM</RefAuthor> <RefAuthor>Miyashiro DK</RefAuthor> <RefAuthor>Yu VL</RefAuthor> <RefTitle>Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy</RefTitle> <RefYear>1991</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>585-90</RefPage> <RefTotal>Chow JW, Fine MJ, Shlaes DM, Quinn JP, Hooper DC, Johnson MP, Ramphal R, Wagener MM, Miyashiro DK, Yu VL. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991;115(8):585-90.</RefTotal> </Reference> <Reference refNo="192"> <RefAuthor>Vidal F</RefAuthor> <RefAuthor>Mensa J</RefAuthor> <RefAuthor>Almela M</RefAuthor> <RefAuthor>Mart&#237;nez JA</RefAuthor> <RefAuthor>Marco F</RefAuthor> <RefAuthor>Casals C</RefAuthor> <RefAuthor>Gatell JM</RefAuthor> <RefAuthor>Soriano E</RefAuthor> <RefAuthor>Jimenez de Anta MT</RefAuthor> <RefTitle>Epidemiology and outcome of Pseudomonas aeruginosa bacteremia, with special emphasis on the influence of antibiotic treatment. Analysis of 189 episodes</RefTitle> <RefYear>1996</RefYear> <RefJournal>Arch Intern Med</RefJournal> <RefPage>2121-6</RefPage> <RefTotal>Vidal F, Mensa J, Almela M, Mart&#237;nez JA, Marco F, Casals C, Gatell JM, Soriano E, Jimenez de Anta MT. Epidemiology and outcome of Pseudomonas aeruginosa bacteremia, with special emphasis on the influence of antibiotic treatment. Analysis of 189 episodes. Arch Intern Med. 1996;156(18):2121-6.</RefTotal> </Reference> <Reference refNo="193"> <RefAuthor>Schiappa DA</RefAuthor> <RefAuthor>Hayden MK</RefAuthor> <RefAuthor>Matushek MG</RefAuthor> <RefAuthor>Hashemi FN</RefAuthor> <RefAuthor>Sullivan J</RefAuthor> <RefAuthor>Smith KY</RefAuthor> <RefAuthor>Miyashiro D</RefAuthor> <RefAuthor>Quinn JP</RefAuthor> <RefAuthor>Weinstein RA</RefAuthor> <RefAuthor>Trenholme GM</RefAuthor> <RefTitle>Ceftazidime-resistant Klebsiella pneumoniae and Escherichia coli bloodstream infection: a case-control and molecular epidemiologic investigation</RefTitle> <RefYear>1996</RefYear> <RefJournal>J Infect Dis</RefJournal> <RefPage>529-36</RefPage> <RefTotal>Schiappa DA, Hayden MK, Matushek MG, Hashemi FN, Sullivan J, Smith KY, Miyashiro D, Quinn JP, Weinstein RA, Trenholme GM. Ceftazidime-resistant Klebsiella pneumoniae and Escherichia coli bloodstream infection: a case-control and molecular epidemiologic investigation. J Infect Dis. 1996;174(3):529-36.</RefTotal> </Reference> <Reference refNo="194"> <RefAuthor>Caballero-Granado FJ</RefAuthor> <RefAuthor>Cisneros JM</RefAuthor> <RefAuthor>Luque R</RefAuthor> <RefAuthor>Torres-Tortosa M</RefAuthor> <RefAuthor>Gamboa F</RefAuthor> <RefAuthor>D&#237;ez F</RefAuthor> <RefAuthor>Villanueva JL</RefAuthor> <RefAuthor>P&#233;rez-Cano R</RefAuthor> <RefAuthor>Pasquau J</RefAuthor> <RefAuthor>Merino D</RefAuthor> <RefAuthor>Menchero A</RefAuthor> <RefAuthor>Mora D</RefAuthor> <RefAuthor>L&#243;pez-Ruz MA</RefAuthor> <RefAuthor>Vergara A</RefAuthor> <RefTitle>Comparative study of bacteremias caused by Enterococcus spp. with and without high-level resistance to gentamicin. The Grupo Andaluz para el estudio de las Enfermedades Infecciosas</RefTitle> <RefYear>1998</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>520-5</RefPage> <RefTotal>Caballero-Granado FJ, Cisneros JM, Luque R, Torres-Tortosa M, Gamboa F, D&#237;ez F, Villanueva JL, P&#233;rez-Cano R, Pasquau J, Merino D, Menchero A, Mora D, L&#243;pez-Ruz MA, Vergara A. Comparative study of bacteremias caused by Enterococcus spp. with and without high-level resistance to gentamicin. The Grupo Andaluz para el estudio de las Enfermedades Infecciosas. J Clin Microbiol. 1998;36(2):520-5.</RefTotal> </Reference> <Reference refNo="195"> <RefAuthor>Ispahani P</RefAuthor> <RefAuthor>Pearson NJ</RefAuthor> <RefAuthor>Greenwood D</RefAuthor> <RefTitle>An analysis of community and hospital-acquired bacteraemia in a large teaching hospital in the United Kingdom</RefTitle> <RefYear>1987</RefYear> <RefJournal>Q J Med</RefJournal> <RefPage>427-40</RefPage> <RefTotal>Ispahani P, Pearson NJ, Greenwood D. An analysis of community and hospital-acquired bacteraemia in a large teaching hospital in the United Kingdom. Q J Med. 1987;63(241):427-40.</RefTotal> </Reference> <Reference refNo="196"> <RefAuthor>Leibovici L</RefAuthor> <RefAuthor>Drucker M</RefAuthor> <RefAuthor>Konigsberger H</RefAuthor> <RefAuthor>Samra Z</RefAuthor> <RefAuthor>Harrari S</RefAuthor> <RefAuthor>Ashkenazi S</RefAuthor> <RefAuthor>Pitlik SD</RefAuthor> <RefTitle>Septic shock in bacteremic patients: risk factors, features and prognosis</RefTitle> <RefYear>1997</RefYear> <RefJournal>Scand J Infect Dis</RefJournal> <RefPage>71-5</RefPage> <RefTotal>Leibovici L, Drucker M, Konigsberger H, Samra Z, Harrari S, Ashkenazi S, Pitlik SD. Septic shock in bacteremic patients: risk factors, features and prognosis. Scand J Infect Dis. 1997;29(1):71-5. DOI: 10.3109&#47;00365549709008668</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.3109&#47;00365549709008668</RefLink> </Reference> <Reference refNo="197"> <RefAuthor>Leibovici L</RefAuthor> <RefAuthor>Shraga I</RefAuthor> <RefAuthor>Drucker M</RefAuthor> <RefAuthor>Konigsberger H</RefAuthor> <RefAuthor>Samra Z</RefAuthor> <RefAuthor>Pitlik SD</RefAuthor> <RefTitle>The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection</RefTitle> <RefYear>1998</RefYear> <RefJournal>J Intern Med</RefJournal> <RefPage>379-86</RefPage> <RefTotal>Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med. 1998;244(5):379-86. DOI: 10.1046&#47;j.1365-2796.1998.00379.x</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1046&#47;j.1365-2796.1998.00379.x</RefLink> </Reference> <Reference refNo="198"> <RefAuthor>Kollef MH</RefAuthor> <RefAuthor>Sherman G</RefAuthor> <RefAuthor>Ward S</RefAuthor> <RefAuthor>Fraser VJ</RefAuthor> <RefTitle>Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients</RefTitle> <RefYear>1999</RefYear> <RefJournal>Chest</RefJournal> <RefPage>462-74</RefPage> <RefTotal>Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115(2):462-74. DOI: 10.1378&#47;chest.115.2.462</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.115.2.462</RefLink> </Reference> <Reference refNo="199"> <RefAuthor>Ibrahim EH</RefAuthor> <RefAuthor>Sherman G</RefAuthor> <RefAuthor>Ward S</RefAuthor> <RefAuthor>Fraser VJ</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting</RefTitle> <RefYear>2000</RefYear> <RefJournal>Chest</RefJournal> <RefPage>146-55</RefPage> <RefTotal>Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118(1):146-55. DOI: 10.1378&#47;chest.118.1.146</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.118.1.146</RefLink> </Reference> <Reference refNo="200"> <RefAuthor>Harbarth S</RefAuthor> <RefAuthor>Ferriere K</RefAuthor> <RefAuthor>Hugonnet S</RefAuthor> <RefAuthor>Ricou B</RefAuthor> <RefAuthor>Suter P</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefTitle>Epidemiology and prognostic determinants of bloodstream infections in surgical intensive care</RefTitle> <RefYear>2002</RefYear> <RefJournal>Arch Surg</RefJournal> <RefPage>1353-9; discussion 1359</RefPage> <RefTotal>Harbarth S, Ferriere K, Hugonnet S, Ricou B, Suter P, Pittet D. Epidemiology and prognostic determinants of bloodstream infections in surgical intensive care. Arch Surg. 2002;137(12):1353-9; discussion 1359. DOI: 10.1001&#47;archsurg.137.12.1353</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;archsurg.137.12.1353</RefLink> </Reference> <Reference refNo="201"> <RefAuthor>Hanon FX</RefAuthor> <RefAuthor>Monnet DL</RefAuthor> <RefAuthor>Sorensen TL</RefAuthor> <RefAuthor>Molbak K</RefAuthor> <RefAuthor>Pedersen G</RefAuthor> <RefAuthor>Schonheyder H</RefAuthor> <RefTitle>Survival of patients with bacteraemia in relation to initial empirical antimicrobial treatment</RefTitle> <RefYear>2002</RefYear> <RefJournal>Scand J Infect Dis</RefJournal> <RefPage>520-8</RefPage> <RefTotal>Hanon FX, Monnet DL, Sorensen TL, Molbak K, Pedersen G, Schonheyder H. Survival of patients with bacteraemia in relation to initial empirical antimicrobial treatment. Scand J Infect Dis. 2002;34(7):520-8. DOI: 10.1080&#47;00365540110080827</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1080&#47;00365540110080827</RefLink> </Reference> <Reference refNo="202"> <RefAuthor>Harbarth S</RefAuthor> <RefAuthor>Garbino J</RefAuthor> <RefAuthor>Pugin J</RefAuthor> <RefAuthor>Romand JA</RefAuthor> <RefAuthor>Lew D</RefAuthor> <RefAuthor>Pittet D</RefAuthor> <RefTitle>Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis</RefTitle> <RefYear>2003</RefYear> <RefJournal>Am J Med</RefJournal> <RefPage>529-35</RefPage> <RefTotal>Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115(7):529-35. DOI: 10.1016&#47;j.amjmed.2003.07.005</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.amjmed.2003.07.005</RefLink> </Reference> <Reference refNo="203"> <RefAuthor>Zaragoza R</RefAuthor> <RefAuthor>Artero A</RefAuthor> <RefAuthor>Camarena JJ</RefAuthor> <RefAuthor>Sancho S</RefAuthor> <RefAuthor>Gonzalez R</RefAuthor> <RefAuthor>Nogueira JM</RefAuthor> <RefTitle>The influence of inadequate empirical antimicrobial treatment on patients with bloodstream infections in an intensive care unit</RefTitle> <RefYear>2003</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>412-8</RefPage> <RefTotal>Zaragoza R, Artero A, Camarena JJ, Sancho S, Gonzalez R, Nogueira JM. The influence of inadequate empirical antimicrobial treatment on patients with bloodstream infections in an intensive care unit. Clin Microbiol Infect. 2003;9(5):412-8. DOI: 10.1046&#47;j.1469-0691.2003.00656.x</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1046&#47;j.1469-0691.2003.00656.x</RefLink> </Reference> <Reference refNo="204"> <RefAuthor>Leone M</RefAuthor> <RefAuthor>Bourgoin A</RefAuthor> <RefAuthor>Cambon S</RefAuthor> <RefAuthor>Dubuc M</RefAuthor> <RefAuthor>Albanese J</RefAuthor> <RefAuthor>Martin C</RefAuthor> <RefTitle>Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>462-7</RefPage> <RefTotal>Leone M, Bourgoin A, Cambon S, Dubuc M, Albanese J, Martin C. Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome. Crit Care Med. 2003;31(2):462-7. DOI: 10.1097&#47;01.CCM.0000050298.59549.4A</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000050298.59549.4A</RefLink> </Reference> <Reference refNo="205"> <RefAuthor>Garnacho-Montero J</RefAuthor> <RefAuthor>Garcia-Garmendia JL</RefAuthor> <RefAuthor>Barrero-Almodovar A</RefAuthor> <RefAuthor>Jimenez-Jimenez FJ</RefAuthor> <RefAuthor>Perez-Paredes C</RefAuthor> <RefAuthor>Ortiz-Leyba C</RefAuthor> <RefTitle>Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2742-51</RefPage> <RefTotal>Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med. 2003;31(12):2742-51. DOI: 10.1097&#47;01.CCM.0000098031.24329.10</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000098031.24329.10</RefLink> </Reference> <Reference refNo="206"> <RefAuthor>Paul M</RefAuthor> <RefAuthor>Benuri-Silbiger I</RefAuthor> <RefAuthor>Soares-Weiser K</RefAuthor> <RefAuthor>Leibovici L</RefAuthor> <RefTitle>Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials</RefTitle> <RefYear>2004</RefYear> <RefJournal>BMJ</RefJournal> <RefPage>668</RefPage> <RefTotal>Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ. 2004;328(7441):668. DOI: 10.1136&#47;bmj.38028.520995.63</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1136&#47;bmj.38028.520995.63</RefLink> </Reference> <Reference refNo="207"> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>Dodek P</RefAuthor> <RefAuthor>Muscedere J</RefAuthor> <RefAuthor>Day A</RefAuthor> <RefAuthor>Cook D</RefAuthor> <RefTitle>Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia</RefTitle> <RefYear>2008</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>737-44</RefPage> <RefTotal>Heyland DK, Dodek P, Muscedere J, Day A, Cook D. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med. 2008;36(3):737-44. DOI: 10.1097&#47;01.CCM.0B013E31816203D6</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0B013E31816203D6</RefLink> </Reference> <Reference refNo="208"> <RefAuthor>Fowler VG Jr</RefAuthor> <RefAuthor>Boucher HW</RefAuthor> <RefAuthor>Corey GR</RefAuthor> <RefAuthor>Abrutyn E</RefAuthor> <RefAuthor>Karchmer AW</RefAuthor> <RefAuthor>Rupp ME</RefAuthor> <RefAuthor>Levine DP</RefAuthor> <RefAuthor>Chambers HF</RefAuthor> <RefAuthor>Tally FP</RefAuthor> <RefAuthor>Vigliani GA</RefAuthor> <RefAuthor>Cabell CH</RefAuthor> <RefAuthor>Link AS</RefAuthor> <RefAuthor>DeMeyer I</RefAuthor> <RefAuthor>Filler SG</RefAuthor> <RefAuthor>Zervos M</RefAuthor> <RefAuthor>Cook P</RefAuthor> <RefAuthor>Parsonnet J</RefAuthor> <RefAuthor>Bernstein JM</RefAuthor> <RefAuthor>Price CS</RefAuthor> <RefAuthor>Forrest GN</RefAuthor> <RefAuthor>F&#228;tkenheuer G</RefAuthor> <RefAuthor>Gareca M</RefAuthor> <RefAuthor>Rehm SJ</RefAuthor> <RefAuthor>Brodt HR</RefAuthor> <RefAuthor>Tice A</RefAuthor> <RefAuthor>Cosgrove SE</RefAuthor> <RefAuthor> S. aureus Endocarditis and Bacteremia Study Group</RefAuthor> <RefTitle>Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus</RefTitle> <RefYear>2006</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>653-65</RefPage> <RefTotal>Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, F&#228;tkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE; S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355(7):653-65. DOI: 10.1056&#47;NEJMoa053783</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa053783</RefLink> </Reference> <Reference refNo="209"> <RefAuthor>Babinchak T</RefAuthor> <RefAuthor>Ellis-Grosse E</RefAuthor> <RefAuthor>Dartois N</RefAuthor> <RefAuthor>Rose GM</RefAuthor> <RefAuthor>Loh E</RefAuthor> <RefTitle>The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data</RefTitle> <RefYear>2005</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>S354-67</RefPage> <RefTotal>Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis. 2005;41 Suppl 5:S354-67. DOI: 10.1086&#47;431676</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;431676</RefLink> </Reference> <Reference refNo="210"> <RefAuthor>Byl B</RefAuthor> <RefAuthor>Jacobs F</RefAuthor> <RefAuthor>Wallemacq P</RefAuthor> <RefAuthor>Rossi C</RefAuthor> <RefAuthor>de Francquen P</RefAuthor> <RefAuthor>Cappello M</RefAuthor> <RefAuthor>Leal T</RefAuthor> <RefAuthor>Thys JP</RefAuthor> <RefTitle>Vancomycin penetration of uninfected pleural fluid exudate after continuous or intermittent infusion</RefTitle> <RefYear>2003</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2015-7</RefPage> <RefTotal>Byl B, Jacobs F, Wallemacq P, Rossi C, de Francquen P, Cappello M, Leal T, Thys JP. Vancomycin penetration of uninfected pleural fluid exudate after continuous or intermittent infusion. Antimicrob Agents Chemother. 2003;47(6):2015-7. DOI: 10.1128&#47;AAC.47.6.2015-2017.2003</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1128&#47;AAC.47.6.2015-2017.2003</RefLink> </Reference> <Reference refNo="211"> <RefAuthor>Cruciani M</RefAuthor> <RefAuthor>Gatti G</RefAuthor> <RefAuthor>Lazzarini L</RefAuthor> <RefAuthor>Furlan G</RefAuthor> <RefAuthor>Broccali G</RefAuthor> <RefAuthor>Malena M</RefAuthor> <RefAuthor>Franchini C</RefAuthor> <RefAuthor>Concia E</RefAuthor> <RefTitle>Penetration of vancomycin into human lung tissue</RefTitle> <RefYear>1996</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>865-9</RefPage> <RefTotal>Cruciani M, Gatti G, Lazzarini L, Furlan G, Broccali G, Malena M, Franchini C, Concia E. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother. 1996;38(5):865-9. DOI: 10.1093&#47;jac&#47;38.5.865</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;jac&#47;38.5.865</RefLink> </Reference> <Reference refNo="212"> <RefAuthor>Kollef MH</RefAuthor> <RefAuthor>Rello J</RefAuthor> <RefAuthor>Cammarata SK</RefAuthor> <RefAuthor>Croos-Dabrera RV</RefAuthor> <RefAuthor>Wunderink RG</RefAuthor> <RefTitle>Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin</RefTitle> <RefYear>2004</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>388-94</RefPage> <RefTotal>Kollef MH, Rello J, Cammarata SK, Croos-Dabrera RV, Wunderink RG. Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intensive Care Med. 2004;30(3):388-94. DOI: 10.1007&#47;s00134-003-2088-1</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-003-2088-1</RefLink> </Reference> <Reference refNo="213"> <RefAuthor>Wunderink RG</RefAuthor> <RefAuthor>Rello J</RefAuthor> <RefAuthor>Cammarata SK</RefAuthor> <RefAuthor>Croos-Dabrera RV</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia</RefTitle> <RefYear>2003</RefYear> <RefJournal>Chest</RefJournal> <RefPage>1789-97</RefPage> <RefTotal>Wunderink RG, Rello J, Cammarata SK, Croos-Dabrera RV, Kollef MH. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest. 2003;124(5):1789-97. DOI: 10.1378&#47;chest.124.5.1789</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.124.5.1789</RefLink> </Reference> <Reference refNo="214"> <RefAuthor>Sharpe JN</RefAuthor> <RefAuthor>Shively EH</RefAuthor> <RefAuthor>Polk HC Jr</RefAuthor> <RefTitle>Clinical and economic outcomes of oral linezolid versus intravenous vancomycin in the treatment of MRSA-complicated, lower-extremity skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus</RefTitle> <RefYear>2005</RefYear> <RefJournal>Am J Surg</RefJournal> <RefPage>425-8</RefPage> <RefTotal>Sharpe JN, Shively EH, Polk HC Jr. Clinical and economic outcomes of oral linezolid versus intravenous vancomycin in the treatment of MRSA-complicated, lower-extremity skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. Am J Surg. 2005;189(4):425-8. DOI: 10.1016&#47;j.amjsurg.2005.01.011</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.amjsurg.2005.01.011</RefLink> </Reference> <Reference refNo="215"> <RefAuthor>Weigelt J</RefAuthor> <RefAuthor>Itani K</RefAuthor> <RefAuthor>Stevens D</RefAuthor> <RefAuthor>Lau W</RefAuthor> <RefAuthor>Dryden M</RefAuthor> <RefAuthor>Knirsch C</RefAuthor> <RefTitle>Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections</RefTitle> <RefYear>2005</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2260-6</RefPage> <RefTotal>Weigelt J, Itani K, Stevens D, Lau W, Dryden M, Knirsch C. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother. 2005;49(6):2260-6. DOI: 10.1128&#47;AAC.49.6.2260-2266.2005</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1128&#47;AAC.49.6.2260-2266.2005</RefLink> </Reference> <Reference refNo="216"> <RefAuthor>Weigelt J</RefAuthor> <RefAuthor>Kaafarani HM</RefAuthor> <RefAuthor>Itani KM</RefAuthor> <RefAuthor>Swanson RN</RefAuthor> <RefTitle>Linezolid eradicates MRSA better than vancomycin from surgical-site infections</RefTitle> <RefYear>2004</RefYear> <RefJournal>Am J Surg</RefJournal> <RefPage>760-6</RefPage> <RefTotal>Weigelt J, Kaafarani HM, Itani KM, Swanson RN. Linezolid eradicates MRSA better than vancomycin from surgical-site infections. Am J Surg. 2004;188(6):760-6. DOI: 10.1016&#47;j.amjsurg.2004.08.045</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.amjsurg.2004.08.045</RefLink> </Reference> <Reference refNo="217"> <RefAuthor>Gang RK</RefAuthor> <RefAuthor>Sanyal SC</RefAuthor> <RefAuthor>Mokaddas E</RefAuthor> <RefAuthor>Lari AR</RefAuthor> <RefTitle>Rifampicin as an adjunct to vancomycin therapy in MRSA septicaemia in burns</RefTitle> <RefYear>1999</RefYear> <RefJournal>Burns</RefJournal> <RefPage>640-4</RefPage> <RefTotal>Gang RK, Sanyal SC, Mokaddas E, Lari AR. Rifampicin as an adjunct to vancomycin therapy in MRSA septicaemia in burns. Burns. 1999;25(7):640-4. DOI: 10.1016&#47;S0305-4179(99)00045-5</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0305-4179(99)00045-5</RefLink> </Reference> <Reference refNo="218"> <RefAuthor>Grif K</RefAuthor> <RefAuthor>Dierich MP</RefAuthor> <RefAuthor>Pfaller K</RefAuthor> <RefAuthor>Miglioli PA</RefAuthor> <RefAuthor>Allerberger F</RefAuthor> <RefTitle>In vitro activity of fosfomycin in combination with various antistaphylococcal substances</RefTitle> <RefYear>2001</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>209-17</RefPage> <RefTotal>Grif K, Dierich MP, Pfaller K, Miglioli PA, Allerberger F. In vitro activity of fosfomycin in combination with various antistaphylococcal substances. J Antimicrob Chemother. 2001;48(2):209-17. DOI: 10.1093&#47;jac&#47;48.2.209</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;jac&#47;48.2.209</RefLink> </Reference> <Reference refNo="219"> <RefAuthor>Yzerman EP</RefAuthor> <RefAuthor>Boelens HA</RefAuthor> <RefAuthor>Vogel M</RefAuthor> <RefAuthor>Verbrugh HA</RefAuthor> <RefTitle>Efficacy and safety of teicoplanin plus rifampicin in the treatment of bacteraemic infections caused by Staphylococcus aureus</RefTitle> <RefYear>1998</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>233-9</RefPage> <RefTotal>Yzerman EP, Boelens HA, Vogel M, Verbrugh HA. Efficacy and safety of teicoplanin plus rifampicin in the treatment of bacteraemic infections caused by Staphylococcus aureus. J Antimicrob Chemother. 1998;42(2):233-9. DOI: 10.1093&#47;jac&#47;42.2.233</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;jac&#47;42.2.233</RefLink> </Reference> <Reference refNo="220"> <RefAuthor>Howden BP</RefAuthor> <RefAuthor>Ward PB</RefAuthor> <RefAuthor>Charles PG</RefAuthor> <RefAuthor>Korman TM</RefAuthor> <RefAuthor>Fuller A</RefAuthor> <RefAuthor>du Cros P</RefAuthor> <RefAuthor>Grabsch EA</RefAuthor> <RefAuthor>Roberts SA</RefAuthor> <RefAuthor>Robson J</RefAuthor> <RefAuthor>Read K</RefAuthor> <RefAuthor>Bak N</RefAuthor> <RefAuthor>Hurley J</RefAuthor> <RefAuthor>Johnson PD</RefAuthor> <RefAuthor>Morris AJ</RefAuthor> <RefAuthor>Mayall BC</RefAuthor> <RefAuthor>Grayson ML</RefAuthor> <RefTitle>Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility</RefTitle> <RefYear>2004</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>521-8</RefPage> <RefTotal>Howden BP, Ward PB, Charles PG, Korman TM, Fuller A, du Cros P, Grabsch EA, Roberts SA, Robson J, Read K, Bak N, Hurley J, Johnson PD, Morris AJ, Mayall BC, Grayson ML. