Severe sepsis is a common disease process in the critically ill and is associated with substantial morbidity and mortality. Continuing research has provided considerable insight into the pathophysiology of sepsis over recent years, enabling various aspects of the sepsis response to be targeted. Discoveries related to the link between coagulation and inflammation have been particularly exciting, leading to the development of recombinant activated protein C. This review will discuss current definitions of sepsis, describe new approaches to classification and diagnosis of patients with sepsis, present recommendations for management, and briefly highlight areas of ongoing and future research. Key words: Sepsis, diagnosis - Sepsis, therapy Intensive care.

Sepsis diagnosis and management: work in progress

Deparment of Intensive Care, Erasme Hospital Free University of Brussels, Brussels, Belgium

Definitions of sepsis

Sepsis vs infection


ecent years have seen great advances in our understanding of the pathophysiology of sepsis and as a result new treatments have become available and more are being developed. In addition, progress has been made in techniques to facilitate the diagnosis of sepsis. In this article we will discuss the recent advances in the diagnosis and management of this important and common problem.

Address reprint requests to: Prof J. L. Vincent, Erasme Hospital, Route de Lennik 808, 1070 Brussels, Belgium. E-mail:

The words “sepsis“ and “infection“ are often used as synonyms, but they are distinct entities. Infection is a microbiological event, caused by bacteria, fungi, viruses etc., while sepsis is the host response to that infection, characterized by the release of many mediators and by a constellation of clinical and laboratory features (Table I), none of which are specific for sepsis. Whenever possible, infection should be defined by the organ primarily infected and the type(s) of microorganisms (e.g., a lung infection due to Pneumococcus or a urinary tract infection due to E. coli). While the presence of infection is essential for a diagnosis of sepsis, sometimes the source of infection cannot be identified, and sometimes the bacteriology remains negative. In some patients with sepsis, the causative infection may never be identified at all; this does not mean the patient does not have an infection, and hence cannot have sepsis, just that we are unable to locate or identify it. To help to rule out an infection, an objective measure such as the



infection.—Common clinical and laboratory features of sepsis. response.9.3 remain useful to clinicians and researchers. organ dysfunction. that while the concept of systemic inflammatory response syndrome (SIRS) remains useful as a concept. sequential organ failure assessment score (SOFA)] to make a composite score. 88 MINERVA ANESTESIOLOGICA In view of these conclusions. and improve the understanding and management of severe sepsis and septic shock. Second. microsatellite.VINCENT SEPSIS DIAGNOSIS AND MANAGEMENT TABLE I. respiratory rate. organ dysfunction) concept. providing insight into the continuum of sepsis. but that they do not allow for precise staging or prognostication of the host response to infection. These genespecific probe nucleotides.8 Polymorphisms in the Toll-like receptor (TLR) and interferon-γ genes have also been identified influencing susceptibility to sepsis. insertion and deletion polymorphisms are all forms of genetic variation that can characterize an individual’s risk for sepsis. nodes. — Fever/hypothermia — Increased cardiac output/low systemic vascular resistance — Increased oxygen consumption — Unexplained tachycardia — Unexplained tachypnea/respiratory alkalosis — Altered white blood cell count — Increased C-reactive protein levels — Increased procalcitonin levels — Unexplained hyperglycemia — Unexplained lactic acidosis — Unexplained respiratory dysfunction (acute lung injury) — Thrombocytopenia/disseminated intravascular coagulation — Unexplained disorientation or confusion — Unexplained alteration in liver function tests — Unexplained alteration in renal function — Capillary leak syndrome M IN CO E RV PY A RI M GH E D T PREDISPOSING FACTORS infection probability score. that the concepts of sepsis (the host response to an infection).6 A polymorphism of the tumor necrosis factor-α (TNF-α) gene. white blood cell count. chronic diseases. such as age. prolonged immunodepressant medications. rather like many cancers are staged using the tumor. as defined in the 1991 North American Consensus Conference. that may influence a patient’s response to infection and/or indicate which therapies are likely to be most effective in that patient.7 A polymorphism within the intron 2 of the interleukin-1 receptor antagonist (IL-1ra) gene (IL-1RN*2) has been associated with reduced IL-1ra production and increased mortality rates. or death. heart rate. C-reactive protein (CRP). the role an individual’s genetic make-up may have on the development of sepsis and the severity of disease when it develops are being explored and various polymorphisms have been shown to influence the risk of infection and/or of mortality from sepsis. 10 Advances in genetics technology have now allowed investigators to design glass slides (chips) with minute quantities of short. may be useful. are arrayed onto the chip surface to produce a DNA microar- ® IC A Marzo 2006 . and an expanded list of signs and symptoms of sepsis may better reflect the clinical response to infection. the participants introduced the PIRO (predisposing factors. metastases (TNM) system. is associated with increased serum levels of TNF and a greater risk of mortality from septic shock. Using the emerging PIRO model could aid physicians in better characterizing heterogeneous groups of septic patients. severe sepsis (sepsis associated with organ dysfunction) and septic shock (sepsis plus arterial hypotension despite adequate fluid resuscitation). etc. gene-specific nucleotides..2 the 29 experts charged with providing “a conceptual and a practical framework to define the systemic inflammatory response to infection” came to the following conclusions: first. Increasingly. Predisposing factors 4 include individual characteristics.1 New concepts In the most recent International Sepsis Consensus Conference. which weights 6 variables [temperature.5 Single nucleotide polymorphisms. the TNF-2 allele.2 a suggested means of staging sepsis. ideally one for each gene in the genome. the diagnostic criteria for SIRS published in 1992 3 are too sensitive and non-specific.

