Clinical Sepsis and Septic Shock

CURRENT CONCEPTS IN CLINICAL SURGERY

Clinical sepsis and septic shock—definition, diagnosisand management principles

Jean-Louis Vincent

Received: 16 April 2008 /Accepted: 18 April 2008 /Published online: 27 June 2008# Springer-Verlag 2008

AbstractIntroduction Sepsis remains a common problem in criticallyill patients.Discussion Considerable advances have been made in ourunderstanding of the pathophysiology of sepsis and recentyears have seen a surge of potential new therapeutic agentsfor sepsis. Definitions have been rethought and strategiesproposed to better characterise patients with sepsis as theimportance of individually targeted treatment packages hasbeen realised. Current management aims to control infec-tion, to achieve haemodynamic stabilisation, to modulatethe immune response and to provide metabolic and organsupport. As new therapies are introduced, treatment re-commendations will need to be adapted accordingly.

Keywords Biomarkers . Severe sepsis . Critically ill .

Vasopressors . Immunomodulation

Introduction

Sepsis is a common event with an estimated 751,000 cases ofsevere sepsis occurring annually in the USA [1]. In Europe,the large observational Sepsis Occurrence in Acutely IllPatients (SOAP) study documented that about 30% of patientsadmitted to an intensive care unit (ICU) had severe sepsis atsome point during their ICU stay [2]. Padkin et al. similarlyreported that 27% of adult ICU patients in the UK met severesepsis criteria in the first 24 h of ICU admission [3]. Otherstudies in individual countries have generally reported slightly

lower rates of severe sepsis, ranging from 8% in Slovakia to17% in Brazil [4–10], but many of these have includedpatients admitted for routine post-operative surveillance whohave much lower rates of sepsis. Direct comparison of theserates is also difficult due to different study design anddefinitions and different admission and discharge criteriaamong units; nevertheless, severe sepsis remains a commonevent on the ICU. Sepsis is associated with considerable riskof death with the SOAP study [2] reporting ICU mortalityrates of 27% for patients with sepsis, increasing to 32% and54% for patients with severe sepsis and septic shock,respectively. Importantly, although there is some evidencethat the mortality rate of patients with sepsis has decreasedslightly in recent years, the incidence of sepsis and, hence, thenumber of sepsis-related deaths is increasing [11, 12].

Definitions

Many terms have been used to define “sepsis” sinceSchottmueller first established a link between the presence ofpathogenic germs into the bloodstream and the development ofsystemic symptoms and signs [13]. However, the ofteninterchangeable use of terms, such as infection, septicaemia,bacteraemia, sepsis syndrome etc., has led to some confusion,although if the basic, relatively straightforward concept ofsepsis is remembered—sepsis is the host response to infection—the associated terminology can also be relatively simple.

The 1991 North American Consensus Conference concept ofsystemic inflammatory response syndrome (SIRS) [14] is nowconsidered outdated and the four SIRS criteria (temperature>38°C or <36°C; heart rate >90 beats per minute; respiratoryrate >20 breaths per minute or PCO2 <32 mmHg; white bloodcell count <12×109/l or <4.0×109/l) have been expanded to alonger list of possible signs of sepsis in the latest definitions

Langenbecks Arch Surg (2008) 393:817–824DOI 10.1007/s00423-008-0343-1

J.-L. Vincent (*)Department of Intensive Care, Erasme University Hospital,Université libre de Bruxelles, Route de Lennik 808,B-1070 Brussels, Belgiume-mail: [email protected]

(Box 1) [15], which were developed in 2001 during a consensusconference of 29 international experts in the field of sepsis,under the auspices of the Society of Critical Care Medicine,the European Society of Intensive Care Medicine, the AmericanCollege of Chest Physicians and the Surgical Infection Societies.

The current definitions of sepsis are, therefore:

& Infection—a pathologic process caused by the invasionof normally sterile tissue or fluid or body cavity bypathogenic or potentially pathogenic microorganisms

& Sepsis—the clinical syndrome defined by the presenceof both infection and a systemic inflammatory response

& Severe sepsis—sepsis complicated by organ dysfunction& Septic shock—severe sepsis plus a state of acute circu-

latory failure characterised by persistent arterial hypo-tension (defined as a systolic arterial pressure below 90mmHg, a mean arterial pressure <60 mmHg or areduction in systolic blood pressure of >40 mmHg frombaseline) unexplained by other causes and despiteadequate volume resuscitation.

