Focus on Intensive Care

European Journal of Trauma

Sepsis Current Aspects of Pathophysiology

and Implications for Diagnosis and
Management
Andreas Kortgen1, Gunther Hofmann2, Michael Bauer1

Abstract
Sepsis is characterized by disrupted inflammatory homeostasis due to infection. While a localized and controlled inflammatory reaction helps to eliminate and
control infection, a dysregulated host response
triggers multiple organ failure determining course
and prognosis. Consequent surgical source control
paralleled by adequate and early antibiotic therapy
remains the cornerstone of care. Nevertheless,
mortality remains as high as 5060% for severe sepsis
and septic shock. As the molecular mechanisms are
becoming increasingly better defined, interventions
aiming to interfere with the host response to infection
have been undertaken, largely with disappointing
results. Thus, many evidence-based recommendations
suggest waiving of resource-consuming interventions,
such as supplementation of antithrombin or immunoglobulins. Nevertheless, several seminal studies have
indicated that meticulous supportive care according
to pathophysiological principles, most notably early
goal-directed therapy, low-dose hydrocortisone and
activated protein C, can disrupt dysfunctional cascades
favorably influencing the course of the disease. In
parallel, there is increasing evidence from national and
international surveys that therapy of severe sepsis on
ICUs worldwide is generally in poor compliance with
current guidelines, while personal perception of the
physicians in charge would suggest high rates of
adherence to evidence-based recommendations.

Thus, strategies of change management, such as

implementation of sepsis bundles, are warranted to
achieve better standards of care toward the aim of
the surviving sepsis campaign, i.e. a reduction of
mortality rates by 25% within the next years.
Key Words
Infection Source control Trauma Host response
Sepsis Bundles Change management Surviving
Sepsis Campaign
Eur J Trauma 2006;32:39
DOI 10.1007/s00068-006-0006-2

Introduction
Mortality of sepsis is still unacceptably high. Although
improvements of general intensive care and organ
support were paralleled by an overall reduction of mortality, mortality rates of sepsis associated with organ
dysfunction, in particular with circulatory shock, are
still in the range of up to 60%. Due to an increase in the
incidence of sepsis the total number of patients dying
is increasing [14], despite some progress with respect
to outcome of patients presenting with severe sepsis.
Improvements in the last years were based on improved general care and several seminal studies evaluating
various treatment strategies which all have demonstrated a reduction of mortality of sepsis: early goal-directed

Department of Anaesthesiology and Intensive Care Therapy,

Friedrich-Schiller-University, Jena, Germany,
2
Department of Traumatology, Friedrich-Schiller-University,
Jena, Germany.
Received: January 15, 2006; revision accepted: January 20, 2006.

European Journal of Trauma 2006 No. 1 Urban & Vogel

Kortgen A, et al. Sepsis Current Aspects

therapy based on the measurement of central venous

oxygen saturation, the use of low-dose hydrocortisone in septic shock and the use of activated protein C
in selected septic patients reflect the most prominent
examples for improvement [24]. In addition, other therapeutic options, like lung-protective ventilation and
intensive insulin therapy, evaluated in a larger collective
of critically ill patients, seem to be promising for septic patients as well [5, 6]. In 2004, the Surviving Sepsis
Campaign (SSC) defined guidelines for the therapy of
sepsis with the objective to reduce relative mortality by
25% with the implementation of this bundle of therapeutic strategies [7, 8] which will depend on effective
measures of change management to implement these
strategies over the given time frame [9].
Epidemiology of Sepsis
Current epidemiological data of sepsis are available
in studies from France, Australia/New Zealand and
Germany. In the latter cross-sectional study 454 intensive care units (ICUs) of 310 hospitals, out of 2,075 ICUs
in 1,380 hospitals in Germany, took part to assess prevalence and mortality of sepsis. Between January 15, 2003
and January 14, 2004 about 3,877 patients were classified
according to the ACCP/SCCM criteria of sepsis. The prevalence of infection was 34.7%. Severe sepsis and septic
shock were identified in 11% and sepsis without organ
failure in 12% of patients. Each year 154,000 patients (incidence 216 per 100,000 inhabitants) suffer from sepsis,
75,000 (incidence 110 per 100,000 inhabitants) of them
from severe sepsis. As about 60,000 patients die each
year, sepsis is the third most common cause of death in
Germany, only exceeded by coronary heart disease and
myocardial infarction. The 90-day-mortality was 54%
for severe sepsis without substantial differences between
tertiary care/university and other hospitals. Most common sources of infection were pulmonary (63%) and
abdominal infections (25.3%) in accordance with other
epidemiological studies of sepsis [1, 10, 11].
In the French cohort study, ICUs were selected
randomly and all patients treated within a period of
2 weeks in the year 2001 fulfilling the criteria of severe
sepsis were investigated. Altogether 3,738 patients were
studied with 14.6% presenting severe sepsis. 30-day
mortality was 35% and 2-month mortality was 41.9%.
In comparison with a former study performed in 1993
in France, incidence of severe sepsis has even increased, while in the same time mortality could be decreased
[12]. This is consistent with epidemiological data from
the USA [1].
Another epidemiological study evaluated the incidence of severe sepsis in Australia and New Zealand

