gms | German Medical Science

GMS German Medical Science — an Interdisciplinary Journal

Association of the Scientific Medical Societies in Germany (AWMF)

ISSN 1612-3174

Prevention, diagnosis, therapy and follow-up care of sepsis: 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))

Review Article

  • corresponding author K. Reinhart - University Hospital Jena, Clinic for Anaesthesiology and Intensive Care Therapy, Jena, Germany
  • corresponding author F. M. Brunkhorst - University Hospital Jena, Clinic for Anaesthesiology and Intensive Care Therapy, Jena, Germany
  • H.-G. Bone - Clinic for Anesthesiology and Operative Intensive Care Medicine, Knappschaftshospital Recklinghausen, Germany
  • J. Bardutzky - Clinic for Neurology, University Hospital Erlangen, Germany
  • C.-E. Dempfle - I. Clinic for Medicine, University Hospital Mannheim, Germany
  • H. Forst - Clinic for Anesthesiology and Operative Intensive Care Medicine, Hospital Augsburg, Germany
  • P. Gastmeier - Institute for Hygiene and Environmental Medicine, Charité University Medicine, Berlin, Germany
  • H. Gerlach - Clinic for Anaesthesia and Operative Intensive Care Medicine, Vivantes Hospital Neukölln, Berlin, Germany
  • M. Gründling - Clinic for Anaesthesia and Intensive Care Medicine, Ernst-Moritz-Arndt-University Greifswald, Germany
  • S. John - Clinic for Medicine 4, University Erlangen-Nürnberg, Germany
  • W. Kern - Institute for Infectology, University Hospital Freiburg, Germany
  • G. Kreymann - Clinic and Policlinic for Intensive Care Medicine, University Hospital Hamburg-Eppendorf, Germany
  • W. Krüger - Clinic for Anaesthesiology and Operative Intensive Care Medicine, Hospital Konstanz, Germany
  • P. Kujath - Clinic for Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
  • G. Marggraf - Clinic for Thorax and Cardivascular Surgery, University Hospital Essen, Germany
  • J. Martin - Clinic for Anaesthesiology, Klinik am Eichert, Göppingen, Germany
  • K. Mayer - Clinic of Medicine II, Justus-Liebig-University Gießen, Germany
  • A. Meier-Hellmann - Clinic for Anesthesia, Intensive Care Medicine and Pain Therapy, HELIOS Hospital Erfurt GmbH, Germany
  • M. Oppert - Clinic for Nephrology and Internal Intensive Care Medicine, Charité University Medicine, Berlin, Germany
  • C. Putensen - Clinic and Policlinic for Anesthesiology and Operative Intensive Care Medicine, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany
  • M. Quintel - Anesthesiology, Rescue and Intensive Care Medicine, University Hospital Göttingen, Germany
  • M. Ragaller - Clinic for Anesthesiology and Intensive Care Therapy, University Hospital Carl Gustav Carus, Technical University Dresden, Germany
  • R. Rossaint - Clinic for Anesthesiology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Germany
  • H. Seifert - Institute for Medical Microbiology, Immunology and Hygiene, Hospital at the University of Köln, Germany
  • C. Spies - Clinic for Anesthesiology and Operative Intensive Care Medicine, Charité University Medicine, Berlin, Germany
  • F. Stüber - University Hospital for Anesthesiology and Pain Therapy, Inselspital Bern, Switzerland
  • N. Weiler - Clinic for Anesthesiology and Operative Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany
  • A. Weimann - Clinic for General and Visceral Surgery, Hospital St. Georg gGmbH Leipzig, Germany
  • K. Werdan - Clinic and Policlinic for Internal Medicine III, Hospital of the Medical Faculty, Martin-Luther-University Halle-Wittenberg, Germany
  • T. Welte - Department of Pneumology, Medical University Hannover, Germany

GMS Ger Med Sci 2010;8:Doc14

doi: 10.3205/000103, urn:nbn:de:0183-0001034

This is the original version of the article.
The translated version can be found at: http://www.egms.de/de/journals/gms/2010-8/000103.shtml

Received: April 21, 2010
Published: June 28, 2010

© 2010 Reinhart et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Abstract

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.

Keywords: guideline, German Sepsis Society, German Sepsis Aid, severe sepsis, septic shock, prevention, diagnosis, treatment, follow-up care


Table of contents

1.
Definition and explanation of the term "guidelines"
2.
Recommendations in accordance with the provisions of S2k guidelines
3.
Definition and diagnosis of sepsis
4.
Diagnosis 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 meningitis
5.
Prevention
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
Vaccinations
6.
Causal treatment
Infectious source control
Antimicrobial therapy
7.
Supportive 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 ventilation
8.
Adjunctive therapy
Recombinant activated protein C (rhAPC)
Antithrombin
Immunoglobulins
Selenium
Other therapeutic approaches
9.
Other 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 blockade
10.
Follow-up care and 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.


2. Recommendations in accordance with the provisions of S2k guidelines

In 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 principle
  • IIa – systematic overview of well-designed cohort studies
  • IIb – one well-designed cohort study or one downgraded RCT
  • IIc – outcomes research, ecological studies
  • IIIa – systematic overview of case-control studies
  • IIIb – one case-control study
  • IV – case series or downgraded cohort/ case-control studies
  • V – expert opinion without explicit critical appraisal or one that is based on physiological models/ lab research

The “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 [1], only to be later disproved be a subsequent large prospective trial [2]. 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 [3]:

  • A – at least 2 studies with evidence level I
  • B – one study with evidence level I or evidence level Ic
  • C – only studies with evidence level II
  • D – at least 2 studies with evidence level III
  • E – level IV or evidence level V

The 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).


3. Definition and diagnosis of sepsis

Preliminary 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 [4], [5], [6], [7], [8]. In approximately 30% of cases, no proof of infection backed by microbiological data can be furnished, although the clinical criteria make an infection likely [9], [10]. 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) [11] 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 [Tab. 1], a prevalence of severe sepsis and septic shock in German ICUs was determined to be 11% and the prevalence of hospital mortality 55% [10]. These criteria differ substantially from the microbiology-driven criteria of the Centers of Disease Control (CDC) [12], 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 [13])
    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 [13], [14], [15], [16]. It must be noted that operative stress and other causes may result in a transitory increase in procalcitonin (PCT) levels [17].
  • In order to shorten the duration of antimicrobial therapy, serial procalcitonin (PCT) measurements may be considered.
    Recommendation level C (evidence level IIb for [18])
    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 [18]. Studies on this subject with larger number of cases are currently underway with the results to be published in 2010.

4. Diagnosis of infection

Blood cultures

  • It 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 [5], [8], [19].
    Recommendation level C (evidence level IIb for [5])
    Comment: Compared with C-reactive protein, procalcitonin carries a higher diagnostic positive predictive value [14], [15], [16], [17] and can be detected sooner in the course of infection [20].
  • It is recommended to collect blood cultures (2–3 sets) as soon as possible before instituting antimicrobial therapy [21], [22].
    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 [23], [24].
    Recommendation level E (evidence level V: expert opinion)
    Comment (also see Table 2 [Tab. 2]): After appropriate skin disinfection, blood cultures should be collected via a peripheral venipuncture [25], [26]. Because of the two-fold increase in the risk of contamination [27], 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 [21], [28]), a sterile needle must be used [29]. 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) [30], [31]; a specified time interval between the collections need not be honored [32], [33].
    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 [34], [35], [36]. 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 [37].

Ventilator-associated pneumonias

Preliminary 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 [38], [39]. 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 [40], 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 [41].

