sepsis is a leading cause of hospital mortality in adult patients , and the incidence is increasing .
there is considerable variation between countries , with a strong correlation between the frequency of sepsis and intensive care unit ( icu ) mortality rates . in a prospective study of 3877 patients in 454 german icus ,
the prevalence of severe sepsis , defined as sepsis associated with organ dysfunction , was 11.0% .
of those with severe sepsis , nearly half had septic shock , defined as sepsis with hypotension despite adequate fluid replacement .
the incidence of severe sepsis was estimated to be 76 - 110 cases / year per 100,000 inhabitants .
patients surviving sepsis have a lower quality of life than the age- and sex - adjusted population as much as 1.5 years later .
the daily cost is estimated to be 1090 euros ( approximately usd $ 1600 ) , and the overall costs per hospital stay are estimated to be 2-fold to 11-fold higher than the general cost per patient .
currently available strategies for the management of sepsis patients include timely patient identification and diagnosis , rapid identification of causative organisms , appropriate and early antimicrobial therapy , improved ventilatory techniques , goal - directed hemodynamic support , targeted immunological therapy , glycemic control , appropriate nutrition , effective supportive therapies , and patient management by highly qualified clinicians and nursing staff .
these multifaceted approaches to patient management , the use of evidence - based methods , and the adoption of incremental , goal - oriented strategies are vital to combat this complex , aggressive , and increasingly prevalent condition .
infectious pathogens possess unique structural components called pathogen - associated molecular patterns ; examples include lipopolysaccharide in gram - negative bacteria and peptidoglycan in gram - positive bacteria .
pattern recognition receptors , which include the cell - surface toll - like receptors and several types of cytoplasmic receptors .
receptor binding results in the activation of intracellular signaling pathways that lead to a variety of responses , including increased transcription of inflammatory cytokines , upregulation of adhesion molecule expression , stimulation of humoral and cell - mediated immune responses , and activation of vascular endothelial cells .
a detailed discussion of the pathogenesis of sepsis is beyond the scope of this article , but the subject has been addressed in a number of recent reviews [ 8 - 11 ] .
an important feature of the pathophysiology of sepsis is the development of a procoagulant state .
disseminated intravascular coagulation , one of the most feared complications of sepsis , is a manifestation of the dysregulation of coagulation seen in this disorder . in severe sepsis ,
treatment of the underlying cause of infection requires early and meticulous attention to source control , including the use of antimicrobial agents and , where appropriate , surgical drainage . physiological support of organ dysfunction with inotropes , mechanical ventilation , and renal replacement therapy
specific drugs such as corticosteroids are broadly used , although the benefit of such therapy remains uncertain .
protein c is a soluble , vitamin k - dependent , plasma serine protease that plays a central role in endogenous anticoagulation .
the activated form is generated when thrombin , bound to the cofactor thrombomodulin , interacts with and cleaves the zymogen protein c. activated protein c ( apc ) is a potent anticoagulant and profibrinolytic enzyme capable of inactivating clotting factors va and viiia and plasminogen activator inhibitor 1 .
the exact role of apc in the treatment of septic shock is eagerly debated , and a recent review from our group gives an overview .
the 23 patients included in this observational study had a 100% risk of death , according to a score based on the response to early continuous veno - venous hemodiafiltration .
the actual 28-day mortality rate of the 23 patients who received apc was only 39% and was associated with a decrease in the magnitude of lactic acidosis and the dose of norepinephrine required . in a double - blind randomized placebo - controlled trial ,
the safety and efficacy of extended apc treatment were evaluated in 64 icus in nine countries .
however , extended apc treatment was not associated with reductions in day-28 all - cause mortality or in - hospital mortality or with an increase in serious adverse events .
heparin used concomitantly with apc was explored in a large randomized study , and no heparin effect on mortality was observed .
further analyses revealed that the coadministration of apc with low - dose heparin in patients with severe sepsis did not increase the incidence of serious bleeding .
fewer ischemic strokes in the heparin group suggest that heparin cessation should be avoided during apc infusion .
finally , recent observational data from a large international sepsis registry demonstrated a beneficial effect of the treatment with apc . in 2002 ,
this international group of investigators developed evidence - based guidelines through a formal and transparent process .
the initial guidelines were published in 2004 , and an updated version was published in 2008 .
the development and publication of guidelines often do not lead to changes in clinical behavior , and guidelines are rarely , if ever , integrated into bedside practice in a timely fashion . recognizing that implementing guidelines presents a significant challenge , the ssc set out to develop and evaluate a multifaceted model to change bedside practice for patients with severe sepsis and septic shock by the definition of  sepsis resuscitation bundles as well as
. a central part of that program was an international registry that providers could use to monitor the performance of their institution and to recruit and enter patients .
a spanish cohort study demonstrated significant benefit after implementing these bundles . in january 2010 , the first analysis of the worldwide registry data described the global initiative and its implementation and reported its impact on process improvement and patient outcomes .
data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality .
compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 years ( p < 0.0001 ) .
the adjusted odds ratio for mortality improved the longer a site was in the ssc , resulting in adjusted absolute decreases of 0.8% per quarter and 5.4% over 2 years ( 95% confidence interval 2.5 - 8.4% ) .
infectious pathogens possess unique structural components called pathogen - associated molecular patterns ; examples include lipopolysaccharide in gram - negative bacteria and peptidoglycan in gram - positive bacteria .
pattern recognition receptors , which include the cell - surface toll - like receptors and several types of cytoplasmic receptors .