in a period of 3 months in 1999 [11]. 3,338 patients at

23 ICUs of 21 universities and tertiary care hospitals
were investigated accounting for 20% of all ICU admittances in this time period. About 20.7% of the patients presented severe sepsis. Calculated incidence of
severe sepsis was 77 per 100,000 inhabitants; 28-day
mortality was 32.4%; in-hospital mortality was 37.5%.
Pulmonary and abdominal infections, as source of sepsis, were found in 50.3 and 19.3%, respectively.
These data suggest that despite some regional differences sepsis still remains the leading problem in
intensive care with an incidence of 100 200 cases per
100,000 inhabitants. Together with the estimated costs
of 20,000 30,000 /case in Europe, the substantial economic impact beside the poor prognosis reflects the
worldwide burden of this syndrome.
Pathophysiology of Sepsis
The Continuum of Infection, Host Response
and Organ Dysfunction
Sepsis is caused by invasion of microorganisms and/or
their products (pathogen-associated molecular patterns
PAMPs) into the blood stream resulting in a systemic
host response as a potential complication of infection of
any site. A dysregulated host response is hold liable for
remote organ failure [13]. Prognosis of severely septic
patients, i.e. patients with organ failure due to sepsis,
remains poor with a hospital mortality rate of 54% in
a recently completed German multicenter study [10].
Activation of immunocompetent cells of the innate
unspecific immune system by recognition of PAMPs
(cell wall products, exotoxins, bacterial DNA, viral
RNA) by specific receptors of immunocompetent cells,
the so-called pattern recognition receptors (PRR),
results in a stereotype host response the systemic
inflammatory response syndrome (SIRS) [13]. PRR,
e.g. toll-like receptors, mediate an activation of intracellular signal-transducing cascades leading to an initiation of gene expression of proinflammatory cytokines
like tumor necrosis factor a (TNF-a) or Interleukin 1
(IL-1) as primary mediators of sepsis. The activation
of monocytes and macrophages and the burst of the
primary mediators initiate the synthesis of further cytokines like IL-6, IL-8, IL-10 or high mobility group
protein B1 (HMGB-1) with manifold synergistic but
also partially antagonistic effects causing a modulation
of the inflammatory response [14, 15]. IL-6 secretion
leads to a reprogramming of hepatic gene expression,
the so-called acute phase response, characterized by
induction of positive acute phase proteins like C-reactive protein or alpha-2 macroglobulin and a significant suppression of the so-called negative acute phase