  • Fresh infiltrates on chest X-ray, leukocytosis or leukopenia and purulent tracheal secretions are sensitive clinical signs of a VAP [42]. It is recommended that the modified “clinical pulmonary infection score (CPIS)” (a score of >6) be used for initial screening (Table 3 [Tab. 3]) [43], [44].
    Recommendation level C (level of evidence IIb for [44])
    Comment: A combination of CPIS (cut-off 6) and procalcitonin (cut-off 2.99 ng/ml) can further increase the diagnostic positive predictive value [45].
  • When pneumonia is suspected, it is recommended to obtain secretions from deep airway segments before initiating antimicrobial therapy [46].
    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 [43], [47], [48]. 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 [49], [50].
    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) [38], [51], [52].
  • The use of routine serological tests is not recommended for diagnosis of a VAP [53], [54].
    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 [53]. 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 [55], [56].
    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 [57], [58], [59].
    Recommendation level C (evidence level IIb for [58], [59])
  • In the presence of purulent secretions from the puncture site, it is recommended to take smears [60] 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 [60])
  • If a catheter-related infection is suspected, it is not recommended to use a guidewire to facilitate introduction of a new catheter [61], [62].
    Recommendation level C (evidence level IIa for [62])
  • There is no evidence that a routine change of intravascular catheters reduces the risk of bacteremia [62], [63]. Hence, it is recommended to change intravascular catheters only in the presence of signs of infection.
    Recommendation level C (evidence level IIa for [62])

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 [53], [64], [65], [66].
    Recommendation level D (evidence level IIIb for [64], [66])
    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 [53], [67]. 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 [53].
    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 [68].
    Recommendation level E (evidence level V: expert opinion)
    Comment: The cumulative incidence of invasive Candida infections in ICU patients is approximately 1–2% [69], [70]. 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 [71].
  • 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 [9], [72]. However, it carries a low positive predictive value for a Candida infection [69].

Acute bacterial meningitis

Preliminary 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) [73]. 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 [74]. The diagnosis of bacterial meningitis rests on a cytological/biochemical analysis of the cerebrospinal fluid (CSF) [75] and is confirmed upon detection of pathogens in the CSF [73], [75]. 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 [73], [75], [76].

  • 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 [75], [76], [77], [78]. 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 [73], [75], [79].
    Recommendation level B (evidence level Ic)
  • Subsequently, it is recommended to initiate a carefully-selected antibiotic therapy without delay [80].
    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%) [75], [76], [81], [82], [83]. 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 [75], [76], [84], [85].
  • It is recommended to institute early dexamethasone therapy prior to or concurrently with the initial antibiotic administration.
    Recommendation level A (evidence level Ia for [16])
    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 [86]. 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 [87], [88]. 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 [88], [89], [90]. Based on the results of the European trial [86] and the data from meta-analyses [87], [88], 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 [76].

5. Prevention

Infection 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 [91], [92], [93], [94], [95], [96], central venous catheter-associated bacteremia [94], [97], [98], [99], [100] and catheter-associated urinary tract infections [101].
    Recommendation level B (evidence level IIc for [94], [100])
  • 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 [102], [103] 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) [102], [103], [104]. 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 [104])

Manipulation of devices

  • Hygienic hand disinfection is recommended before and after each patient encounter [105], [106].
    Recommendation level A (evidence level Ia for [105])
    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 [106], [107].
  • It is recommended to use aseptic techniques during the placement of central venous catheters and other comparable central intravascular catheters [108].
    Recommendation level A (evidence level Ib for [108])
    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 [109].
    Recommendation level A (evidence level Ic)
  • A routine change of intravascular and urinary catheters is not recommended [62].
    Recommendation level B (evidence level Ib for [62])
  • The use of endotracheal tubes enabling subglottic suction may be considered because it is associated with reduced incidence of pneumonia [110], [111].
    Recommendation level C (evidence level IIb for [111])

Body position

  • Unless 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 [112])
    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 [113], [114], [115], [116]. 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 [117], [118] 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 [119]. 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 [120], the 30° elevation did not result in a reduction of VAP incidence.

Nutrition

  • According to a meta-analysis, early oral or enteral nutrition led to a reduction of infections and duration of inpatient stays [121] 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 [121])
    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 [122].

Immunonutrition

  • The 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 [123], [124].
    Recommendation level A (evidence level Ia for [124])

Insulin therapy

  • The 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 [125])
    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 [126], [127]. 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 [128] in the incidence of severe hypoglycemic episodes (<40 mg/dl; [2.2 mmol/l]). A meta-analysis published in 2008 [125], 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 [129] and a subsequent more recent meta-analysis that included this study [130] 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 [131]. 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 [132].

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 [133], [134], [135]. 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) [136]. One study demonstrated similar positive effects of both SOD and SDD on improved survival [137].

  • 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 [137])
    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 [138]. 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 [135]. 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) [139]. Two long-term studies revealed no relevant antibiotic resistance issues after years of SDD use [140], [141]. 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 [138].
    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 [137]. 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 [Tab. 4]).
    (Upon reaching a consensus, further data on resistance relating to the above-mentioned 3-arm study were published online [142]. 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 care

  • It is recommended to use oral antiseptics for infection prevention.
    Recommendation level A (evidence level Ia for [143])
    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 [143], [144], [145], [146]. However, a meta-analysis on 1,650 patients showed that this conferred no survival advantage [143].

Preemptive antifungal therapy

  • The effectiveness and safety of a preemptive antifungal therapy in intensive care patients have not been sufficiently studied [147], [148]; hence, an intervention of this kind is not recommended.
    Recommendation level E (evidence level V: expert opinion)

Coated vascular catheters

  • When the frequency of infections remains high despite intensive control measures [149], [150], [151], [152], 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 [153]; however, it remains to be elucidated how the effects of their routine use reflect on the incidence of antibiotic resistance.

Staffing

  • It is recommended to ensure qualitatively and quantitatively adequate staffing in ICUs [154], [155], [156], [157], [158], [159], [160], [161].
    Recommendation level C (evidence level IIb for [161])
    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 [161].

Vaccinations

  • It 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 [162])
    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 [163], [164]. 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 [162], [165]. Measuring post-vaccination antibody titers for the purpose of assessing the indication for an early booster vaccination or antibiotic prophylaxis is controversial [163]. 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 [162], [165])
  • 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: [166]) (except in nephrotic syndrome).
    Recommendation level C (evidence level IIb for [167], [168])
    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 [169].

6. Causal treatment

Infectious 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 [170], [171]. 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 [172], [173]. Surgical infectious source control may be accomplished by one or more measures:

1.
Removal of implants (catheter [174], vascular prostheses [175], osteosynthesis material [176], joint replacement [177])
2.
Incision or CT-guided drainage of abscesses [178]
3.
Wound opening and necrectomy, amputation and fasciotomy [179]
4.
Treatment of peritonitis, anastomotic insufficiency and ileus by peritoneal lavage, drainage or enterostomy [172], [180]
5.
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 [172], [180].
    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 [181].

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 [182], [183]. Substantially increased mortality is primarily associated with sepsis caused by pneumonia, abdominal and skin and soft tissue infections [184] 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 [22].
    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 [30], [185], [186], [187], [188], [189], [190], [191], [192], [193], [194], [195], [196], [197], [198], [199], [200], [201], [202], [203], [204], [205].
  • 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 [18])
  • 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 [206], 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 [207]. 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 [208]. Tigecyclin is approved for use in intraabdominal infections and severe skin and soft tissue infections. Case reports on septic patients, however, do exist [209].
  • In pulmonary MRSA infections, it is not recommended to employ monotherapy with glycopeptides because glycopeptides display limited tissue penetration due to their molecular size [210], [211], [212].
    Recommendation level C (evidence level 2b for [212])
    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 [212], while in another study [213] 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 [212], [213] as well as in skin and soft tissue infections, treatment with linezolid is recommended as it is superior to vancomycin monotherapy [214], [215], [216].
    Recommendation level C (evidence level IIb for [215], [216])
    Comment: Glycopeptides display limited penetration into tissues due to their molecular size [212]. 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 [217] 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 [218]. For the combination of teicoplanin and rifampicin only one case series exists which suggests efficacy and safety [219]. In individual case series, the combination of rifampicin and fusidic acid has been used [220]. 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 [221].
    Recommendation level B (evidence level Ib for [221])
  • Antimycotic therapy is recommended in candidemia [222], [223].
    Recommendation level C (evidence level IIb for [223])
  • 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 [224].
    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 [69], [225]. 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 [226]. See [227] on therapy of neutropenic patients.

7. Supportive therapy

Hemodynamic stabilization

Preliminary remarks: The goal of hemodynamic stabilization is to achieve an adequate cellular oxygen supply immediately upon recognition of severe sepsis or septic shock [228].

  • 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 [229], [230], [231], [232].