categorized by microorganism and site of infection.17 Diagnosis of sepsis Sepsis represents a major diagnostic problem for the intensivist and considerable effort is being concentrated on finding a sensitive and specific diagnostic marker.. skin and soft tissue infections. CRP levels are widely used as a relatively non-specific marker of inflammation. classifying the relative importance of infections on outcome is difficult. 3 MINERVA ANESTESIOLOGICA Organ dysfunction in severe sepsis is not a simple present or not variable. this could be a useful means of better characterizing the different risks associated with infections caused by different organisms in different sites. 24 and the identification of a marker that would allow a clear diagnosis of sepsis would certainly help improve outcomes in these patients. RESPONSE The degree of host response can be assessed according to the presence or absence of various clinical and laboratory features and to the degree of elevation of. one of the most commonly used being the SOFA score. For each infection site and organism.16 The degree of organ involvement can be assessed with various scoring systems.g. but a continuous spectrum involving many organs and varying with time and treatment. while few would argue that an E. for the cell or tissue of interest. These can be used to generate an expression profile. many have been suggested 18-22 and a non-exhaustive list of proposed markers of sepsis is shown in Table II. Gram-negative versus Gram positive. severity. Cohen et al. responsible organism(s) (e. such as site (e. can have an effect on the host response and outcome.g. Using a systematic literature review and surveying 510 articles describing the outcome of infections. and may influence choice of treatment.6 Genomics and the broader field of proteomics are likely to become increasingly routinely used in patient management.15 Improving our assessment of the host response could help direct therapies more appropriately. MRSA versus MSSA). lung versus urinary tract). and the level of evidence available to support the mortality risk (level A representing evidence from more than 5 studies with more than 100 patients. CRP is an acute phase protein that was first described in the early 1930s.SEPSIS DIAGNOSIS AND MANAGEMENT VINCENT INFECTION Characteristics of the particular infection.13 M IN CO E RV PY A RI M GH E D T ORGAN DYSFUNCTION Vol. but had better outcomes than patients who developed septic shock later during their ICU stay. They suggested this system be termed the grading system for site and severity of infection (GSSSI) and although it needs to be validated. Procalcitonin (PCT) and CRP are 2 candidate markers of sepsis that have received a lot of attention.12 recently generated specific risk codes for bacteremia. CRP. A recent study showed that patients who developed septic shock within 24 h of ICU admission were more severely ill. procalcitonin (PCT) etc. Volk et al.11 However.12 The timing of onset of infection may also influence outcomes. coli urinary tract infection is likely to be less life-threatening than a meningococcal meningitis. meningitis. the transcriptome.14 The host response will vary between patients and over time in the same patient. for example.. white cell count.25-27 Concentrations above 10 mg/dL on admission have been associated with particularly ® IC ray. peritonitis. A 89 .23. 72. N. pneumonia. through to level E insufficient evidence from case reports). Studies have shown that early therapy is critical in improving outcomes from sepsis. a two-digit code was generated according to the mortality rate associated with that infection (from 1: ≤5% to 4: >30%). and urinary tract infections. described an early hyperinflammatory phase followed by immunoparalysis based on the level of HLA-DR monocyte surface expression in septic patients. and many studies have demonstrated increased CRP levels in patients with sepsis.