Diagnosis

Diagnosing infection, and hence sepsis, in the ICU patientis often difficult because of the frequently multiple andcomplex underlying disease processes present in such

patients, and the likelihood that the patient is alreadyreceiving or has recently received at least one antimicrobialagent rendering culture-based diagnosis of infection moredifficult. The list of signs of sepsis suggested by the 2001Sepsis Definitions Conference [15] are a useful guide todiagnosis and when present without any other possible ex-planation should increase suspicion of sepsis. However,none of the signs is specific for sepsis on its own. Forexample, fever in the ICU patient can have many causes,both infectious and non-infectious [16]; a raised whiteblood cell count can be found in many inflammatory pro-cesses; lactic acidosis is often compensated for by hyper-ventilation, so that tachypnoea is not specific for sepsis;tachycardia can be the result of circulatory alterationsassociated with any type of shock, not just septic shock.

General signs and symptoms

Rigours, fever (sometimes hypothermia)

Tachypnoea/respiratory alkalosis

Positive fluid balance, oedema

Generalised haematological/inflammatory reaction

Increased (sometimes decreased) white blood cell count

Increased inflammatory markers (C-reactive protein, procalcitonin, interleukin-6)

Haemodynamic alterations

Arterial hypotension

Unexplained tachycardia

Increased cardiac output/low systemic vascular resistance/high SvO2

Altered skin perfusion

Decreased urine output

Unexplained hyperlactataemia/increased base deficit

Signs of organ dysfunction

Hypoxaemia (acute lung injury)

Altered mental status

Unexplained alteration in renal function

Hyperglycaemia

Thrombocytopaenia/disseminated intravascular coagulation

Unexplained alteration in liver function tests (hyperbilirubinaemia)

Intolerance to feeding (altered gastrointestinal motility)

Box 1. Some signs of sepsis [15]

818 Langenbecks Arch Surg (2008) 393:817–824

Diagnosis must thus rely on a strong clinical suspicionsupported by the combined presence of several of the signsof sepsis.

With difficulties in diagnosis and an increasing realisa-tion of the importance of early resuscitation and therapy onoutcomes from severe sepsis [17–19], attempts have beenmade to identify a marker of sepsis, which could be used torapidly determine or rule out the diagnosis, and to followthe course of the disease as, for example, cardiac troponinsand creatine kinase are used to diagnose acute myocardialinfarction. The ideal marker of infection should be sensitiveenough to detect the presence of infection in patients withminimal or even no host response, specific enough todiscriminate infection from other stimuli that may induce asystemic inflammatory response, should be present early inthe course of the disease, should be rapidly and conve-niently measured and should be of prognostic significance[20]. Potential candidates for this role have included acutephase proteins, e.g. C-reactive protein or procalcitonin [21,22]; cytokines, e.g. interleukin (IL)-6, IL-8, IL-10 [23–26];endotoxin levels [27]; and a biphasic activated partialthromboplastin time waveform [28, 29] to mention just afew. However, although many of these individual markershave shown merit, none fits all the criteria for an “ideal”marker and a combination of markers may be more useful.Zakariah et al. recently suggested that the combination ofpresence of a biphasic aPTT waveform and raised procalci-tonin levels had increased specificity compared to eithermarker alone [30]. Peres Bota et al. proposed an infectionprobability score (IPS) that combines several simple andcommonly measured variables (body temperature, heartrate, respiratory rate, white blood cell count, C-reactiveprotein and sequential organ failure assessment score) topredict the likelihood of infection [31]. In a recentprospective study, using an IPS cut-off of 14, the IPS hada positive predictive value of 80% and a negative predictivevalue of 86%, supporting its potential role in the diagnosisof infection [32].

In the future, the development of proteomic, genomicand microarray techniques, which combine numerousfactors in one test, will enable physicians to diagnosisinfection and sepsis from a single blood sample. Based onmultiple inflammatory and infection markers, the patient’scurrent pro-/anti-inflammatory balance, the presence ofgenetic factors that may impact on the likelihood ofdeveloping sepsis and potentially other factors, couldgenerate an individualised pattern that would provide thephysician with the likelihood of infection in that patient[33–35]. Repeated sampling could help monitor responseto therapy and guide ongoing therapeutic decision making[36]. Considerable work remains to identify exactly whichmediators and markers should be included in these arraysand to create adequate computational bioinformatics that

will enable rapid and accurate interpretation of the largeamounts of information generated so that this approach canbe used where it is most needed, at the patient’s bedside[37].

Management

In addition to basic standard of care and individual organsupport, the management of the patient with severe sepsisessentially comprises four key factors: infection control,haemodynamic support, immunomodulatory interventionsand metabolic/endocrine support. For clarity, we willdiscuss these four components separately, although, inreality, the various parts are often instituted simultaneously.

Infection control

Control of infection relies on two components: removal ofan infected focus and appropriate antimicrobial therapy.