Measures for initial hemodynamic stabilization

  • Volume 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) [22].
  • The target parameter is central venous oxygen saturation (ScvO2) of >70% [228]. 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 [228])
    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 ventilation
    • MAP ≥65 mmHg
    • Diuresis ≥0.5 ml/kg/hr
    • Central venous oxygen saturation (ScvO2) ≥70% [228]
    • Lactate ≤1.5 mmol/l or a decrease in [blood] lactate levels
Recommendation level C (Evidence level IIc for [228])
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 [111], [233], [234], [235].

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 therapy

  • According 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 [236], [237], [238], [239])
    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 [237]. 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) [240]. 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 [238], [239], 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.htm
  • According 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 [236])

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 [241].
    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 [242], [243], [244].
    Recommendation level C (evidence level IIb for [243])
  • The use of dopexamine in the treatment of patients with severe sepsis or septic shock is not recommended [245], [246], [247], [248], [249].
    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 [250]. We recommend administration of noradrenalin as the substance of first-choice [241], [251].
    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 [182], [183]. 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 [252]. A combination of epinephrine and dobutamine is not recommended [253].
  • 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 [254], [255], [256], [257], 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 [256], [258]. 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 [259]. 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 [260], [261], [262], [263], [264], [265].
    Recommendation level A (evidence level Ia for [264])

Renal replacement therapy

Preliminary remarks: The appearance of acute kidney injury (AKI) (Table 5 [Tab. 5]) in patients with severe sepsis and septic shock is an independent risk factor for mortality in this patient population [266]. 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 [267] and IIa for [268], [269])
    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 [268], [269]. Even when only randomized trials were considered in these analyses, no difference was revealed [269]. To date, five prospective randomized trials have been published on this topic [267], [270], [271], [272], [273]. Four of them showed no difference in mortality, and one study determined a significantly higher mortality in the continuous renal replacement therapy arm [272]. 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 [267].
  • CVVH is recommended in hemodynamically instable patients because this technique is better tolerated in comparison to conventional IHD [274] and it facilitates easier fluid balancing [270], [272].
    Recommendation level C (evidence level IIb for [270], [272], [274])
  • 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 [267], [275], [276].
    Recommendation level B (evidence level Ib for [267] and II a for [275], [276])
    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 [270], [274], yet without demonstrating an improvement in organ perfusion [274] or in survival rates [270]. 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 [267], [271], [273], [277]. 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 [267], [275], [276]. As for fluid balance management, two studies showed a significant improvement in balance targets with the use of continuous renal replacement therapy [270], [272].
  • 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 [278], [279].
    Recommendation level B (evidence level Ib for [280])
    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 [280], [281], [282], [283], [284], [285]. 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 [282], [283], IHD daily [284]). Nevertheless, these studies did not reveal any survival benefits [280], [281], [285]. 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 [280]. 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 [286], [287], [288]. Beyond a renal indication, its use in therefore not recommended.
    Recommendation level C (evidence level IIb for [286])
    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 ventilation

  • It is recommended to keep the oximetric oxygen saturation above 90% [289].
    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 [Tab. 6]) with a low tidal volume (6 ml/kg standard body weight) and a plateau pressure of <30 cm H2O (Table 7) [290], [291].
    Recommendation level A (evidence level Ib for [290], [292])
    Comment: Standard body weight should be routinely measured in all ventilated patients (Table 7 [Tab. 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 [293]. Even in the presence of a low plateau pressure, high tidal volume ventilation leads to increased mortality [294].
  • It is recommended that mechanical ventilation always be performed with positive end-expiratory pressures (PEEP) [291].
    Recommendation level B (evidence level Ic)
    Comment: No recommendation can currently be made about the level of PEEP. The values listed in Table 7 [Tab. 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 [295], [296].
    → Recommendation level D (evidence level IIIb [295])
    Comment: Permissive hypercapnia should be tolerated only up to a pH value of 7.2 in the absence of buffering [297].
  • 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 [298])
    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 [298], [299].
  • Routine therapy with inhalation nitrogen monoxide (NO) is not recommended.
    Recommendation level A (evidence level Ib for [300], [301])
    Comment: A survival advantage was recorded in ICU patients with ALI/ARDS who received inhalation nitrogen monoxide (NO) therapy [300], [301], [302].
  • 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 [303], [304], [305] (see Figure 1 [Fig. 1] as an example)
    Recommendation level A (evidence level Ib for [304], [305])

8. Adjunctive therapy

Definition

Adjunctive therapy is treatment used together with and in addition to causal and supportive sepsis therapy.

Glucocorticosteroids

  • The use of high-dose glucocorticosteroids is not recommended in treatment of patients with severe sepsis or septic shock [306], [307].
    Recommendation level A (evidence level Ib for [306], [307])
  • 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 [308])
    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 [309]. The inter-assay variance of cortisol determinations is significant [310]. The only biologically active part is free cortisol (comprising 10% of the total plasma cortisol) [311]. 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 [312]. 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 [313]. It is recommended that therapy be gradually tapered off according to clinical judgment.

Insulin therapy

  • An 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 [236].
  • 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 [131]. 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 [314]. 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 [315])
    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 [315], [316])
    Comment: The rationale for the use of rhAPC rests on data from 2 controlled randomized trials [315], [316]], while further data on safety are based on post-approval non-randomized trials [317]. 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 [318], 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 [319]).
  • 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 [320])
    Comment: Contrary to the initial belief, concomitant administration of heparin does not increase the risk of hemorrhage [320].

Antithrombin

  • Antithrombin therapy is not recommended.
    Recommendation level B (according to evidence level Ib for [321])
    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 [321]. The lack of efficacy of antithrombin in patients with severe sepsis may be caused by adjunctive heparin therapy [321]. While on antithrombin therapy, patients also run an increased risk of hemorrhage.

Immunoglobulins

Preliminary remarks: A most recent meta-analysis [322] 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 [322])
    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 [323], 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 [322], [324])
    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 [324] conducted on 624 patients showed no improvement in the survival rate.

Selenium

  • The use of selenium in the treatment of patients with severe sepsis or septic shock may be considered.
    Recommendation level C (evidence level Ia for [325])
    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 [325]. 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 [326]. A large, multi-center, randomized trial is needed for unequivocal determination of selenium's efficacy.

Other therapeutic approaches

  • Ibuprofen [327], growth hormones [328], prostaglandins [329], [330], [331], [332], pentoxifyllin [333], [334], [335], high-dose N-acetylcysteine [336], granulocyte colony-stimulating factor [337], [338], [339], [340], [341], 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)

9. Other supportive therapies

Deep venous thrombosis (DVT) prophylaxis

  • Currently, 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 [22], [342], 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 [343], but its incidence may be significantly reduced with the use of pharmacological DVT prophylaxis [344], [345]. In the presence of an underlying kidney failure, the LMWH dose must be properly adjusted [346]. 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 [347].
    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 [347].
    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 [348]. 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 [347].
    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 [347].
    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 [349], [350]. The proportion of patients able to receive enteral nutrition increases with implementation of a protocol [351], [352]. 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 [353] 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 nutrition

  • It 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 [354], [355]. 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 [356]. 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 [357])
    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 [358]. 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 [357]. These results were confirmed in a meta-analysis of the available trials [359]. A randomized trial compared an early enteral immunonutrition with a parenteral nutrition in critically ill patients without severe sepsis [360]. 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 [361]. Previous studies already indicated that this diet significantly reduced the duration of ventilation and shortened the ICU inpatient stays [362]. 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 [363].

Glutamine

  • It 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 [364], [365]. 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 [366]. 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 [364], [365].
  • 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 [359]. 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 [367].

Ulcer prophylaxis

  • It 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 [368], [369], [370], [371].
  • Stress ulcer prophylaxis with histamine-2 receptor blockers or with proton pump inhibitors (PPIs) is recommended [370], [371], [372].
    Recommendation level B (evidence level Ib for [371], [372])
    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 [373], [374].
  • It is recommended to carry out recurrence prophylaxis with proton pump inhibitors (PPIs).
    Recommendation level A (evidence level Ia for [375])
  • Enteral nutrition is recommended as a supporting additional measure for stress ulcer prophylaxis [376].
    Recommendation level E (evidence level V: expert opinion)

The use of bicarbonate in lactic acidosis

  • Bicarbonate 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 [377], [378])
    Comment: Hemodynamic improvements or a reduced need for vasopressors were not shown in two studies [377], [378]. There are no available studies for bicarbonate use at a pH level of 7.15.

