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)).

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 1(st) revision of the S-2k guideline of the German Sepsis Society in collaboration with 17 German medical scientific societies and one self-help group provides state-of-the-art information (results of controlled clinical trials and expert knowledge) on the effective and appropriate medical care (prevention, diagnosis, therapy and follow-up care) of critically ill patients with severe sepsis or septic shock. The guideline had been developed according to the "German Instrument for Methodological Guideline Appraisal" of the Association of the Scientific Medical Societies (AWMF). In view of the inevitable advancements in scientific knowledge and technical expertise, revisions, updates and amendments must be periodically initiated. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources.

Table of contents

Definition and explanation of the term "guidelines"

Recommendations in accordance with the provisions of S2k guidelines

Definition and diagnosis of sepsis

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

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

Causal treatment

Infectious source control

Antimicrobial therapy

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

Adjunctive therapy

Recombinant activated protein C (rhAPC)

Antithrombin

Immunoglobulins

Selenium

Other therapeutic approaches

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

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).

Table 1

Diagnostic criteria for sepsis, severe sepsis and septic shock (modified after [411]), in line with the ACCP/SCCM consensus conference criteria [11].

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].

Table 2

Collection, storage and transport of blood cultures [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].

Table 3

Modified “clinical pulmonary infection score (CPIS)” [43]

→ 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 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 HO. 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)).

Table 4

SDD and SOD regimens according to Krüger WA, IntensivNews 2009, mod. after: de Smet et al, New Engl J Med. 2009;360:20-31 [137]. In a modified form, following mouth cleansing and oral suction, SDD or SOD may also be administered with a syringe as oral suspensions: 10 ml q.i.d. according to the following formulation: 1.0 g polymyxin E = Colistin (alternatively, 0.5 g polymyxin B), 800 mg of tobramycin, 2.5 g of amphotericin B ad 100 mL distilled water)

(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:

Removal of implants (catheter [174], vascular prostheses [175], osteosynthesis material [176], joint replacement [177])

Incision or CT-guided drainage of abscesses [178]

Wound opening and necrectomy, amputation and fasciotomy [179]

Treatment of peritonitis, anastomotic insufficiency and ileus by peritoneal lavage, drainage or enterostomy [172], [180]

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 , 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, ScvO) 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 ScvO 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 ScvO to >70% contributes to increased survival remains unresolved. It has also not yet been clarified whether intermittent measurements of ScvO 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 recommende [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.

Table 5

Definition of criteria for acute kidney injury (AKI) [412]

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].

Table 6

Definition of acute lung injury (ALI) and adult respiratory distress syndrome (ARDS)

→ 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].

Table 7

Ventilation management in ALI/ARDS patients according to the recommendations by ARDSNET [290], modified as per [22].

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)

Figure 1

An example of a weaning scheme after Kuhlen (modified after [303, 413])

→ 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.

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)

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 O-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.