& Any infected focus must be identified by repeatedclinical examination and available imaging techniquesand removed, with surgical intervention, when neces-sary. The ‘big five’ of sepsis should be rememberedwhen trying to identify a source, with the searchinitially focusing on the lungs, abdomen, urine, woundsand catheters. Simple factors such as removing apotentially infected catheter should not be forgotten inthe rush to resuscitate the patient with severe sepsis.

& Appropriate antimicrobial therapy. All appropriatecultures (blood, urine, wound fluid, cerebrospinal fluid,respiratory secretions, ascitic fluid etc., as indicated)should be taken before antimicrobial therapy is started,remembering, however, that a delay in initiation ofantimicrobial therapy is associated with worse out-comes. Kumar et al. [19] reported that only 50% ofpatients received effective antimicrobial treatment with-in 6 h of documented hypotension in patients withseptic shock, but those who received effective antimi-crobial therapy within the first hour of documentedhypotension had increased survival rates. The latestguidelines recommend that intravenous antibiotic ther-apy be started as early as possible and within the firsthour of recognition of septic shock [38].The causative microorganism(s) is often difficult toidentify and no organism will be isolated in as manyas 40% of ICU patients with sepsis [2, 39]. Empiricantibiotics should be started with a spectrum coveringany likely infectious agents as determined by the likelysource(s) in that patient and local patterns of microor-ganism prevalence and antimicrobial resistance. Thechoice of empiric antimicrobial agent is vitally

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important as patients who receive appropriate anti-biotics have better outcomes than patients who receiveinitially ineffective antibiotics [40–42]. Making thecorrect choice of empiric agent(s) is not always easyand infectious disease specialists should be involved inantimicrobial selection decisions whenever possible[43]. Once started, antimicrobial drugs should becontinued for 7–10 days with longer courses consid-ered in patients who have a slow clinical response orimmunological deficiencies, including neutropaenia[38]. In the future, biomarkers of infection may beused to determine the need for continued antibiotictherapy.

Haemodynamic stabilisation and support

One of the most important facets concerning haemody-namic resuscitation is that it should be initiated as soon aspossible. Rivers et al. [17] reported that early goal-directedresuscitation (with fluids, transfusion and vasoactive agentsgiven according to protocol to achieve a central venouspressure (CVP) of 8–12 mmHg, a mean arterial pressurebetween 65–90 mmHg and a central venous oxygensaturation of at least 70%) in patients with septic shock inthe emergency room before admission to the ICU wasassociated with improved outcomes compared to patientswho received standard treatment, stressing the importanceof early effective resuscitation.

Haemodynamic stabilisation can essentially be separatedinto two key components: administration of fluids (includ-ing blood) and use of vasoactive agents.

1. Fluid administration. There is no evidence to supportone type of fluid over another and fluid resuscitationcan be achieved with either colloid or crystalloid, or inpractice generally a combination of the two. Thequantity of fluid is perhaps more important than thetype. Fluid resuscitation should be performed accordingto a fluid challenge technique, and fluids alone aresometimes sufficient to restore haemodynamic stability.When performing a fluid challenge, four factors mustbe considered: the type of fluid to be administered (e.g.colloid or crystalloid), the rate of fluid administration(e.g. 500–1,000 ml over 30 min), the critical end pointsto be achieved (e.g. mean arterial pressure >70 mmHg,heart rate <110 beats/min) and the safety limits (e.g.CVP <15 mmHg) [44]. Repeated fluid challengesshould be performed to assess ongoing requirementsfor fluids.Optimal “transfusion triggers” in critically ill patientsremain unclear and may vary among patients and even

in individual patients overtime. The “early goal-directed therapy” suggested by Rivers et al. used atarget haematocrit of 30% [17], but some recommendthat, outside the initial 6-h period after diagnosis, redblood cell transfusion should be given when haemo-globin decreases to <7.0g/dl to target a haemoglobin of7.0–9.0g/dl (70–90g/l) in adults [38]. However, there issome suggestion that transfusion thresholds can be re-evaluated towards higher levels [45]. There is anongoing multicentre European study comparing a bloodtransfusion strategy to maintain haemoglobin con-centrations above 9g/dl with one maintaining theconcentration between 7–9g/dl. Until further data areavailable, the need for blood transfusion should becarefully assessed in terms of risks and benefits foreach patient. For example, the benefits of transfusingan older patient with a history of ischaemic heartdisease may be greater than the risks and a relativelyliberal approach to transfusion may be warranted,while in a younger, previously healthy, patient, risksmay outweigh the benefits and transfusions could berestricted [46].