Blood products

  • With 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 [379]. In patients with severe sepsis, blood transfusion can lead to an increase in O2 availability, but not to an increase in O2-utilization [380], [381]. On the use of RBC transfusion in severe sepsis or septic shock and impaired tissue perfusion, see the section on Hemodynamic stabilization [22].

Erythropoietin

  • Erythropoietin 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 [382], [383]. To date, a reduction in mortality through the administration of erythropoietin has only been established in a subgroup of intensive care trauma patients [382], [383]. 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% [383]. Patients with sepsis have a higher risk of developing TRALI after FFP administration [383]. At this time there is no indication for the use of fresh frozen plasma (FFP) in the absence of a clinically manifest bleeding tendency [384].

Sedation, analgesia, delirium and neuromuscular blockade

Monitoring of sedation, analgesia and delirium
  • The 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 [385])
    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 [385], [386], [387] 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 [388].
    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 [389])
    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) [389] 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 delirium
  • It is recommended to administer adequate analgesia to critically ill ICU patients.
    Recommendation level A (evidence level Ib for [390])
  • It is recommended to limit the use of deep sedation only to a few specific indications.
    Recommendation level A (evidence level Ib for [385], [387])
    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 [385]. 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 [385].
Etomidate
  • If 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 [391], possibly aggravating an existing adrenal insufficiency in septic shock [392]. Already one intubation dose of etomidate may worsen the outcome of septic patients due to the suppression of steroid synthesis [392], [393]. 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 [394].
Neuromuscular blockade
  • It 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 [395], [396], [397], [398], [399], [400]. Should muscle relaxants nevertheless be required, monitoring of the depth of the blockade using Train-of-Four is obligatory [401].

10. Follow-up and rehabilitation

Introduction: In addition to the limitations to the health-related quality of life that have been compiled with validated test instruments (e.g. SF-36) [402], [403], [404] 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 [405]. 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 [406]. 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 [406]. The issues of delirium during intensive therapy and persistent residual neurocognitive impairments, post-traumatic distress disorder (PTSD) and states of depression [407], [408] 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 [409].

  • 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 [410] about the consequences of sepsis, to be distributed free of charge to the patients, family members and physicians responsible for their subsequent care.

Appendix

Coding for sepsis, severe sepsis and septic shock in ICD-10-GM

From 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 determination
    • Tachycardia with a heart rate of ≥90/min
    • Tachypnea (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
  • Positive 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 determination
    • Tachycardia with a heart rate of ≥90/min
    • Tachypnea (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
Definition 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 determination
  • Tachycardia with a heart rate of ≥90/min
  • Tachypnea (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 [Tab. 1]).


Notes

Collaboration

The 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-, Thorax- und Gefäßchirurgie (DGHTG; [G.M.]), Deutsche Gesellschaft für Internistische Intensivmedizin und Notfallmedizin (DGIIN; [T.W.]), Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP; [T.W.]), Deutsche Gesellschaft für Ernährungsmedizin (DGEM; [A.W.]), Deutsche Gesellschaft für Neurologie (DGN; [J.B.]), Deutsche Gesellschaft für Kardiologie (DGK; [K.W]), Deutsche Gesellschaft für Innere Medizin (DGIM; [K.W.]), Deutsche Gesellschaft für Infektiologie (DGI; [W.K.]), Nationales Referenzzentrum für Surveillance von nosokomialen Infektionen (NRZ; [P.G.]), Deutsche Gesellschaft für Nephrologie (DGfN; [S.J., M.O.]), Deutsche Gesellschaft für Hygiene und Mikrobiologie e.V. (DGHM; [H.S.]), Deutsche Gesellschaft für Klinische Chemie und Laboratoriumsmedizin (DGKL), Deutsche Gesellschaft für Neurochirurgie (DGNC), Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG),

and support groups:

Deutsche Sepsis-Hilfe e.V. (DSH; [F.M.B.])

Approved by the directors of the involved medical scientific societies on February 15th 2010.

Remark

The guidelines apply to standard situations and take into account current scientific knowledge. They should not limit the physician’s therapeutic autonomy. These guidelines were developed by the authors with great care; however, no responsibility can be assumed for accuracy – particularly as related to dosing information.

AWMF guideline register

The guidelines are registered in the AWMF register with the no. 079/001 (http://leitlinien.net/079-001.htm).

Conflicts of interest

The declarations of conflict of interest of all authors can be viewed on request.