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis. 2004;38(4):521-8. DOI: 10.1086&#47;381202</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;381202</RefLink> </Reference> <Reference refNo="221"> <RefAuthor>Baddour LM</RefAuthor> <RefAuthor>Yu VL</RefAuthor> <RefAuthor>Klugman KP</RefAuthor> <RefAuthor>Feldman C</RefAuthor> <RefAuthor>Ortqvist A</RefAuthor> <RefAuthor>Rello J</RefAuthor> <RefAuthor>Morris AJ</RefAuthor> <RefAuthor>Luna CM</RefAuthor> <RefAuthor>Snydman DR</RefAuthor> <RefAuthor>Ko WC</RefAuthor> <RefAuthor>Chedid MB</RefAuthor> <RefAuthor>Hui DS</RefAuthor> <RefAuthor>Andremont A</RefAuthor> <RefAuthor>Chiou CC</RefAuthor> <RefAuthor> International Pneumococcal Study Group</RefAuthor> <RefTitle>Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia</RefTitle> <RefYear>2004</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>440-4</RefPage> <RefTotal>Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A, Rello J, Morris AJ, Luna CM, Snydman DR, Ko WC, Chedid MB, Hui DS, Andremont A, Chiou CC; International Pneumococcal Study Group. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med. 2004;170(4):440-4. DOI: 10.1164&#47;rccm.200311-1578OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200311-1578OC</RefLink> </Reference> <Reference refNo="222"> <RefAuthor>Nguyen MH</RefAuthor> <RefAuthor>Peacock JE Jr</RefAuthor> <RefAuthor>Tanner DC</RefAuthor> <RefAuthor>Morris AJ</RefAuthor> <RefAuthor>Nguyen ML</RefAuthor> <RefAuthor>Snydman DR</RefAuthor> <RefAuthor>Wagener MM</RefAuthor> <RefAuthor>Yu VL</RefAuthor> <RefTitle>Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study</RefTitle> <RefYear>1995</RefYear> <RefJournal>Arch Intern Med</RefJournal> <RefPage>2429-35</RefPage> <RefTotal>Nguyen MH, Peacock JE Jr, Tanner DC, Morris AJ, Nguyen ML, Snydman DR, Wagener MM, Yu VL. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med. 1995;155(22):2429-35.</RefTotal> </Reference> <Reference refNo="223"> <RefAuthor>Jacobs S</RefAuthor> <RefAuthor>Price Evans DA</RefAuthor> <RefAuthor>Tariq M</RefAuthor> <RefAuthor>Al Omar NF</RefAuthor> <RefTitle>Fluconazole improves survival in septic shock: a randomized double-blind prospective study</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1938-46</RefPage> <RefTotal>Jacobs S, Price Evans DA, Tariq M, Al Omar NF. Fluconazole improves survival in septic shock: a randomized double-blind prospective study. Crit Care Med. 2003;31(7):1938-46. DOI: 10.1097&#47;01.CCM.0000074724.71242.88</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000074724.71242.88</RefLink> </Reference> <Reference refNo="224"> <RefAuthor>Bochud PY</RefAuthor> <RefAuthor>Glauser MP</RefAuthor> <RefAuthor>Calandra T</RefAuthor> <RefTitle>Antibiotics in sepsis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>S33-48</RefPage> <RefTotal>Bochud PY, Glauser MP, Calandra T. Antibiotics in sepsis. Intensive Care Med. 2001;27 Suppl 1:S33-48.</RefTotal> </Reference> <Reference refNo="225"> <RefAuthor>Sobel JD</RefAuthor> <RefAuthor>Rex JH</RefAuthor> <RefTitle>Invasive candidiasis: turning risk into a practical prevention policy&#63;</RefTitle> <RefYear>2001</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>187-90</RefPage> <RefTotal>Sobel JD, Rex JH. Invasive candidiasis: turning risk into a practical prevention policy&#63; Clin Infect Dis. 2001;33(2):187-90. DOI: 10.1086&#47;321812</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1086&#47;321812</RefLink> </Reference> <Reference refNo="226"> <RefAuthor>Link H</RefAuthor> <RefAuthor>Bohme A</RefAuthor> <RefAuthor>Cornely OA</RefAuthor> <RefAuthor>Hoffken K</RefAuthor> <RefAuthor>Kellner O</RefAuthor> <RefAuthor>Kern WV</RefAuthor> <RefAuthor>Mahlberg R</RefAuthor> <RefAuthor>Maschmeyer G</RefAuthor> <RefAuthor>Nowrousian MR</RefAuthor> <RefAuthor>Ostermann H</RefAuthor> <RefAuthor>Ruhnke M</RefAuthor> <RefAuthor>Sezer O</RefAuthor> <RefAuthor>Schiel X</RefAuthor> <RefAuthor>Wilhelm M</RefAuthor> <RefAuthor>Auner HW</RefAuthor> <RefAuthor> Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)</RefAuthor> <RefAuthor> Group Interventional Therapy of Unexplained Fever</RefAuthor> <RefAuthor>Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society)</RefAuthor> <RefTitle>Antimicrobial therapy of unexplained fever in neutropenic patients - guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society)</RefTitle> <RefYear>2003</RefYear> <RefJournal>Ann Hematol</RefJournal> <RefPage>S105-17</RefPage> <RefTotal>Link H, Bohme A, Cornely OA, Hoffken K, Kellner O, Kern WV, Mahlberg R, Maschmeyer G, Nowrousian MR, Ostermann H, Ruhnke M, Sezer O, Schiel X, Wilhelm M, Auner HW; Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO); Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society). Antimicrobial therapy of unexplained fever in neutropenic patients - guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society). Ann Hematol. 2003;82 Suppl 2:S105-17.</RefTotal> </Reference> <Reference refNo="227"> <RefAuthor>Maschmeyer G</RefAuthor> <RefAuthor>B&#246;hme A</RefAuthor> <RefAuthor>Buchheidt D</RefAuthor> <RefAuthor>Cornely OA</RefAuthor> <RefAuthor>Fricke HJ</RefAuthor> <RefAuthor>Karthaus M</RefAuthor> <RefAuthor>Lehrnbecher T</RefAuthor> <RefAuthor>Link H</RefAuthor> <RefAuthor>Shah PM</RefAuthor> <RefAuthor>Wilhelm M</RefAuthor> <RefTitle>Diagnostik und Therapie von Infektionen bei Patienten in der H&#228;matologie und Onkologie: Leitlinien der Sektion Infektionen in der H&#228;matologie&#47;Onkologie der Paul-Ehrlich-Gesellschaft e.V</RefTitle> <RefYear>2004</RefYear> <RefJournal>Chemother J</RefJournal> <RefPage>134-141</RefPage> <RefTotal>Maschmeyer G, B&#246;hme A, Buchheidt D, Cornely OA, Fricke HJ, Karthaus M, Lehrnbecher T, Link H, Shah PM, Wilhelm M. Diagnostik und Therapie von Infektionen bei Patienten in der H&#228;matologie und Onkologie: Leitlinien der Sektion Infektionen in der H&#228;matologie&#47;Onkologie der Paul-Ehrlich-Gesellschaft e.V. Chemother J. 2004;13(3):134-141. Available from: http:&#47;&#47;www.wissenschaftliche-verlagsgesellschaft.de&#47;CTJ&#47;CTJ2004&#47;CTJ3-2004&#47;Consensus-haematologie.pdf</RefTotal> <RefLink>http:&#47;&#47;www.wissenschaftliche-verlagsgesellschaft.de&#47;CTJ&#47;CTJ2004&#47;CTJ3-2004&#47;Consensus-haematologie.pdf</RefLink> </Reference> <Reference refNo="228"> <RefAuthor>Rivers E</RefAuthor> <RefAuthor>Nguyen B</RefAuthor> <RefAuthor>Havstad S</RefAuthor> <RefAuthor>Ressler J</RefAuthor> <RefAuthor>Muzzin A</RefAuthor> <RefAuthor>Knoblich B</RefAuthor> <RefAuthor>Peterson E</RefAuthor> <RefAuthor>Tomlanovich M</RefAuthor> <RefAuthor> Early Goal-Directed Therapy Collaborative Group</RefAuthor> <RefTitle>Early goal-directed therapy in the treatment of severe sepsis and septic shock</RefTitle> <RefYear>2001</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1368-77</RefPage> <RefTotal>Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-77. DOI: 10.1056&#47;NEJMoa010307</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa010307</RefLink> </Reference> <Reference refNo="229"> <RefAuthor>Swenson JD</RefAuthor> <RefAuthor>Bull D</RefAuthor> <RefAuthor>Stringham J</RefAuthor> <RefTitle>Subjective assessment of left ventricular preload using transesophageal echocardiography: corresponding pulmonary artery occlusion pressures</RefTitle> <RefYear>2001</RefYear> <RefJournal>J Cardiothorac Vasc Anesth</RefJournal> <RefPage>580-3</RefPage> <RefTotal>Swenson JD, Bull D, Stringham J. Subjective assessment of left ventricular preload using transesophageal echocardiography: corresponding pulmonary artery occlusion pressures. J Cardiothorac Vasc Anesth. 2001;15(5):580-3. DOI: 10.1053&#47;jcan.2001.26535</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1053&#47;jcan.2001.26535</RefLink> </Reference> <Reference refNo="230"> <RefAuthor>Buhre W</RefAuthor> <RefAuthor>Buhre K</RefAuthor> <RefAuthor>Kazmaier S</RefAuthor> <RefAuthor>Sonntag H</RefAuthor> <RefAuthor>Weyland A</RefAuthor> <RefTitle>Assessment of cardiac preload by indicator dilution and transoesophageal echocardiography</RefTitle> <RefYear>2001</RefYear> <RefJournal>Eur J Anaesthesiol</RefJournal> <RefPage>662-7</RefPage> <RefTotal>Buhre W, Buhre K, Kazmaier S, Sonntag H, Weyland A. Assessment of cardiac preload by indicator dilution and transoesophageal echocardiography. Eur J Anaesthesiol. 2001;18(10):662-7.</RefTotal> </Reference> <Reference refNo="231"> <RefAuthor>Kumar A</RefAuthor> <RefAuthor>Anel R</RefAuthor> <RefAuthor>Bunnell E</RefAuthor> <RefAuthor>Habet K</RefAuthor> <RefAuthor>Zanotti S</RefAuthor> <RefAuthor>Marshall S</RefAuthor> <RefAuthor>Neumann A</RefAuthor> <RefAuthor>Ali A</RefAuthor> <RefAuthor>Cheang M</RefAuthor> <RefAuthor>Kavinsky C</RefAuthor> <RefAuthor>Parrillo JE</RefAuthor> <RefTitle>Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects</RefTitle> <RefYear>2004</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>691-9</RefPage> <RefTotal>Kumar A, Anel R, Bunnell E, Habet K, Zanotti S, Marshall S, Neumann A, Ali A, Cheang M, Kavinsky C, Parrillo JE. Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects. Crit Care Med. 2004;32(3):691-9. DOI: 10.1097&#47;01.CCM.0000114996.68110.C9</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000114996.68110.C9</RefLink> </Reference> <Reference refNo="232"> <RefAuthor>Godje O</RefAuthor> <RefAuthor>Peyerl M</RefAuthor> <RefAuthor>Seebauer T</RefAuthor> <RefAuthor>Lamm P</RefAuthor> <RefAuthor>Mair H</RefAuthor> <RefAuthor>Reichart B</RefAuthor> <RefTitle>Central venous pressure, pulmonary capillary wedge pressure and intrathoracic blood volumes as preload indicators in cardiac surgery patients</RefTitle> <RefYear>1998</RefYear> <RefJournal>Eur J Cardiothorac Surg</RefJournal> <RefPage>533-9; discussion 539-40</RefPage> <RefTotal>Godje O, Peyerl M, Seebauer T, Lamm P, Mair H, Reichart B. Central venous pressure, pulmonary capillary wedge pressure and intrathoracic blood volumes as preload indicators in cardiac surgery patients. Eur J Cardiothorac Surg. 1998;13(5):533-9; discussion 539-40. DOI: 10.1016&#47;S1010-7940(98)00063-3</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S1010-7940(98)00063-3</RefLink> </Reference> <Reference refNo="233"> <RefAuthor>Nguyen HB</RefAuthor> <RefAuthor>Corbett SW</RefAuthor> <RefAuthor>Steele R</RefAuthor> <RefAuthor>Banta J</RefAuthor> <RefAuthor>Clark RT</RefAuthor> <RefAuthor>Hayes SR</RefAuthor> <RefAuthor>Edwards J</RefAuthor> <RefAuthor>Cho TW</RefAuthor> <RefAuthor>Wittlake WA</RefAuthor> <RefTitle>Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1105-12</RefPage> <RefTotal>Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, Edwards J, Cho TW, Wittlake WA. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med. 2007;35(4):1105-12. DOI: 10.1097&#47;01.CCM.0000259463.33848.3D</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000259463.33848.3D</RefLink> </Reference> <Reference refNo="234"> <RefAuthor>Ferrer R</RefAuthor> <RefAuthor>Artigas A</RefAuthor> <RefAuthor>Levy MM</RefAuthor> <RefAuthor>Blanco J</RefAuthor> <RefAuthor>Gonz&#225;lez-D&#237;az G</RefAuthor> <RefAuthor>Garnacho-Montero J</RefAuthor> <RefAuthor>Ib&#225;&#241;ez J</RefAuthor> <RefAuthor>Palencia E</RefAuthor> <RefAuthor>Quintana M</RefAuthor> <RefAuthor>de la Torre-Prados MV</RefAuthor> <RefAuthor> Edusepsis Study Group</RefAuthor> <RefTitle>Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain</RefTitle> <RefYear>2008</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>2294-303</RefPage> <RefTotal>Ferrer R, Artigas A, Levy MM, Blanco J, Gonz&#225;lez-D&#237;az G, Garnacho-Montero J, Ib&#225;&#241;ez J, Palencia E, Quintana M, de la Torre-Prados MV; Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299(19):2294-303. DOI: 10.1001&#47;jama.299.19.2294</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.299.19.2294</RefLink> </Reference> <Reference refNo="235"> <RefAuthor>Kortgen A</RefAuthor> <RefAuthor>Niederpr&#252;m P</RefAuthor> <RefAuthor>Bauer M</RefAuthor> <RefTitle>Implementation of an evidence-based &#34;standard operating procedure&#34; and outcome in septic shock</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>943-9</RefPage> <RefTotal>Kortgen A, Niederpr&#252;m P, Bauer M. Implementation of an evidence-based &#34;standard operating procedure&#34; and outcome in septic shock. Crit Care Med. 2006;34(4):943-9. DOI: 10.1097&#47;01.CCM.0000206112.32673.D4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000206112.32673.D4</RefLink> </Reference> <Reference refNo="236"> <RefAuthor>Brunkhorst FM</RefAuthor> <RefAuthor>Engel C</RefAuthor> <RefAuthor>Bloos F</RefAuthor> <RefAuthor>Meier-Hellmann A</RefAuthor> <RefAuthor>Ragaller M</RefAuthor> <RefAuthor>Weiler N</RefAuthor> <RefAuthor>Moerer O</RefAuthor> <RefAuthor>Gruendling M</RefAuthor> <RefAuthor>Oppert M</RefAuthor> <RefAuthor>Grond S</RefAuthor> <RefAuthor>Olthoff D</RefAuthor> <RefAuthor>Jaschinski U</RefAuthor> <RefAuthor>John S</RefAuthor> <RefAuthor>Rossaint R</RefAuthor> <RefAuthor>Welte T</RefAuthor> <RefAuthor>Schaefer M</RefAuthor> <RefAuthor>Kern P</RefAuthor> <RefAuthor>Kuhnt E</RefAuthor> <RefAuthor>Kiehntopf M</RefAuthor> <RefAuthor>Hartog C</RefAuthor> <RefAuthor>Natanson C</RefAuthor> <RefAuthor>Loeffler M</RefAuthor> <RefAuthor>Reinhart K</RefAuthor> <RefAuthor> German Competence Network Sepsis (SepNet)</RefAuthor> <RefTitle>Intensive insulin therapy and pentastarch resuscitation in severe sepsis</RefTitle> <RefYear>2008</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>125-39</RefPage> <RefTotal>Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-39. DOI: 10.1056&#47;NEJMoa070716</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa070716</RefLink> </Reference> <Reference refNo="237"> <RefAuthor>Schortgen F</RefAuthor> <RefAuthor>Lacherade JC</RefAuthor> <RefAuthor>Bruneel F</RefAuthor> <RefAuthor>Cattaneo I</RefAuthor> <RefAuthor>Hemery F</RefAuthor> <RefAuthor>Lemaire F</RefAuthor> <RefAuthor>Brochard L</RefAuthor> <RefTitle>Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study</RefTitle> <RefYear>2001</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>911-6</RefPage> <RefTotal>Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357(9260):911-6. DOI: 10.1016&#47;S0140-6736(00)04211-2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(00)04211-2</RefLink> </Reference> <Reference refNo="238"> <RefAuthor>Zarychanski R</RefAuthor> <RefAuthor>Turgeon A</RefAuthor> <RefAuthor>Fergusson D</RefAuthor> <RefAuthor>Cook D</RefAuthor> <RefAuthor>H&#233;bert P</RefAuthor> <RefAuthor>Bagshaw S</RefAuthor> <RefAuthor>Monsour D</RefAuthor> <RefAuthor>McIntyre L</RefAuthor> <RefTitle>Renal Outcomes Following Hydroxyethyl Strach Resuscitation: A Meta-Analysis Of Randomized Trials</RefTitle> <RefYear>2008</RefYear> <RefJournal>Clinical &#38; Investigative Medicine</RefJournal> <RefPage>26</RefPage> <RefTotal>Zarychanski R, Turgeon A, Fergusson D, Cook D, H&#233;bert P, Bagshaw S, Monsour D, McIntyre L. Renal Outcomes Following Hydroxyethyl Strach Resuscitation: A Meta-Analysis Of Randomized Trials. Clinical &#38; Investigative Medicine. 2008;31(Suppl 4):26.</RefTotal> </Reference> <Reference refNo="239"> <RefAuthor>Dart AB</RefAuthor> <RefAuthor>Mutter TC</RefAuthor> <RefAuthor>Ruth CA</RefAuthor> <RefAuthor>Taback SP</RefAuthor> <RefTitle>Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function</RefTitle> <RefYear>2010</RefYear> <RefJournal>Cochrane Database Syst Rev</RefJournal> <RefPage>CD007594</RefPage> <RefTotal>Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2010;(1):CD007594. DOI: 10.1002&#47;14651858.CD007594.pub2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1002&#47;14651858.CD007594.pub2</RefLink> </Reference> <Reference refNo="240"> <RefAuthor>Finfer S</RefAuthor> <RefAuthor>Bellomo R</RefAuthor> <RefAuthor>Boyce N</RefAuthor> <RefAuthor>French J</RefAuthor> <RefAuthor>Myburgh J</RefAuthor> <RefAuthor>Norton R</RefAuthor> <RefAuthor> SAFE Study Investigators</RefAuthor> <RefTitle>A comparison of albumin and saline for fluid resuscitation in the intensive care unit</RefTitle> <RefYear>2004</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>2247-56</RefPage> <RefTotal>Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-56. DOI: 10.1056&#47;NEJMoa040232</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa040232</RefLink> </Reference> <Reference refNo="241"> <RefAuthor>Meier-Hellmann A</RefAuthor> <RefTitle>H&#228;modynamische Stabilisierung in der Sepsis</RefTitle> <RefYear>2000</RefYear> <RefJournal>An&#228;sthesiologie &#38; Intensivmedizin</RefJournal> <RefPage>601-13</RefPage> <RefTotal>Meier-Hellmann A. H&#228;modynamische Stabilisierung in der Sepsis. An&#228;sthesiologie &#38; Intensivmedizin. 2000;41(7):601-13.</RefTotal> </Reference> <Reference refNo="242"> <RefAuthor>Gattinoni L</RefAuthor> <RefAuthor>Brazzi L</RefAuthor> <RefAuthor>Pelosi P</RefAuthor> <RefAuthor>Latini R</RefAuthor> <RefAuthor>Tognoni G</RefAuthor> <RefAuthor>Pesenti A</RefAuthor> <RefAuthor>Fumagalli R</RefAuthor> <RefTitle>A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group</RefTitle> <RefYear>1995</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1025-32</RefPage> <RefTotal>Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med. 1995;333(16):1025-32. DOI: 10.1056&#47;NEJM199510193331601</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199510193331601</RefLink> </Reference> <Reference refNo="243"> <RefAuthor>Kern JW</RefAuthor> <RefAuthor>Shoemaker WC</RefAuthor> <RefTitle>Meta-analysis of hemodynamic optimization in high-risk patients</RefTitle> <RefYear>2002</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1686-92</RefPage> <RefTotal>Kern JW, Shoemaker WC. Meta-analysis of hemodynamic optimization in high-risk patients. Crit Care Med. 2002;30(8):1686-92. DOI: 10.1097&#47;00003246-200208000-00002</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200208000-00002</RefLink> </Reference> <Reference refNo="244"> <RefAuthor>Hayes MA</RefAuthor> <RefAuthor>Yau EH</RefAuthor> <RefAuthor>Timmins AC</RefAuthor> <RefAuthor>Hinds CJ</RefAuthor> <RefAuthor>Watson D</RefAuthor> <RefTitle>Response of critically ill patients to treatment aimed at achieving supranormal oxygen delivery and consumption. Relationship to outcome</RefTitle> <RefYear>1993</RefYear> <RefJournal>Chest</RefJournal> <RefPage>886-95</RefPage> <RefTotal>Hayes MA, Yau EH, Timmins AC, Hinds CJ, Watson D. Response of critically ill patients to treatment aimed at achieving supranormal oxygen delivery and consumption. Relationship to outcome. Chest. 1993;103(3):886-95. DOI: 10.1378&#47;chest.103.3.886</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.103.3.886</RefLink> </Reference> <Reference refNo="245"> <RefAuthor>Meier-Hellmann A</RefAuthor> <RefAuthor>Bredle DL</RefAuthor> <RefAuthor>Specht M</RefAuthor> <RefAuthor>Hannemann L</RefAuthor> <RefAuthor>Reinhart K</RefAuthor> <RefTitle>Dopexamine increases splanchnic blood flow but decreases gastric mucosal pH in severe septic patients treated with dobutamine</RefTitle> <RefYear>1999</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2166-71</RefPage> <RefTotal>Meier-Hellmann A, Bredle DL, Specht M, Hannemann L, Reinhart K. Dopexamine increases splanchnic blood flow but decreases gastric mucosal pH in severe septic patients treated with dobutamine. Crit Care Med. 1999;27(10):2166-71. DOI: 10.1097&#47;00003246-199910000-00015</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199910000-00015</RefLink> </Reference> <Reference refNo="246"> <RefAuthor>Bennett ED</RefAuthor> <RefTitle>Dopexamine: much more than a vasoactive agent</RefTitle> <RefYear>1998</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1621-2</RefPage> <RefTotal>Bennett ED. Dopexamine: much more than a vasoactive agent. Crit Care Med. 1998;26(10):1621-2. DOI: 10.1097&#47;00003246-199810000-00002</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199810000-00002</RefLink> </Reference> <Reference refNo="247"> <RefAuthor>Byers RJ</RefAuthor> <RefAuthor>Eddleston JM</RefAuthor> <RefAuthor>Pearson RC</RefAuthor> <RefAuthor>Bigley G</RefAuthor> <RefAuthor>McMahon RF</RefAuthor> <RefTitle>Dopexamine reduces the incidence of acute inflammation in the gut mucosa after abdominal surgery in high-risk patients</RefTitle> <RefYear>1999</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1787-93</RefPage> <RefTotal>Byers RJ, Eddleston JM, Pearson RC, Bigley G, McMahon RF. Dopexamine reduces the incidence of acute inflammation in the gut mucosa after abdominal surgery in high-risk patients. Crit Care Med. 1999;27(9):1787-93. DOI: 10.1097&#47;00003246-199909000-00014</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199909000-00014</RefLink> </Reference> <Reference refNo="248"> <RefAuthor>Kiefer P</RefAuthor> <RefAuthor>Tugtekin I</RefAuthor> <RefAuthor>Wiedeck H</RefAuthor> <RefAuthor>Bracht H</RefAuthor> <RefAuthor>Geldner G</RefAuthor> <RefAuthor>Georgieff M</RefAuthor> <RefAuthor>Radermacher P</RefAuthor> <RefTitle>Effect of a dopexamine-induced increase in cardiac index on splanchnic hemodynamics in septic shock</RefTitle> <RefYear>2000</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>775-9</RefPage> <RefTotal>Kiefer P, Tugtekin I, Wiedeck H, Bracht H, Geldner G, Georgieff M, Radermacher P. Effect of a dopexamine-induced increase in cardiac index on splanchnic hemodynamics in septic shock. Am J Respir Crit Care Med. 2000;161(3 Pt 1):775-9.