2. Vasoactive agents. Vasopressor therapy is often neededto maintain perfusion in patients with septic shock andis frequently started early, even before hypovolaemiahas been fully corrected. The debate as to whichvasoactive agent is best for patients with severe sepsisand septic shock continues and with no consistentevidence for or against individual drugs, currentchoices largely come down to personal preference.Dopamine and norepinephrine are generally acceptedas first-choice agents with epinephrine being reservedfor patients who do not response to maximum doses ofthese agents [38, 47]. In patients with refractory shockdespite adequate fluid resuscitation and high-doseconventional vasopressors, use of low doses of vaso-pressin (infusion rates of 0.01–0.04U/min) may beconsidered [38]. Vasopressin has little pressor effect innormal subjects [48], but in patients with septic shock,who have inappropriately low plasma vasopressin concen-trations [49], low doses have been shown to increasemean arterial pressure and allow a reduction in require-ments of other vasopressors [50–53]. Dobutamine isgenerally recommended as the inotropic agent ofchoice in patients with sepsis-associated myocardialdysfunction and is frequently also used in combinationwith dopamine or norepinephrine.Which endpoints should be targeted for vasoactivetherapy remain unclear, but normalisation of globalhaemodynamic parameters does not necessarily indi-


cate that tissue perfusion and oxygenation are adequate[54, 55]. Nevertheless, until we have better means ofmeasuring and monitoring tissue oxygenation, ongoingvasoactive therapy must be based on clinical responseand global haemodynamic and oxygenation parameters,including mixed venous oxygen saturation and bloodlactate levels.

Immunomodulatory therapies

Drotrecogin alfa (activated )

Only one immunomodulatory drug, drotrecogin alfa (acti-vated), has been demonstrated to improve outcomes inpatients with severe sepsis and a high risk of death [39].Later studies reported that drotrecogin alfa (activated) is noteffective in patients with a low risk of death [56] or inpaediatric patients [57]. Administration of drotrecogin alfa(activated) is associated with an increased risk of bleedingand is expensive. Since the initial Recombinant HumanActivated Protein C Worldwide Evaluation in Severe Sepsis(PROWESS) study results [39], intensivists have been splitregarding the risk/benefit ratio of this agent and the subjecthas generated heated debate and argument. As a result, thelatest Surviving Sepsis Campaign guidelines [38] onlysuggest (rather than making a clear recommendation) thatdrotrecogin alfa (activated) be used in patients with severesepsis, a high risk of death and no contraindications (activeinternal bleeding; recent haemorrhagic stroke, intracranialor intraspinal surgery or severe head trauma; trauma withan increased risk of life-threatening bleeding; presence ofan epidural catheter; and intracranial neoplasm or masslesion or evidence of cerebral herniation). In addition, apost hoc analysis of a subgroup of patients who hadundergone recent surgery (i.e. within 30 days beforeenrolment) and had single-organ dysfunction indicated thatthe patients in this subgroup who received drotrecogin alfa(activated) had higher 28-day mortality rates than did thepatients in this group who received placebo (20.7% vs.14.1%, p=0.03). In response to these results and furtheranalysis of the PROWESS data which suggested a lesserefficacy in surgical patients, an additional warning wasintroduced to the prescribing information for drotrecoginalfa (activated), stating that the drug should not be used inpatients with recent surgery and single organ dysfunction.In view of the continuing controversy surrounding thisdrug, the European Medicines Agency mandated that EliLilly conduct a new multicentre, randomised, placebo-controlled trial of drotrecogin alfa (activated) in thecurrently indicated population with 28-day mortality asthe primary outcome measure.

Metabolic Support

Corticosteroids

The use of corticosteroids in patients with severe sepsis hasalso been a subject of controversy in recent years. In arandomised controlled trial of 300 patients with septicshock, those with relative adrenal insufficiency (as assessedby non-response to the corticotrophin test) who weretreated with hydrocortisone (50 mg intravenously every6 h) and fludrocortisone (50 μg per os daily) for 7 days hada reduced mortality compared to non-responders treatedwith placebo (53% vs. 63%, hazard ratio 0.67, 95%confidence interval 0.47–0.95, p=0.02) [58]. In the recentCorticosteroid Therapy of Septic Shock study [59], how-ever, which included 499 patients with septic shock andrandomised them to receive 50 mg of intravenous hydro-cortisone or placebo every 6 h for 5 days with a taperingdose over the subsequent 6 days, there was no significanteffect of hydrocortisone on the rate of death in patients withseptic shock at 28 days, regardless of the patients’ adrenalresponsiveness to corticotropin. Patients treated withhydrocortisone did seem to have faster resolution of shock.It is therefore suggested that hydrocortisone be given onlyto adult septic shock patients after it has been confirmedthat their blood pressure is poorly responsive to fluidresuscitation and vasopressor therapy [38].