References

1.
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.
2.
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/S0140-6736(95)90865-X External link
3.
Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1989;95(2 Suppl):2S-4S.
4.
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/NEJMoa022139 External link
5.
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.
6.
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: 10.1086/514153 External link
7.
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.
8.
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.
9.
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.
10.
Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulmé 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/s00134-001-1143-z External link
11.
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.
12.
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.
13.
Clec'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: 10.1097/01.CCM.0000126263.00551.06 External link
14.
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.
15.
Müller B, Becker KL, Schächinger 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: 10.1097/00003246-200004000-00011 External link
16.
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/s001340051134 External link
17.
Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schüttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med. 1998;24(7):680-4. DOI: 10.1007/s001340050644 External link
18.
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/rccm.200708-1238OC External link
19.
Smith-Elekes S, Weinstein MP. Blood cultures. Infect Dis Clin North Am. 1993;7(2):221-34.
20.
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/jc.79.6.1605 External link
21.
Reimer LG, Wilson ML, Weinstein MP. Update on detection of bacteremia and fungemia. Clin Microbiol Rev. 1997;10(3):444-65.
22.
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: 10.1097/01.CCM.0000117317.18092.E4 External link
23.
Shafazand S, Weinacker AB. Blood cultures in the critical care unit: improving utilization and yield. Chest. 2002;122(5):1727-36. DOI: 10.1378/chest.122.5.1727 External link
24.
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: 10.1097/00003246-199706000-00016 External link
25.
Shahar E, Wohl-Gottesman BS, Shenkman L. Contamination of blood cultures during venepuncture: fact or myth? Postgrad Med J. 1990;66(782):1053-8. DOI: 10.1136/pgmj.66.782.1053 External link
26.
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.
27.
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: 10.1097/00003246-200201000-00002 External link
28.
Wilson ML. General principles of specimen collection and transport. Clin Infect Dis. 1996;22(5):766-77.
29.
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.
30.
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.
31.
Washington JA 2nd. Blood cultures: principles and techniques. Mayo Clin Proc. 1975;50(2):91-8.
32.
Li J, Plorde JJ, Carlson LG. Effects of volume and periodicity on blood cultures. J Clin Microbiol. 1994;32(11):2829-31.
33.
Seifert H, Abele-Horn M, Fätkenheuer G, Glück T, Jansen B, Kern WV, Mack D, Plum G, Reinert RR, Roos R, Salzberger B, Shah PM, Ullmann U, Weiß M, Welte T, Wisplinghoff H. MiQ 3a: Blutkulturdiagnostik Sepsis, Endokarditis, Katheterinfektionen, Teil I. München: Urban & Fischer; 2007. Available from: http://www.dgho-infektionen.de/agiho/content/e2735/e15963/e15977/index_ger.html External link
34.
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/s00134-009-1705-z External link
35.
Lehmann LE, Alvarez J, Hunfeld KP, Goglio A, Kost GJ, Louie RF, Raglio A, Regueiro BJ, Wissing H, Stüber F. Potential clinical utility of polymerase chain reaction in microbiological testing for sepsis. Crit Care Med. 2009;37(12):3085-90. DOI: 10.1097/CCM.0b013e3181b033d7 External link
36.
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/CCM.0b013e31816f487c External link
37.
Schrenzel J. Clinical relevance of new diagnostic methods for bloodstream infections. Int J Antimicrob Agents. 2007;30(Suppl 1):S2-6. DOI: 10.1016/j.ijantimicag.2007.06.030 External link
38.
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/rccm.200405-644ST External link
39.
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 [S3-guideline on ambulant acquired pneumonia and deep airway infections]. Pneumologie. 2005;59(9):612-64.
40.
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/BF00255791 External link
41.
Gastmeier P, Sohr D, Geffers C, Ruden H, Vonberg RP, Welte T. Early- and late-onset pneumonia: is this still a useful classification? Antimicrob Agents Chemother. 2009;53(7):2714-8. DOI: 10.1128/AAC.01070-08 External link
42.
Wunderink RG. Clinical criteria in the diagnosis of ventilator-associated pneumonia. Chest. 2000;117(4 Suppl 2):191S-194S. DOI: 10.1378/chest.117.4_suppl_2.191S External link
43.
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.
44.
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/rccm.200212-1449OC External link
45.
Ramirez P, Garcia MA, Ferrer M, Aznar J, Valencia M, Sahuquillo JM, Menéndez R, Asenjo MA, Torres A. Sequential measurements of procalcitonin levels in diagnosing ventilator-associated pneumonia. Eur Respir J. 2008;31(2):356-62. DOI: 10.1183/09031936.00086707 External link
46.
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/chest.127.2.589 External link
47.
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/s00134-003-2125-0 External link
48.
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/NEJMoa052904 External link
49.
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/chest.117.4_suppl_2.198S External link
50.
Cook D, Mandell L. Endotracheal aspiration in the diagnosis of ventilator-associated pneumonia. Chest. 2000;117(4 Suppl 2):195S-197S. DOI: 10.1378/chest.117.4_suppl_2.195S External link
51.
Mauch H, Wagner J. Heft 7: Infektionen der tiefen Atemwege, Teil 1. In: Podbielski A, Herrmann M, Kniehl E, Mauch H, editors. MIQ – Qualitätsstandards in der mikrobiologisch-infektiologischen Diagnostik. München: Urban & Fischer; 1999.
52.
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.
53.
Llewelyn M, Cohen J. Diagnosis of infection in sepsis. Intensive Care Med. 2001;27 Suppl 1:S10-32.
54.
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.
55.
Dobbins BM, Kite P, Wilcox MH. Diagnosis of central venous catheter related sepsis – a critical look inside. J Clin Pathol. 1999;52(3):165-72. DOI: 10.1136/jcp.52.3.165 External link
56.
Sherertz RJ. Surveillance for infections associated with vascular catheters. Infect Control Hosp Epidemiol. 1996;17(11):746-52. DOI: 10.1086/647222 External link
57.
Blot F, Nitenberg G, Chachaty E, Raynard B, Germann N, Antoun S, Laplanche A, Brun-Buisson C, Tancrède 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/S0140-6736(98)11134-0 External link
58.
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/s00134-005-2600-x External link
59.
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: 10.1097/01.CCM.0000157968.98476.F3 External link
60.
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.
61.
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.
62.
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: 10.1097/00003246-199708000-00033 External link
63.
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.
64.
Brook I, Frazier EH. Aerobic and anaerobic microbiology of retroperitoneal abscesses. Clin Infect Dis. 1998;26(4):938-41. DOI: 10.1086/513947 External link
65.
Nichols RL, Smith JW. Wound and intraabdominal infections: microbiological considerations and approaches to treatment. Clin Infect Dis. 1993;16 Suppl 4:S266-72.
66.
Brook I, Frazier EH. Microbiology of subphrenic abscesses: a 14-year experience. Am Surg. 1999;65(11):1049-53.
67.
Marshall JC, Innes M. Intensive care unit management of intra-abdominal infection. Crit Care Med. 2003;31(8):2228-37. DOI: 10.1097/01.CCM.0000087326.59341.51 External link
68.
Büchner T, Fegeler W, Bernhardt H, Brockmeyer N, Duswald KH, Herrmann M, Heuser D, Jehn U, Just-Nübling G, Karthaus M, Maschmeyer G, Müller FM, Müller 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/s10096-002-0730-4 External link
69.
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: 10.1086/321811 External link
70.
Petri MG, Konig J, Moecke HP, Gramm HJ, Barkow H, Kujath P, Dennhart R, Schäfer H, Meyer N, Kalmar P, Thülig P, Müller 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/s001340050334 External link
71.
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: 10.1086/380796 External link
72.
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/s-2003-37913 External link
73.
Wildemann B. Meningitis. Fortschr Neurol Psychiatr. 2005;73(2):102-17; quiz 118-9. DOI: 10.1055/s-2004-818425 External link
74.
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/NEJMoa040845 External link
75.
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: 10.1086/425368 External link
76.
Diener HC, Ackermann H. Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme; 2005.
77.
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.
78.
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/NEJMoa010399 External link
79.
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/S0163-4453(99)90095-6 External link
80.
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.
81.
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.
82.
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.
83.
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://jcm.asm.org/cgi/reprint/19/2/187 External link
84.
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/JCM.43.7.3390-3397.2005 External link
85.
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: 10.1086/321885 External link
86.
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/NEJMoa021334 External link
87.
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/S1473-3099(04)00937-5 External link
88.
van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2007;(1):CD004405. DOI: 10.1002/14651858.CD004405.pub2 External link
89.
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/S0140-6736(02)09458-8 External link
90.
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/NEJMoa065711 External link
91.
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: 10.1177/0885713X9601100208 External link
92.
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: 10.1097/00003246-200211000-00001 External link
93.
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/j.jhin.2004.03.002 External link
94.
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/chest.125.6.2224 External link
95.
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: 10.1097/01.ta.0000223971.25845.b3 External link
96.
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/qshc.2005.016576 External link
97.
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: 10.1097/01.CCM.0000069513.15417.1C External link
98.
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/chest.126.5.1612 External link
99.
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: 10.1097/01.CCM.0000142399.70913.2F External link
100.
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/NEJMoa061115 External link
101.
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: 10.1086/503837 External link
102.
Centers for Disease Control and Prevention. CDC definitions. 2008. Available from: http://www.cdc.gov/ncidod/dhqp/nhsn.html External link
103.
Nationales Referenzzentrum für die Surveillance von nosokomialen Infektionen [homepage on the Internet]. Berlin: NRZ; c2005. Available from: http://www.nrz-hygiene.de External link
104.
Gastmeier P, Geffers C, Brandt C, Zuschneid I, Sohr D, Schwab F, Behnke M, Daschner F, Rüden H. Effectiveness of a nationwide nosocomial infection surveillance system for reducing nosocomial infections. J Hosp Infect. 2006;64(1):16-22. DOI: 10.1016/j.jhin.2006.04.017 External link
105.