</RefTotal> </Reference> <Reference refNo="249"> <RefAuthor>Schmidt W</RefAuthor> <RefAuthor>H&#228;cker A</RefAuthor> <RefAuthor>Gebhard MM</RefAuthor> <RefAuthor>Martin E</RefAuthor> <RefAuthor>Schmidt H</RefAuthor> <RefTitle>Dopexamine attenuates endotoxin-induced microcirculatory changes in rat mesentery: role of beta2 adrenoceptors</RefTitle> <RefYear>1998</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1639-45</RefPage> <RefTotal>Schmidt W, H&#228;cker A, Gebhard MM, Martin E, Schmidt H. Dopexamine attenuates endotoxin-induced microcirculatory changes in rat mesentery: role of beta2 adrenoceptors. Crit Care Med. 1998;26(10):1639-45. DOI: 10.1097&#47;00003246-199810000-00012</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199810000-00012</RefLink> </Reference> <Reference refNo="250"> <RefAuthor>M&#252;llner M</RefAuthor> <RefAuthor>Urbanek B</RefAuthor> <RefAuthor>Havel C</RefAuthor> <RefAuthor>Losert H</RefAuthor> <RefAuthor>Waechter F</RefAuthor> <RefAuthor>Gamper G</RefAuthor> <RefTitle>Vasopressors for shock</RefTitle> <RefYear>2004</RefYear> <RefJournal>Cochrane Database Syst Rev</RefJournal> <RefPage>CD003709</RefPage> <RefTotal>M&#252;llner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock. Cochrane Database Syst Rev. 2004;(3):CD003709. DOI: 10.1002&#47;14651858.CD003709.pub2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1002&#47;14651858.CD003709.pub2</RefLink> </Reference> <Reference refNo="251"> <RefAuthor>Martin C</RefAuthor> <RefAuthor>Viviand X</RefAuthor> <RefAuthor>Leone M</RefAuthor> <RefAuthor>Thirion X</RefAuthor> <RefTitle>Effect of norepinephrine on the outcome of septic shock</RefTitle> <RefYear>2000</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2758-65</RefPage> <RefTotal>Martin C, Viviand X, Leone M, Thirion X. Effect of norepinephrine on the outcome of septic shock. Crit Care Med. 2000;28(8):2758-65. DOI: 10.1097&#47;00003246-200008000-00012</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200008000-00012</RefLink> </Reference> <Reference refNo="252"> <RefAuthor>Annane D</RefAuthor> <RefAuthor>Vignon P</RefAuthor> <RefAuthor>Renault A</RefAuthor> <RefAuthor>Bollaert PE</RefAuthor> <RefAuthor>Charpentier C</RefAuthor> <RefAuthor>Martin C</RefAuthor> <RefAuthor>Troch&#233; G</RefAuthor> <RefAuthor>Ricard JD</RefAuthor> <RefAuthor>Nitenberg G</RefAuthor> <RefAuthor>Papazian L</RefAuthor> <RefAuthor>Azoulay E</RefAuthor> <RefAuthor>Bellissant E</RefAuthor> <RefAuthor> CATS Study Group</RefAuthor> <RefTitle>Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial</RefTitle> <RefYear>2007</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>676-84</RefPage> <RefTotal>Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troch&#233; G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E; CATS Study Group. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007;370(9588):676-84. DOI: 10.1016&#47;S0140-6736(07)61344-0</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(07)61344-0</RefLink> </Reference> <Reference refNo="253"> <RefAuthor>Prielipp RC</RefAuthor> <RefAuthor>MacGregor DA</RefAuthor> <RefAuthor>Royster RL</RefAuthor> <RefAuthor>Kon ND</RefAuthor> <RefAuthor>Hines MH</RefAuthor> <RefAuthor>Butterworth JF 4th</RefAuthor> <RefTitle>Dobutamine antagonizes epinephrine&#39;s biochemical and cardiotonic effects: results of an in vitro model using human lymphocytes and a clinical study in patients recovering from cardiac surgery</RefTitle> <RefYear>1998</RefYear> <RefJournal>Anesthesiology</RefJournal> <RefPage>49-57</RefPage> <RefTotal>Prielipp RC, MacGregor DA, Royster RL, Kon ND, Hines MH, Butterworth JF 4th. Dobutamine antagonizes epinephrine&#39;s biochemical and cardiotonic effects: results of an in vitro model using human lymphocytes and a clinical study in patients recovering from cardiac surgery. Anesthesiology. 1998;89(1):49-57. DOI: 10.1097&#47;00000542-199807000-00010</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00000542-199807000-00010</RefLink> </Reference> <Reference refNo="254"> <RefAuthor>D&#252;nser MW</RefAuthor> <RefAuthor>Mayr AJ</RefAuthor> <RefAuthor>Ulmer H</RefAuthor> <RefAuthor>Knotzer H</RefAuthor> <RefAuthor>Sumann G</RefAuthor> <RefAuthor>Pajk W</RefAuthor> <RefAuthor>Friesenecker B</RefAuthor> <RefAuthor>Hasibeder WR</RefAuthor> <RefTitle>Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study</RefTitle> <RefYear>2003</RefYear> <RefJournal>Circulation</RefJournal> <RefPage>2313-9</RefPage> <RefTotal>D&#252;nser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk W, Friesenecker B, Hasibeder WR. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. 2003;107(18):2313-9. DOI: 10.1161&#47;01.CIR.0000066692.71008.BB</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1161&#47;01.CIR.0000066692.71008.BB</RefLink> </Reference> <Reference refNo="255"> <RefAuthor>Tsuneyoshi I</RefAuthor> <RefAuthor>Yamada H</RefAuthor> <RefAuthor>Kakihana Y</RefAuthor> <RefAuthor>Nakamura M</RefAuthor> <RefAuthor>Nakano Y</RefAuthor> <RefAuthor>Boyle WA 3rd</RefAuthor> <RefTitle>Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock</RefTitle> <RefYear>2001</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>487-93</RefPage> <RefTotal>Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA 3rd. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med. 2001;29(3):487-93. DOI: 10.1097&#47;00003246-200103000-00004</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200103000-00004</RefLink> </Reference> <Reference refNo="256"> <RefAuthor>Malay MB</RefAuthor> <RefAuthor>Ashton RC Jr</RefAuthor> <RefAuthor>Landry DW</RefAuthor> <RefAuthor>Townsend RN</RefAuthor> <RefTitle>Low-dose vasopressin in the treatment of vasodilatory septic shock</RefTitle> <RefYear>1999</RefYear> <RefJournal>J Trauma</RefJournal> <RefPage>699-703</RefPage> <RefTotal>Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. 1999;47(4):699-703. DOI: 10.1097&#47;00005373-199910000-00014</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00005373-199910000-00014</RefLink> </Reference> <Reference refNo="257"> <RefAuthor>Patel BM</RefAuthor> <RefAuthor>Chittock DR</RefAuthor> <RefAuthor>Russell JA</RefAuthor> <RefAuthor>Walley KR</RefAuthor> <RefTitle>Beneficial effects of short-term vasopressin infusion during severe septic shock</RefTitle> <RefYear>2002</RefYear> <RefJournal>Anesthesiology</RefJournal> <RefPage>576-82</RefPage> <RefTotal>Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 2002;96(3):576-82. DOI: 10.1097&#47;00000542-200203000-00011</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00000542-200203000-00011</RefLink> </Reference> <Reference refNo="258"> <RefAuthor>D&#252;nser MW</RefAuthor> <RefAuthor>Mayr AJ</RefAuthor> <RefAuthor>T&#252;r A</RefAuthor> <RefAuthor>Pajk W</RefAuthor> <RefAuthor>Barbara F</RefAuthor> <RefAuthor>Knotzer H</RefAuthor> <RefAuthor>Ulmer H</RefAuthor> <RefAuthor>Hasibeder WR</RefAuthor> <RefTitle>Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1394-8</RefPage> <RefTotal>D&#252;nser MW, Mayr AJ, T&#252;r A, Pajk W, Barbara F, Knotzer H, Ulmer H, Hasibeder WR. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med. 2003;31(5):1394-8. DOI: 10.1097&#47;01.CCM.0000059722.94182.79</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000059722.94182.79</RefLink> </Reference> <Reference refNo="259"> <RefAuthor>Russell JA</RefAuthor> <RefAuthor>Walley KR</RefAuthor> <RefAuthor>Singer J</RefAuthor> <RefAuthor>Gordon AC</RefAuthor> <RefAuthor>H&#233;bert PC</RefAuthor> <RefAuthor>Cooper DJ</RefAuthor> <RefAuthor>Holmes CL</RefAuthor> <RefAuthor>Mehta S</RefAuthor> <RefAuthor>Granton JT</RefAuthor> <RefAuthor>Storms MM</RefAuthor> <RefAuthor>Cook DJ</RefAuthor> <RefAuthor>Presneill JJ</RefAuthor> <RefAuthor>Ayers D</RefAuthor> <RefAuthor> VASST Investigators</RefAuthor> <RefTitle>Vasopressin versus norepinephrine infusion in patients with septic shock</RefTitle> <RefYear>2008</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>877-87</RefPage> <RefTotal>Russell JA, Walley KR, Singer J, Gordon AC, H&#233;bert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-87. DOI: 10.1056&#47;NEJMoa067373</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa067373</RefLink> </Reference> <Reference refNo="260"> <RefAuthor>Bellomo R</RefAuthor> <RefAuthor>Chapman M</RefAuthor> <RefAuthor>Finfer S</RefAuthor> <RefAuthor>Hickling K</RefAuthor> <RefAuthor>Myburgh J</RefAuthor> <RefTitle>Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group</RefTitle> <RefYear>2000</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>2139-43</RefPage> <RefTotal>Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356(9248):2139-43. DOI: 10.1016&#47;S0140-6736(00)03495-4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(00)03495-4</RefLink> </Reference> <Reference refNo="261"> <RefAuthor>Marik PE</RefAuthor> <RefAuthor>Iglesias J</RefAuthor> <RefTitle>Low-dose dopamine does not prevent acute renal failure in patients with septic shock and oliguria. NORASEPT II Study Investigators</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Med</RefJournal> <RefPage>387-90</RefPage> <RefTotal>Marik PE, Iglesias J. Low-dose dopamine does not prevent acute renal failure in patients with septic shock and oliguria. NORASEPT II Study Investigators. Am J Med. 1999;107(4):387-90. DOI: 10.1016&#47;S0002-9343(99)00246-6</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0002-9343(99)00246-6</RefLink> </Reference> <Reference refNo="262"> <RefAuthor>Chertow GM</RefAuthor> <RefAuthor>Sayegh MH</RefAuthor> <RefAuthor>Allgren RL</RefAuthor> <RefAuthor>Lazarus JM</RefAuthor> <RefTitle>Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure&#63; Auriculin Anaritide Acute Renal Failure Study Group</RefTitle> <RefYear>1996</RefYear> <RefJournal>Am J Med</RefJournal> <RefPage>49-53</RefPage> <RefTotal>Chertow GM, Sayegh MH, Allgren RL, Lazarus JM. Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure&#63; Auriculin Anaritide Acute Renal Failure Study Group. Am J Med. 1996;101(1):49-53. DOI: 10.1016&#47;S0002-9343(96)00075-7</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0002-9343(96)00075-7</RefLink> </Reference> <Reference refNo="263"> <RefAuthor>Kellum JA</RefAuthor> <RefAuthor>M Decker J</RefAuthor> <RefTitle>Use of dopamine in acute renal failure: a meta-analysis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1526-31</RefPage> <RefTotal>Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001;29(8):1526-31. DOI: 10.1097&#47;00003246-200108000-00005</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200108000-00005</RefLink> </Reference> <Reference refNo="264"> <RefAuthor>Marik PE</RefAuthor> <RefTitle>Low-dose dopamine: a systematic review</RefTitle> <RefYear>2002</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>877-83</RefPage> <RefTotal>Marik PE. Low-dose dopamine: a systematic review. Intensive Care Med. 2002;28(7):877-83. DOI: 10.1007&#47;s00134-002-1346-y</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-002-1346-y</RefLink> </Reference> <Reference refNo="265"> <RefAuthor>Debaveye YA</RefAuthor> <RefAuthor>Van den Berghe GH</RefAuthor> <RefTitle>Is there still a place for dopamine in the modern intensive care unit&#63;</RefTitle> <RefYear>2004</RefYear> <RefJournal>Anesth Analg</RefJournal> <RefPage>461-8</RefPage> <RefTotal>Debaveye YA, Van den Berghe GH. Is there still a place for dopamine in the modern intensive care unit&#63; Anesth Analg. 2004;98(2):461-8. DOI: 10.1213&#47;01.ANE.0000096188.35789.37</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1213&#47;01.ANE.0000096188.35789.37</RefLink> </Reference> <Reference refNo="266"> <RefAuthor>Oppert M</RefAuthor> <RefAuthor>Engel C</RefAuthor> <RefAuthor>Brunkhorst FM</RefAuthor> <RefAuthor>Bogatsch H</RefAuthor> <RefAuthor>Reinhart K</RefAuthor> <RefAuthor>Frei U</RefAuthor> <RefAuthor>Eckardt KU</RefAuthor> <RefAuthor>Loeffler M</RefAuthor> <RefAuthor>John S</RefAuthor> <RefAuthor> German Competence Network Sepsis (Sepnet)</RefAuthor> <RefTitle>Acute renal failure in patients with severe sepsis and septic shock--a significant independent risk factor for mortality: results from the German Prevalence Study</RefTitle> <RefYear>2008</RefYear> <RefJournal>Nephrol Dial Transplant</RefJournal> <RefPage>904-9</RefPage> <RefTotal>Oppert M, Engel C, Brunkhorst FM, Bogatsch H, Reinhart K, Frei U, Eckardt KU, Loeffler M, John S; German Competence Network Sepsis (Sepnet). Acute renal failure in patients with severe sepsis and septic shock--a significant independent risk factor for mortality: results from the German Prevalence Study. Nephrol Dial Transplant. 2008;23(3):904-9. DOI: 10.1093&#47;ndt&#47;gfm610</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;ndt&#47;gfm610</RefLink> </Reference> <Reference refNo="412"> <RefAuthor>Mehta RL</RefAuthor> <RefAuthor>Kellum JA</RefAuthor> <RefAuthor>Shah SV</RefAuthor> <RefAuthor>Molitoris BA</RefAuthor> <RefAuthor>Ronco C</RefAuthor> <RefAuthor>Warnock DG</RefAuthor> <RefAuthor>Levin A</RefAuthor> <RefAuthor> Acute Kidney Injury Network</RefAuthor> <RefTitle>Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R31</RefPage> <RefTotal>Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A; Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. DOI: 10.1186&#47;cc5713</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc5713</RefLink> </Reference> <Reference refNo="267"> <RefAuthor>Vinsonneau C</RefAuthor> <RefAuthor>Camus C</RefAuthor> <RefAuthor>Combes A</RefAuthor> <RefAuthor>Costa de Beauregard MA</RefAuthor> <RefAuthor>Klouche K</RefAuthor> <RefAuthor>Boulain T</RefAuthor> <RefAuthor>Pallot JL</RefAuthor> <RefAuthor>Chiche JD</RefAuthor> <RefAuthor>Taupin P</RefAuthor> <RefAuthor>Landais P</RefAuthor> <RefAuthor>Dhainaut JF</RefAuthor> <RefAuthor> Hemodiafe Study Group</RefAuthor> <RefTitle>Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial</RefTitle> <RefYear>2006</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>379-85</RefPage> <RefTotal>Vinsonneau C, Camus C, Combes A, Costa de Beauregard MA, Klouche K, Boulain T, Pallot JL, Chiche JD, Taupin P, Landais P, Dhainaut JF; Hemodiafe Study Group. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet. 2006;368(9533):379-85. DOI: 10.1016&#47;S0140-6736(06)69111-3</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(06)69111-3</RefLink> </Reference> <Reference refNo="268"> <RefAuthor>Kellum JA</RefAuthor> <RefAuthor>Angus DC</RefAuthor> <RefAuthor>Johnson JP</RefAuthor> <RefAuthor>Leblanc M</RefAuthor> <RefAuthor>Griffin M</RefAuthor> <RefAuthor>Ramakrishnan N</RefAuthor> <RefAuthor>Linde-Zwirble WT</RefAuthor> <RefTitle>Continuous versus intermittent renal replacement therapy: a meta-analysis</RefTitle> <RefYear>2002</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>29-37</RefPage> <RefTotal>Kellum JA, Angus DC, Johnson JP, Leblanc M, Griffin M, Ramakrishnan N, Linde-Zwirble WT. Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive Care Med. 2002;28(1):29-37. DOI: 10.1007&#47;s00134-001-1159-4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-001-1159-4</RefLink> </Reference> <Reference refNo="269"> <RefAuthor>Tonelli M</RefAuthor> <RefAuthor>Manns B</RefAuthor> <RefAuthor>Feller-Kopman D</RefAuthor> <RefTitle>Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery</RefTitle> <RefYear>2002</RefYear> <RefJournal>Am J Kidney Dis</RefJournal> <RefPage>875-85</RefPage> <RefTotal>Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis. 2002;40(5):875-85. DOI: 10.1053&#47;ajkd.2002.36318</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1053&#47;ajkd.2002.36318</RefLink> </Reference> <Reference refNo="270"> <RefAuthor>Augustine JJ</RefAuthor> <RefAuthor>Sandy D</RefAuthor> <RefAuthor>Seifert TH</RefAuthor> <RefAuthor>Paganini EP</RefAuthor> <RefTitle>A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF</RefTitle> <RefYear>2004</RefYear> <RefJournal>Am J Kidney Dis</RefJournal> <RefPage>1000-7</RefPage> <RefTotal>Augustine JJ, Sandy D, Seifert TH, Paganini EP. A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis. 2004;44(6):1000-7. DOI: 10.1053&#47;j.ajkd.2004.08.022</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1053&#47;j.ajkd.2004.08.022</RefLink> </Reference> <Reference refNo="271"> <RefAuthor>Gasparovi V</RefAuthor> <RefAuthor>Filipovi-Grci I</RefAuthor> <RefAuthor>Merkler M</RefAuthor> <RefAuthor>Pisl Z</RefAuthor> <RefTitle>Continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD)--what is the procedure of choice in critically ill patients&#63;</RefTitle> <RefYear>2003</RefYear> <RefJournal>Ren Fail</RefJournal> <RefPage>855-62</RefPage> <RefTotal>Gasparovi V, Filipovi-Grci I, Merkler M, Pisl Z. Continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD)--what is the procedure of choice in critically ill patients&#63; Ren Fail. 2003;25(5):855-62. DOI: 10.1081&#47;JDI-120024300</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1081&#47;JDI-120024300</RefLink> </Reference> <Reference refNo="272"> <RefAuthor>Mehta RL</RefAuthor> <RefAuthor>McDonald B</RefAuthor> <RefAuthor>Gabbai FB</RefAuthor> <RefAuthor>Pahl M</RefAuthor> <RefAuthor>Pascual MT</RefAuthor> <RefAuthor>Farkas A</RefAuthor> <RefAuthor>Kaplan RM</RefAuthor> <RefAuthor> Collaborative Group for Treatment of ARF in the ICU</RefAuthor> <RefTitle>A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure</RefTitle> <RefYear>2001</RefYear> <RefJournal>Kidney Int</RefJournal> <RefPage>1154-63</RefPage> <RefTotal>Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MT, Farkas A, Kaplan RM; Collaborative Group for Treatment of ARF in the ICU. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int. 2001;60(3):1154-63. DOI: 10.1046&#47;j.1523-1755.2001.0600031154.x</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1046&#47;j.1523-1755.2001.0600031154.x</RefLink> </Reference> <Reference refNo="273"> <RefAuthor>Uehlinger DE</RefAuthor> <RefAuthor>Jakob SM</RefAuthor> <RefAuthor>Ferrari P</RefAuthor> <RefAuthor>Eichelberger M</RefAuthor> <RefAuthor>Huynh-Do U</RefAuthor> <RefAuthor>Marti HP</RefAuthor> <RefAuthor>Mohaupt MG</RefAuthor> <RefAuthor>Vogt B</RefAuthor> <RefAuthor>Rothen HU</RefAuthor> <RefAuthor>Regli B</RefAuthor> <RefAuthor>Takala J</RefAuthor> <RefAuthor>Frey FJ</RefAuthor> <RefTitle>Comparison of continuous and intermittent renal replacement therapy for acute renal failure</RefTitle> <RefYear>2005</RefYear> <RefJournal>Nephrol Dial Transplant</RefJournal> <RefPage>1630-7</RefPage> <RefTotal>Uehlinger DE, Jakob SM, Ferrari P, Eichelberger M, Huynh-Do U, Marti HP, Mohaupt MG, Vogt B, Rothen HU, Regli B, Takala J, Frey FJ. Comparison of continuous and intermittent renal replacement therapy for acute renal failure. Nephrol Dial Transplant. 2005;20(8):1630-7. DOI: 10.1093&#47;ndt&#47;gfh880</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;ndt&#47;gfh880</RefLink> </Reference> <Reference refNo="274"> <RefAuthor>John S</RefAuthor> <RefAuthor>Griesbach D</RefAuthor> <RefAuthor>Baumgartel M</RefAuthor> <RefAuthor>Weihprecht H</RefAuthor> <RefAuthor>Schmieder RE</RefAuthor> <RefAuthor>Geiger H</RefAuthor> <RefTitle>Effects of continuous haemofiltration vs intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: a prospective, randomized clinical trial</RefTitle> <RefYear>2001</RefYear> <RefJournal>Nephrol Dial Transplant</RefJournal> <RefPage>320-7</RefPage> <RefTotal>John S, Griesbach D, Baumgartel M, Weihprecht H, Schmieder RE, Geiger H. Effects of continuous haemofiltration vs intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: a prospective, randomized clinical trial. Nephrol Dial Transplant. 2001;16(2):320-7. DOI: 10.1093&#47;ndt&#47;16.2.320</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;ndt&#47;16.2.320</RefLink> </Reference> <Reference refNo="275"> <RefAuthor>Kielstein JT</RefAuthor> <RefAuthor>Kretschmer U</RefAuthor> <RefAuthor>Ernst T</RefAuthor> <RefAuthor>Hafer C</RefAuthor> <RefAuthor>Bahr MJ</RefAuthor> <RefAuthor>Haller H</RefAuthor> <RefAuthor>Fliser D</RefAuthor> <RefTitle>Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study</RefTitle> <RefYear>2004</RefYear> <RefJournal>Am J Kidney Dis</RefJournal> <RefPage>342-9</RefPage> <RefTotal>Kielstein JT, Kretschmer U, Ernst T, Hafer C, Bahr MJ, Haller H, Fliser D. Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study. Am J Kidney Dis. 2004;43(2):342-9. DOI: 10.1053&#47;j.ajkd.2003.10.021</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1053&#47;j.ajkd.2003.10.021</RefLink> </Reference> <Reference refNo="276"> <RefAuthor>Schortgen F</RefAuthor> <RefAuthor>Soubrier N</RefAuthor> <RefAuthor>Delclaux C</RefAuthor> <RefAuthor>Thuong M</RefAuthor> <RefAuthor>Girou E</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefAuthor>Lemaire F</RefAuthor> <RefAuthor>Brochard L</RefAuthor> <RefTitle>Hemodynamic tolerance of intermittent hemodialysis in critically ill patients: usefulness of practice guidelines</RefTitle> <RefYear>2000</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>197-202</RefPage> <RefTotal>Schortgen F, Soubrier N, Delclaux C, Thuong M, Girou E, Brun-Buisson C, Lemaire F, Brochard L. Hemodynamic tolerance of intermittent hemodialysis in critically ill patients: usefulness of practice guidelines. Am J Respir Crit Care Med. 2000;162(1):197-202.