Tight glucose control

Tight glucose control may result in improved survival rates[60], but although tight control of blood sugar would appearto be a relatively simple and inexpensive strategy, it is in factquite difficult to implement. In particular, the risk of hypo-glycaemia cannot be neglected. A recent multicentre study inGermany comparing intensive insulin therapy to maintaineuglycaemia with conventional insulin therapy was stoppedearly because the intensive insulin protocol was associatedwith a higher rate of severe hypoglycaemia and of seriousadverse events [61]. A reasonable recommendation is to giveinsulin by a validated protocol to achieve glucose levels at<150 mg/dl [38], pending the results of a large Australasian–Canadian study (Normoglycaemia in Intensive Care Eval-uation and Survival Using Glucose Algorithm Regulation,www.clinicaltrials.gov identifier NCT00220987).

Nutritional support

Nutritional support is important in all critically illpatients. Immunonutrition, in which enteral feeds aresupplemented with various immune-enhancing agentsincluding arginine, mRNA and omega-3 fatty acids,


http://www.clinicaltrials.gov

may have beneficial effects by improving host response[62]. However, not all clinical trials have supported thisfinding [63] and the administration of arginine mayactually result in worse outcomes [64]. Glutamine supple-mentation is more likely to improve outcomes. Theoptimal composition of immune-enhanced feeds in septicpatients needs to be studied further before any clearrecommendations can be made.

Management principles

The approach to management can be broadly divided intofactors that should form part of initial resuscitation of thepatient with severe sepsis and be completed as soon aspossible after diagnosis and components that can beperformed after the initial resuscitation, although shouldstill not be unnecessarily delayed (Box 2). A recent studyhas suggested that earlier implementation of some of thecomponents of later management may be associated withimproved survival [65]. Importantly, as the evidence basechanges with results from new studies and guidelines areupdated, management principles or checklists will need tobe adapted accordingly.

Conclusion

The impact of severe sepsis is high, but progress is beingmade in early diagnosis, classification and therapy. Phys-icians must be keenly aware of the possibility of sepsis as adiagnosis and alert to the various indicative signs and symp-toms. Early diagnosis will become easier as biochemical andgenetic markers become more clearly defined. Rapid in-

stitution of appropriate infection control strategies, haemo-dynamic stabilisation protocols and immunomodulatorystrategies where appropriate can improve outcomes. As ourunderstanding of the pathophysiology of sepsis continues toexpand, other immunomodulatory strategies will undoubt-edly be developed and will need to be incorporated intocurrent management protocols.

References

1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, CarcilloJ, Pinsky MR (2001) Epidemiology of severe sepsis in the UnitedStates: analysis of incidence, outcome, and associated costs ofcare. Crit Care Med 29:1303–1310

Initial resuscitation:• Take relevant cultures (including blood cultures) prior to antibiotic administration• Administer broad-spectrum antibiotics (likely to cover the incriminated pathogens)

as soon as possible• Control the source of sepsis as soon as possible• Measure serum lactate concentrations• Fluid challenge (initially with crystalloids) with predefined goals and limits• Administer vasopressors for hypotension not responding to fluids to maintain the

minimal arterial pressure compatible with adequate tissue perfusion• Consider maintaining central venous oxygen saturation > 70% or mixed venous

oxygen saturation > 65 %

Further resuscitation:• Add dobutamine if perfusion remains inadequate – doses of 5 (to 10) mcg/kg/min

are usually sufficient• Consider albumin infusion if further fluids are required in hypoalbuminaemic

patients• Give drotrecogin alfa (activated) in severe cases unless there is excessive risk of

bleeding• Consider hydrocortisone (50 mg qid) in severe septic shock but only for the

duration of shock • Consider vasopressin administration in shock states (doses of 0.03-0.04 U/min)• If receiving mechanical ventilation, avoid large tidal volumes and high airway

pressures• Maintain blood glucose < 150 mg/dL with a continuous insulin drip

Box 2.


2. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, GerlachH, Moreno R, Carlet J, Le Gall JR, Payen D (2006) Sepsis inEuropean intensive care units: results of the SOAP study. CritCare Med 34:344–353

3. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K(2003) Epidemiology of severe sepsis occurring in the first 24hrsin intensive care units in England, Wales, and Northern Ireland.Crit Care Med 31:2332–2338

4. Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, Fang Q, Xu Q,Wang D, Jin Y, Yuan S, Wang J, Du Z, Sun Y, Fang X (2007)Epidemiology of severe sepsis in critically ill surgical patientsin ten university hospitals in China. Crit Care Med 35:2538–2546

5. Zahorec R, Firment J, Strakova J, Mikula J, Malik P, Novak I,Zeman J, Chlebo P (2005) Epidemiology of severe sepsis inintensive care units in the Slovak Republic. Infection 33:122–128

6. Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J (2004)Adult-population incidence of severe sepsis in Australian and NewZealand intensive care units. Intensive Care Med 30: 589–596

7. Brun-Buisson C, Meshaka P, Pinton P, Vallet B (2004)EPISEPSIS: a reappraisal of the epidemiology and outcomeof severe sepsis in French intensive care units. Intensive CareMed 30:580–588

8. Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H,Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K,Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F,Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K(2007) Epidemiology of sepsis in Germany: results from a nationalprospective multicenter study. Intensive Care Med 33:606–618

9. Silva E, Pedro MA, Sogayar AC, Mohovic T, Silva CL,Janiszewski M, Cal RG, de Sousa EF, Abe TP, de Andrade J,de Matos JD, Rezende E, Assuncao M, Avezum A, Rocha PC,de Matos GF, Bento AM, Correa AD, Vieira PC, Knobel E (2004)Brazilian Sepsis Epidemiological Study (BASES study). Crit Care8:R251–R260

10. Karlsson S, Varpula M, Ruokonen E, Pettila V, Parviainen I,Ala-Kokko TI, Kolho E, Rintala EM (2007) Incidence, treatment,and outcome of severe sepsis in ICU-treated adults in Finland: theFinnsepsis study. Intensive Care Med 33:435–443

11. Martin GS, Mannino DM, Eaton S, Moss M (2003) Theepidemiology of sepsis in the United States from 1979 through2000. N Engl J Med 348:1546–1554

12. Harrison DA, Welch CA, Eddleston JM (2006) The epidemiologyof severe sepsis in England, Wales and Northern Ireland, 1996 to2004: secondary analysis of a high quality clinical database, theICNARC Case Mix Programme Database. Crit Care 10:R42

13. Schottmueller H (1914) Wesen und Behandlung der Sepsis. InnMed 31:257–280

14. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, KnausWA, Schein RM, Sibbald WJ (1992) Definition for sepsis andorgan failure and guidelines for the use of innovative therapies insepsis. Chest 101:1644–1655

15. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D,Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions confer-ence. Intensive Care Med 29:530–538

16. Circiumaru B, Baldock G, Cohen J (1999) A prospective study offever in the intensive care unit. Intensive Care Med 25:668–673

17. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B,Peterson E, Tomlanovich M (2001) Early goal-directed therapy inthe treatment of severe sepsis and septic shock. N Engl J Med345:1368–1377

18. Vincent JL, Bernard GR, Beale R, Doig C, Putensen C, DhainautJF, Artigas A, Fumagalli R, Macias W, Wright T, Wong K, SundinDP, Turlo MA, Janes JM (2005) Drotrecogin alfa (activated)

treatment in severe sepsis from the global open-label trialENHANCE. Crit Care Med 33:2266–2277

19. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, SharmaS, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D,Kumar A, Cheang M (2006) Duration of hypotension beforeinitiation of effective antimicrobial therapy is the criticaldeterminant of survival in human septic shock. Crit Care Med34:1589–1596

20. Chan YL, Tseng CP, Tsay PK, Chang SS, Chiu TF, Chen JC (2004)Procalcitonin as a marker of bacterial infection in the emergencydepartment: an observational study. Crit Care 8:R12–R20

21. Lobo SM, Lobo FR, Bota DP, Lopes-Ferreira F, Soliman HM, MelotC, Vincent JL (2003) C-reactive protein levels correlate with mortalityand organ failure in critically ill patients. Chest 123:2043–2049

22. Ugarte H, Silva E, Mercan D, de Mendonça A, Vincent JL (1999)Procalcitonin as a marker of infection in the intensive care unit.Crit Care Med 27:498–504

23. Damas P, Ledoux D, Nys M, Vrindts Y, DeGroote D, FranchimontP, Lamy M (1992) Cytokines serum levels during severe sepsis inhuman IL6 as a marker of severity. Ann Surg 215:356–362

24. Casey LC, Balk RA, Bone RC (1993) Plasma cytokine andendotoxin levels correlate with survival in patients with the sepsissyndrome. Ann Intern Med 119:771–778

25. Pinsky MR, Vincent JL, Deviere J, Alegre M, Schandene L, KahnRJ, Vandenbussche P, Content J, Dupont E (1993) Serum cytokinelevels in human septic shock: relation to multiple-systems organfailure and mortality. Chest 103:565–575