Boyce JM, Pittet D; Healthcare Infection Control Practices Advisory Committee; HICPAC/SHEA/APIC/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/SHEA/APIC/IDSA Hand Hygiene Task Force; Society for Healthcare Epidemiology of America/Association for Professionals in Infection Control/Infectious Diseases Society of America. MMWR Recomm Rep. 2002;51(RR-16):1-45, quiz CE1-4.
106.
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/S0140-6736(00)02814-2 External link
107.
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/jac/dkn199 External link
108.
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: 10.1086/646902 External link
109.
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.
110.
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/j.amjmed.2004.07.051 External link
111.
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/rccm.200705-761OC External link
112.
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/S0140-6736(98)12251-1 External link
113.
Kollef MH. Ventilator-associated pneumonia: A multivariate analysis. JAMA. 1993;270(16):1965-70.
114.
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/jama.279.10.781 External link
115.
Ibánez J, Penafiel A, Raurich JM, Marse P, Jordá 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: 10.1177/0148607192016005419 External link
116.
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/s-2002-35720 External link
117.
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.
118.
Torres A, Serra-Batlles J, Ros E, Piera C, Puig de la Bellacasa J, Cobos A, Lomeña F, Rodríguez-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.
119.
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/s00134-003-2077-4 External link
120.
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: 10.1097/01.CCM.0000198529.76602.5E External link
121.
Lewis S, Egger M, Sylvester P, Thomas S. Early enteral feeding versus "nil by mouth" after gastrointestinal surgery: systematic review and meta-analysis of controlled trails. BMJ. 2001;323(7316):773-6. DOI: 10.1136/bmj.323.7316.773 External link
122.
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/j.clnu.2006.01.015 External link
123.
Heyland D, Novak F, Drover J, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA. 2001;286(8):944-53. DOI: 10.1001/jama.286.8.944 External link
124.
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: 10.1097/00000658-199904000-00004 External link
125.
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/jama.300.8.933 External link
126.
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/NEJMoa011300 External link
127.
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: 10.4065/79.8.992 External link
128.
van den Berghe G, et al. Intensive Insulin Therapy Study in Medical Intensive Care Patients. ESICM. Amsterdam; September 2005.
129.
Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert 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/NEJMoa0810625 External link
130.
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/cmaj.090206 External link
131.
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/cc5110 External link
132.
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/diacare.27.2.553 External link
133.
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/archsurg.134.2.170 External link
134.
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/j.jhin.2006.10.014 External link
135.
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/rccm.2105141 External link
136.
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.
137.
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/NEJMoa0800394 External link
138.
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/S0140-6736(03)14409-1 External link
139.
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/S0140-6736(03)14409-1 External link
140.
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/s00134-006-0304-5 External link
141.
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: 10.1097/01.CCM.0000079606.16776.C5 External link
142.
Oostdijk EA, de Smet AM, Blok HE, Thieme Groen ES, van Asselt GJ, Benus RF, Bernards SA, Frénay 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/rccm.200908-1210OC External link
143.
Chlebicki MP, Safdar N. Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med. 2007;35(2):595-602. DOI: 10.1097/01.CCM.0000253395.70708.AC External link
144.
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/jama.296.20.2460 External link
145.
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/j.jhin.2007.03.025 External link
146.
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/bmj.39136.528160.BE External link
147.
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: 10.1097/01.CCM.0000147726.62304.7F External link
148.
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: 10.1097/01.CCM.0000181726.32675.37 External link
149.
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/jama.281.3.261 External link
150.
Geffers C, Zuschneid I, Eckmanns T, Rüden 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.
151.
Walder B, Pittet D, Tramèr 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: 10.1086/502005 External link
152.
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.
153.
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/jac/dkl522 External link
154.
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: 10.1086/647262 External link
155.
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: 10.1097/00006454-199711000-00008 External link
156.
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: 10.1086/501789 External link
157.
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/mpd.2002.127279 External link
158.
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: 10.1086/501690 External link
159.
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: 10.1086/501677 External link
160.
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/j.jhin.2005.10.012 External link
161.
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: 10.1097/01.CCM.0000251125.08629.3F External link
162.
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: 10.1080/10245330600938463 External link
163.
Landgren O, Björkholm M, Konradsen HB, Söderqvist 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's lymphoma. J Intern Med. 2004;255(6):664-73. DOI: 10.1111/j.1365-2796.2004.01312.x External link
164.
Cherif H, Landgren O, Konradsen HB, Kalin M, Björkholm 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/j.vaccine.2005.07.054 External link
165.
Davies JM, Barnes R, Milligan D; British Committee for Standards in Haematology. Working Party of the Haematology/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.
166.
Robert Koch-Institut. Empfehlungen der Ständigen Impfkommission (STIKO) am Robert Koch-Institut/Stand: Juli 2009. Epid Bull. 2009;30:279-99. Available from: http://www.rki.de/cln_178/nn_1378492/DE/Content/Infekt/EpidBull/Archiv/2009/30__09,templateId=raw,property=publicationFile.pdf/30_09.pdf External link
167.
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/NEJMoa022678 External link
168.
Vila-Córcoles A, Ochoa-Gondar O, Hospital I, Ansa X, Vilanova A, Rodríguez 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: 10.1086/507340 External link
169.
Ortqvist A, Hedlund J, Burman LA, Elbel E, Höfer M, Leinonen M, Lindblad I, Sundelöf 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/S0140-6736(97)07358-3 External link
170.
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/s004230050169 External link
171.
Barie PS, Williams MD, McCollam JS, Bates BM, Qualy RL, Lowry SF, Fry DE; PROWESS Surgical Evaluation Committee. Benefit/risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis. Am J Surg. 2004;188(3):212-20. DOI: 10.1016/j.amjsurg.2004.06.008 External link
172.
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/s002689910007 External link
173.
Kaiser RE, Cerra FB. Progressive necrotizing surgical infections--a unified approach. J Trauma. 1981;21(5):349-55. DOI: 10.1097/00005373-198105000-00003 External link
174.
Byrnes MC, Coopersmith CM. Prevention of catheter-related blood stream infection. Curr Opin Crit Care. 2007;13(4):411-5. DOI: 10.1097/MCC.0b013e3281f8d279 External link
175.
Zühlke H. Autologe Verfahren zur Therapie von Gefäßinfektionen [Autologous procedure for the treatment of vascular infections]. Gefäßchirurgie. 2006;11(6):409-422. DOI: 10.1007/s00772-006-0491-y External link
176.
Arens S, Hansis M. Implantate in der Unfallchirurgie: Osteosynthese mit Titan. Dtsch Arztebl. 1998;95(24):1516-1518.
177.
Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections. Infect Dis Clin North Am. 2005;19(4):885-914. DOI: 10.1016/j.idc.2005.07.010 External link
178.
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/j.jinf.2006.03.004 External link
179.
Schneider JI. Rapid infectious killers. Emerg Med Clin North Am. 2004;22(4):1099-115. DOI: 10.1016/j.emc.2004.05.007 External link
180.
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: 10.1097/01.CCM.0000253399.03545.2D External link
181.
Pieracci FM, Barie PS. Intra-abdominal infections. Curr Opin Crit Care. 2007;13(4):440-9. DOI: 10.1097/MCC.0b013e32825a6720 External link
182.
Klompas M, Yokoe DS. Automated surveillance of health care-associated infections. Clin Infect Dis. 2009;48(9):1268-75. DOI: 10.1086/597591 External link
183.
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/ic.1999.v27.a98878 External link
184.
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/s00134-006-0517-7 External link
185.
Freid MA, Vosti KL. The importance of underlying disease in patients with gram-negative bacteremia. Arch Intern Med. 1968;121(5):418-23.
186.
McCabe WR, Jackson GG. Gram negative bacteremia: I. Etiology and Ecology. Arch Intern Med. 1962;110(6):847-855.
187.
Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Arch Intern Med. 1971;127(1):120-8.
188.
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.
189.
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: 10.1016/0002-9343(80)90102-3 External link
190.
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.
191.
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.
192.
Vidal F, Mensa J, Almela M, Martínez 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.
193.
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.
194.
Caballero-Granado FJ, Cisneros JM, Luque R, Torres-Tortosa M, Gamboa F, Díez F, Villanueva JL, Pérez-Cano R, Pasquau J, Merino D, Menchero A, Mora D, López-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.
195.
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.
196.
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: 10.3109/00365549709008668 External link
197.
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/j.1365-2796.1998.00379.x External link
198.
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/chest.115.2.462 External link
199.
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/chest.118.1.146 External link
200.
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/archsurg.137.12.1353 External link
201.
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: 10.1080/00365540110080827 External link
202.
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/j.amjmed.2003.07.005 External link
203.
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/j.1469-0691.2003.00656.x External link
204.
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: 10.1097/01.CCM.0000050298.59549.4A External link
205.
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: 10.1097/01.CCM.0000098031.24329.10 External link
206.
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/bmj.38028.520995.63 External link
207.
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: 10.1097/01.CCM.0B013E31816203D6 External link
208.
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, Fätkenheuer 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/NEJMoa053783 External link
209.