</RefTotal> </Reference> <Reference refNo="277"> <RefAuthor>Misset B</RefAuthor> <RefAuthor>Timsit JF</RefAuthor> <RefAuthor>Chevret S</RefAuthor> <RefAuthor>Renaud B</RefAuthor> <RefAuthor>Tamion F</RefAuthor> <RefAuthor>Carlet J</RefAuthor> <RefTitle>A randomized cross-over comparison of the hemodynamic response to intermittent hemodialysis and continuous hemofiltration in ICU patients with acute renal failure</RefTitle> <RefYear>1996</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>742-6</RefPage> <RefTotal>Misset B, Timsit JF, Chevret S, Renaud B, Tamion F, Carlet J. A randomized cross-over comparison of the hemodynamic response to intermittent hemodialysis and continuous hemofiltration in ICU patients with acute renal failure. Intensive Care Med. 1996;22(8):742-6. DOI: 10.1007&#47;BF01709515</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;BF01709515</RefLink> </Reference> <Reference refNo="278"> <RefAuthor>Faulhaber-Walter R</RefAuthor> <RefAuthor>Hafer C</RefAuthor> <RefAuthor>Jahr N</RefAuthor> <RefAuthor>Vahlbruch J</RefAuthor> <RefAuthor>Hoy L</RefAuthor> <RefAuthor>Haller H</RefAuthor> <RefAuthor>Fliser D</RefAuthor> <RefAuthor>Kielstein JT</RefAuthor> <RefTitle>The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit</RefTitle> <RefYear>2009</RefYear> <RefJournal>Nephrol Dial Transplant</RefJournal> <RefPage>2179-86</RefPage> <RefTotal>Faulhaber-Walter R, Hafer C, Jahr N, Vahlbruch J, Hoy L, Haller H, Fliser D, Kielstein JT. The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit. Nephrol Dial Transplant. 2009;24(7):2179-86. DOI: 10.1093&#47;ndt&#47;gfp035</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1093&#47;ndt&#47;gfp035</RefLink> </Reference> <Reference refNo="279"> <RefAuthor>Bellomo R</RefAuthor> <RefAuthor>Cass A</RefAuthor> <RefAuthor>Cole L</RefAuthor> <RefAuthor>Finfer S</RefAuthor> <RefAuthor>Gallagher M</RefAuthor> <RefAuthor>Lo S</RefAuthor> <RefAuthor>McArthur C</RefAuthor> <RefAuthor>McGuinness S</RefAuthor> <RefAuthor>Myburgh J</RefAuthor> <RefAuthor>Norton R</RefAuthor> <RefAuthor>Scheinkestel C</RefAuthor> <RefAuthor>Su S</RefAuthor> <RefAuthor> RENAL Replacement Therapy Study Investigators</RefAuthor> <RefTitle>Intensity of continuous renal-replacement therapy in critically ill patients</RefTitle> <RefYear>2009</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1627-38</RefPage> <RefTotal>Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S, Myburgh J, Norton R, Scheinkestel C, Su S; RENAL Replacement Therapy Study Investigators. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009;361(17):1627-38. DOI: 10.1056&#47;NEJMoa0902413</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa0902413</RefLink> </Reference> <Reference refNo="280"> <RefAuthor>Palevsky PM</RefAuthor> <RefAuthor>Zhang JH</RefAuthor> <RefAuthor>O&#39;Connor TZ</RefAuthor> <RefAuthor>Chertow GM</RefAuthor> <RefAuthor>Crowley ST</RefAuthor> <RefAuthor>Choudhury D</RefAuthor> <RefAuthor>Finkel K</RefAuthor> <RefAuthor>Kellum JA</RefAuthor> <RefAuthor>Paganini E</RefAuthor> <RefAuthor>Schein RM</RefAuthor> <RefAuthor>Smith MW</RefAuthor> <RefAuthor>Swanson KM</RefAuthor> <RefAuthor>Thompson BT</RefAuthor> <RefAuthor>Vijayan A</RefAuthor> <RefAuthor>Watnick S</RefAuthor> <RefAuthor>Star RA</RefAuthor> <RefAuthor>Peduzzi P</RefAuthor> <RefAuthor> VA&#47;NIH Acute Renal Failure Trial Network</RefAuthor> <RefTitle>Intensity of renal support in critically ill patients with acute kidney injury</RefTitle> <RefYear>2008</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>7-20</RefPage> <RefTotal>Palevsky PM, Zhang JH, O&#39;Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan A, Watnick S, Star RA, Peduzzi P; VA&#47;NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7-20. DOI: 10.1056&#47;NEJMoa0802639</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa0802639</RefLink> </Reference> <Reference refNo="281"> <RefAuthor>Bouman CS</RefAuthor> <RefAuthor>Oudemans-Van Straaten HM</RefAuthor> <RefAuthor>Tijssen JG</RefAuthor> <RefAuthor>Zandstra DF</RefAuthor> <RefAuthor>Kesecioglu J</RefAuthor> <RefTitle>Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial</RefTitle> <RefYear>2002</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2205-11</RefPage> <RefTotal>Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J. Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial. Crit Care Med. 2002;30(10):2205-11. DOI: 10.1097&#47;00003246-200210000-00005</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200210000-00005</RefLink> </Reference> <Reference refNo="282"> <RefAuthor>Ronco C</RefAuthor> <RefAuthor>Bellomo R</RefAuthor> <RefAuthor>Homel P</RefAuthor> <RefAuthor>Brendolan A</RefAuthor> <RefAuthor>Dan M</RefAuthor> <RefAuthor>Piccinni P</RefAuthor> <RefAuthor>La Greca G</RefAuthor> <RefTitle>Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial</RefTitle> <RefYear>2000</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>26-30</RefPage> <RefTotal>Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000;356(9223):26-30. DOI: 10.1016&#47;S0140-6736(00)02430-2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(00)02430-2</RefLink> </Reference> <Reference refNo="283"> <RefAuthor>Saudan P</RefAuthor> <RefAuthor>Niederberger M</RefAuthor> <RefAuthor>De Seigneux S</RefAuthor> <RefAuthor>Romand J</RefAuthor> <RefAuthor>Pugin J</RefAuthor> <RefAuthor>Perneger T</RefAuthor> <RefAuthor>Martin PY</RefAuthor> <RefTitle>Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure</RefTitle> <RefYear>2006</RefYear> <RefJournal>Kidney Int</RefJournal> <RefPage>1312-7</RefPage> <RefTotal>Saudan P, Niederberger M, De Seigneux S, Romand J, Pugin J, Perneger T, Martin PY. Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int. 2006;70(7):1312-7. DOI: 10.1038&#47;sj.ki.5001705</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1038&#47;sj.ki.5001705</RefLink> </Reference> <Reference refNo="284"> <RefAuthor>Schiffl H</RefAuthor> <RefAuthor>Lang SM</RefAuthor> <RefAuthor>Fischer R</RefAuthor> <RefTitle>Daily hemodialysis and the outcome of acute renal failure</RefTitle> <RefYear>2002</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>305-10</RefPage> <RefTotal>Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med. 2002;346(5):305-10. DOI: 10.1056&#47;NEJMoa010877</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa010877</RefLink> </Reference> <Reference refNo="285"> <RefAuthor>Tolwani AJ</RefAuthor> <RefAuthor>Campbell RC</RefAuthor> <RefAuthor>Stofan BS</RefAuthor> <RefAuthor>Lai KR</RefAuthor> <RefAuthor>Oster RA</RefAuthor> <RefAuthor>Wille KM</RefAuthor> <RefTitle>Standard versus high-dose CVVHDF for ICU-related acute renal failure</RefTitle> <RefYear>2008</RefYear> <RefJournal>J Am Soc Nephrol</RefJournal> <RefPage>1233-8</RefPage> <RefTotal>Tolwani AJ, Campbell RC, Stofan BS, Lai KR, Oster RA, Wille KM. Standard versus high-dose CVVHDF for ICU-related acute renal failure. J Am Soc Nephrol. 2008;19(6):1233-8. DOI: 10.1681&#47;ASN.2007111173</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1681&#47;ASN.2007111173</RefLink> </Reference> <Reference refNo="286"> <RefAuthor>De Vriese AS</RefAuthor> <RefAuthor>Colardyn FA</RefAuthor> <RefAuthor>Philippe JJ</RefAuthor> <RefAuthor>Vanholder RC</RefAuthor> <RefAuthor>De Sutter JH</RefAuthor> <RefAuthor>Lameire NH</RefAuthor> <RefTitle>Cytokine removal during continuous hemofiltration in septic patients</RefTitle> <RefYear>1999</RefYear> <RefJournal>J Am Soc Nephrol</RefJournal> <RefPage>846-53</RefPage> <RefTotal>De Vriese AS, Colardyn FA, Philippe JJ, Vanholder RC, De Sutter JH, Lameire NH. Cytokine removal during continuous hemofiltration in septic patients. J Am Soc Nephrol. 1999;10(4):846-53.</RefTotal> </Reference> <Reference refNo="287"> <RefAuthor>van Deuren M</RefAuthor> <RefAuthor>van der Meer JW</RefAuthor> <RefTitle>Hemofiltration in septic patients is not able to alter the plasma concentration of cytokines therapeutically</RefTitle> <RefYear>2000</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1176-8</RefPage> <RefTotal>van Deuren M, van der Meer JW. Hemofiltration in septic patients is not able to alter the plasma concentration of cytokines therapeutically. Intensive Care Med. 2000;26(9):1176-8. DOI: 10.1007&#47;s001340000583</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s001340000583</RefLink> </Reference> <Reference refNo="288"> <RefAuthor>Payen D</RefAuthor> <RefAuthor>Mateo J</RefAuthor> <RefAuthor>Cavaillon JM</RefAuthor> <RefAuthor>Fraisse F</RefAuthor> <RefAuthor>Floriot C</RefAuthor> <RefAuthor>Vicaut E</RefAuthor> <RefAuthor> Hemofiltration and Sepsis Group of the Coll&#232;ge National de R&#233;animation et de M&#233;decine d&#39;Urgence des H&#244;pitaux extra-Universitaires</RefAuthor> <RefTitle>Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: a randomized controlled trial</RefTitle> <RefYear>2009</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>803-10</RefPage> <RefTotal>Payen D, Mateo J, Cavaillon JM, Fraisse F, Floriot C, Vicaut E; Hemofiltration and Sepsis Group of the Coll&#232;ge National de R&#233;animation et de M&#233;decine d&#39;Urgence des H&#244;pitaux extra-Universitaires. Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: a randomized controlled trial. Crit Care Med. 2009;37(3):803-10. DOI: 10.1097&#47;CCM.0b013e3181962316</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;CCM.0b013e3181962316</RefLink> </Reference> <Reference refNo="289"> <RefAuthor>Hopkins RO</RefAuthor> <RefAuthor>Weaver LK</RefAuthor> <RefAuthor>Pope D</RefAuthor> <RefAuthor>Orme JF</RefAuthor> <RefAuthor>Bigler ED</RefAuthor> <RefAuthor>Larson LV</RefAuthor> <RefTitle>Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>50-6</RefPage> <RefTotal>Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson LV. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160(1):50-6.</RefTotal> </Reference> <Reference refNo="290"> <RefAuthor>Acute Respiratory Distress Syndrome Network</RefAuthor> <RefTitle>Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome</RefTitle> <RefYear>2000</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1301-8</RefPage> <RefTotal>Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-8. DOI: 10.1056&#47;NEJM200005043421801</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM200005043421801</RefLink> </Reference> <Reference refNo="291"> <RefAuthor>Amato MB</RefAuthor> <RefAuthor>Barbas CS</RefAuthor> <RefAuthor>Medeiros DM</RefAuthor> <RefAuthor>Magaldi RB</RefAuthor> <RefAuthor>Schettino GP</RefAuthor> <RefAuthor>Lorenzi-Filho G</RefAuthor> <RefAuthor>Kairalla RA</RefAuthor> <RefAuthor>Deheinzelin D</RefAuthor> <RefAuthor>Munoz C</RefAuthor> <RefAuthor>Oliveira R</RefAuthor> <RefAuthor>Takagaki TY</RefAuthor> <RefAuthor>Carvalho CR</RefAuthor> <RefTitle>Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome</RefTitle> <RefYear>1998</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>347-54</RefPage> <RefTotal>Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-54. DOI: 10.1056&#47;NEJM199802053380602</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199802053380602</RefLink> </Reference> <Reference refNo="292"> <RefAuthor>Villar J</RefAuthor> <RefAuthor>Kacmarek RM</RefAuthor> <RefAuthor>Perez-Mendez L</RefAuthor> <RefAuthor>Aguirre-Jaime A</RefAuthor> <RefTitle>A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1311-8</RefPage> <RefTotal>Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med. 2006;34(5):1311-8. DOI: 10.1097&#47;01.CCM.0000215598.84885.01</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000215598.84885.01</RefLink> </Reference> <Reference refNo="293"> <RefAuthor>Terragni PP</RefAuthor> <RefAuthor>Rosboch G</RefAuthor> <RefAuthor>Tealdi A</RefAuthor> <RefAuthor>Corno E</RefAuthor> <RefAuthor>Menaldo E</RefAuthor> <RefAuthor>Davini O</RefAuthor> <RefAuthor>Gandini G</RefAuthor> <RefAuthor>Herrmann P</RefAuthor> <RefAuthor>Mascia L</RefAuthor> <RefAuthor>Quintel M</RefAuthor> <RefAuthor>Slutsky AS</RefAuthor> <RefAuthor>Gattinoni L</RefAuthor> <RefAuthor>Ranieri VM</RefAuthor> <RefTitle>Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome</RefTitle> <RefYear>2007</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>160-6</RefPage> <RefTotal>Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, Slutsky AS, Gattinoni L, Ranieri VM. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007;175(2):160-6. DOI: 10.1164&#47;rccm.200607-915OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200607-915OC</RefLink> </Reference> <Reference refNo="294"> <RefAuthor>Hager DN</RefAuthor> <RefAuthor>Krishnan JA</RefAuthor> <RefAuthor>Hayden DL</RefAuthor> <RefAuthor>Brower RG</RefAuthor> <RefAuthor> ARDS Clinical Trials Network</RefAuthor> <RefTitle>Tidal volume reduction in patients with acute lung injury when plateau pressures are not high</RefTitle> <RefYear>2005</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>1241-5</RefPage> <RefTotal>Hager DN, Krishnan JA, Hayden DL, Brower RG; ARDS Clinical Trials Network. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med. 2005;172(10):1241-5. DOI: 10.1164&#47;rccm.200501-048CP</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200501-048CP</RefLink> </Reference> <Reference refNo="295"> <RefAuthor>Bidani A</RefAuthor> <RefAuthor>Tzouanakis AE</RefAuthor> <RefAuthor>Cardenas VJ Jr</RefAuthor> <RefAuthor>Zwischenberger JB</RefAuthor> <RefTitle>Permissive hypercapnia in acute respiratory failure</RefTitle> <RefYear>1994</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>957-62</RefPage> <RefTotal>Bidani A, Tzouanakis AE, Cardenas VJ Jr, Zwischenberger JB. Permissive hypercapnia in acute respiratory failure. JAMA. 1994;272(12):957-62.</RefTotal> </Reference> <Reference refNo="296"> <RefAuthor>Hickling KG</RefAuthor> <RefAuthor>Walsh J</RefAuthor> <RefAuthor>Henderson S</RefAuthor> <RefAuthor>Jackson R</RefAuthor> <RefTitle>Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study</RefTitle> <RefYear>1994</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1568-78</RefPage> <RefTotal>Hickling KG, Walsh J, Henderson S, Jackson R. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med. 1994;22(10):1568-78. DOI: 10.1097&#47;00003246-199422100-00011</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199422100-00011</RefLink> </Reference> <Reference refNo="297"> <RefAuthor>Martin GS</RefAuthor> <RefAuthor>Bernard GR</RefAuthor> <RefAuthor> International Sepsis Forum</RefAuthor> <RefTitle>Airway and lung in sepsis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>S63-79</RefPage> <RefTotal>Martin GS, Bernard GR; International Sepsis Forum. Airway and lung in sepsis. Intensive Care Med. 2001;27 Suppl 1:S63-79.</RefTotal> </Reference> <Reference refNo="298"> <RefAuthor>Gattinoni L</RefAuthor> <RefAuthor>Tognoni G</RefAuthor> <RefAuthor>Pesenti A</RefAuthor> <RefAuthor>Taccone P</RefAuthor> <RefAuthor>Mascheroni D</RefAuthor> <RefAuthor>Labarta V</RefAuthor> <RefAuthor>Malacrida R</RefAuthor> <RefAuthor>Di Giulio P</RefAuthor> <RefAuthor>Fumagalli R</RefAuthor> <RefAuthor>Pelosi P</RefAuthor> <RefAuthor>Brazzi L</RefAuthor> <RefAuthor>Latini R</RefAuthor> <RefAuthor> Prone-Supine Study Group</RefAuthor> <RefTitle>Effect of prone positioning on the survival of patients with acute respiratory failure</RefTitle> <RefYear>2001</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>568-73</RefPage> <RefTotal>Gattinoni L, Tognoni G, Pesenti A, Taccone P, Mascheroni D, Labarta V, Malacrida R, Di Giulio P, Fumagalli R, Pelosi P, Brazzi L, Latini R; Prone-Supine Study Group. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001;345(8):568-73. DOI: 10.1056&#47;NEJMoa010043</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa010043</RefLink> </Reference> <Reference refNo="299"> <RefAuthor>Guerin C</RefAuthor> <RefAuthor>Gaillard S</RefAuthor> <RefAuthor>Lemasson S</RefAuthor> <RefAuthor>Ayzac L</RefAuthor> <RefAuthor>Girard R</RefAuthor> <RefAuthor>Beuret P</RefAuthor> <RefAuthor>Palmier B</RefAuthor> <RefAuthor>Le QV</RefAuthor> <RefAuthor>Sirodot M</RefAuthor> <RefAuthor>Rosselli S</RefAuthor> <RefAuthor>Cadiergue V</RefAuthor> <RefAuthor>Sainty JM</RefAuthor> <RefAuthor>Barbe P</RefAuthor> <RefAuthor>Combourieu E</RefAuthor> <RefAuthor>Debatty D</RefAuthor> <RefAuthor>Rouffineau J</RefAuthor> <RefAuthor>Ezingeard E</RefAuthor> <RefAuthor>Millet O</RefAuthor> <RefAuthor>Guelon D</RefAuthor> <RefAuthor>Rodriguez L</RefAuthor> <RefAuthor>Martin O</RefAuthor> <RefAuthor>Renault A</RefAuthor> <RefAuthor>Sibille JP</RefAuthor> <RefAuthor>Kaidomar M</RefAuthor> <RefTitle>Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial</RefTitle> <RefYear>2004</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>2379-87</RefPage> <RefTotal>Guerin C, Gaillard S, Lemasson S, Ayzac L, Girard R, Beuret P, Palmier B, Le QV, Sirodot M, Rosselli S, Cadiergue V, Sainty JM, Barbe P, Combourieu E, Debatty D, Rouffineau J, Ezingeard E, Millet O, Guelon D, Rodriguez L, Martin O, Renault A, Sibille JP, Kaidomar M. Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial. JAMA. 2004;292(19):2379-87. DOI: 10.1001&#47;jama.292.19.2379</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.292.19.2379</RefLink> </Reference> <Reference refNo="300"> <RefAuthor>Lundin S</RefAuthor> <RefAuthor>Mang H</RefAuthor> <RefAuthor>Smithies M</RefAuthor> <RefAuthor>Stenqvist O</RefAuthor> <RefAuthor>Frostell C</RefAuthor> <RefAuthor> The European Study Group of Inhaled Nitric Oxide</RefAuthor> <RefTitle>Inhalation of nitric oxide in acute lung injury: results of a European multicentre study</RefTitle> <RefYear>1999</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>911-9</RefPage> <RefTotal>Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C; The European Study Group of Inhaled Nitric Oxide. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med. 1999;25(9):911-9. DOI: 10.1007&#47;s001340050982</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s001340050982</RefLink> </Reference> <Reference refNo="301"> <RefAuthor>Taylor RW</RefAuthor> <RefAuthor>Zimmerman JL</RefAuthor> <RefAuthor>Dellinger RP</RefAuthor> <RefAuthor>Straube RC</RefAuthor> <RefAuthor>Criner GJ</RefAuthor> <RefAuthor>Davis K Jr</RefAuthor> <RefAuthor>Kelly KM</RefAuthor> <RefAuthor>Smith TC</RefAuthor> <RefAuthor>Small RJ</RefAuthor> <RefAuthor> Inhaled Nitric Oxide in ARDS Study Group</RefAuthor> <RefTitle>Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial</RefTitle> <RefYear>2004</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>1603-9</RefPage> <RefTotal>Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K Jr, Kelly KM, Smith TC, Small RJ; Inhaled Nitric Oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291(13):1603-9. DOI: 10.1001&#47;jama.291.13.1603</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.291.13.1603</RefLink> </Reference> <Reference refNo="302"> <RefAuthor>Sokol J</RefAuthor> <RefAuthor>Jacobs SE</RefAuthor> <RefAuthor>Bohn D</RefAuthor> <RefTitle>Inhaled nitric oxide for acute hypoxic respiratory failure in children and adults: a meta-analysis</RefTitle> <RefYear>2003</RefYear> <RefJournal>Anesth Analg</RefJournal> <RefPage>989-98</RefPage> <RefTotal>Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxic respiratory failure in children and adults: a meta-analysis. Anesth Analg. 2003;97(4):989-98. DOI: 10.1213&#47;01.ANE.0000078819.48523.26</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1213&#47;01.ANE.0000078819.48523.26</RefLink> </Reference> <Reference refNo="303"> <RefAuthor>Esteban A</RefAuthor> <RefAuthor>Al&#237;a I</RefAuthor> <RefAuthor>Gordo F</RefAuthor> <RefAuthor>Fern&#225;ndez R</RefAuthor> <RefAuthor>Solsona JF</RefAuthor> <RefAuthor>Vallverd&#250; I</RefAuthor> <RefAuthor>Mac&#237;as S</RefAuthor> <RefAuthor>Allegue JM</RefAuthor> <RefAuthor>Blanco J</RefAuthor> <RefAuthor>Carriedo D</RefAuthor> <RefAuthor>Le&#243;n M</RefAuthor> <RefAuthor>de la Cal MA</RefAuthor> <RefAuthor>Taboada F</RefAuthor> <RefAuthor>Gonzalez de Velasco J</RefAuthor> <RefAuthor>Palaz&#243;n E</RefAuthor> <RefAuthor>Carrizosa F</RefAuthor> <RefAuthor>Tom&#225;s R</RefAuthor> <RefAuthor>Suarez J</RefAuthor> <RefAuthor>Goldwasser RS</RefAuthor> <RefAuthor> The Spanish Lung Failure Collaborative Group</RefAuthor> <RefTitle>Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation</RefTitle> <RefYear>1997</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>459-65</RefPage> <RefTotal>Esteban A, Al&#237;a I, Gordo F, Fern&#225;ndez R, Solsona JF, Vallverd&#250; I, Mac&#237;as S, Allegue JM, Blanco J, Carriedo D, Le&#243;n M, de la Cal MA, Taboada F, Gonzalez de Velasco J, Palaz&#243;n E, Carrizosa F, Tom&#225;s R, Suarez J, Goldwasser RS; The Spanish Lung Failure Collaborative Group. Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation. Am J Respir Crit Care Med. 1997;156(2 Pt 1):459-65.</RefTotal> </Reference> <Reference refNo="304"> <RefAuthor>Esteban A</RefAuthor> <RefAuthor>Alia I</RefAuthor> <RefAuthor>Tobin MJ</RefAuthor> <RefAuthor>Gil A</RefAuthor> <RefAuthor>Gordo F</RefAuthor> <RefAuthor>Vallverdu I</RefAuthor> <RefAuthor>Al&#237;a I</RefAuthor> <RefAuthor>Tobin MJ</RefAuthor> <RefAuthor>Gil A</RefAuthor> <RefAuthor>Gordo F</RefAuthor> <RefAuthor>Vallverd&#250; I</RefAuthor> <RefAuthor>Blanch L</RefAuthor> <RefAuthor>Bonet A</RefAuthor> <RefAuthor>V&#225;zquez A</RefAuthor> <RefAuthor>de Pablo R</RefAuthor> <RefAuthor>Torres A</RefAuthor> <RefAuthor>de La Cal MA</RefAuthor> <RefAuthor>Mac&#237;as S</RefAuthor> <RefTitle>Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>512-8</RefPage> <RefTotal>Esteban A, Alia I, Tobin MJ, Gil A, Gordo F, Vallverdu I, Al&#237;a I, Tobin MJ, Gil A, Gordo F, Vallverd&#250; I, Blanch L, Bonet A, V&#225;zquez A, de Pablo R, Torres A, de La Cal MA, Mac&#237;as S. Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med. 1999;159(2):512-8.