26. Friedman G, Jankowski S, Marchant A, Goldman M, Kahn RJ,Vincent JL (1997) Blood interleukin-10 levels parallel the severityof septic shock. J Crit Care 12:183–187

27. Marshall JC, Foster D, Vincent JL, Cook DJ, Cohen J, DellingerRP, Opal S, Abraham E, Brett SJ, Smith T, Mehta S, Derzko A,Romaschin A (2004) Diagnostic and prognostic implicationsof endotoxemia in critical illness: results of the MEDIC study.J Infect Dis 190:527–534

28. Toh CH, Ticknor LO, Downey C, Giles AR, Paton RC, Wenstone R(2003) Early identification of sepsis and mortality risks throughsimple, rapid clot-waveform analysis. Implications of lipoprotein-complexedC reactive protein formation. Intensive CareMed 29:55–61

29. Dempfle CE, Lorenz S, Smolinski M, Wurst M, West S, Houdijk WP,Quintel M, Borggrefe M (2004) Utility of activated partial throm-boplastin time waveform analysis for identification of sepsis and overtdisseminated intravascular coagulation in patients admitted to asurgical intensive care unit. Crit Care Med 32: 520–524

30. Zakariah AN, Cozzi SM, Van Nuffelen M, Clausi CM, Pradier O,Vincent JL (2008) Combination of biphasic transmittance wave-form with blood procalcitonin levels for diagnosis of sepsis inacutely ill patients. Crit Care Med 36(5):1507–1512

31. Peres-Bota D, Melot C, Lopes Ferreira F, Vincent JL (2003)Infection probability score (IPS): a simple method to help assessthe probability of infection in critically patients. Crit Care Med31:2579–2584

32. Martini A, Gottin L, Mélot C, Vincent JL (2008) A prospectiveevaluation of the infection probability score (IPS) in the intensivecare unit. J Infect 56:313–318

33. Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, ChoRJ, Chen RO, Brownstein BH, Cobb JP, Tschoeke SK, Miller-Graziano C, Moldawer LL, Mindrinos MN, Davis RW, TompkinsRG, Lowry SF (2005) A network-based analysis of systemicinflammation in humans. Nature 437:1032–1037

34. Johnson SB, Lissauer M, Bochicchio GV, Moore R, Cross AS,Scalea TM (2007) Gene expression profiles differentiate betweensterile SIRS and early sepsis. Ann Surg 245:611–621

35. Lissauer ME, Johnson SB, Siuzdak G, Bochicchio G, WhitefordC, Nussbaumer B, Moore R, Scalea TM (2007) Coagulation and


complement protein differences between septic and uninfectedsystemic inflammatory response syndrome patients. J Trauma62:1082–1094

36. Carrigan SD, Scott G, Tabrizian M (2004) Toward resolving thechallenges of sepsis diagnosis. Clin Chem 50:1301–1314

37. Abraham E (2005) Immunological monitoring, functionalgenomics and proteomics. In: Fink MP, Sibbald WJ, Suter PM(eds) Intensive Care Medicine in 10 Years. Springer, Heidelberg,pp 189–200

38. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, JaeschkeR, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T,Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, RanieriM, Ramsay G, Sevransky J, Thompson BT, Townsend S, VenderJS, Zimmerman JL, Vincent JL (2008) Surviving sepsis campaign:international guidelines for management of severe sepsis andseptic shock: 2008. Intensive Care Med 34:17–60

39. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF,Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD,Ely EW, Fisher CJ Jr. (2001) Efficacy and safety of recombinanthuman activated protein C for severe sepsis. N Engl J Med344:699–709

40. Leone M, Bourgoin A, Cambon S, Dubuc M, Albanese J, MartinC (2003) Empirical antimicrobial therapy of septic shock patients:adequacy and impact on the outcome. Crit Care Med 31:462–467

41. Valles J, Rello J, Ochagavia A, Garnacho J, Alcala MA (2003)Community-acquired bloodstream infection in critically ill adultpatients: impact of shock and inappropriate antibiotic therapy onsurvival. Chest 123:1615–1624

42. Garnacho-Montero J, Ortiz-Leyba C, Herrera-Melero I, Aldabo-Pallas T, Cayuela-Dominguez A, Marquez-Vacaro JA, Carbajal-Guerrero J, Garcia-Garmendia JL (2008) Mortality and morbidityattributable to inadequate empirical antimicrobial therapy inpatients admitted to the ICU with sepsis: a matched cohort study.J Antimicrob Chemother 61:436–441

43. Byl B, Clevenbergh P, Jacobs F, Struelens MJ, Zech F, Kentos A,Thys JP (1999) Impact of infectious diseases specialists and micro-biological data on the appropriateness of antimicrobial therapyforbacteremia. Clin Infect Dis 29:60–66