the presence of several features can help increase the diagnostic likelihood in a patient with a suggestive clinical picture. while declining values were associated with a more favorable prognosis.34 Hemodynamic resuscitation Another basic aspect of the management of the patient with severe sepsis or septic shock is optimal resuscitation. IL-6. however. PCT has more rapid kinetics.5 mL/kg/h. or a worsening of the peripheral capillary circulation.36 Infectious disease specialists who are familiar with local hospital and community pathogens and resistance patterns should be involved in antimicrobial selection decisions in all patients with severe sepsis. mixed venous oxygen saturation (SvO2) <70%. ® IC Management A appropriateness of antimicrobial treatment strategies. and increasing or persistently high levels indicated a poor prognosis. The rapid and accurate identification of the nature of the infection is also of critical importance. are eagerly awaited. PAF TNF-receptors IL-1 receptor antagonist. IFN-γ. and modulation of the host response. blood lactate concentration >1.33-35 yet a recent study of septic ICU patients found that in as many as 1/3 of patients the first line choice of antibiotic was inappropriate. IL-1 receptors Complement factors Endothelin-1 ICAM-1. IL-4. and a diagnosis of sepsis cannot conclusively be made on the basis of the presence of any one item. The choice of one fluid type over another and the ideal endpoint of fluid resuscitation have generated considerable debate and a discussion of these aspects is beyond the remit of this paper. and appropriate antimicrobial therapy must be started without delay. Usually the criteria for starting resuscitation include: mean arterial pressure <65 mmHg. In addition. Patients who receive appropriate antibiotics have a better outcome than those who are initially treated with an ineffective antibiotic. The results of ongoing studies into markers of sepsis. such as the The Genetic and Inflammatory Markers of Sepsis (GenIMS) study. hemodynamic resuscitation and organ support.28 PCT was described more recently as a potential marker of infection and is not yet routinely measured in many hospital laboratories. 31. IL-2.29. being produced and cleared more rapidly than CRP. Treatment of infection The source of infection must be identified wherever possible and eliminated by surgical removal of an infected focus when applicable. If the causative microorganism(s) is unknown.VINCENT SEPSIS DIAGNOSIS AND MANAGEMENT TABLE II. so may be better able to identify infection early and to follow disease progress. none of the markers currently available is specific to sepsis. IL-10. PCT may be superior to CRP in discriminating infectious from other inflammatory diseases. — — — — — — — — — — — — — — — — White blood cell count C-reactive protein Procalcitonin Endotoxin Cytokines – IL-1. 29. Marzo 2006 .—Some of the suggested markers of sepsis. and vasoactive agents when required. 30 Indeed several studies have shown that PCT levels are correlated with the severity of sepsis as measured by the APACHE II or sequential organ failure assessment scores. 32 Importantly. As an example. TNF. VCAM-1 Phospholipase A2 PGE2 Nitrates/nitrites Lactoferrin Elastase Neopterin M IN CO E RV PY A RI M GH E D T high mortality rates. IL-8. urine output <0. identifying fungal or resistant organism more rapidly would notably improve the 90 MINERVA ANESTESIOLOGICA The management of sepsis can be considered in 3 sections: treatment of infection.20. empiric antibiotics should be started based on the likely culprit and local antibiotic patterns of prevalence and resistance. essentially involving administration of sufficient fluids.5 mEq/L.