receptor binding results in the activation of intracellular signaling pathways that lead to a variety of responses , including increased transcription of inflammatory cytokines , upregulation of adhesion molecule expression , stimulation of humoral and cell - mediated immune responses , and activation of vascular endothelial cells .
a detailed discussion of the pathogenesis of sepsis is beyond the scope of this article , but the subject has been addressed in a number of recent reviews [ 8 - 11 ] .
an important feature of the pathophysiology of sepsis is the development of a procoagulant state .
disseminated intravascular coagulation , one of the most feared complications of sepsis , is a manifestation of the dysregulation of coagulation seen in this disorder .
in severe sepsis , treatment of the underlying cause of infection requires early and meticulous attention to source control , including the use of antimicrobial agents and , where appropriate , surgical drainage . physiological support of organ dysfunction with inotropes , mechanical ventilation , and renal replacement therapy
specific drugs such as corticosteroids are broadly used , although the benefit of such therapy remains uncertain .
protein c is a soluble , vitamin k - dependent , plasma serine protease that plays a central role in endogenous anticoagulation .
the activated form is generated when thrombin , bound to the cofactor thrombomodulin , interacts with and cleaves the zymogen protein c. activated protein c ( apc ) is a potent anticoagulant and profibrinolytic enzyme capable of inactivating clotting factors va and viiia and plasminogen activator inhibitor 1 .
the exact role of apc in the treatment of septic shock is eagerly debated , and a recent review from our group gives an overview .
the 23 patients included in this observational study had a 100% risk of death , according to a score based on the response to early continuous veno - venous hemodiafiltration .
the actual 28-day mortality rate of the 23 patients who received apc was only 39% and was associated with a decrease in the magnitude of lactic acidosis and the dose of norepinephrine required . in a double - blind randomized placebo - controlled trial ,
the safety and efficacy of extended apc treatment were evaluated in 64 icus in nine countries .
however , extended apc treatment was not associated with reductions in day-28 all - cause mortality or in - hospital mortality or with an increase in serious adverse events .
heparin used concomitantly with apc was explored in a large randomized study , and no heparin effect on mortality was observed .
further analyses revealed that the coadministration of apc with low - dose heparin in patients with severe sepsis did not increase the incidence of serious bleeding .
fewer ischemic strokes in the heparin group suggest that heparin cessation should be avoided during apc infusion .
finally , recent observational data from a large international sepsis registry demonstrated a beneficial effect of the treatment with apc .
this international group of investigators developed evidence - based guidelines through a formal and transparent process .
the initial guidelines were published in 2004 , and an updated version was published in 2008 .
the development and publication of guidelines often do not lead to changes in clinical behavior , and guidelines are rarely , if ever , integrated into bedside practice in a timely fashion . recognizing that implementing guidelines presents a significant challenge , the ssc set out to develop and evaluate a multifaceted model to change bedside practice for patients with severe sepsis and septic shock by the definition of  sepsis resuscitation bundles as well as
. a central part of that program was an international registry that providers could use to monitor the performance of their institution and to recruit and enter patients .
a spanish cohort study demonstrated significant benefit after implementing these bundles . in january 2010 ,
the first analysis of the worldwide registry data described the global initiative and its implementation and reported its impact on process improvement and patient outcomes .
data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality .
compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 years ( p < 0.0001 ) .
( p = 0.001 ) . the adjusted odds ratio for mortality improved the longer a site was in the ssc , resulting in adjusted absolute decreases of 0.8% per quarter and 5.4% over 2 years ( 95% confidence interval 2.5 - 8.4% ) .
the management of sepsis in hospitals is significantly better today than it was 10 years ago .
however , sepsis - associated mortality rates remain unacceptably high , and new strategies to improve patient outcomes will have to be embraced further still .
the recent improvement in outcomes of patients with severe sepsis and septic shock has been characterized by the successive introduction of multiple interventions and therapies , which is an ongoing process .
the results of the aforementioned studies   demonstrate that the use of a multifaceted performance improvement initiative was successful in changing sepsis treatment behavior as evidenced by a significant increase in compliance with sepsis performance measures .
this compliance was associated with a significant reduction in hospital mortality in patients with severe sepsis and septic shock over the duration of the 2-year study , but the study design does not allow us to say , with certainty , whether this was due to some or all bundle elements , increased awareness of severe sepsis , or other unrelated factors .
there are still many unanswered questions - including the mortality trend in hospitals that have not implemented the bundles and confirmation of which components of the bundles reduce mortality - that could provide direction for future research .
the results of this study should encourage similar efforts to implement guidelines and treatment protocols as a means to improve outcomes .
finally , the importance of the wholehearted involvement of the entire health care team and the provision of strong public and political support in achieving these objectives can not be stressed enough .
 although several successful clinical trials in the last 2 - 3 years have been greeted with enthusiasm by intensivists , severe sepsis and septic shock still have increasing incidence and more or less unchanged mortality . within the last few years 
 , the progress in sepsis research covering definitions , epidemiology , pathophysiology , diagnosis , and standard and adjunctive therapy as well as general measures such as treatment bundles is encouraging . in this report , 
 a small selection of recent publications , focusing on the current discussion of activated protein c as well as the relevance of the surviving sepsis campaign bundle therapy , is presented and the possible impact on clinical routine is discussed . 
Introduction and context
Recent advances
Pathophysiology
Activated protein C
Implementing treatment bundles
Implications for clinical practice
Competing Interest