European Journal of Trauma 2006 No. 1 Urban & Vogel

Kortgen A, et al. Sepsis Current Aspects

proteins, especially albumin [16]. Hyperinflammatory

responses with uncontrolled inflammation and organ
dysfunction as well as hypoinflammatory responses
with immunoparalysis and uncontrolled infection can
be associated with fatal outcome (Figure 1) [13, 15,
17, 18]. Modern biochip technology allows for a broad
assessment of a whole array of inflammatory genes and
gene products which is likely to challenge our current
understanding of SIRS [19].
Activation of monocytes/macrophages and neutrophils with excretion of proinflammatory cytokines
influence cascade systems, like the coagulation and the
complement system, and different organ systems
and lead to endothelial dysfunction with capillary
leakage, blood pooling and perfusion disorders. Macroand microcirculatory failure along with pulmonary failure result in tissue hypoxia (Figures 1 and 2) [2, 20
23]. Apart from hypoxia-induced necrosis apoptosis,
the programmed cell death induced by cytokines and
mitochondrial dysfunction/hypoxia contributes to organ dysfunction (Figure 1) [24, 25]. The balance of oxygen demand and supply is reflected in mixed and central
venous oxygen saturation. Thus, consequent restoration of a normal central venous oxygen saturation can
prevent tissue hypoxia and the dependent organ injury
[4]. A single organ dysfunction may affect the function
of remote organs. Especially injury of the vulnerable
hepatosplanchnic area with the translocation of gutderived bacteria and toxins in the portal vein and the
lymphatic system with a systemic spill-over amplifies

Systemic
inflammatory
response
syndrome

systemic activation of the innate immune system in

the sense of a vicious circle [20, 26]. Independent of
the trigger, the final pathway is the progressive loss of
vital cells with multiple organ dysfunction and ultimately
irreversible multiple organ failure.
Diagnosis of Sepsis
The Golden Hour of Septic Shock
As timely initiation of therapy may prevent the development and progression of multiple organ dysfunction,
early diagnosis of sepsis is crucial. Unfortunately, until
now definite diagnosis of sepsis cannot be based on a
single parameter. Therefore, sepsis, severe sepsis and
septic shock are defined by a combination of vital signs,
laboratory parameters, hemodynamic values and clinical signs of organ dysfunction, according to the ACCP/
SCCM criteria [27]. A discrimination between noninfectious and septic inflammatory response with the
use of these parameters is not achievable [28]. Furthermore, microbiological proof of infection is often not
successful. Blood cultures are negative in the majority of
septic patients [29], and results of other microbiological
investigations are misleading in many cases. Interpretation of microbiological findings in critically ill patients
is difficult and a differentiation between colonization
and infection is sometimes not possible. In addition, the
results are available only after days of cultivation, i.e. too
late to guide antibiotic treatment, in the most important
time period the initial stage of sepsis. Culture-independent diagnostic tests based on PCR for prokaryotic

Complement,...
Activation of
the innate
immune system

TNF
IL-1
IL-6
IL-8
MIF
HMGB-1 ...

humoral

cellular

early organ
failure

ROS, proteases

PMN

PAMPs:
LPS, LTA, Zymosan....

anergy, HLA-DR

M
Compensatory
antiinflammatory
response syndrome
immune paralysis

systemic bacteremia,
progression of infection

European Journal of Trauma 2006 No. 1 Urban & Vogel

IL-4
IL-10

late organ
failure

translocation

Figure 1. Immune dysfunction and

pathogenesis of organ failure.

Kortgen A, et al. Sepsis Current Aspects

Oxygenation failure
(e.g. ARDS)
inadequate systemic oxygen
supply (e.g. septic cardiomyopathy)
Oxygen uptake:
alveoles
blood

regional distribution
disturbances
(e.g. splanchnic area)

convective transport:
lungs
tissues
oxygen release
blood
cells

microvascular failure
Cellular oxygen
utilisation
mitochondria

mitochondrial dysfunction

Tissue hypoxia
Figure 2. Disturbances of oxygen
supply and utilization.

DNA are promising tools that may be of great value in

future to detect causative organisms in a therapy-relevant time frame. In a series of studies, procalcitonin
was able to improve discrimination between infectious
and other reasons for inflammatory response and organ
dysfunction. Above a threshold value of 2 ng/ml a septic cause is very likely [30, 31]. Efficiency of therapeutic
measures like source control and antibiotic therapy are
reflected in a timely manner with procalcitonin. Unfortunately, other causes of transient elevations of procalcitonin, like surgical trauma or ischemia/reperfusion, have
been described as well [32]. For this scope, improvements
with modern genomic and proteomic assays are also
expected in future.
Monitoring of organ function and calculation of
scores like the sequential (sepsis-related) organ failure
assessment (SOFA) score requires measurement of
laboratory parameters like blood gas analysis, lactate,
bilirubin, creatinine, blood count and coagulation analysis. Prognosis of multiple organ dysfunction in sepsis is
dependent on the kind of affected organs, the number
of failing organs and the extent of functional impairment. Early lactate clearance, i.e. the relative reduction
of blood lactate concentration in the early course of
therapy, reflected efficiency of initial resuscitation therapy and predicted prognosis in an observational study
[33]. Indocyanine green clearance is a good parameter
for global liver function and perfusion and correlates
well with the outcome in critically ill patients. It has a
higher sensitivity to detect hepatic dysfunction than the
conventional static laboratory assessments of liver func-