there were no other safety concerns with drotrecogin α (activated) in the PROWESS study. This study. recombinant activated protein C. With indications that the coagulation system was keenly involved in the pathogenesis of sepsis. 3 MINERVA ANESTESIOLOGICA Fluid resuscitation should be commenced as early as possible in the course of septic shock (even before ICU admission). the safety limits (e. central venous pressure not higher than 15 mmHg). drotrecogin α (activated) use is contraindicated in patients with active internal bleeding.g. 45 Children were not included in the PROWESS study.24 The results confirmed the efficacy and safety of drotrecogin α (activated). 72.43 As a result of the inherent risk of bleeding. randomized. Drotrecogin α (activated) is expensive. A fluid challenge comprises 4 components: the type of fluid to be administered (e. or severe head trauma. A further prospective study was conducted in 361 centers to confirm these findings and provide additional safety data.41 Given at a dose of 24 µg/kg of body weight/h for 96 h. N. 40 and a randomized. trauma with an increased risk of life-threatening bleeding. it has been shown to be comparable to other accepted ICU interventions. and that severe thrombocytopenia and meningitis may be risk factors for serious bleeding events in patients receiving the drug. and such decisions can be facilitated by repeated fluid challenges.42 Apart from an increased risk of bleeding. controlled.SEPSIS DIAGNOSIS AND MANAGEMENT VINCENT M IN CO E RV PY A RI M GH E D T Modulation of the host response DROTRECOGIN ALFA (ACTIVATED) The development and licensing of drotrecogin α (activated). recent hemorrhagic stroke.44. pharmacodynamic effects.g.8% in the placebo group to 24. and intracranial neoplasm or mass lesion or evidence of cerebral herniation. The Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study was a multicenter. drotrecogin α (activated) reduced mortality rates from 30. 16 patients treated. natural or artificial colloids.. suggested that results from open label studies and although drotrecogin α (activated) has the same pharmacokinetics. the spotlight fell on mediators of the coagulation pathway and their potential ability to influence sepsis outcomes. A further analysis of the safety profile of drotrecogin α (activated) in more than 6 500 patients who had received the drug in clinical trials or commercially reported that 43% of bleeding events that occurred in patients who received drotrecogin α (activated) were procedurerelated. enrolled 2 375 adult patients and treated them with the same dose of drotrecogin α (activated) as in the PROWESS study. marked a turn-up on the rather downward sloping history of anti-sepsis therapeutics. If a surgical procedure is necessary during treatment. mostly associated with invasive procedures.23 Requirements for fluid infusion may be difficult to determine. but in cost-effectiveness analyses. controlled trial involving 1 690 patients from 164 centers in 11 countries.. intracranial or intraspinal surgery.46 a phase III randomized controlled trial in children with ® IC A 91 .39. presence of an epidural catheter. in which multiple immunomodulatory agents have fallen to the wayside as one after another clinical trial failed to show that they had any beneficial effect on outcome.37.g. mean arterial pressure >70 mmHg. and safety profile in the pediatric population. Drotrecogin α (activated)-treated patients also showed significantly faster resolution of cardiovascular and respiratory dysfunction and significantly slower onset of hematological organ dysfunction than patients who received placebo. the infusion should be stopped 2 h prior to the intervention and restarted 12 h after adequate hemostasis has been obtained. heart rate <110 beats/min). which equated to one additional life saved for every Vol. 500 to 1 000 mL over 30 min). the endpoints (e. ENHANCE...g. double-blinded clinical trial comparing the 2 drugs is currently underway in Europe. the rate of fluid infusion (e. crystalloids).7% in the treatment group. The choice of vasoactive agent has also been the subject of considerable debate with conflicting opinions in particular regarding the supremacy of dopamine or norepinephrine. 38 Current guidelines recommend either drug as a first-line agent.