44. Vincent JL, Weil MH (2006) Fluid challenge revisited. Crit CareMed 34:1333–1337

45. Vincent JL, Sakr Y, Sprung CL, Harboe S, Damas P (2008) Areblood transfusions associated with greater mortality rates. Anes-thesiology 108:31–39

46. Deans KJ, Minneci PC, Suffredini AF, Danner RL, Hoffman WD,Ciu X, Klein HG, Schechter AN, Banks SM, Eichacker PQ,Natanson C (2007) Randomization in clinical trials of titratedtherapies: unintended consequences of using fixed treatmentprotocols. Crit Care Med 35:1509–1516

47. Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB,Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, TotaroR, Vincent JL, Zanotti-Cavazzoni S (2004) Practice parameters forhemodynamic support of sepsis in adult patients: 2004 update.Crit Care Med 32:1928–1948

48. Grollman A, Geiling EMK (1932) The cardiovascular and meta-bolic reactions of man to the intramuscular injection of posteriorpituitary liquid (Pituitrin), Pitressin and pitochin. J Pharmacol ExpTher 16:447–460

49. LandryDW,LevinHR,Gallant EM,AshtonRC Jr., Seo S,D'AlessandroD, Oz MC, Oliver JA (1997) Vasopressin deficiency contributes to thevasodilation of septic shock. Circulation 95: 1122–1125

50. Landry DW, Levin HR, Gallant EM, Seo S, D'Alessandro D,Oz MC, Oliver JA (1997) Vasopressin pressor hypersensitivity invasodilatory septic shock. Crit Care Med 25:1279–1282

51. Malay MB, Ashton RC Jr., Landry DW, Townsend RN (1999)Low-dose vasopressin in the treatment of vasodilatory septicshock. J Trauma 47:699–703

52. Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y,Boyle WA III (2001) Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit CareMed 29:487–493

53. Holmes CL, Walley KR, Chittock DR, Lehman T, Russell JA(2001) The effects of vasopressin on hemodynamics and renalfunction in severe septic shock: a case series. Intensive Care Med27:1416–1421

54. Rady MY, Rivers EP, Nowak RM (1996) Resuscitation of thecritically ill in the ED: responses of blood pressure, heart rate,shock index, central venous oxygen saturation, and lactate. Am JEmerg Med 14:218–225

55. Vincent JL, De Backer D (2004) Oxygen transport—the oxygendelivery controversy. Intensive Care Med 30:1990–1996

56. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, TrzaskomaBL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R,Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL(2005) Drotrecogin alfa [activated] for adults with severe sepsisand a low risk of death. N Engl J Med 353:1332–1341

57. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, MaciasWL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP,Giroir B (2007) Drotrecogin alfa (activated) in children withsevere sepsis: a multicentre phase III randomised controlled trial.Lancet 369:836–843

58. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B,Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G,Chaumet-Riffaut P, Bellissant E (2002) Effect of treatment withlow doses of hydrocortisone and fludrocortisone on mortality inpatients with septic shock. JAMA 288:862–871

59. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K,Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF,Reinhart K, Cuthbertson BH, Payen D, Briegel J (2008)Hydrocortisone therapy for patients with septic shock. N Engl JMed 358:111–124

60. Van den Berghe G, Wouters P, Weekers F, Verwaest C,Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, LauwersP, Bouillon R (2001) Intensive insulin therapy in the critically illpatient. N Engl J Med 345:1359–1367

61. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, RagallerM, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S,Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M,Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, LoefflerM, Reinhart K (2008) Intensive insulin therapy and pentastarchresuscitation in severe sepsis. N Engl J Med 358:125–139

62. Galban C, Montejo JC, Mesejo A, Marco P, Celaya S, Sanchez-Segura JM, Farre M, Bryg DJ (2000) An immune-enhancingenteral diet reduces mortality rate and episodes of bacteremia inseptic intensive care unit patients. Crit Care Med 28:643–648

63. Bertolini G, Iapichino G, Radrizzani D, Facchini R, Simini B,Bruzzone P, Zanforlin G, Tognoni G (2003) Early enteral immuno-nutrition in patients with severe sepsis: results of an interim analy-sis of a randomized multicentre clinical trial. Intensive Care Med29:834–840

64. Vincent JL (2007) Metabolic support in sepsis and multipleorgan failure: more questions than answers.. Crit Care Med 35:S436–S440

65. Zambon M, Ceola M, Castro R, Gullo A, Vincent JL (2008)Implementation of the Surviving Sepsis Campaign guidelines forsevere sepsis and septic shock: We could go faster. J Crit Care (inpress)


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Clinical Sepsis and Septic Shock