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: 10.1086/431676 External link
210.
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/AAC.47.6.2015-2017.2003 External link
211.
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/jac/38.5.865 External link
212.
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/s00134-003-2088-1 External link
213.
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/chest.124.5.1789 External link
214.
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/j.amjsurg.2005.01.011 External link
215.
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/AAC.49.6.2260-2266.2005 External link
216.
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/j.amjsurg.2004.08.045 External link
217.
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/S0305-4179(99)00045-5 External link
218.
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/jac/48.2.209 External link
219.
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/jac/42.2.233 External link
220.
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: 10.1086/381202 External link
221.
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/rccm.200311-1578OC External link
222.
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.
223.
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: 10.1097/01.CCM.0000074724.71242.88 External link
224.
Bochud PY, Glauser MP, Calandra T. Antibiotics in sepsis. Intensive Care Med. 2001;27 Suppl 1:S33-48.
225.
Sobel JD, Rex JH. Invasive candidiasis: turning risk into a practical prevention policy? Clin Infect Dis. 2001;33(2):187-90. DOI: 10.1086/321812 External link
226.
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.
227.
Maschmeyer G, Böhme 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 Hämatologie und Onkologie: Leitlinien der Sektion Infektionen in der Hämatologie/Onkologie der Paul-Ehrlich-Gesellschaft e.V. Chemother J. 2004;13(3):134-141. Available from: http://www.wissenschaftliche-verlagsgesellschaft.de/CTJ/CTJ2004/CTJ3-2004/Consensus-haematologie.pdf External link
228.
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/NEJMoa010307 External link
229.
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/jcan.2001.26535 External link
230.
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.
231.
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: 10.1097/01.CCM.0000114996.68110.C9 External link
232.
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/S1010-7940(98)00063-3 External link
233.
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: 10.1097/01.CCM.0000259463.33848.3D External link
234.
Ferrer R, Artigas A, Levy MM, Blanco J, González-Díaz G, Garnacho-Montero J, Ibáñez 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/jama.299.19.2294 External link
235.
Kortgen A, Niederprüm P, Bauer M. Implementation of an evidence-based "standard operating procedure" and outcome in septic shock. Crit Care Med. 2006;34(4):943-9. DOI: 10.1097/01.CCM.0000206112.32673.D4 External link
236.
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/NEJMoa070716 External link
237.
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/S0140-6736(00)04211-2 External link
238.
Zarychanski R, Turgeon A, Fergusson D, Cook D, Hébert P, Bagshaw S, Monsour D, McIntyre L. Renal Outcomes Following Hydroxyethyl Strach Resuscitation: A Meta-Analysis Of Randomized Trials. Clinical & Investigative Medicine. 2008;31(Suppl 4):26.
239.
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: 10.1002/14651858.CD007594.pub2 External link
240.
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/NEJMoa040232 External link
241.
Meier-Hellmann A. Hämodynamische Stabilisierung in der Sepsis. Anästhesiologie & Intensivmedizin. 2000;41(7):601-13.
242.
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/NEJM199510193331601 External link
243.
Kern JW, Shoemaker WC. Meta-analysis of hemodynamic optimization in high-risk patients. Crit Care Med. 2002;30(8):1686-92. DOI: 10.1097/00003246-200208000-00002 External link
244.
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/chest.103.3.886 External link
245.
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: 10.1097/00003246-199910000-00015 External link
246.
Bennett ED. Dopexamine: much more than a vasoactive agent. Crit Care Med. 1998;26(10):1621-2. DOI: 10.1097/00003246-199810000-00002 External link
247.
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: 10.1097/00003246-199909000-00014 External link
248.
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.
249.
Schmidt W, Häcker 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: 10.1097/00003246-199810000-00012 External link
250.
Müllner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock. Cochrane Database Syst Rev. 2004;(3):CD003709. DOI: 10.1002/14651858.CD003709.pub2 External link
251.
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: 10.1097/00003246-200008000-00012 External link
252.
Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troché 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/S0140-6736(07)61344-0 External link
253.
Prielipp RC, MacGregor DA, Royster RL, Kon ND, Hines MH, Butterworth JF 4th. Dobutamine antagonizes epinephrine'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: 10.1097/00000542-199807000-00010 External link
254.
Dünser 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: 10.1161/01.CIR.0000066692.71008.BB External link
255.
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: 10.1097/00003246-200103000-00004 External link
256.
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: 10.1097/00005373-199910000-00014 External link
257.
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: 10.1097/00000542-200203000-00011 External link
258.
Dünser MW, Mayr AJ, Tür 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: 10.1097/01.CCM.0000059722.94182.79 External link
259.
Russell JA, Walley KR, Singer J, Gordon AC, Hébert 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/NEJMoa067373 External link
260.
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/S0140-6736(00)03495-4 External link
261.
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/S0002-9343(99)00246-6 External link
262.
Chertow GM, Sayegh MH, Allgren RL, Lazarus JM. Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure? Auriculin Anaritide Acute Renal Failure Study Group. Am J Med. 1996;101(1):49-53. DOI: 10.1016/S0002-9343(96)00075-7 External link
263.
Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001;29(8):1526-31. DOI: 10.1097/00003246-200108000-00005 External link
264.
Marik PE. Low-dose dopamine: a systematic review. Intensive Care Med. 2002;28(7):877-83. DOI: 10.1007/s00134-002-1346-y External link
265.
Debaveye YA, Van den Berghe GH. Is there still a place for dopamine in the modern intensive care unit? Anesth Analg. 2004;98(2):461-8. DOI: 10.1213/01.ANE.0000096188.35789.37 External link
266.
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/ndt/gfm610 External link
267.
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/S0140-6736(06)69111-3 External link
268.
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/s00134-001-1159-4 External link
269.
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/ajkd.2002.36318 External link
270.
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/j.ajkd.2004.08.022 External link
271.
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? Ren Fail. 2003;25(5):855-62. DOI: 10.1081/JDI-120024300 External link
272.
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/j.1523-1755.2001.0600031154.x External link
273.
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/ndt/gfh880 External link
274.
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/ndt/16.2.320 External link
275.
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/j.ajkd.2003.10.021 External link
276.
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.
277.
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/BF01709515 External link
278.
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/ndt/gfp035 External link
279.
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/NEJMoa0902413 External link
280.
Palevsky PM, Zhang JH, O'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/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/NEJMoa0802639 External link
281.
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: 10.1097/00003246-200210000-00005 External link
282.
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/S0140-6736(00)02430-2 External link
283.
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/sj.ki.5001705 External link
284.
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/NEJMoa010877 External link
285.
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/ASN.2007111173 External link
286.
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.
287.
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/s001340000583 External link
288.
Payen D, Mateo J, Cavaillon JM, Fraisse F, Floriot C, Vicaut E; Hemofiltration and Sepsis Group of the Collège National de Réanimation et de Médecine d'Urgence des Hôpitaux 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/CCM.0b013e3181962316 External link
289.
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.
290.
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/NEJM200005043421801 External link
291.
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/NEJM199802053380602 External link
292.
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: 10.1097/01.CCM.0000215598.84885.01 External link
293.
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/rccm.200607-915OC External link
294.
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/rccm.200501-048CP External link
295.
Bidani A, Tzouanakis AE, Cardenas VJ Jr, Zwischenberger JB. Permissive hypercapnia in acute respiratory failure. JAMA. 1994;272(12):957-62.
296.
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: 10.1097/00003246-199422100-00011 External link
297.
Martin GS, Bernard GR; International Sepsis Forum. Airway and lung in sepsis. Intensive Care Med. 2001;27 Suppl 1:S63-79.
298.
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/NEJMoa010043 External link
299.
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/jama.292.19.2379 External link
300.
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/s001340050982 External link
301.
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/jama.291.13.1603 External link
302.
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: 10.1213/01.ANE.0000078819.48523.26 External link
303.
Esteban A, Alía I, Gordo F, Fernández R, Solsona JF, Vallverdú I, Macías S, Allegue JM, Blanco J, Carriedo D, León M, de la Cal MA, Taboada F, Gonzalez de Velasco J, Palazón E, Carrizosa F, Tomás 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.
304.
Esteban A, Alia I, Tobin MJ, Gil A, Gordo F, Vallverdu I, Alía I, Tobin MJ, Gil A, Gordo F, Vallverdú I, Blanch L, Bonet A, Vázquez A, de Pablo R, Torres A, de La Cal MA, Macías 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.
305.
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/NEJM199612193352502 External link
306.
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.
307.
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.
308.
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/NEJMoa071366 External link
309.
Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med. 2003;31(1):141-5. DOI: 10.1097/00003246-200301000-00022 External link
310.
Zaloga GP, Marik P. Hypothalamic-pituitary-adrenal insufficiency. Crit Care Clin. 2001;17(1):25-41. DOI: 10.1016/S0749-0704(05)70150-0 External link
311.
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/jcem-53-1-58 External link
312.
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/s001340101073 External link
313.
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 "low-dose" 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/rccm.200205-446OC External link
314.