patients with relative adrenal insufficiency (as assessed by non-response to a corticotrophin test) were treated with hydrocortisone (50 mg i. and blocked the endotoxin-induced release of TNF. or are almost.VINCENT SEPSIS DIAGNOSIS AND MANAGEMENT M IN CO E RV PY A RI M GH E D T STEROIDS In a randomized controlled trial conducted in 19 ICUs across France and including 300 patients with septic shock.49 However.56 In a porcine model of sepsis. hazard ratio 0.51 In acute illness.55 Replacing lipoproteins may therefore represent a novel method of treating sepsis.02). in particular the 92 MINERVA ANESTESIOLOGICA severe sepsis has recently been discontinued for lack of efficacy. noted that intensive insulin therapy also increases HDL and LDL levels and multivariate analysis suggested that it was this change in lipid levels.g. Drotrecogin α (activated) is currently licensed for use in adult patients with severe sepsis and a high risk of mortality (e. Here we will briefly mention just some of the many agents under research. every 6 h) and fludrocortisone (50 µg per os daily) or placebo for 7 days. Once in the circulation. high density lipoproteins (HDL). This decision is supported by the recent Administration of Drotrecogin alfa [activated] in Early Severe Sepsis (ADDRESS) study that failed to show effectiveness of drotrecogin α (activated) in patients with less severe disease. At present. A further study from Van den Berghe et al. with longer courses (>5 days) of lower dose corticosteroids (≤300 mg hydrocortisone or equivalent).1 mmol/L improved outcomes predominantly by reducing deaths from sepsis-induced multiple organ failure.54 The incidence of nosocomial infections was also reduced. an emulsion ® IC mechanisms of cell-to-cell signaling and the importance of apoptosis.50 Nevertheless. studies have indicated that steroids can increase the response to adrenergic agents. and apolipoprotein A. as assessed by the APACHE II score). Indeed. LPS can also form complexes with serum lipoproteins.47-0. The future As our understanding of the pathophysiology of sepsis improves. at the clinical trial stage. steroid use in sepsis should be administered only in the presence of shock. including low density lipoproteins (LDL). mortality at 28 days and hospital mortality were reduced. endotoxin binds to LPS binding protein (LBP).49 Another meta-analysis reached similar conclusions.. some questions remain unanswered. The LPS-LPB complex can also interact with soluble CD14 and this can then interact with another receptor on the endothelial cell. Recent studies have indicated that intensive insulin therapy to maintain blood glucose levels less than 6. focusing on those that are. Interestingly. Experimental studies in human volunteers and animal models did indeed show that HDL reduced flu-like symptoms during endotoxemia. 53 this reducing LPS clearance.95. Treated patients had a reduced mortality compared to non-responders treated with placebo (53% vs 63%. or enhance hemodynamic support. IL-6 and IL-8. overall use of corticosteroids did not significantly affect mortality.v. lipoprotein levels are reduced. A Marzo 2006 . rather than an effect on glucose levels. which itself lacks surface CD14. that contributed to the beneficial effects of this approach on mortality and morbidity.52. 95% CI 0. P=0.48 In a recent meta-analysis of randomized studies in patients with severe sepsis or septic shock treated with corticosteroids. including the optimal test for adrenal insufficiency and whether the results can be extrapolated to patients with severe sepsis not in shock. which provide a means of eliminating LPS from the circulation. It is not entirely clear whether steroids treat sepsis per se. HDL administration also reduced CD14 expression on monocytes.67. more potential therapeutic targets become apparent. LPS) is a component of the Gram-negative bacterial cell wall and is a key initiator of sepsis. New anti-endotoxin agents Endotoxin (lipopolysaccharide. and the LPS-LPB complex interacts with CD14 on the surface of monocytes and macrophages resulting in cellular activation.