</RefTotal> </Reference> <Reference refNo="305"> <RefAuthor>Ely EW</RefAuthor> <RefAuthor>Baker AM</RefAuthor> <RefAuthor>Dunagan DP</RefAuthor> <RefAuthor>Burke HL</RefAuthor> <RefAuthor>Smith AC</RefAuthor> <RefAuthor>Kelly PT</RefAuthor> <RefAuthor>Johnson MM</RefAuthor> <RefAuthor>Browder RW</RefAuthor> <RefAuthor>Bowton DL</RefAuthor> <RefAuthor>Haponik EF</RefAuthor> <RefTitle>Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously</RefTitle> <RefYear>1996</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1864-9</RefPage> <RefTotal>Ely EW, Baker AM, Dunagan DP, Burke HL, Smith AC, Kelly PT, Johnson MM, Browder RW, Bowton DL, Haponik EF. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med. 1996;335(25):1864-9. DOI: 10.1056&#47;NEJM199612193352502</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199612193352502</RefLink> </Reference> <Reference refNo="413"> <RefAuthor>Ely EW</RefAuthor> <RefAuthor>Bennett PA</RefAuthor> <RefAuthor>Bowton DL</RefAuthor> <RefAuthor>Murphy SM</RefAuthor> <RefAuthor>Florance AM</RefAuthor> <RefAuthor>Haponik EF</RefAuthor> <RefTitle>Large scale implementation of a respiratory therapist-driven protocol for ventilator weaning</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>439-46</RefPage> <RefTotal>Ely EW, Bennett PA, Bowton DL, Murphy SM, Florance AM, Haponik EF. Large scale implementation of a respiratory therapist-driven protocol for ventilator weaning. Am J Respir Crit Care Med. 1999;159(2):439-46.</RefTotal> </Reference> <Reference refNo="306"> <RefAuthor>Bone RC</RefAuthor> <RefAuthor>Fisher CJ Jr</RefAuthor> <RefAuthor>Clemmer TP</RefAuthor> <RefAuthor>Slotman GJ</RefAuthor> <RefAuthor>Metz CA</RefAuthor> <RefAuthor>Balk RA</RefAuthor> <RefTitle>A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock</RefTitle> <RefYear>1987</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>653-8</RefPage> <RefTotal>Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):653-8.</RefTotal> </Reference> <Reference refNo="307"> <RefAuthor>The Veterans Administration Systemic Sepsis Cooperative Study Group</RefAuthor> <RefTitle>Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis</RefTitle> <RefYear>1987</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>659-65</RefPage> <RefTotal>The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med. 1987;317(11):659-65.</RefTotal> </Reference> <Reference refNo="308"> <RefAuthor>Sprung CL</RefAuthor> <RefAuthor>Annane D</RefAuthor> <RefAuthor>Keh D</RefAuthor> <RefAuthor>Moreno R</RefAuthor> <RefAuthor>Singer M</RefAuthor> <RefAuthor>Freivogel K</RefAuthor> <RefAuthor>Weiss YG</RefAuthor> <RefAuthor>Benbenishty J</RefAuthor> <RefAuthor>Kalenka A</RefAuthor> <RefAuthor>Forst H</RefAuthor> <RefAuthor>Laterre PF</RefAuthor> <RefAuthor>Reinhart K</RefAuthor> <RefAuthor>Cuthbertson BH</RefAuthor> <RefAuthor>Payen D</RefAuthor> <RefAuthor>Briegel J</RefAuthor> <RefAuthor> CORTICUS Study Group</RefAuthor> <RefTitle>Hydrocortisone therapy for patients with septic shock</RefTitle> <RefYear>2008</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>111-24</RefPage> <RefTotal>Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-24. DOI: 10.1056&#47;NEJMoa071366</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa071366</RefLink> </Reference> <Reference refNo="309"> <RefAuthor>Marik PE</RefAuthor> <RefAuthor>Zaloga GP</RefAuthor> <RefTitle>Adrenal insufficiency during septic shock</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>141-5</RefPage> <RefTotal>Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med. 2003;31(1):141-5. DOI: 10.1097&#47;00003246-200301000-00022</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200301000-00022</RefLink> </Reference> <Reference refNo="310"> <RefAuthor>Zaloga GP</RefAuthor> <RefAuthor>Marik P</RefAuthor> <RefTitle>Hypothalamic-pituitary-adrenal insufficiency</RefTitle> <RefYear>2001</RefYear> <RefJournal>Crit Care Clin</RefJournal> <RefPage>25-41</RefPage> <RefTotal>Zaloga GP, Marik P. Hypothalamic-pituitary-adrenal insufficiency. Crit Care Clin. 2001;17(1):25-41. DOI: 10.1016&#47;S0749-0704(05)70150-0</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0749-0704(05)70150-0</RefLink> </Reference> <Reference refNo="311"> <RefAuthor>Dunn JF</RefAuthor> <RefAuthor>Nisula BC</RefAuthor> <RefAuthor>Rodbard D</RefAuthor> <RefTitle>Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma</RefTitle> <RefYear>1981</RefYear> <RefJournal>J Clin Endocrinol Metab</RefJournal> <RefPage>58-68</RefPage> <RefTotal>Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):58-68. DOI: 10.1210&#47;jcem-53-1-58</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1210&#47;jcem-53-1-58</RefLink> </Reference> <Reference refNo="312"> <RefAuthor>Beishuizen A</RefAuthor> <RefAuthor>Thijs LG</RefAuthor> <RefAuthor>Vermes I</RefAuthor> <RefTitle>Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma</RefTitle> <RefYear>2001</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1584-91</RefPage> <RefTotal>Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med. 2001;27(10):1584-91. DOI: 10.1007&#47;s001340101073</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s001340101073</RefLink> </Reference> <Reference refNo="313"> <RefAuthor>Keh D</RefAuthor> <RefAuthor>Boehnke T</RefAuthor> <RefAuthor>Weber-Cartens S</RefAuthor> <RefAuthor>Schulz C</RefAuthor> <RefAuthor>Ahlers O</RefAuthor> <RefAuthor>Bercker S</RefAuthor> <RefAuthor>Volk HD</RefAuthor> <RefAuthor>Doecke WD</RefAuthor> <RefAuthor>Falke KJ</RefAuthor> <RefAuthor>Gerlach H</RefAuthor> <RefTitle>Immunologic and hemodynamic effects of &#34;low-dose&#34; hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study</RefTitle> <RefYear>2003</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>512-20</RefPage> <RefTotal>Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of &#34;low-dose&#34; hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003;167(4):512-20. DOI: 10.1164&#47;rccm.200205-446OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200205-446OC</RefLink> </Reference> <Reference refNo="314"> <RefAuthor>Ali NA</RefAuthor> <RefAuthor>O&#39;Brien JM Jr</RefAuthor> <RefAuthor>Dungan K</RefAuthor> <RefAuthor>Phillips G</RefAuthor> <RefAuthor>Marsh CB</RefAuthor> <RefAuthor>Lemeshow S</RefAuthor> <RefAuthor>Connors AF Jr</RefAuthor> <RefAuthor>Preiser JC</RefAuthor> <RefTitle>Glucose variability and mortality in patients with sepsis</RefTitle> <RefYear>2008</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2316-21</RefPage> <RefTotal>Ali NA, O&#39;Brien JM Jr, Dungan K, Phillips G, Marsh CB, Lemeshow S, Connors AF Jr, Preiser JC. Glucose variability and mortality in patients with sepsis. Crit Care Med. 2008;36(8):2316-21. DOI: 10.1097&#47;CCM.0b013e3181810378</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;CCM.0b013e3181810378</RefLink> </Reference> <Reference refNo="315"> <RefAuthor>Bernard GR</RefAuthor> <RefAuthor>Vincent JL</RefAuthor> <RefAuthor>Laterre PF</RefAuthor> <RefAuthor>LaRosa SP</RefAuthor> <RefAuthor>Dhainaut JF</RefAuthor> <RefAuthor>Lopez-Rodriguez A</RefAuthor> <RefAuthor>Steingrub JS</RefAuthor> <RefAuthor>Garber GE</RefAuthor> <RefAuthor>Helterbrand JD</RefAuthor> <RefAuthor>Ely EW</RefAuthor> <RefAuthor>Fisher CJ Jr</RefAuthor> <RefAuthor> Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group</RefAuthor> <RefTitle>Efficacy and safety of recombinant human activated protein C for severe sepsis</RefTitle> <RefYear>2001</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>699-709</RefPage> <RefTotal>Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. DOI: 10.1056&#47;NEJM200103083441001</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM200103083441001</RefLink> </Reference> <Reference refNo="316"> <RefAuthor>Abraham E</RefAuthor> <RefAuthor>Laterre PF</RefAuthor> <RefAuthor>Garg R</RefAuthor> <RefAuthor>Levy H</RefAuthor> <RefAuthor>Talwar D</RefAuthor> <RefAuthor>Trzaskoma BL</RefAuthor> <RefAuthor>Fran&#231;ois B</RefAuthor> <RefAuthor>Guy JS</RefAuthor> <RefAuthor>Br&#252;ckmann M</RefAuthor> <RefAuthor>Rea-Neto A</RefAuthor> <RefAuthor>Rossaint R</RefAuthor> <RefAuthor>Perrotin D</RefAuthor> <RefAuthor>Sablotzki A</RefAuthor> <RefAuthor>Arkins N</RefAuthor> <RefAuthor>Utterback BG</RefAuthor> <RefAuthor>Macias WL</RefAuthor> <RefAuthor> Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group</RefAuthor> <RefTitle>Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death</RefTitle> <RefYear>2005</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1332-41</RefPage> <RefTotal>Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Fran&#231;ois B, Guy JS, Br&#252;ckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353(13):1332-41. DOI: 10.1056&#47;NEJMoa050935</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa050935</RefLink> </Reference> <Reference refNo="317"> <RefAuthor>Vincent JL</RefAuthor> <RefAuthor>Nadel S</RefAuthor> <RefAuthor>Kutsogiannis DJ</RefAuthor> <RefAuthor>Gibney RT</RefAuthor> <RefAuthor>Yan SB</RefAuthor> <RefAuthor>Wyss VL</RefAuthor> <RefAuthor>Bailey JE</RefAuthor> <RefAuthor>Mitchell CL</RefAuthor> <RefAuthor>Sarwat S</RefAuthor> <RefAuthor>Shinall SM</RefAuthor> <RefAuthor>Janes JM</RefAuthor> <RefTitle>Drotrecogin alfa (activated) in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies</RefTitle> <RefYear>2005</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R331-43</RefPage> <RefTotal>Vincent JL, Nadel S, Kutsogiannis DJ, Gibney RT, Yan SB, Wyss VL, Bailey JE, Mitchell CL, Sarwat S, Shinall SM, Janes JM. Drotrecogin alfa (activated) in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies. Crit Care. 2005;9(4):R331-43. DOI: 10.1186&#47;cc3538</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc3538</RefLink> </Reference> <Reference refNo="318"> <RefAuthor>Oxman AD</RefAuthor> <RefAuthor>Guyatt GH</RefAuthor> <RefTitle>A consumer&#39;s guide to subgroup analyses</RefTitle> <RefYear>1992</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>78-84</RefPage> <RefTotal>Oxman AD, Guyatt GH. A consumer&#39;s guide to subgroup analyses. Ann Intern Med. 1992;116(1):78-84.</RefTotal> </Reference> <Reference refNo="320"> <RefAuthor>Levi M</RefAuthor> <RefAuthor>Levy M</RefAuthor> <RefAuthor>Williams MD</RefAuthor> <RefAuthor>Douglas I</RefAuthor> <RefAuthor>Artigas A</RefAuthor> <RefAuthor>Antonelli M</RefAuthor> <RefAuthor>Wyncoll D</RefAuthor> <RefAuthor>Janes J</RefAuthor> <RefAuthor>Booth FV</RefAuthor> <RefAuthor>Wang D</RefAuthor> <RefAuthor>Sundin DP</RefAuthor> <RefAuthor>Macias WL</RefAuthor> <RefAuthor> Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group</RefAuthor> <RefTitle>Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated)</RefTitle> <RefYear>2007</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>483-90</RefPage> <RefTotal>Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, Wyncoll D, Janes J, Booth FV, Wang D, Sundin DP, Macias WL; Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med. 2007;176(5):483-90. DOI: 10.1164&#47;rccm.200612-1803OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200612-1803OC</RefLink> </Reference> <Reference refNo="321"> <RefAuthor>Warren BL</RefAuthor> <RefAuthor>Eid A</RefAuthor> <RefAuthor>Singer P</RefAuthor> <RefAuthor>Pillay SS</RefAuthor> <RefAuthor>Carl P</RefAuthor> <RefAuthor>Novak I</RefAuthor> <RefAuthor>Chalupa P</RefAuthor> <RefAuthor>Atherstone A</RefAuthor> <RefAuthor>P&#233;nzes I</RefAuthor> <RefAuthor>K&#252;bler A</RefAuthor> <RefAuthor>Knaub S</RefAuthor> <RefAuthor>Keinecke HO</RefAuthor> <RefAuthor>Heinrichs H</RefAuthor> <RefAuthor>Schindel F</RefAuthor> <RefAuthor>Juers M</RefAuthor> <RefAuthor>Bone RC</RefAuthor> <RefAuthor>Opal SM</RefAuthor> <RefAuthor> KyberSept Trial Study Group</RefAuthor> <RefTitle>Caring for the critically ill patient: High-dose antithrombin III in severe sepsis: a randomized controlled trial</RefTitle> <RefYear>2001</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>1869-78</RefPage> <RefTotal>Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, P&#233;nzes I, K&#252;bler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM; KyberSept Trial Study Group. Caring for the critically ill patient: High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286(15):1869-78. DOI: 10.1001&#47;jama.286.15.1869</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.286.15.1869</RefLink> </Reference> <Reference refNo="322"> <RefAuthor>Kreymann KG</RefAuthor> <RefAuthor>de Heer G</RefAuthor> <RefAuthor>Nierhaus A</RefAuthor> <RefAuthor>Kluge S</RefAuthor> <RefTitle>Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2677-85</RefPage> <RefTotal>Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007;35(12):2677-85. DOI: 10.1097&#47;01.CCM.0000295263.12774.97</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000295263.12774.97</RefLink> </Reference> <Reference refNo="323"> <RefAuthor>Laupland KB</RefAuthor> <RefAuthor>Kirkpatrick AW</RefAuthor> <RefAuthor>Delaney A</RefAuthor> <RefTitle>Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2686-92</RefPage> <RefTotal>Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med. 2007;35(12):2686-92. DOI: 10.1097&#47;01.CCM.0000295312.13466.1C</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000295312.13466.1C</RefLink> </Reference> <Reference refNo="324"> <RefAuthor>Werdan K</RefAuthor> <RefAuthor>Pilz G</RefAuthor> <RefAuthor>Bujdoso O</RefAuthor> <RefAuthor>Fraunberger P</RefAuthor> <RefAuthor>Neeser G</RefAuthor> <RefAuthor>Schmieder RE</RefAuthor> <RefAuthor>Schmieder RE</RefAuthor> <RefAuthor>Viell B</RefAuthor> <RefAuthor>Marget W</RefAuthor> <RefAuthor>Seewald M</RefAuthor> <RefAuthor>Walger P</RefAuthor> <RefAuthor>Stuttmann R</RefAuthor> <RefAuthor>Speichermann N</RefAuthor> <RefAuthor>Peckelsen C</RefAuthor> <RefAuthor>Kurowski V</RefAuthor> <RefAuthor>Osterhues HH</RefAuthor> <RefAuthor>Verner L</RefAuthor> <RefAuthor>Neumann R</RefAuthor> <RefAuthor>M&#252;ller-Werdan U</RefAuthor> <RefAuthor> Score-Based Immunoglobulin Therapy of Sepsis (SBITS) Study Group</RefAuthor> <RefTitle>Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2693-701</RefPage> <RefTotal>Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, Schmieder RE, Viell B, Marget W, Seewald M, Walger P, Stuttmann R, Speichermann N, Peckelsen C, Kurowski V, Osterhues HH, Verner L, Neumann R, M&#252;ller-Werdan U; Score-Based Immunoglobulin Therapy of Sepsis (SBITS) Study Group. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med. 2007;35(12):2693-701. DOI: 10.1097&#47;01.CCM.0000295426.37471.79</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000295426.37471.79</RefLink> </Reference> <Reference refNo="325"> <RefAuthor>Heyland DK</RefAuthor> <RefTitle>Selenium supplementation in critically ill patients: can too much of a good thing be a bad thing&#63;</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>153</RefPage> <RefTotal>Heyland DK. Selenium supplementation in critically ill patients: can too much of a good thing be a bad thing&#63; Crit Care. 2007;11(4):153. DOI: 10.1186&#47;cc5975</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc5975</RefLink> </Reference> <Reference refNo="326"> <RefAuthor>Forceville X</RefAuthor> <RefAuthor>Laviolle B</RefAuthor> <RefAuthor>Annane D</RefAuthor> <RefAuthor>Vitoux D</RefAuthor> <RefAuthor>Bleichner G</RefAuthor> <RefAuthor>Korach JM</RefAuthor> <RefAuthor>Cantais E</RefAuthor> <RefAuthor>Georges H</RefAuthor> <RefAuthor>Soubirou JL</RefAuthor> <RefAuthor>Combes A</RefAuthor> <RefAuthor>Bellissant E</RefAuthor> <RefTitle>Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R73</RefPage> <RefTotal>Forceville X, Laviolle B, Annane D, Vitoux D, Bleichner G, Korach JM, Cantais E, Georges H, Soubirou JL, Combes A, Bellissant E. Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study. Crit Care. 2007;11(4):R73. DOI: 10.1186&#47;cc5960</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc5960</RefLink> </Reference> <Reference refNo="327"> <RefAuthor>Bernard GR</RefAuthor> <RefAuthor>Wheeler AP</RefAuthor> <RefAuthor>Russell JA</RefAuthor> <RefAuthor>Schein R</RefAuthor> <RefAuthor>Summer WR</RefAuthor> <RefAuthor>Steinberg KP</RefAuthor> <RefAuthor>Fulkerson WJ</RefAuthor> <RefAuthor>Wright PE</RefAuthor> <RefAuthor>Christman BW</RefAuthor> <RefAuthor>Dupont WD</RefAuthor> <RefAuthor>Higgins SB</RefAuthor> <RefAuthor>Swindell BB</RefAuthor> <RefAuthor> The Ibuprofen in Sepsis Study Group</RefAuthor> <RefTitle>The effects of ibuprofen on the physiology and survival of patients with sepsis</RefTitle> <RefYear>1997</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>912-8</RefPage> <RefTotal>Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB; The Ibuprofen in Sepsis Study Group. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med. 1997;336(13):912-8. DOI: 10.1056&#47;NEJM199703273361303</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199703273361303</RefLink> </Reference> <Reference refNo="328"> <RefAuthor>Takala J</RefAuthor> <RefAuthor>Ruokonen E</RefAuthor> <RefAuthor>Webster NR</RefAuthor> <RefAuthor>Nielsen MS</RefAuthor> <RefAuthor>Zandstra DF</RefAuthor> <RefAuthor>Vundelinckx G</RefAuthor> <RefAuthor>Hinds CJ</RefAuthor> <RefTitle>Increased mortality associated with growth hormone treatment in critically ill adults</RefTitle> <RefYear>1999</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>785-92</RefPage> <RefTotal>Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341(11):785-92. DOI: 10.1056&#47;NEJM199909093411102</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199909093411102</RefLink> </Reference> <Reference refNo="329"> <RefAuthor>Holcroft JW</RefAuthor> <RefAuthor>Vassar MJ</RefAuthor> <RefAuthor>Weber CJ</RefAuthor> <RefTitle>Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome. A prospective trial</RefTitle> <RefYear>1986</RefYear> <RefJournal>Ann Surg</RefJournal> <RefPage>371-8</RefPage> <RefTotal>Holcroft JW, Vassar MJ, Weber CJ. Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome. A prospective trial. Ann Surg. 1986;203(4):371-8. DOI: 10.1097&#47;00000658-198604000-00006</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00000658-198604000-00006</RefLink> </Reference> <Reference refNo="330"> <RefAuthor>Bone RC</RefAuthor> <RefAuthor>Slotman G</RefAuthor> <RefAuthor>Maunder R</RefAuthor> <RefAuthor>Silverman H</RefAuthor> <RefAuthor>Hyers TM</RefAuthor> <RefAuthor>Kerstein MD</RefAuthor> <RefAuthor>Ursprung JJ</RefAuthor> <RefAuthor> Prostaglandin E1 Study Group</RefAuthor> <RefTitle>Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome</RefTitle> <RefYear>1989</RefYear> <RefJournal>Chest</RefJournal> <RefPage>114-9</RefPage> <RefTotal>Bone RC, Slotman G, Maunder R, Silverman H, Hyers TM, Kerstein MD, Ursprung JJ; Prostaglandin E1 Study Group. Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Chest. 1989;96(1):114-9. DOI: 10.1378&#47;chest.96.1.114</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.96.1.114</RefLink> </Reference> <Reference refNo="331"> <RefAuthor>Silverman HJ</RefAuthor> <RefAuthor>Slotman G</RefAuthor> <RefAuthor>Bone RC</RefAuthor> <RefAuthor>Maunder R</RefAuthor> <RefAuthor>Hyers TM</RefAuthor> <RefAuthor>Kerstein MD</RefAuthor> <RefAuthor>Ursprung JJ</RefAuthor> <RefAuthor> Prostaglandin E1 Study Group</RefAuthor> <RefTitle>Effects of prostaglandin E1 on oxygen delivery and consumption in patients with the adult respiratory distress syndrome: Results from the prostaglandin E1 multicenter trial</RefTitle> <RefYear>1990</RefYear> <RefJournal>Chest</RefJournal> <RefPage>405-10</RefPage> <RefTotal>Silverman HJ, Slotman G, Bone RC, Maunder R, Hyers TM, Kerstein MD, Ursprung JJ; Prostaglandin E1 Study Group. Effects of prostaglandin E1 on oxygen delivery and consumption in patients with the adult respiratory distress syndrome: Results from the prostaglandin E1 multicenter trial. Chest. 1990;98(2):405-10. DOI: 10.1378&#47;chest.98.2.405</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.98.2.405</RefLink> </Reference> <Reference refNo="332"> <RefAuthor>Abraham E</RefAuthor> <RefAuthor>Baughman R</RefAuthor> <RefAuthor>Fletcher E</RefAuthor> <RefAuthor>Heard S</RefAuthor> <RefAuthor>Lamberti J</RefAuthor> <RefAuthor>Levy H</RefAuthor> <RefAuthor>Nelson L</RefAuthor> <RefAuthor>Rumbak M</RefAuthor> <RefAuthor>Steingrub J</RefAuthor> <RefAuthor>Taylor J</RefAuthor> <RefAuthor>Park YC</RefAuthor> <RefAuthor>Hynds JM</RefAuthor> <RefAuthor>Freitag J</RefAuthor> <RefAuthor> TLC C-53 ARDS Study Group</RefAuthor> <RefTitle>Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial</RefTitle> <RefYear>1999</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1478-85</RefPage> <RefTotal>Abraham E, Baughman R, Fletcher E, Heard S, Lamberti J, Levy H, Nelson L, Rumbak M, Steingrub J, Taylor J, Park YC, Hynds JM, Freitag J; TLC C-53 ARDS Study Group. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. Crit Care Med. 1999;27(8):1478-85. DOI: 10.1097&#47;00003246-199908000-00013</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199908000-00013</RefLink> </Reference> <Reference refNo="333"> <RefAuthor>Yang S</RefAuthor> <RefAuthor>Zhou M</RefAuthor> <RefAuthor>Koo DJ</RefAuthor> <RefAuthor>Chaudry IH</RefAuthor> <RefAuthor>Wang P</RefAuthor> <RefTitle>Pentoxifylline prevents the transition from the hyperdynamic to hypodynamic response during sepsis</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Physiol</RefJournal> <RefPage>H1036-44</RefPage> <RefTotal>Yang S, Zhou M, Koo DJ, Chaudry IH, Wang P. Pentoxifylline prevents the transition from the hyperdynamic to hypodynamic response during sepsis. Am J Physiol. 1999;277(3 Pt 2):H1036-44.