tion [34], and timely improvement of indocyanine green

clearance is paralleled by improvement of the outcome
[35].
Current Guidelines for Therapy of Sepsis
Time is Tissue
The different treatment modalities of sepsis can
be generally divided into causal therapies, supportive
intensive care and adjunctive therapeutic measures.
The currently published guidelines for the therapy
of severe sepsis and septic shock of the SSC in many
points stress the importance of timely and aggressive initiation of therapy. Thus, the well-established
concept of the golden hour must be extended from
other shock states also to the field of sepsis. While an
in-depth description of the recommended therapy according to the SSC is beyond the scope of this review,
it is becoming increasingly clear that there is a huge gap
between available data, individual recognition by critical care physicians and their timely implementation at
the bedside (lag phenomenon). Hence, recommended
evidence-based therapeutic measures are summarized in
Table 1, but we will focus on aspects, how to implement
these therapies in daily practice, as well as on specific
considerations regarding source control in trauma/orthopedic patients.
Surgical Source Control
Considerations in Orthopedic Trauma
Identification of a potential orthopedic focus relies on
cross-sectional imaging techniques while conventional

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Kortgen A, et al. Sepsis Current Aspects

X-ray is of limited significance. Contrast-enhanced MRI

is the most sensitive technique to identify a potential
focus as periosseous edema formation; changes in vascular flow patterns as well as changes in bone marrow
density can be visualized [36, 37]. However, metallic implants will hamper any MRI diagnostics. Sonography,
only if MRI is not an option, can help to identify liquid
retentions at the bedside.
Scintigraphy using various tracers (99mTc-MDP,
111
In, 67Ga-citrate) is characterized by a high sensitivity either in the conventional or leukocyte-labeling
technique. Unfortunately, specificity is low but can be
increased by combining different nuclides (99mTc-MDP
and 111In). Negative scintigraphy almost certainly rules
out the presence of a focus, while a positive result frequently requires sophisticated differential diagnostic
work-up. Delayed fracture healing, pseudarthroses,
diabetic neuropathy, endoprothetic materials, myositis ossificans, heterotopic ossification and aseptic inflammatory reactions are among the most frequent
differential diagnoses. Localization of the lesion regarding its association with soft tissue or bone even when
different cross-sections are analyzed poses problems.
Positron-emmission-tomography using 18Fluorine-desoxy-glucose to assess glucose metabolism noninvasively
is increasingly used to identify inflammatory reaction
based on increased energy metabolism in activated
macrophages and neutrophils, since sensitivity and
specificity is superior compared to the aforementioned
imaging techniques [38].
Once a focus is identified, rapid, complete and
aggressive source control is mandatory applying concepts derived from oncological surgery. Existing scar
tissue and fistulae along with results obtained by imaging techniques must be taken into consideration when
Table 1. Evidence-based therapy of severe sepsis and septic shock.
Causal therapies
Source control
Broad-spectrum antibiotics
Supportive therapies
Initial goal-directed resuscitation
Lung-protective ventilation
Glycemic control
Use of sedation protocols
Deep vein thrombosis prophylaxis
Stress ulcer prophylaxis
Adjunctive therapies
Low-dose hydrocortisone in septic shock
Recombinant human-activated protein C
in patients with high risk of death