63 and correlate with outcome.59 and lipid A analogs. Early diagnosis is vital in improving outcomes and development of more effective markers of sepsis will help in allowing treatments to be instituted as early as possible in the disease process. HMGB1 induces the activation of transcription factors and the release of pro-inflammatory mediators by monocytes and endothelial cells. Sepsis treatment must be seen as a package. and the success of drotrecogin α (activated) has given new impetus to the search for effective diagnostic and therapeutic strategies in patients with sepsis. It is unlikely that one agent will ever be discovered to cure all patients with sepsis. in patients the onset is often difficult to define and many patients will be diagnosed relatively late. Attempts to characterize patients. treatment protocols must be adapted accordingly. 66 In animal models of sepsis. 70 However.57 A clinical trial with this phospholipid emulsion is ongoing. and at present hemofiltration is not recommended unless there is co-existing renal failure. and the package contents varying with time in the same patient. and other immunomodulatory strategies as they become available. even when given late after sepsis induction. N. macrophage migration inhibitory factor (MIF) induces the production of various pro-inflammatory mediators. However. such as the PIRO system. improved survival and reduced sepsis-induced organ injury. 3 MINERVA ANESTESIOLOGICA of phospholipid. lowered serum endotoxin and TNF-α levels significantly. also improved survival in a mouse model of sepsis. and is released from endotoxin-stimulated macrophages some 8-12 h after the release of the early cytokines.SEPSIS DIAGNOSIS AND MANAGEMENT VINCENT M IN CO E RV PY A RI M GH E D T Macrophage migration inhibitory factor (MIF) By modulating the expression of TLR4.39 Severe sepsis and septic shock are still associated with high mortality rates. this strategy could improve outcomes. and attenuated increases in systemic and pulmonary vascular resistances. preserved cardiac output and ejection fraction.60 rationale that by removing inflammatory mediators. very much a work in progress. which inhibits HMGB1 production in vivo. making the longer time-frame of HMGB1 of particular interest as it may be effective even when targeted later in the sepsis process. but must now be combined with drotrecogin alfa (activated) if there is no contraindication.65. ® IC Conclusions A 93 . and as new interventions undergo clinical testing. with different patients requiring different packages. hemoperfusion per se removes all mediators both good and bad and may not be beneficial in all patients at all times.58 extracorporeal endotoxin absorption. Other anti-endotoxin strategies currently undergoing clinical testing include anti-CD14 antibodies. the signal-transducing molecule in the LPS receptor complex.63 and animal studies have demonstrated improved survival with MIF neutralization. This is a rapidly moving field. 72.62. 64 High-mobility group B-1 protein High-mobility group B-1 protein (HMGB1) acts as a late mediator of systemic inflammation. will help in identifying which therapies are best given to which patients and when. further study is needed to determine which technique may be most beneficial.61 MIF levels are raised in patients with sepsis 62. Hemoperfusion strategies Blood purification systems have been proposed for the treatment of sepsis based on the Vol.67 Ethyl pyruvate. the predominant lipid in HDL. Appropriate infection control strategies and adequate haemodynamic stabilization remain essential. but progress is being made. Some studies have suggested that coupled plasma filtration adsorption (CPFA) improves blood pressure and restores immune function in patients with septic shock 69. and one chemotherapy drug is not active against all cancers. just as one antibiotic cannot treat all infections.68 Unlike many animal models when the onset of sepsis is determined artificially. anti-HMGB1 antibodies.

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