Ali NA, O'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/CCM.0b013e3181810378 External link
315.
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/NEJM200103083441001 External link
316.
Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann 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/NEJMoa050935 External link
317.
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/cc3538 External link
318.
Oxman AD, Guyatt GH. A consumer's guide to subgroup analyses. Ann Intern Med. 1992;116(1):78-84.
319.
Finfer S, Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Gårdlund 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/s00134-008-1266-6 External link
320.
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/rccm.200612-1803OC External link
321.
Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Pénzes I, Kübler 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/jama.286.15.1869 External link
322.
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: 10.1097/01.CCM.0000295263.12774.97 External link
323.
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: 10.1097/01.CCM.0000295312.13466.1C External link
324.
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, Müller-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: 10.1097/01.CCM.0000295426.37471.79 External link
325.
Heyland DK. Selenium supplementation in critically ill patients: can too much of a good thing be a bad thing? Crit Care. 2007;11(4):153. DOI: 10.1186/cc5975 External link
326.
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/cc5960 External link
327.
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/NEJM199703273361303 External link
328.
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/NEJM199909093411102 External link
329.
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: 10.1097/00000658-198604000-00006 External link
330.
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/chest.96.1.114 External link
331.
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/chest.98.2.405 External link
332.
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: 10.1097/00003246-199908000-00013 External link
333.
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.
334.
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/archsurg.133.1.94 External link
335.
Lauterbach R, Pawlik D, Kowalczyk D, Ksycínski 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: 10.1097/00003246-199904000-00042 External link
336.
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: 10.1097/00003246-199906000-00028 External link
337.
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: 10.1097/00003246-199802000-00035 External link
338.
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: 10.1097/00003246-199605000-00016 External link
339.
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.
340.
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: 10.1097/00003246-199804000-00027 External link
341.
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: 10.1097/01.CCM.0000048629.32625.5D External link
342.
Pérez J, Dellinger RP; International Sepsis Forum. Other supportive therapies in sepsis. Intensive Care Med. 2001;27(Suppl 1):S116-27.
343.
Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med. 1982;10(7):448-50. DOI: 10.1097/00003246-198207000-00006 External link
344.
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.
345.
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/NEJM199909093411103 External link
346.
Cestac P, Bagheri H, Lapeyre-Mestre M, Sié P, Fouladi A, Maupas E, Léger 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: 10.2165/00002018-200326030-00005 External link
347.
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/j.clnu.2006.01.021 External link
348.
Sandström R, Drott C, Hyltander A, Arfvidsson B, Scherstén T, Wickström 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.
349.
Koretz RL, Avenell A, Lipman TO, Braunschweig CL, Milne AC. Does enteral nutrition affect clinical outcome? A systematic review of the randomized trials. Am J Gastroenterol. 2007;102(2):412-29; quiz 468. DOI: 10.1111/j.1572-0241.2006.01024.x External link
350.
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: 10.1097/01.CCM.0000150960.36228.C0 External link
351.
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/chest.125.4.1446 External link
352.
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/j.clnu.2005.08.013 External link
353.
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/s00134-004-2511-2 External link
354.
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: 10.1177/0148607198022004217 External link
355.
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/bjs.1800700113 External link
356.
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: 10.1097/00005373-199707000-00013 External link
357.
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.
358.
Galbán C, Montejo JC, Mesejo A, Marco P, Celaya S, Sánchez-Segura JM, Farré 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: 10.1097/00003246-200003000-00007 External link
359.
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: 10.1177/0148607103027005355 External link
360.
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/s00134-006-0238-y External link
361.
Pontes-Arruda A, Aragão 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: 10.1097/01.CCM.0000234033.65657.B6 External link
362.
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: 10.1097/00003246-199908000-00001 External link
363.
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: 10.1097/01.CCM.0000206111.23629.0A External link
364.
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: 10.1097/01.CCM.0000196829.30741.D4 External link
365.
Déchelotte P, Hasselmann M, Cynober L, Allaouchiche B, Coëffier 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: 10.1097/01.CCM.0000201004.30750.D1 External link
366.
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: 10.1097/00003246-200209000-00013 External link
367.
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/PNS2006505 External link
368.
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.
369.
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: 10.1016/0002-9610(81)90191-4 External link
370.
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/NEJM199803193381203 External link
371.
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: 10.1097/01.CCM.0000157751.92249.32 External link
372.
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/A:1018810325370 External link
373.
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/cmaj.1040876 External link
374.
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/jama.294.23.2989 External link
375.
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/NEJM200008033430501 External link
376.
MacLaren R, Jarvis CL, Fish DN. Use of enteral nutrition for stress ulcer prophylaxis. Ann Pharmacother. 2001;35(12):1614-23. DOI: 10.1345/aph.1A083 External link
377.
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.
378.
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: 10.1097/00003246-199111000-00008 External link
379.
Hébert 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/NEJM199902113400601 External link
380.
Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA. 1993;269(23):3024-9.
381.
Lorente JA, Landín L, De Pablo R, Renes E, Rodríguez-Díaz R, Liste D. Effects of blood transfusion on oxygen transport variables in severe sepsis. Crit Care Med. 1993;21(9):1312-8. DOI: 10.1097/00003246-199309000-00013 External link
382.
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/NEJMoa071533 External link
383.
Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, O'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/rccm.200702-271OC External link
384.
Vorstand und Wissenschaftlicher Beirat der Bundesärztekammer. Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten. Köln: Deutscher Ärzte-Verlag; 2003. Available from: http://www.bundesaerztekammer.de/downloads/Blutkomponentenpdf.pdf External link
385.
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/S0140-6736(08)60105-1 External link
386.
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: 10.1097/00003246-199912000-00001 External link
387.
Kress JP, Pohlman AS, O'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/NEJM200005183422002 External link
388.
Martin J, Bäsell K, Bürkle H, Hommel J, Huth G, Kessler P, Kretz FJ, Putensen C, Quintel M, Tonner P, Tryba M, Scholz J, Schüttler J, Wappler F, Spies C. Analgesie und Sedierung in der Intensivmedizin - Kurzversion. Anästhesiol Intensivmed. 2005;46(1):S1-S20. Available from: http://www.bda.de/downloads/Leitlinie-Analgosedierung.pdf External link
389.
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: 10.1097/00003246-200112000-00004 External link
390.
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: 10.1097/01.CCM.0000215454.50964.F8 External link
391.
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.
392.
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/jc.2005-1107 External link
393.
Malerba G, Romano-Girard F, Cravoisy A, Dousset B, Nace L, Lévy 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/s00134-004-2550-8 External link
394.
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/cc5916 External link
395.
Rossiter A, Souney PF, McGowan S, Carvajal P. Pancuronium-induced prolonged neuromuscular blockade. Crit Care Med. 1991;19(12):1583-7. DOI: 10.1097/00003246-199112000-00023 External link
396.
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: 10.1097/00003246-199010000-00025 External link
397.
Vanderheyden BA, Reynolds HN, Gerold KB, Emanuele T. Prolonged paralysis after long-term vecuronium infusion. Crit Care Med. 1992;20(2):304-7. DOI: 10.1097/00003246-199202000-00019 External link
398.
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: 10.1213/00000539-199404000-00027 External link
399.
Manthous CA, Chatila W. Prolonged weakness after the withdrawal of atracurium. Am J Respir Crit Care Med. 1994;150(5 Pt 1):1441-3.
400.
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: 10.1097/00000539-199507000-00002 External link
401.
Lagneau F, D'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/s00134-002-1508-y External link
402.
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: 10.1097/00003246-200011000-00006 External link
403.
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/cc5047 External link
404.
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/cc2818 External link
405.
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/jnnp.47.11.1223 External link
406.
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/S0300-2977(00)00019-X External link
407.
Schelling G. Post-traumatic stress disorder in somatic disease: lessons from critically ill patients. Prog Brain Res. 2008;167:229-37. DOI: 10.1016/S0079-6123(07)67016-2 External link
408.
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/s00134-009-1396-5 External link
409.
Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ. Randomized, controlled clinical trials in sepsis: has methodological quality improved over time? Crit Care Med. 2002;30(2):461-72. DOI: 10.1097/00003246-200202000-00032 External link
410.
Deutsche Sepsis-Hilfe e.V. Sepsis Information für Patienten & Angehörige. 3 ed. Jena: Deutsche Sepsis-Hilfe e.V.; 2009. Available from: http://www.sepsis-gesellschaft.de/DSG/Deutsch/Was+ist+Sepsis%3F/Informationen+fuer+Laien/Patientenbroschuere?sid=x6l4xfz0uT2LruJvxg0rNM&iid=1 External link
411.
Gramm HJ, Hannemann L, Reinhart K, Lode H. Sepsis: ein Begriff im Wandel: Möglichkeiten und Grenzen der Diagnose anhand klinischer Kriterien [Sepsis: a conception in change: Possibilities and limitations of diagnosis based on clinical criteria]. Dtsch Med Wochenschr. 1995;120(14):498-502.
412.
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/cc5713 External link
413.
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.