European Journal of Trauma 2006 No. 1 Urban & Vogel

planning the surgical approach. In this respect, filling

fistulae with methylene blue can be helpful. Radical
debridement of bones and joints is always the initial step
possibly omitting a tourniquet [39]. Removal of any implants along with nonvital tissues, until well-perfused
areas are reached, is essential. Radical debridement is
followed by extensive lavage preferably applying 35 l
of Ringers, using a jet lavage system [40]. Fixation is
mandatory and can be achieved at the extremities with
a fixateur externe to immobilize the infected site. While
adjuvant application of spacers that are coated with
antibiotics is considered effective, this cannot replace
the radical excision of infected tissue and material. Temporary closure until staged repair will be achieved by
occlusion under vacuum in most cases. Application of
suture material in the wound grounds should be avoided. Specimens of the infected material help to guide appropriate and targeted antibiotic therapy which is also
important to reduce the systemic burden of spreading
bacteria during programmed revision surgery. Revisions
are required every 25 days including a new extraction
of specimen for microbiology, resection of nonvital
material and temporary vacuum occlusion until final
closure can be achieved.
Performance and Perception: Implementation
of Evidence-Based Treatment in Daily Care
It is meanwhile an increasingly recognized problem
that it takes a too long time period from discovery and
evaluation of novel therapies to their implementation
in broad daily routine. Some of the factors that may
explain this rather incomprehensible situation are: insufficient continuous medical education, lack of awareness, doubts in the generalizability of study results,
scientific ignorance, failure of communication, lack of incentives, costs of new therapies but primarily insufficient
change management. Moreover, physicians often seem
to be unwilling to change their routine. The gap between
best and actual patient care may in the worst case be
associated with increased morbidity and mortality [41].
In the last years, several seminal studies have been
published that described considerable improvement of
outcome with various different treatment modalities in
critically ill and septic patients. Their implementation
in clinical practice in the form of bundles of therapies
seems promising regarding the outcome of patients.
Unfortunately, the already mentioned study of the German Competence Network Sepsis (SepNet) revealed a
poor performance of the realization of evidence-based
new therapies, e.g. only 4% of patients with sepsis and
acute pulmonary failure were ventilated with low tidal
volumes, defined as 6 ml/kg bodyweight, although 90%

Kortgen A, et al. Sepsis Current Aspects

of the interviewed intensivists declared to practice low

tidal volume ventilation generally [42]. The SSC therefore initiated a project to raise awareness of clinicians
and ultimately to improve the standard of care. A consensus committee published evidence-based guidelines
for therapy of severe sepsis and septic shock [7]. To allow implementation of these guidelines in daily practice,
therapeutic bundles have been defined. The goal of the
Sepsis Resuscitation Bundle is the early identification
of patients at risk, obtainment of blood cultures, administration of broad-spectrum antibiotics and initiation of
early goal-directed therapy. The rapid and aggressive
management of this bundle determines the early course
of the disease. According to management tools quality
assessment of implementation of this bundle should be
performed within 6 h individually in each patient. An
additional Sepsis Management Bundle defines further treatment modalities to be accomplished within
24 h. These are the administration of low dose hydrocortisone in septic shock patients and the administration
of rhAPC according to local policies as well as achievement of glycemic control and limited inspiratory plateau pressures (for further informations see: http://www.
survivingsepsis.org and http://www.IHI.org). A recently
published observational study reported a 52% compliance for a modified 6 h bundle and a 30% compliance
for the 24-h bundle, with a relative risk of 2.12 and 1.76,
respectively, for the noncompliant group [43].
For efficient implementation of new bundles, change
behavior strategies like motivation and education of the
team workers are warranted as well as a good definition
of the therapy algorithm and inclusion criteria. The key
process for a continuous quality improvement is closing
the loop by formal evaluation of the targeted changes
(Figure 3). In a single-center study, the implementation
of a standard operating procedure for therapy of sepsis
resulted in higher realization and earlier initiation of the
different therapies paralleled by a significant reduction
of mortality by septic shock [9].
In conclusion, progress has been made over the
past several years to improve care for the septic patient.
Further improvement can be achieved on a short term

via tools of change management, while the advent of

molecular biology is likely going to affect the outcome
even more profoundly over the next decades.

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do
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act
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Author for Correspondence

Michael Bauer, MD
Department of Anaesthesiology and Intensive
Care Therapy
Friedrich-Schiller-University
Erlanger Allee 101
07740 Jena Germany
Fax: +(49/3641) 9323112
e-mail: Michael.Bauer@med.uni-jena.de