</RefTotal> </Reference> <Reference refNo="334"> <RefAuthor>Staubach KH</RefAuthor> <RefAuthor>Schroder J</RefAuthor> <RefAuthor>Stuber F</RefAuthor> <RefAuthor>Gehrke K</RefAuthor> <RefAuthor>Traumann E</RefAuthor> <RefAuthor>Zabel P</RefAuthor> <RefTitle>Effect of pentoxifylline in severe sepsis: results of a randomized, double-blind, placebo-controlled study</RefTitle> <RefYear>1998</RefYear> <RefJournal>Arch Surg</RefJournal> <RefPage>94-100</RefPage> <RefTotal>Staubach KH, Schroder J, Stuber F, Gehrke K, Traumann E, Zabel P. Effect of pentoxifylline in severe sepsis: results of a randomized, double-blind, placebo-controlled study. Arch Surg. 1998;133(1):94-100. DOI: 10.1001&#47;archsurg.133.1.94</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;archsurg.133.1.94</RefLink> </Reference> <Reference refNo="335"> <RefAuthor>Lauterbach R</RefAuthor> <RefAuthor>Pawlik D</RefAuthor> <RefAuthor>Kowalczyk D</RefAuthor> <RefAuthor>Ksyc&#237;nski W</RefAuthor> <RefAuthor>Helwich E</RefAuthor> <RefAuthor>Zembala M</RefAuthor> <RefTitle>Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebo-controlled, double-blind trial</RefTitle> <RefYear>1999</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>807-14</RefPage> <RefTotal>Lauterbach R, Pawlik D, Kowalczyk D, Ksyc&#237;nski W, Helwich E, Zembala M. Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebo-controlled, double-blind trial. Crit Care Med. 1999;27(4):807-14. DOI: 10.1097&#47;00003246-199904000-00042</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199904000-00042</RefLink> </Reference> <Reference refNo="336"> <RefAuthor>Molnar Z</RefAuthor> <RefAuthor>Shearer E</RefAuthor> <RefAuthor>Lowe D</RefAuthor> <RefTitle>N-Acetylcysteine treatment to prevent the progression of multisystem organ failure: a prospective, randomized, placebo-controlled study</RefTitle> <RefYear>1999</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1100-4</RefPage> <RefTotal>Molnar Z, Shearer E, Lowe D. N-Acetylcysteine treatment to prevent the progression of multisystem organ failure: a prospective, randomized, placebo-controlled study. Crit Care Med. 1999;27(6):1100-4. DOI: 10.1097&#47;00003246-199906000-00028</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199906000-00028</RefLink> </Reference> <Reference refNo="337"> <RefAuthor>Zhang P</RefAuthor> <RefAuthor>Bagby GJ</RefAuthor> <RefAuthor>Stoltz DA</RefAuthor> <RefAuthor>Summer WR</RefAuthor> <RefAuthor>Nelson S</RefAuthor> <RefTitle>Enhancement of peritoneal leukocyte function by granulocyte colony-stimulating factor in rats with abdominal sepsis</RefTitle> <RefYear>1998</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>315-21</RefPage> <RefTotal>Zhang P, Bagby GJ, Stoltz DA, Summer WR, Nelson S. Enhancement of peritoneal leukocyte function by granulocyte colony-stimulating factor in rats with abdominal sepsis. Crit Care Med. 1998;26(2):315-21. DOI: 10.1097&#47;00003246-199802000-00035</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199802000-00035</RefLink> </Reference> <Reference refNo="338"> <RefAuthor>Lundblad R</RefAuthor> <RefAuthor>Nesland JM</RefAuthor> <RefAuthor>Giercksky KE</RefAuthor> <RefTitle>Granulocyte colony-stimulating factor improves survival rate and reduces concentrations of bacteria, endotoxin, tumor necrosis factor, and endothelin-1 in fulminant intra-abdominal sepsis in rats</RefTitle> <RefYear>1996</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>820-6</RefPage> <RefTotal>Lundblad R, Nesland JM, Giercksky KE. Granulocyte colony-stimulating factor improves survival rate and reduces concentrations of bacteria, endotoxin, tumor necrosis factor, and endothelin-1 in fulminant intra-abdominal sepsis in rats. Crit Care Med. 1996;24(5):820-6. DOI: 10.1097&#47;00003246-199605000-00016</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199605000-00016</RefLink> </Reference> <Reference refNo="339"> <RefAuthor>Karzai W</RefAuthor> <RefAuthor>von Specht BU</RefAuthor> <RefAuthor>Parent C</RefAuthor> <RefAuthor>Haberstroh J</RefAuthor> <RefAuthor>Wollersen K</RefAuthor> <RefAuthor>Natanson C</RefAuthor> <RefAuthor>Banks SM</RefAuthor> <RefAuthor>Eichacker PQ</RefAuthor> <RefTitle>G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>1377-82</RefPage> <RefTotal>Karzai W, von Specht BU, Parent C, Haberstroh J, Wollersen K, Natanson C, Banks SM, Eichacker PQ. G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects. Am J Respir Crit Care Med. 1999;159(5 Pt 1):1377-82.</RefTotal> </Reference> <Reference refNo="340"> <RefAuthor>Heard SO</RefAuthor> <RefAuthor>Fink MP</RefAuthor> <RefAuthor>Gamelli RL</RefAuthor> <RefAuthor>Solomkin JS</RefAuthor> <RefAuthor>Joshi M</RefAuthor> <RefAuthor>Trask AL</RefAuthor> <RefAuthor>Fabian TC</RefAuthor> <RefAuthor>Hudson LD</RefAuthor> <RefAuthor>Gerold KB</RefAuthor> <RefAuthor>Logan ED</RefAuthor> <RefAuthor> The Filgrastim Study Group</RefAuthor> <RefTitle>Effect of prophylactic administration of recombinant human granulocyte colony-stimulating factor (filgrastim) on the frequency of nosocomial infections in patients with acute traumatic brain injury or cerebral hemorrhage</RefTitle> <RefYear>1998</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>748-54</RefPage> <RefTotal>Heard SO, Fink MP, Gamelli RL, Solomkin JS, Joshi M, Trask AL, Fabian TC, Hudson LD, Gerold KB, Logan ED; The Filgrastim Study Group. Effect of prophylactic administration of recombinant human granulocyte colony-stimulating factor (filgrastim) on the frequency of nosocomial infections in patients with acute traumatic brain injury or cerebral hemorrhage. Crit Care Med. 1998;26(4):748-54. DOI: 10.1097&#47;00003246-199804000-00027</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199804000-00027</RefLink> </Reference> <Reference refNo="341"> <RefAuthor>Root RK</RefAuthor> <RefAuthor>Lodato RF</RefAuthor> <RefAuthor>Patrick W</RefAuthor> <RefAuthor>Cade JF</RefAuthor> <RefAuthor>Fotheringham N</RefAuthor> <RefAuthor>Milwee S</RefAuthor> <RefAuthor>Vincent JL</RefAuthor> <RefAuthor>Torres A</RefAuthor> <RefAuthor>Rello J</RefAuthor> <RefAuthor>Nelson S</RefAuthor> <RefAuthor> Pneumonia Sepsis Study Group</RefAuthor> <RefTitle>Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>367-73</RefPage> <RefTotal>Root RK, Lodato RF, Patrick W, Cade JF, Fotheringham N, Milwee S, Vincent JL, Torres A, Rello J, Nelson S; Pneumonia Sepsis Study Group. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med. 2003;31(2):367-73. DOI: 10.1097&#47;01.CCM.0000048629.32625.5D</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000048629.32625.5D</RefLink> </Reference> <Reference refNo="342"> <RefAuthor>P&#233;rez J</RefAuthor> <RefAuthor>Dellinger RP</RefAuthor> <RefAuthor> International Sepsis Forum</RefAuthor> <RefTitle>Other supportive therapies in sepsis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>S116-27</RefPage> <RefTotal>P&#233;rez J, Dellinger RP; International Sepsis Forum. Other supportive therapies in sepsis. Intensive Care Med. 2001;27(Suppl 1):S116-27.</RefTotal> </Reference> <Reference refNo="343"> <RefAuthor>Cade JF</RefAuthor> <RefTitle>High risk of the critically ill for venous thromboembolism</RefTitle> <RefYear>1982</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>448-50</RefPage> <RefTotal>Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med. 1982;10(7):448-50. DOI: 10.1097&#47;00003246-198207000-00006</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-198207000-00006</RefLink> </Reference> <Reference refNo="344"> <RefAuthor>Belch JJ</RefAuthor> <RefAuthor>Lowe GD</RefAuthor> <RefAuthor>Ward AG</RefAuthor> <RefAuthor>Forbes CD</RefAuthor> <RefAuthor>Prentice CR</RefAuthor> <RefTitle>Prevention of deep vein thrombosis in medical patients by low-dose heparin</RefTitle> <RefYear>1981</RefYear> <RefJournal>Scott Med J</RefJournal> <RefPage>115-7</RefPage> <RefTotal>Belch JJ, Lowe GD, Ward AG, Forbes CD, Prentice CR. Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J. 1981;26(2):115-7.</RefTotal> </Reference> <Reference refNo="345"> <RefAuthor>Samama MM</RefAuthor> <RefAuthor>Cohen AT</RefAuthor> <RefAuthor>Darmon JY</RefAuthor> <RefAuthor>Desjardins L</RefAuthor> <RefAuthor>Eldor A</RefAuthor> <RefAuthor>Janbon C</RefAuthor> <RefAuthor>Leizorovicz A</RefAuthor> <RefAuthor>Nguyen H</RefAuthor> <RefAuthor>Olsson CG</RefAuthor> <RefAuthor>Turpie AG</RefAuthor> <RefAuthor>Weisslinger N</RefAuthor> <RefAuthor> Prophylaxis in Medical Patients with Enoxaparin Study Group</RefAuthor> <RefTitle>A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients</RefTitle> <RefYear>1999</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>793-800</RefPage> <RefTotal>Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N; Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999;341(11):793-800. DOI: 10.1056&#47;NEJM199909093411103</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199909093411103</RefLink> </Reference> <Reference refNo="346"> <RefAuthor>Cestac P</RefAuthor> <RefAuthor>Bagheri H</RefAuthor> <RefAuthor>Lapeyre-Mestre M</RefAuthor> <RefAuthor>Si&#233; P</RefAuthor> <RefAuthor>Fouladi A</RefAuthor> <RefAuthor>Maupas E</RefAuthor> <RefAuthor>L&#233;ger P</RefAuthor> <RefAuthor>Fontan B</RefAuthor> <RefAuthor>Massip P</RefAuthor> <RefAuthor>Montastruc JL</RefAuthor> <RefTitle>Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients</RefTitle> <RefYear>2003</RefYear> <RefJournal>Drug Saf</RefJournal> <RefPage>197-207</RefPage> <RefTotal>Cestac P, Bagheri H, Lapeyre-Mestre M, Si&#233; P, Fouladi A, Maupas E, L&#233;ger P, Fontan B, Massip P, Montastruc JL. Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients. Drug Saf. 2003;26(3):197-207. DOI: 10.2165&#47;00002018-200326030-00005</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.2165&#47;00002018-200326030-00005</RefLink> </Reference> <Reference refNo="347"> <RefAuthor>Kreymann KG</RefAuthor> <RefAuthor>Berger MM</RefAuthor> <RefAuthor>Deutz NE</RefAuthor> <RefAuthor>Hiesmayr M</RefAuthor> <RefAuthor>Jolliet P</RefAuthor> <RefAuthor>Kazandjiev G</RefAuthor> <RefAuthor>Nitenberg G</RefAuthor> <RefAuthor>van den Berghe G</RefAuthor> <RefAuthor>Wernerman J</RefAuthor> <RefAuthor> DGEM (German Society for Nutritional Medicine)</RefAuthor> <RefAuthor>Ebner C</RefAuthor> <RefAuthor>Hartl W</RefAuthor> <RefAuthor>Heymann C</RefAuthor> <RefAuthor>Spies C</RefAuthor> <RefAuthor> ESPEN (European Society for Parenteral and Enteral Nutrition)</RefAuthor> <RefTitle>ESPEN Guidelines on Enteral Nutrition: Intensive care</RefTitle> <RefYear>2006</RefYear> <RefJournal>Clin Nutr</RefJournal> <RefPage>210-23</RefPage> <RefTotal>Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, Nitenberg G, van den Berghe G, Wernerman J; DGEM (German Society for Nutritional Medicine), Ebner C, Hartl W, Heymann C, Spies C; ESPEN (European Society for Parenteral and Enteral Nutrition). ESPEN Guidelines on Enteral Nutrition: Intensive care. Clin Nutr. 2006;25(2):210-23. DOI: 10.1016&#47;j.clnu.2006.01.021</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.clnu.2006.01.021</RefLink> </Reference> <Reference refNo="348"> <RefAuthor>Sandstr&#246;m R</RefAuthor> <RefAuthor>Drott C</RefAuthor> <RefAuthor>Hyltander A</RefAuthor> <RefAuthor>Arfvidsson B</RefAuthor> <RefAuthor>Scherst&#233;n T</RefAuthor> <RefAuthor>Wickstr&#246;m I</RefAuthor> <RefAuthor>Lundholm K</RefAuthor> <RefTitle>The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study</RefTitle> <RefYear>1993</RefYear> <RefJournal>Ann Surg</RefJournal> <RefPage>185-95</RefPage> <RefTotal>Sandstr&#246;m R, Drott C, Hyltander A, Arfvidsson B, Scherst&#233;n T, Wickstr&#246;m I, Lundholm K. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg. 1993;217(2):185-95.</RefTotal> </Reference> <Reference refNo="349"> <RefAuthor>Koretz RL</RefAuthor> <RefAuthor>Avenell A</RefAuthor> <RefAuthor>Lipman TO</RefAuthor> <RefAuthor>Braunschweig CL</RefAuthor> <RefAuthor>Milne AC</RefAuthor> <RefTitle>Does enteral nutrition affect clinical outcome&#63; A systematic review of the randomized trials</RefTitle> <RefYear>2007</RefYear> <RefJournal>Am J Gastroenterol</RefJournal> <RefPage>412-29; quiz 468</RefPage> <RefTotal>Koretz RL, Avenell A, Lipman TO, Braunschweig CL, Milne AC. Does enteral nutrition affect clinical outcome&#63; A systematic review of the randomized trials. Am J Gastroenterol. 2007;102(2):412-29; quiz 468. DOI: 10.1111&#47;j.1572-0241.2006.01024.x</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1111&#47;j.1572-0241.2006.01024.x</RefLink> </Reference> <Reference refNo="350"> <RefAuthor>Peter JV</RefAuthor> <RefAuthor>Moran JL</RefAuthor> <RefAuthor>Phillips-Hughes J</RefAuthor> <RefTitle>A metaanalysis of treatment outcomes of early enteral versus early parenteral nutrition in hospitalized patients</RefTitle> <RefYear>2005</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>213-20; discussion 260-1</RefPage> <RefTotal>Peter JV, Moran JL, Phillips-Hughes J. A metaanalysis of treatment outcomes of early enteral versus early parenteral nutrition in hospitalized patients. Crit Care Med. 2005;33(1):213-20; discussion 260-1. DOI: 10.1097&#47;01.CCM.0000150960.36228.C0</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000150960.36228.C0</RefLink> </Reference> <Reference refNo="351"> <RefAuthor>Barr J</RefAuthor> <RefAuthor>Hecht M</RefAuthor> <RefAuthor>Flavin KE</RefAuthor> <RefAuthor>Khorana A</RefAuthor> <RefAuthor>Gould MK</RefAuthor> <RefTitle>Outcomes in critically ill patients before and after the implementation of an evidence-based nutritional management protocol</RefTitle> <RefYear>2004</RefYear> <RefJournal>Chest</RefJournal> <RefPage>1446-57</RefPage> <RefTotal>Barr J, Hecht M, Flavin KE, Khorana A, Gould MK. Outcomes in critically ill patients before and after the implementation of an evidence-based nutritional management protocol. Chest. 2004;125(4):1446-57. DOI: 10.1378&#47;chest.125.4.1446</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1378&#47;chest.125.4.1446</RefLink> </Reference> <Reference refNo="352"> <RefAuthor>Petros S</RefAuthor> <RefAuthor>Engelmann L</RefAuthor> <RefTitle>Enteral nutrition delivery and energy expenditure in medical intensive care patients</RefTitle> <RefYear>2006</RefYear> <RefJournal>Clin Nutr</RefJournal> <RefPage>51-9</RefPage> <RefTotal>Petros S, Engelmann L. Enteral nutrition delivery and energy expenditure in medical intensive care patients. Clin Nutr. 2006;25(1):51-9. DOI: 10.1016&#47;j.clnu.2005.08.013</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;j.clnu.2005.08.013</RefLink> </Reference> <Reference refNo="353"> <RefAuthor>Simpson F</RefAuthor> <RefAuthor>Doig GS</RefAuthor> <RefTitle>Parenteral vs enteral nutrition in the critically ill patient: a meta-analysis of trials using the intention to treat principle</RefTitle> <RefYear>2005</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>12-23</RefPage> <RefTotal>Simpson F, Doig GS. Parenteral vs enteral nutrition in the critically ill patient: a meta-analysis of trials using the intention to treat principle. Intensive Care Med. 2005;31(1):12-23. DOI: 10.1007&#47;s00134-004-2511-2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-004-2511-2</RefLink> </Reference> <Reference refNo="354"> <RefAuthor>Druml W</RefAuthor> <RefAuthor>Fischer M</RefAuthor> <RefAuthor>Ratheiser K</RefAuthor> <RefTitle>Use of intravenous lipids in critically ill patients with sepsis without and with hepatic failure</RefTitle> <RefYear>1998</RefYear> <RefJournal>JPEN J Parenter Enteral Nutr</RefJournal> <RefPage>217-23</RefPage> <RefTotal>Druml W, Fischer M, Ratheiser K. Use of intravenous lipids in critically ill patients with sepsis without and with hepatic failure. JPEN J Parenter Enteral Nutr. 1998;22(4):217-23. DOI: 10.1177&#47;0148607198022004217</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1177&#47;0148607198022004217</RefLink> </Reference> <Reference refNo="355"> <RefAuthor>Stoner HB</RefAuthor> <RefAuthor>Little RA</RefAuthor> <RefAuthor>Frayn KN</RefAuthor> <RefAuthor>Elebute AE</RefAuthor> <RefAuthor>Tresadern J</RefAuthor> <RefAuthor>Gross E</RefAuthor> <RefTitle>The effect of sepsis on the oxidation of carbohydrate and fat</RefTitle> <RefYear>1983</RefYear> <RefJournal>Br J Surg</RefJournal> <RefPage>32-5</RefPage> <RefTotal>Stoner HB, Little RA, Frayn KN, Elebute AE, Tresadern J, Gross E. The effect of sepsis on the oxidation of carbohydrate and fat. Br J Surg. 1983;70(1):32-5. DOI: 10.1002&#47;bjs.1800700113</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1002&#47;bjs.1800700113</RefLink> </Reference> <Reference refNo="356"> <RefAuthor>Battistella FD</RefAuthor> <RefAuthor>Widergren JT</RefAuthor> <RefAuthor>Anderson JT</RefAuthor> <RefAuthor>Siepler JK</RefAuthor> <RefAuthor>Weber JC</RefAuthor> <RefAuthor>MacColl K</RefAuthor> <RefTitle>A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition</RefTitle> <RefYear>1997</RefYear> <RefJournal>J Trauma</RefJournal> <RefPage>52-8; discussion 58-60</RefPage> <RefTotal>Battistella FD, Widergren JT, Anderson JT, Siepler JK, Weber JC, MacColl K. A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition. J Trauma. 1997;43(1):52-8; discussion 58-60. DOI: 10.1097&#47;00005373-199707000-00013</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00005373-199707000-00013</RefLink> </Reference> <Reference refNo="357"> <RefAuthor>Bertolini G</RefAuthor> <RefAuthor>Iapichino G</RefAuthor> <RefAuthor>Radrizzani D</RefAuthor> <RefAuthor>Facchini R</RefAuthor> <RefAuthor>Simini B</RefAuthor> <RefAuthor>Bruzzone P</RefAuthor> <RefAuthor>Zanforlin G</RefAuthor> <RefAuthor>Tognoni G</RefAuthor> <RefTitle>Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial</RefTitle> <RefYear>2003</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>834-40</RefPage> <RefTotal>Bertolini G, Iapichino G, Radrizzani D, Facchini R, Simini B, Bruzzone P, Zanforlin G, Tognoni G. Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial. Intensive Care Med. 2003;29(5):834-40.</RefTotal> </Reference> <Reference refNo="358"> <RefAuthor>Galb&#225;n C</RefAuthor> <RefAuthor>Montejo JC</RefAuthor> <RefAuthor>Mesejo A</RefAuthor> <RefAuthor>Marco P</RefAuthor> <RefAuthor>Celaya S</RefAuthor> <RefAuthor>S&#225;nchez-Segura JM</RefAuthor> <RefAuthor>Farr&#233; M</RefAuthor> <RefAuthor>Bryg DJ</RefAuthor> <RefTitle>An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients</RefTitle> <RefYear>2000</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>643-8</RefPage> <RefTotal>Galb&#225;n C, Montejo JC, Mesejo A, Marco P, Celaya S, S&#225;nchez-Segura JM, Farr&#233; M, Bryg DJ. An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med. 2000;28(3):643-8. DOI: 10.1097&#47;00003246-200003000-00007</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200003000-00007</RefLink> </Reference> <Reference refNo="359"> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>Dhaliwal R</RefAuthor> <RefAuthor>Drover JW</RefAuthor> <RefAuthor>Gramlich L</RefAuthor> <RefAuthor>Dodek P</RefAuthor> <RefAuthor> Canadian Critical Care Clinical Practice Guidelines Committee</RefAuthor> <RefTitle>Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients</RefTitle> <RefYear>2003</RefYear> <RefJournal>JPEN J Parenter Enteral Nutr</RefJournal> <RefPage>355-73</RefPage> <RefTotal>Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P; Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003;27(5):355-73. DOI: 10.1177&#47;0148607103027005355</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1177&#47;0148607103027005355</RefLink> </Reference> <Reference refNo="360"> <RefAuthor>Radrizzani D</RefAuthor> <RefAuthor>Bertolini G</RefAuthor> <RefAuthor>Facchini R</RefAuthor> <RefAuthor>Simini B</RefAuthor> <RefAuthor>Bruzzone P</RefAuthor> <RefAuthor>Zanforlin G</RefAuthor> <RefAuthor>Tognoni G</RefAuthor> <RefAuthor>Iapichino G</RefAuthor> <RefTitle>Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe sepsis: a randomized clinical trial</RefTitle> <RefYear>2006</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1191-8</RefPage> <RefTotal>Radrizzani D, Bertolini G, Facchini R, Simini B, Bruzzone P, Zanforlin G, Tognoni G, Iapichino G. Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe sepsis: a randomized clinical trial. Intensive Care Med. 2006;32(8):1191-8. DOI: 10.1007&#47;s00134-006-0238-y</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-006-0238-y</RefLink> </Reference> <Reference refNo="361"> <RefAuthor>Pontes-Arruda A</RefAuthor> <RefAuthor>Arag&#227;o AM</RefAuthor> <RefAuthor>Albuquerque JD</RefAuthor> <RefTitle>Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2325-33</RefPage> <RefTotal>Pontes-Arruda A, Arag&#227;o AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006;34(9):2325-33. DOI: 10.1097&#47;01.CCM.0000234033.65657.B6</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000234033.65657.B6</RefLink> </Reference> <Reference refNo="362"> <RefAuthor>Gadek JE</RefAuthor> <RefAuthor>DeMichele SJ</RefAuthor> <RefAuthor>Karlstad MD</RefAuthor> <RefAuthor>Pacht ER</RefAuthor> <RefAuthor>Donahoe M</RefAuthor> <RefAuthor>Albertson TE</RefAuthor> <RefAuthor>Van Hoozen C</RefAuthor> <RefAuthor>Wennberg AK</RefAuthor> <RefAuthor>Nelson JL</RefAuthor> <RefAuthor>Noursalehi M</RefAuthor> <RefAuthor> Enteral Nutrition in ARDS Study Group</RefAuthor> <RefTitle>Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome</RefTitle> <RefYear>1999</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1409-20</RefPage> <RefTotal>Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, Van Hoozen C, Wennberg AK, Nelson JL, Noursalehi M; Enteral Nutrition in ARDS Study Group. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med. 1999;27(8):1409-20. DOI: 10.1097&#47;00003246-199908000-00001</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199908000-00001</RefLink> </Reference> <Reference refNo="363"> <RefAuthor>Singer P</RefAuthor> <RefAuthor>Theilla M</RefAuthor> <RefAuthor>Fisher H</RefAuthor> <RefAuthor>Gibstein L</RefAuthor> <RefAuthor>Grozovski E</RefAuthor> <RefAuthor>Cohen J</RefAuthor> <RefTitle>Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1033-8</RefPage> <RefTotal>Singer P, Theilla M, Fisher H, Gibstein L, Grozovski E, Cohen J. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med. 2006;34(4):1033-8. DOI: 10.1097&#47;01.CCM.0000206111.23629.0A</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000206111.23629.0A</RefLink> </Reference> <Reference refNo="364"> <RefAuthor>Bakalar B</RefAuthor> <RefAuthor>Duska F</RefAuthor> <RefAuthor>Pachl J</RefAuthor> <RefAuthor>Fric M</RefAuthor> <RefAuthor>Otahal M</RefAuthor> <RefAuthor>Pazout J</RefAuthor> <RefAuthor>Andel M</RefAuthor> <RefTitle>Parenterally administered dipeptide alanyl-glutamine prevents worsening of insulin sensitivity in multiple-trauma patients</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>381-6</RefPage> <RefTotal>Bakalar B, Duska F, Pachl J, Fric M, Otahal M, Pazout J, Andel M. Parenterally administered dipeptide alanyl-glutamine prevents worsening of insulin sensitivity in multiple-trauma patients. Crit Care Med. 2006;34(2):381-6. DOI: 10.1097&#47;01.CCM.0000196829.30741.D4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000196829.30741.D4</RefLink> </Reference> <Reference refNo="365"> <RefAuthor>D&#233;chelotte P</RefAuthor> <RefAuthor>Hasselmann M</RefAuthor> <RefAuthor>Cynober L</RefAuthor> <RefAuthor>Allaouchiche B</RefAuthor> <RefAuthor>Co&#235;ffier M</RefAuthor> <RefAuthor>Hecketsweiler B</RefAuthor> <RefAuthor>Merle V</RefAuthor> <RefAuthor>Mazerolles M</RefAuthor> <RefAuthor>Samba D</RefAuthor> <RefAuthor>Guillou YM</RefAuthor> <RefAuthor>Petit J</RefAuthor> <RefAuthor>Mansoor O</RefAuthor> <RefAuthor>Colas G</RefAuthor> <RefAuthor>Cohendy R</RefAuthor> <RefAuthor>Barnoud D</RefAuthor> <RefAuthor>Czernichow P</RefAuthor> <RefAuthor>Bleichner G</RefAuthor> <RefTitle>L-alanyl-L-glutamine dipeptide-supplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: the French controlled, randomized, double-blind, multicenter study</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>598-604</RefPage> <RefTotal>D&#233;chelotte P, Hasselmann M, Cynober L, Allaouchiche B, Co&#235;ffier M, Hecketsweiler B, Merle V, Mazerolles M, Samba D, Guillou YM, Petit J, Mansoor O, Colas G, Cohendy R, Barnoud D, Czernichow P, Bleichner G. L-alanyl-L-glutamine dipeptide-supplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: the French controlled, randomized, double-blind, multicenter study. Crit Care Med. 2006;34(3):598-604. DOI: 10.1097&#47;01.CCM.0000201004.30750.D1</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000201004.30750.D1</RefLink> </Reference> <Reference refNo="366"> <RefAuthor>Goeters C</RefAuthor> <RefAuthor>Wenn A</RefAuthor> <RefAuthor>Mertes N</RefAuthor> <RefAuthor>Wempe C</RefAuthor> <RefAuthor>Van Aken H</RefAuthor> <RefAuthor>Stehle P</RefAuthor> <RefAuthor>Bone HG</RefAuthor> <RefTitle>Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients</RefTitle> <RefYear>2002</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2032-7</RefPage> <RefTotal>Goeters C, Wenn A, Mertes N, Wempe C, Van Aken H, Stehle P, Bone HG. Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients. Crit Care Med. 2002;30(9):2032-7. DOI: 10.1097&#47;00003246-200209000-00013</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200209000-00013</RefLink> </Reference> <Reference refNo="367"> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>Dhaliwal R</RefAuthor> <RefAuthor>Day AG</RefAuthor> <RefAuthor>Muscedere J</RefAuthor> <RefAuthor>Drover J</RefAuthor> <RefAuthor>Suchner U</RefAuthor> <RefAuthor>Cook D</RefAuthor> <RefAuthor> Canadian Critical Care Trials Group</RefAuthor> <RefTitle>REducing Deaths due to OXidative Stress (The REDOXS Study): Rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients</RefTitle> <RefYear>2006</RefYear> <RefJournal>Proc Nutr Soc</RefJournal> <RefPage>250-63</RefPage> <RefTotal>Heyland DK, Dhaliwal R, Day AG, Muscedere J, Drover J, Suchner U, Cook D; Canadian Critical Care Trials Group. REducing Deaths due to OXidative Stress (The REDOXS Study): Rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients. Proc Nutr Soc. 2006;65(3):250-63. DOI: 10.1079&#47;PNS2006505</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1079&#47;PNS2006505</RefLink> </Reference> <Reference refNo="368"> <RefAuthor>Cook DJ</RefAuthor> <RefAuthor>Reeve BK</RefAuthor> <RefAuthor>Guyatt GH</RefAuthor> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>Griffith LE</RefAuthor> <RefAuthor>Buckingham L</RefAuthor> <RefAuthor>Tryba M</RefAuthor> <RefTitle>Stress ulcer prophylaxis in critically ill patients: Resolving discordant meta-analyses</RefTitle> <RefYear>1996</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>308-14</RefPage> <RefTotal>Cook DJ, Reeve BK, Guyatt GH, Heyland DK, Griffith LE, Buckingham L, Tryba M. Stress ulcer prophylaxis in critically ill patients: Resolving discordant meta-analyses. JAMA. 1996;275(4):308-14.</RefTotal> </Reference> <Reference refNo="369"> <RefAuthor>Basso N</RefAuthor> <RefAuthor>Bagarani M</RefAuthor> <RefAuthor>Materia A</RefAuthor> <RefAuthor>Fiorani S</RefAuthor> <RefAuthor>Lunardi P</RefAuthor> <RefAuthor>Speranza V</RefAuthor> <RefTitle>Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients: Controlled, randomized trial</RefTitle> <RefYear>1981</RefYear> <RefJournal>Am J Surg</RefJournal> <RefPage>339-41</RefPage> <RefTotal>Basso N, Bagarani M, Materia A, Fiorani S, Lunardi P, Speranza V. Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients: Controlled, randomized trial. Am J Surg. 1981;141(3):339-41. DOI: 10.1016&#47;0002-9610(81)90191-4</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;0002-9610(81)90191-4</RefLink> </Reference> <Reference refNo="370"> <RefAuthor>Cook D</RefAuthor> <RefAuthor>Guyatt G</RefAuthor> <RefAuthor>Marshall J</RefAuthor> <RefAuthor>Leasa D</RefAuthor> <RefAuthor>Fuller H</RefAuthor> <RefAuthor>Hall R</RefAuthor> <RefAuthor>Peters S</RefAuthor> <RefAuthor>Rutledge F</RefAuthor> <RefAuthor>Griffith L</RefAuthor> <RefAuthor>McLellan A</RefAuthor> <RefAuthor>Wood G</RefAuthor> <RefAuthor>Kirby A</RefAuthor> <RefAuthor> Canadian Critical Care Trials Group</RefAuthor> <RefTitle>A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation</RefTitle> <RefYear>1998</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>791-7</RefPage> <RefTotal>Cook D, Guyatt G, Marshall J, Leasa D, Fuller H, Hall R, Peters S, Rutledge F, Griffith L, McLellan A, Wood G, Kirby A; Canadian Critical Care Trials Group. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med. 1998;338(12):791-7. DOI: 10.1056&#47;NEJM199803193381203</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199803193381203</RefLink> </Reference> <Reference refNo="371"> <RefAuthor>Conrad SA</RefAuthor> <RefAuthor>Gabrielli A</RefAuthor> <RefAuthor>Margolis B</RefAuthor> <RefAuthor>Quartin A</RefAuthor> <RefAuthor>Hata JS</RefAuthor> <RefAuthor>Frank WO</RefAuthor> <RefAuthor>Bagin RG</RefAuthor> <RefAuthor>Rock JA</RefAuthor> <RefAuthor>Hepburn B</RefAuthor> <RefAuthor>Laine L</RefAuthor> <RefTitle>Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients</RefTitle> <RefYear>2005</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>760-5</RefPage> <RefTotal>Conrad SA, Gabrielli A, Margolis B, Quartin A, Hata JS, Frank WO, Bagin RG, Rock JA, Hepburn B, Laine L. Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients. Crit Care Med. 2005;33(4):760-5. DOI: 10.1097&#47;01.CCM.0000157751.92249.32</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000157751.92249.32</RefLink> </Reference> <Reference refNo="372"> <RefAuthor>Levy MJ</RefAuthor> <RefAuthor>Seelig CB</RefAuthor> <RefAuthor>Robinson NJ</RefAuthor> <RefAuthor>Ranney JE</RefAuthor> <RefTitle>Comparison of omeprazole and ranitidine for stress ulcer prophylaxis</RefTitle> <RefYear>1997</RefYear> <RefJournal>Dig Dis Sci</RefJournal> <RefPage>1255-9</RefPage> <RefTotal>Levy MJ, Seelig CB, Robinson NJ, Ranney JE. Comparison of omeprazole and ranitidine for stress ulcer prophylaxis. Dig Dis Sci. 1997;42(6):1255-9. DOI: 10.1023&#47;A:1018810325370</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1023&#47;A:1018810325370</RefLink> </Reference> <Reference refNo="373"> <RefAuthor>Dial S</RefAuthor> <RefAuthor>Alrasadi K</RefAuthor> <RefAuthor>Manoukian C</RefAuthor> <RefAuthor>Huang A</RefAuthor> <RefAuthor>Menzies D</RefAuthor> <RefTitle>Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies</RefTitle> <RefYear>2004</RefYear> <RefJournal>CMAJ</RefJournal> <RefPage>33-8</RefPage> <RefTotal>Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33-8. DOI: 10.1503&#47;cmaj.1040876</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1503&#47;cmaj.1040876</RefLink> </Reference> <Reference refNo="374"> <RefAuthor>Dial S</RefAuthor> <RefAuthor>Delaney JA</RefAuthor> <RefAuthor>Barkun AN</RefAuthor> <RefAuthor>Suissa S</RefAuthor> <RefTitle>Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease</RefTitle> <RefYear>2005</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>2989-95</RefPage> <RefTotal>Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294(23):2989-95. DOI: 10.1001&#47;jama.294.23.2989</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1001&#47;jama.294.23.2989</RefLink> </Reference> <Reference refNo="375"> <RefAuthor>Lau JY</RefAuthor> <RefAuthor>Sung JJ</RefAuthor> <RefAuthor>Lee KK</RefAuthor> <RefAuthor>Yung MY</RefAuthor> <RefAuthor>Wong SK</RefAuthor> <RefAuthor>Wu JC</RefAuthor> <RefAuthor>Chan FK</RefAuthor> <RefAuthor>Ng EK</RefAuthor> <RefAuthor>You JH</RefAuthor> <RefAuthor>Lee CW</RefAuthor> <RefAuthor>Chan AC</RefAuthor> <RefAuthor>Chung SC</RefAuthor> <RefTitle>Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers</RefTitle> <RefYear>2000</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>310-6</RefPage> <RefTotal>Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, Chan FK, Ng EK, You JH, Lee CW, Chan AC, Chung SC. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med. 2000;343(5):310-6. DOI: 10.1056&#47;NEJM200008033430501</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM200008033430501</RefLink> </Reference> <Reference refNo="376"> <RefAuthor>MacLaren R</RefAuthor> <RefAuthor>Jarvis CL</RefAuthor> <RefAuthor>Fish DN</RefAuthor> <RefTitle>Use of enteral nutrition for stress ulcer prophylaxis</RefTitle> <RefYear>2001</RefYear> <RefJournal>Ann Pharmacother</RefJournal> <RefPage>1614-23</RefPage> <RefTotal>MacLaren R, Jarvis CL, Fish DN. Use of enteral nutrition for stress ulcer prophylaxis. Ann Pharmacother. 2001;35(12):1614-23. DOI: 10.1345&#47;aph.1A083</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1345&#47;aph.1A083</RefLink> </Reference> <Reference refNo="377"> <RefAuthor>Cooper DJ</RefAuthor> <RefAuthor>Walley KR</RefAuthor> <RefAuthor>Wiggs BR</RefAuthor> <RefAuthor>Russell JA</RefAuthor> <RefTitle>Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: A prospective, controlled clinical study</RefTitle> <RefYear>1990</RefYear> <RefJournal>Ann Intern Med</RefJournal> <RefPage>492-8</RefPage> <RefTotal>Cooper DJ, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: A prospective, controlled clinical study. Ann Intern Med. 1990;112(7):492-8.</RefTotal> </Reference> <Reference refNo="378"> <RefAuthor>Mathieu D</RefAuthor> <RefAuthor>Neviere R</RefAuthor> <RefAuthor>Billard V</RefAuthor> <RefAuthor>Fleyfel M</RefAuthor> <RefAuthor>Wattel F</RefAuthor> <RefTitle>Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study</RefTitle> <RefYear>1991</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1352-6</RefPage> <RefTotal>Mathieu D, Neviere R, Billard V, Fleyfel M, Wattel F. Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Crit Care Med. 1991;19(11):1352-6. DOI: 10.1097&#47;00003246-199111000-00008</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199111000-00008</RefLink> </Reference> <Reference refNo="379"> <RefAuthor>H&#233;bert PC</RefAuthor> <RefAuthor>Wells G</RefAuthor> <RefAuthor>Blajchman MA</RefAuthor> <RefAuthor>Marshall J</RefAuthor> <RefAuthor>Martin C</RefAuthor> <RefAuthor>Pagliarello G</RefAuthor> <RefAuthor>Tweeddale M</RefAuthor> <RefAuthor>Schweitzer I</RefAuthor> <RefAuthor>Yetisir E</RefAuthor> <RefAuthor> Transfusion Requirements in Critical Care Investigators</RefAuthor> <RefAuthor> Canadian Critical Care Trials Group</RefAuthor> <RefTitle>A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care</RefTitle> <RefYear>1999</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>409-17</RefPage> <RefTotal>H&#233;bert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E; Transfusion Requirements in Critical Care Investigators; Canadian Critical Care Trials Group. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340(6):409-17. DOI: 10.1056&#47;NEJM199902113400601</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM199902113400601</RefLink> </Reference> <Reference refNo="380"> <RefAuthor>Marik PE</RefAuthor> <RefAuthor>Sibbald WJ</RefAuthor> <RefTitle>Effect of stored-blood transfusion on oxygen delivery in patients with sepsis</RefTitle> <RefYear>1993</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>3024-9</RefPage> <RefTotal>Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA. 1993;269(23):3024-9.</RefTotal> </Reference> <Reference refNo="381"> <RefAuthor>Lorente JA</RefAuthor> <RefAuthor>Land&#237;n L</RefAuthor> <RefAuthor>De Pablo R</RefAuthor> <RefAuthor>Renes E</RefAuthor> <RefAuthor>Rodr&#237;guez-D&#237;az R</RefAuthor> <RefAuthor>Liste D</RefAuthor> <RefTitle>Effects of blood transfusion on oxygen transport variables in severe sepsis</RefTitle> <RefYear>1993</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1312-8</RefPage> <RefTotal>Lorente JA, Land&#237;n L, De Pablo R, Renes E, Rodr&#237;guez-D&#237;az R, Liste D. Effects of blood transfusion on oxygen transport variables in severe sepsis. Crit Care Med. 1993;21(9):1312-8. DOI: 10.1097&#47;00003246-199309000-00013</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199309000-00013</RefLink> </Reference> <Reference refNo="382"> <RefAuthor>Corwin HL</RefAuthor> <RefAuthor>Gettinger A</RefAuthor> <RefAuthor>Fabian TC</RefAuthor> <RefAuthor>May A</RefAuthor> <RefAuthor>Pearl RG</RefAuthor> <RefAuthor>Heard S</RefAuthor> <RefAuthor>An R</RefAuthor> <RefAuthor>Bowers PJ</RefAuthor> <RefAuthor>Burton P</RefAuthor> <RefAuthor>Klausner MA</RefAuthor> <RefAuthor>Corwin MJ</RefAuthor> <RefAuthor> EPO Critical Care Trials Group</RefAuthor> <RefTitle>Efficacy and safety of epoetin alfa in critically ill patients</RefTitle> <RefYear>2007</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>965-76</RefPage> <RefTotal>Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ; EPO Critical Care Trials Group. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357(10):965-76. DOI: 10.1056&#47;NEJMoa071533</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJMoa071533</RefLink> </Reference> <Reference refNo="383"> <RefAuthor>Gajic O</RefAuthor> <RefAuthor>Rana R</RefAuthor> <RefAuthor>Winters JL</RefAuthor> <RefAuthor>Yilmaz M</RefAuthor> <RefAuthor>Mendez JL</RefAuthor> <RefAuthor>Rickman OB</RefAuthor> <RefAuthor>O&#39;Byrne MM</RefAuthor> <RefAuthor>Evenson LK</RefAuthor> <RefAuthor>Malinchoc M</RefAuthor> <RefAuthor>DeGoey SR</RefAuthor> <RefAuthor>Afessa B</RefAuthor> <RefAuthor>Hubmayr RD</RefAuthor> <RefAuthor>Moore SB</RefAuthor> <RefTitle>Transfusion-related acute lung injury in the critically ill: prospective nested case-control study</RefTitle> <RefYear>2007</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>886-91</RefPage> <RefTotal>Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, O&#39;Byrne MM, Evenson LK, Malinchoc M, DeGoey SR, Afessa B, Hubmayr RD, Moore SB. Transfusion-related acute lung injury in the critically ill: prospective nested case-control study. Am J Respir Crit Care Med. 2007;176(9):886-91. DOI: 10.1164&#47;rccm.200702-271OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200702-271OC</RefLink> </Reference> <Reference refNo="384"> <RefAuthor>Vorstand und Wissenschaftlicher Beirat der Bundes&#228;rztekammer</RefAuthor> <RefTitle></RefTitle> <RefYear>2003</RefYear> <RefBookTitle>Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten</RefBookTitle> <RefPage></RefPage> <RefTotal>Vorstand und Wissenschaftlicher Beirat der Bundes&#228;rztekammer. Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten. K&#246;ln: Deutscher &#196;rzte-Verlag; 2003. Available from: http:&#47;&#47;www.bundesaerztekammer.de&#47;downloads&#47;Blutkomponentenpdf.pdf</RefTotal> <RefLink>http:&#47;&#47;www.bundesaerztekammer.de&#47;downloads&#47;Blutkomponentenpdf.pdf</RefLink> </Reference> <Reference refNo="385"> <RefAuthor>Girard TD</RefAuthor> <RefAuthor>Kress JP</RefAuthor> <RefAuthor>Fuchs BD</RefAuthor> <RefAuthor>Thomason JW</RefAuthor> <RefAuthor>Schweickert WD</RefAuthor> <RefAuthor>Pun BT</RefAuthor> <RefAuthor>Taichman DB</RefAuthor> <RefAuthor>Dunn JG</RefAuthor> <RefAuthor>Pohlman AS</RefAuthor> <RefAuthor>Kinniry PA</RefAuthor> <RefAuthor>Jackson JC</RefAuthor> <RefAuthor>Canonico AE</RefAuthor> <RefAuthor>Light RW</RefAuthor> <RefAuthor>Shintani AK</RefAuthor> <RefAuthor>Thompson JL</RefAuthor> <RefAuthor>Gordon SM</RefAuthor> <RefAuthor>Hall JB</RefAuthor> <RefAuthor>Dittus RS</RefAuthor> <RefAuthor>Bernard GR</RefAuthor> <RefAuthor>Ely EW</RefAuthor> <RefTitle>Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial</RefTitle> <RefYear>2008</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>126-34</RefPage> <RefTotal>Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, Taichman DB, Dunn JG, Pohlman AS, Kinniry PA, Jackson JC, Canonico AE, Light RW, Shintani AK, Thompson JL, Gordon SM, Hall JB, Dittus RS, Bernard GR, Ely EW. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371(9607):126-34. DOI: 10.1016&#47;S0140-6736(08)60105-1</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0140-6736(08)60105-1</RefLink> </Reference> <Reference refNo="386"> <RefAuthor>Brook AD</RefAuthor> <RefAuthor>Ahrens TS</RefAuthor> <RefAuthor>Schaiff R</RefAuthor> <RefAuthor>Prentice D</RefAuthor> <RefAuthor>Sherman G</RefAuthor> <RefAuthor>Shannon W</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation</RefTitle> <RefYear>1999</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2609-15</RefPage> <RefTotal>Brook AD, Ahrens TS, Schaiff R, Prentice D, Sherman G, Shannon W, Kollef MH. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999;27(12):2609-15. DOI: 10.1097&#47;00003246-199912000-00001</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199912000-00001</RefLink> </Reference> <Reference refNo="387"> <RefAuthor>Kress JP</RefAuthor> <RefAuthor>Pohlman AS</RefAuthor> <RefAuthor>O&#39;Connor MF</RefAuthor> <RefAuthor>Hall JB</RefAuthor> <RefTitle>Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation</RefTitle> <RefYear>2000</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1471-7</RefPage> <RefTotal>Kress JP, Pohlman AS, O&#39;Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471-7. DOI: 10.1056&#47;NEJM200005183422002</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1056&#47;NEJM200005183422002</RefLink> </Reference> <Reference refNo="388"> <RefAuthor>Martin J</RefAuthor> <RefAuthor>B&#228;sell K</RefAuthor> <RefAuthor>B&#252;rkle H</RefAuthor> <RefAuthor>Hommel J</RefAuthor> <RefAuthor>Huth G</RefAuthor> <RefAuthor>Kessler P</RefAuthor> <RefAuthor>Kretz FJ</RefAuthor> <RefAuthor>Putensen C</RefAuthor> <RefAuthor>Quintel M</RefAuthor> <RefAuthor>Tonner P</RefAuthor> <RefAuthor>Tryba M</RefAuthor> <RefAuthor>Scholz J</RefAuthor> <RefAuthor>Sch&#252;ttler J</RefAuthor> <RefAuthor>Wappler F</RefAuthor> <RefAuthor>Spies C</RefAuthor> <RefTitle>Analgesie und Sedierung in der Intensivmedizin - Kurzversion</RefTitle> <RefYear>2005</RefYear> <RefJournal>An&#228;sthesiol Intensivmed</RefJournal> <RefPage>S1-S20</RefPage> <RefTotal>Martin J, B&#228;sell K, B&#252;rkle H, Hommel J, Huth G, Kessler P, Kretz FJ, Putensen C, Quintel M, Tonner P, Tryba M, Scholz J, Sch&#252;ttler J, Wappler F, Spies C. Analgesie und Sedierung in der Intensivmedizin - Kurzversion. An&#228;sthesiol Intensivmed. 2005;46(1):S1-S20. Available from: http:&#47;&#47;www.bda.de&#47;downloads&#47;Leitlinie-Analgosedierung.pdf</RefTotal> <RefLink>http:&#47;&#47;www.bda.de&#47;downloads&#47;Leitlinie-Analgosedierung.pdf</RefLink> </Reference> <Reference refNo="389"> <RefAuthor>Payen JF</RefAuthor> <RefAuthor>Bru O</RefAuthor> <RefAuthor>Bosson JL</RefAuthor> <RefAuthor>Lagrasta A</RefAuthor> <RefAuthor>Novel E</RefAuthor> <RefAuthor>Deschaux I</RefAuthor> <RefAuthor>Lavagne P</RefAuthor> <RefAuthor>Jacquot C</RefAuthor> <RefTitle>Assessing pain in critically ill sedated patients by using a behavioral pain scale</RefTitle> <RefYear>2001</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2258-63</RefPage> <RefTotal>Payen JF, Bru O, Bosson JL, Lagrasta A, Novel E, Deschaux I, Lavagne P, Jacquot C. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med. 2001;29(12):2258-63. DOI: 10.1097&#47;00003246-200112000-00004</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200112000-00004</RefLink> </Reference> <Reference refNo="390"> <RefAuthor>Richman PS</RefAuthor> <RefAuthor>Baram D</RefAuthor> <RefAuthor>Varela M</RefAuthor> <RefAuthor>Glass PS</RefAuthor> <RefTitle>Sedation during mechanical ventilation: a trial of benzodiazepine and opiate in combination</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1395-401</RefPage> <RefTotal>Richman PS, Baram D, Varela M, Glass PS. Sedation during mechanical ventilation: a trial of benzodiazepine and opiate in combination. Crit Care Med. 2006;34(5):1395-401. DOI: 10.1097&#47;01.CCM.0000215454.50964.F8</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;01.CCM.0000215454.50964.F8</RefLink> </Reference> <Reference refNo="391"> <RefAuthor>Wagner RL</RefAuthor> <RefAuthor>White PF</RefAuthor> <RefAuthor>Kan PB</RefAuthor> <RefAuthor>Rosenthal MH</RefAuthor> <RefAuthor>Feldman D</RefAuthor> <RefTitle>Inhibition of adrenal steroidogenesis by the anesthetic etomidate</RefTitle> <RefYear>1984</RefYear> <RefJournal>N Engl J Med</RefJournal> <RefPage>1415-21</RefPage> <RefTotal>Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med. 1984;310(22):1415-21.</RefTotal> </Reference> <Reference refNo="392"> <RefAuthor>den Brinker M</RefAuthor> <RefAuthor>Joosten KF</RefAuthor> <RefAuthor>Liem O</RefAuthor> <RefAuthor>de Jong FH</RefAuthor> <RefAuthor>Hop WC</RefAuthor> <RefAuthor>Hazelzet JA</RefAuthor> <RefAuthor>van Dijk M</RefAuthor> <RefAuthor>Hokken-Koelega AC</RefAuthor> <RefTitle>Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality</RefTitle> <RefYear>2005</RefYear> <RefJournal>J Clin Endocrinol Metab</RefJournal> <RefPage>5110-7</RefPage> <RefTotal>den Brinker M, Joosten KF, Liem O, de Jong FH, Hop WC, Hazelzet JA, van Dijk M, Hokken-Koelega AC. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab. 2005;90(9):5110-7. DOI: 10.1210&#47;jc.2005-1107</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1210&#47;jc.2005-1107</RefLink> </Reference> <Reference refNo="393"> <RefAuthor>Malerba G</RefAuthor> <RefAuthor>Romano-Girard F</RefAuthor> <RefAuthor>Cravoisy A</RefAuthor> <RefAuthor>Dousset B</RefAuthor> <RefAuthor>Nace L</RefAuthor> <RefAuthor>L&#233;vy B</RefAuthor> <RefAuthor>Bollaert PE</RefAuthor> <RefTitle>Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation</RefTitle> <RefYear>2005</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>388-92</RefPage> <RefTotal>Malerba G, Romano-Girard F, Cravoisy A, Dousset B, Nace L, L&#233;vy B, Bollaert PE. Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med. 2005;31(3):388-92. DOI: 10.1007&#47;s00134-004-2550-8</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-004-2550-8</RefLink> </Reference> <Reference refNo="394"> <RefAuthor>Ray DC</RefAuthor> <RefAuthor>McKeown DW</RefAuthor> <RefTitle>Effect of induction agent on vasopressor and steroid use, and outcome in patients with septic shock</RefTitle> <RefYear>2007</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R56</RefPage> <RefTotal>Ray DC, McKeown DW. Effect of induction agent on vasopressor and steroid use, and outcome in patients with septic shock. Crit Care. 2007;11(3):R56. DOI: 10.1186&#47;cc5916</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc5916</RefLink> </Reference> <Reference refNo="395"> <RefAuthor>Rossiter A</RefAuthor> <RefAuthor>Souney PF</RefAuthor> <RefAuthor>McGowan S</RefAuthor> <RefAuthor>Carvajal P</RefAuthor> <RefTitle>Pancuronium-induced prolonged neuromuscular blockade</RefTitle> <RefYear>1991</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1583-7</RefPage> <RefTotal>Rossiter A, Souney PF, McGowan S, Carvajal P. Pancuronium-induced prolonged neuromuscular blockade. Crit Care Med. 1991;19(12):1583-7. DOI: 10.1097&#47;00003246-199112000-00023</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199112000-00023</RefLink> </Reference> <Reference refNo="396"> <RefAuthor>Partridge BL</RefAuthor> <RefAuthor>Abrams JH</RefAuthor> <RefAuthor>Bazemore C</RefAuthor> <RefAuthor>Rubin R</RefAuthor> <RefTitle>Prolonged neuromuscular blockade after long-term infusion of vecuronium bromide in the intensive care unit</RefTitle> <RefYear>1990</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>1177-9</RefPage> <RefTotal>Partridge BL, Abrams JH, Bazemore C, Rubin R. Prolonged neuromuscular blockade after long-term infusion of vecuronium bromide in the intensive care unit. Crit Care Med. 1990;18(10):1177-9. DOI: 10.1097&#47;00003246-199010000-00025</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199010000-00025</RefLink> </Reference> <Reference refNo="397"> <RefAuthor>Vanderheyden BA</RefAuthor> <RefAuthor>Reynolds HN</RefAuthor> <RefAuthor>Gerold KB</RefAuthor> <RefAuthor>Emanuele T</RefAuthor> <RefTitle>Prolonged paralysis after long-term vecuronium infusion</RefTitle> <RefYear>1992</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>304-7</RefPage> <RefTotal>Vanderheyden BA, Reynolds HN, Gerold KB, Emanuele T. Prolonged paralysis after long-term vecuronium infusion. Crit Care Med. 1992;20(2):304-7. DOI: 10.1097&#47;00003246-199202000-00019</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-199202000-00019</RefLink> </Reference> <Reference refNo="398"> <RefAuthor>Meyer KC</RefAuthor> <RefAuthor>Prielipp RC</RefAuthor> <RefAuthor>Grossman JE</RefAuthor> <RefAuthor>Coursin DB</RefAuthor> <RefTitle>Prolonged weakness after infusion of atracurium in two intensive care unit patients</RefTitle> <RefYear>1994</RefYear> <RefJournal>Anesth Analg</RefJournal> <RefPage>772-4</RefPage> <RefTotal>Meyer KC, Prielipp RC, Grossman JE, Coursin DB. Prolonged weakness after infusion of atracurium in two intensive care unit patients. Anesth Analg. 1994;78(4):772-4. DOI: 10.1213&#47;00000539-199404000-00027</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1213&#47;00000539-199404000-00027</RefLink> </Reference> <Reference refNo="399"> <RefAuthor>Manthous CA</RefAuthor> <RefAuthor>Chatila W</RefAuthor> <RefTitle>Prolonged weakness after the withdrawal of atracurium</RefTitle> <RefYear>1994</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>1441-3</RefPage> <RefTotal>Manthous CA, Chatila W. Prolonged weakness after the withdrawal of atracurium. Am J Respir Crit Care Med. 1994;150(5 Pt 1):1441-3.</RefTotal> </Reference> <Reference refNo="400"> <RefAuthor>Prielipp RC</RefAuthor> <RefAuthor>Coursin DB</RefAuthor> <RefAuthor>Scuderi PE</RefAuthor> <RefAuthor>Bowton DL</RefAuthor> <RefAuthor>Ford SR</RefAuthor> <RefAuthor>Cardenas VJ Jr</RefAuthor> <RefAuthor>Vender J</RefAuthor> <RefAuthor>Howard D</RefAuthor> <RefAuthor>Casale EJ</RefAuthor> <RefAuthor>Murray MJ</RefAuthor> <RefTitle>Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients</RefTitle> <RefYear>1995</RefYear> <RefJournal>Anesth Analg</RefJournal> <RefPage>3-12</RefPage> <RefTotal>Prielipp RC, Coursin DB, Scuderi PE, Bowton DL, Ford SR, Cardenas VJ Jr, Vender J, Howard D, Casale EJ, Murray MJ. Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients. Anesth Analg. 1995;81(1):3-12. DOI: 10.1097&#47;00000539-199507000-00002</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00000539-199507000-00002</RefLink> </Reference> <Reference refNo="401"> <RefAuthor>Lagneau F</RefAuthor> <RefAuthor>D&#39;Honneur G</RefAuthor> <RefAuthor>Plaud B</RefAuthor> <RefAuthor>Mantz J</RefAuthor> <RefAuthor>Gillart T</RefAuthor> <RefAuthor>Duvaldestin P</RefAuthor> <RefAuthor>Marty J</RefAuthor> <RefAuthor>Clyti N</RefAuthor> <RefAuthor>Pourriat JL</RefAuthor> <RefTitle>A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients</RefTitle> <RefYear>2002</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1735-41</RefPage> <RefTotal>Lagneau F, D&#39;Honneur G, Plaud B, Mantz J, Gillart T, Duvaldestin P, Marty J, Clyti N, Pourriat JL. A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients. Intensive Care Med. 2002;28(12):1735-41. DOI: 10.1007&#47;s00134-002-1508-y</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-002-1508-y</RefLink> </Reference> <Reference refNo="402"> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>Hopman W</RefAuthor> <RefAuthor>Coo H</RefAuthor> <RefAuthor>Tranmer J</RefAuthor> <RefAuthor>McColl MA</RefAuthor> <RefTitle>Long-term health-related quality of life in survivors of sepsis. Short Form 36: a valid and reliable measure of health-related quality of life</RefTitle> <RefYear>2000</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>3599-605</RefPage> <RefTotal>Heyland DK, Hopman W, Coo H, Tranmer J, McColl MA. Long-term health-related quality of life in survivors of sepsis. Short Form 36: a valid and reliable measure of health-related quality of life. Crit Care Med. 2000;28(11):3599-605. DOI: 10.1097&#47;00003246-200011000-00006</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200011000-00006</RefLink> </Reference> <Reference refNo="403"> <RefAuthor>Korosec Jagodic H</RefAuthor> <RefAuthor>Jagodic K</RefAuthor> <RefAuthor>Podbregar M</RefAuthor> <RefTitle>Long-term outcome and quality of life of patients treated in surgical intensive care: a comparison between sepsis and trauma</RefTitle> <RefYear>2006</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R134</RefPage> <RefTotal>Korosec Jagodic H, Jagodic K, Podbregar M. Long-term outcome and quality of life of patients treated in surgical intensive care: a comparison between sepsis and trauma. Crit Care. 2006;10(5):R134. DOI: 10.1186&#47;cc5047</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc5047</RefLink> </Reference> <Reference refNo="404"> <RefAuthor>Granja C</RefAuthor> <RefAuthor>Dias C</RefAuthor> <RefAuthor>Costa-Pereira A</RefAuthor> <RefAuthor>Sarmento A</RefAuthor> <RefTitle>Quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness</RefTitle> <RefYear>2004</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R91-8</RefPage> <RefTotal>Granja C, Dias C, Costa-Pereira A, Sarmento A. Quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness. Crit Care. 2004;8(2):R91-8. DOI: 10.1186&#47;cc2818</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1186&#47;cc2818</RefLink> </Reference> <Reference refNo="405"> <RefAuthor>Bolton CF</RefAuthor> <RefAuthor>Gilbert JJ</RefAuthor> <RefAuthor>Hahn AF</RefAuthor> <RefAuthor>Sibbald WJ</RefAuthor> <RefTitle>Polyneuropathy in critically ill patients</RefTitle> <RefYear>1984</RefYear> <RefJournal>J Neurol Neurosurg Psychiatry</RefJournal> <RefPage>1223-31</RefPage> <RefTotal>Bolton CF, Gilbert JJ, Hahn AF, Sibbald WJ. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry. 1984;47(11):1223-31. DOI: 10.1136&#47;jnnp.47.11.1223</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1136&#47;jnnp.47.11.1223</RefLink> </Reference> <Reference refNo="406"> <RefAuthor>Tepper M</RefAuthor> <RefAuthor>Rakic S</RefAuthor> <RefAuthor>Haas JA</RefAuthor> <RefAuthor>Woittiez AJ</RefAuthor> <RefTitle>Incidence and onset of critical illness polyneuropathy in patients with septic shock</RefTitle> <RefYear>2000</RefYear> <RefJournal>Neth J Med</RefJournal> <RefPage>211-4</RefPage> <RefTotal>Tepper M, Rakic S, Haas JA, Woittiez AJ. Incidence and onset of critical illness polyneuropathy in patients with septic shock. Neth J Med. 2000;56(6):211-4. DOI: 10.1016&#47;S0300-2977(00)00019-X</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0300-2977(00)00019-X</RefLink> </Reference> <Reference refNo="407"> <RefAuthor>Schelling G</RefAuthor> <RefTitle>Post-traumatic stress disorder in somatic disease: lessons from critically ill patients</RefTitle> <RefYear>2008</RefYear> <RefJournal>Prog Brain Res</RefJournal> <RefPage>229-37</RefPage> <RefTotal>Schelling G. Post-traumatic stress disorder in somatic disease: lessons from critically ill patients. Prog Brain Res. 2008;167:229-37. DOI: 10.1016&#47;S0079-6123(07)67016-2</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1016&#47;S0079-6123(07)67016-2</RefLink> </Reference> <Reference refNo="408"> <RefAuthor>Davydow DS</RefAuthor> <RefAuthor>Gifford JM</RefAuthor> <RefAuthor>Desai SV</RefAuthor> <RefAuthor>Bienvenu OJ</RefAuthor> <RefAuthor>Needham DM</RefAuthor> <RefTitle>Depression in general intensive care unit survivors: a systematic review</RefTitle> <RefYear>2009</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>796-809</RefPage> <RefTotal>Davydow DS, Gifford JM, Desai SV, Bienvenu OJ, Needham DM. Depression in general intensive care unit survivors: a systematic review. Intensive Care Med. 2009;35(5):796-809. DOI: 10.1007&#47;s00134-009-1396-5</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-009-1396-5</RefLink> </Reference> <Reference refNo="409"> <RefAuthor>Graf J</RefAuthor> <RefAuthor>Doig GS</RefAuthor> <RefAuthor>Cook DJ</RefAuthor> <RefAuthor>Vincent JL</RefAuthor> <RefAuthor>Sibbald WJ</RefAuthor> <RefTitle>Randomized, controlled clinical trials in sepsis: has methodological quality improved over time&#63;</RefTitle> <RefYear>2002</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>461-72</RefPage> <RefTotal>Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ. Randomized, controlled clinical trials in sepsis: has methodological quality improved over time&#63; Crit Care Med. 2002;30(2):461-72. DOI: 10.1097&#47;00003246-200202000-00032</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1097&#47;00003246-200202000-00032</RefLink> </Reference> <Reference refNo="142"> <RefAuthor>Oostdijk EA</RefAuthor> <RefAuthor>de Smet AM</RefAuthor> <RefAuthor>Blok HE</RefAuthor> <RefAuthor>Thieme Groen ES</RefAuthor> <RefAuthor>van Asselt GJ</RefAuthor> <RefAuthor>Benus RF</RefAuthor> <RefAuthor>Bernards SA</RefAuthor> <RefAuthor>Fr&#233;nay IH</RefAuthor> <RefAuthor>Jansz AR</RefAuthor> <RefAuthor>de Jongh BM</RefAuthor> <RefAuthor>Kaan JA</RefAuthor> <RefAuthor>Leverstein-van Hall MA</RefAuthor> <RefAuthor>Mascini EM</RefAuthor> <RefAuthor>Pauw W</RefAuthor> <RefAuthor>Sturm PD</RefAuthor> <RefAuthor>Thijsen SF</RefAuthor> <RefAuthor>Kluytmans JA</RefAuthor> <RefAuthor>Bonten MJ</RefAuthor> <RefTitle>Ecological effects of selective decontamination on resistant gram-negative bacterial colonization</RefTitle> <RefYear>2010</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>452-7</RefPage> <RefTotal>Oostdijk EA, de Smet AM, Blok HE, Thieme Groen ES, van Asselt GJ, Benus RF, Bernards SA, Fr&#233;nay IH, Jansz AR, de Jongh BM, Kaan JA, Leverstein-van Hall MA, Mascini EM, Pauw W, Sturm PD, Thijsen SF, Kluytmans JA, Bonten MJ. Ecological effects of selective decontamination on resistant gram-negative bacterial colonization. Am J Respir Crit Care Med. 2010;181(5):452-7. DOI: 10.1164&#47;rccm.200908-1210OC</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1164&#47;rccm.200908-1210OC</RefLink> </Reference> <Reference refNo="166"> <RefAuthor>Robert Koch-Institut</RefAuthor> <RefTitle>Empfehlungen der St&#228;ndigen Impfkommission (STIKO) am Robert Koch-Institut&#47;Stand: Juli 2009</RefTitle> <RefYear>2009</RefYear> <RefJournal>Epid Bull</RefJournal> <RefPage>279-99</RefPage> <RefTotal>Robert Koch-Institut. Empfehlungen der St&#228;ndigen Impfkommission (STIKO) am Robert Koch-Institut&#47;Stand: Juli 2009. Epid Bull. 2009;30:279-99. Available from: http:&#47;&#47;www.rki.de&#47;cln&#95;178&#47;nn&#95;1378492&#47;DE&#47;Content&#47;Infekt&#47;EpidBull&#47;Archiv&#47;2009&#47;30&#95;&#95;09,templateId&#61;raw,property&#61;publicationFile.pdf&#47;30&#95;09.pdf</RefTotal> <RefLink>http:&#47;&#47;www.rki.de&#47;cln&#95;178&#47;nn&#95;1378492&#47;DE&#47;Content&#47;Infekt&#47;EpidBull&#47;Archiv&#47;2009&#47;30&#95;&#95;09,templateId&#61;raw,property&#61;publicationFile.pdf&#47;30&#95;09.pdf</RefLink> </Reference> <Reference refNo="319"> <RefAuthor>Finfer S</RefAuthor> <RefAuthor>Ranieri VM</RefAuthor> <RefAuthor>Thompson BT</RefAuthor> <RefAuthor>Barie PS</RefAuthor> <RefAuthor>Dhainaut JF</RefAuthor> <RefAuthor>Douglas IS</RefAuthor> <RefAuthor>G&#229;rdlund B</RefAuthor> <RefAuthor>Marshall JC</RefAuthor> <RefAuthor>Rhodes A</RefAuthor> <RefTitle>Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock</RefTitle> <RefYear>2008</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1935-47</RefPage> <RefTotal>Finfer S, Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, G&#229;rdlund B, Marshall JC, Rhodes A. Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock. Intensive Care Med. 2008;34(11):1935-47. DOI: 10.1007&#47;s00134-008-1266-6</RefTotal> <RefLink>http:&#47;&#47;dx.doi.org&#47;10.1007&#47;s00134-008-1266-6</RefLink> </Reference> <Reference refNo="410"> <RefAuthor>Deutsche Sepsis-Hilfe e.V.</RefAuthor> <RefTitle></RefTitle> <RefYear>2009</RefYear> <RefBookTitle>Sepsis Information f&#252;r Patienten &#38; Angeh&#246;rige</RefBookTitle> <RefPage></RefPage> <RefTotal>Deutsche Sepsis-Hilfe e.V. Sepsis Information f&#252;r Patienten &#38; Angeh&#246;rige. 3 ed. Jena: Deutsche Sepsis-Hilfe e.V.; 2009. Available from: http:&#47;&#47;www.sepsis-gesellschaft.de&#47;DSG&#47;Deutsch&#47;Was&#43;ist&#43;Sepsis&#37;3F&#47;Informationen&#43;fuer&#43;Laien&#47;Patientenbroschuere&#63;sid&#61;x6l4xfz0uT2LruJvxg0rNM&#38;iid&#61;1</RefTotal> <RefLink>http:&#47;&#47;www.sepsis-gesellschaft.de&#47;DSG&#47;Deutsch&#47;Was&#43;ist&#43;Sepsis&#37;3F&#47;Informationen&#43;fuer&#43;Laien&#47;Patientenbroschuere&#63;sid&#61;x6l4xfz0uT2LruJvxg0rNM&#38;iid&#61;1</RefLink> </Reference> </References> <Media> <Tables> <Table format="png"> <MediaNo>1</MediaNo> <MediaID language="en">1en</MediaID> <MediaID language="de">1de</MediaID> <Caption language="en"><Pgraph><Mark1>Table 1: Diagnostic criteria for sepsis, severe sepsis and septic shock (modified after &#91;411&#93;), in line with the ACCP&#47;SCCM consensus conference criteria &#91;11&#93;.</Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Tabelle 1: Diagnosekriterien f&#252;r Sepsis, schwere Sepsis und septischen Schock (mod. nach &#91;411&#93;) entsprechend den ACCP&#47;SCCM Konsensus-Konferenz Kriterien &#91;11&#93;.</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>2</MediaNo> <MediaID language="en">2en</MediaID> <MediaID language="de">2de</MediaID> <Caption language="en"><Pgraph><Mark1>Table 2: Collection, storage and transport of blood cultures &#91;33&#93;</Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Tabelle 2: Entnahme, Lagerung und Transport von Blutkulturen &#91;33&#93;.</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>3</MediaNo> <MediaID language="en">3en</MediaID> <MediaID language="de">3de</MediaID> <Caption language="en"><Pgraph><Mark1>Table 3: Modified &#8220;clinical pulmonary infection score (CPIS)&#8221; &#91;43&#93;</Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Tabelle 3: Modifizierter &#8222;Klinischer Pulmonaler Infektions Score (CPIS)&#8220; &#91;43&#93;</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>4</MediaNo> <MediaID language="en">4en</MediaID> <MediaID language="de">4de</MediaID> <Caption language="en"><Pgraph><Mark1>Table 4: SDD and SOD regimens according to Kr&#252;ger WA, IntensivNews 2009, mod. after: de Smet et al, New Engl J Med. 2009;360:20-31 &#91;137&#93;. In a modified form, following mouth cleansing and oral suction, SDD or SOD may also be administered with a syringe as oral suspensions: 10 ml q.i.d. according to the following formulation: 1.0 g polymyxin E &#61; Colistin (alternatively, 0.5 g polymyxin B), 800 mg of tobramycin, 2.5 g of amphotericin B ad 100 mL distilled water)</Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Tabelle 4: SDD- und SOD-Regime nach Kr&#252;ger WA, IntensivNews 2009, mod. nach: de Smet et al, New Engl J Med 2009; 360:20-31 &#91;137&#93;. In modifizierter Form kann SDD oder SOD nach der Mundpflege und nach oralem Absaugen auch mit einer Spritze als orale Suspension gegeben werden: 4 x t&#228;glich 10 mL nach folgender Rezeptur: 1,0 g Polymyxin E &#61; Colistin (oder alternativ 0,5 g Polymyxin B), 800 mg Tobramycin, 2,5 g Amphotericin B ad 100 mL Aqua dest.)</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>5</MediaNo> <MediaID language="en">5en</MediaID> <MediaID language="de">5de</MediaID> <Caption language="en"><Pgraph><Mark1>Table 5: Definition of criteria for acute kidney injury (AKI) &#91;412&#93;</Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Tabelle 5: Definition des ANV &#8211; Acute Kidney Injury (AKI) Kriterien &#91;412&#93;</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>6</MediaNo> <MediaID language="en">6en</MediaID> <MediaID language="de">6de</MediaID> <Caption language="en"><Pgraph><Mark1>Table 6: Definition of acute lung injury (ALI) and adult respiratory distress syndrome (ARDS)</Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Tabelle 6: Definition des Acute Lung Injury (ALI) und des Adult Respiratory Distress Syndrome (ARDS)</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>7</MediaNo> <MediaID language="en">7en</MediaID> <MediaID language="de">7de</MediaID> <Caption language="en"><Pgraph><Mark1>Table 7: Ventilation management in ALI&#47;ARDS patients according to the recommendations by ARDSNET &#91;290&#93;, modified as per &#91;22&#93;.</Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Tabelle 7: Beatmungsmanagement von Patienten mit ALI&#47;ARDS gem&#228;&#223; den Empfehlungen des ARDSNET &#91;290&#93;, modifiziert nach &#91;22&#93;.</Mark1></Pgraph></Caption> </Table> <NoOfTables>7</NoOfTables> </Tables> <Figures> <Figure format="png" height="726" width="620"> <MediaNo>1</MediaNo> <MediaID language="en">1en</MediaID> <MediaID language="de">1de</MediaID> <Caption language="en"><Pgraph><Mark1>Figure 1: An example of a weaning scheme after Kuhlen (modified after &#91;303, 413&#93;) </Mark1></Pgraph></Caption> <Caption language="de"><Pgraph><Mark1>Abbildung 1: Beispiel eines Weaning-Schema&#8217;s nach Kuhlen (modifiziert nach &#91;303&#93;, &#91;413&#93;) </Mark1></Pgraph></Caption> </Figure> <NoOfPictures>1</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>