Early Interventionsin Severesepsis and Septic Shock JOB

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712 MINERVA ANESTESIOLOGICA June 2012

E X P E R T O P I N I O N

S

epsis represents a continuum beginning witha host-pathogen interaction that triggers a

complex interplay between pro-inflammatory,anti-inflammatory and apoptotic mediators.1As the disease progresses, organ dysfunction canresult from circulatory insufficiency from hypo-volemia, myocardial depression, increased meta-bolic demands and vasoregulatory perfusion ab-normalities. ese hemodynamic perturbationslead to an imbalance between systemic oxygensupply and demand, leading to global tissue hy-poxia and shock. ese pathogenic events signif-icantly contribute to the morbidity and mortal-

ity in early sepsis.2, 3

A critical decrease in systemic oxygen delivery(DO2) is followed by an increase in the systemicoxygen extraction ratio (O2ER) and a decreasein central venous oxygen saturation (ScvO2) ormixed venous oxygen saturation (SvO2). is in-crease in OER is a compensatory mechanism tomatch systemic oxygen demands. When the lim-it of this compensatory mechanism (OER>50 to60%) is reached, anaerobic metabolism ensuresleading to lactate production.4In this critical de-livery dependent or hypodynamic phase, lactateconcentrations are inversely related to DO2andScvO2/SvO2 (Figure 1).5 is phase can occur

with normal vital signs and is commonly referred

Early interventions in severe sepsis and septic shock:a review of the evidence one decade later

E. P. RIVERS 1, M. KATRANJI 2, K. A. JAEHNE 1, S. BROWN 1G. ABOU DAGHER 1, C. CANNON 3, V. COBA 1

1Department of Emergency Medicine and Surgery, Henry Ford Hospital, Wayne State University, Detroit, MI, USA;2Department of Medicine, Pulmonary and Critical Care Medicine, Pontiac Osteopathic Hospital, Pontiac, MI, USA;3

Department of Emergency Medicine, University of Kansas, Medical Center, Kansas City, KS, USA

A B S T R A C Te outcomes of acute myocardial infarction, trauma, and stroke have improved by implementing processes thatprovide early diagnosis and aggressive interventions at the most proximal point of disease presentation. A commonfeature in these conditions is the implementation of early intervention strategies. One decade ago, a similar approachto sepsis began when a prospective randomized trial compared early goal-directed therapy (EGDT) to standard careusing specific criteria for the early identification of high risk patients with infection. e components of EGDT werederived from expert consensus opinion to produce a protocol to reverse the hemodynamic perturbations of hypovo-lemia, vasodysregulation, myocardial suppression and increased metabolic demands for patients with severe sepsis inthe intensive care unit (ICU). However, EGDT was provided at the most proximal phase of disease presentation in the

Emergency Department (ED). With EGDT, a reduction in mortality of over 16% was shown over standard care. Sincethe EGDT study was published a decade ago, significant emphasis worldwide has been placed on a comprehensiveapproach to the first 6 hours of sepsis management which is commonly referred to as the resuscitation bundle (RB).e RB consists of early diagnosis, risk stratification using lactate levels, hemodynamic response after a fluid challenge,antibiotics, source control and hemodynamic optimization or EGDT. is review will examine one decade of evidencefor the components of the RB examining its impact on systemic inflammation, the progression of organ failure, healthcare resource consumption and mortality in severe sepsis and septic shock. (Minerva Anestesiol 2012;78:712-24)

Key words: Sepsis - Shock, septic - Lactatic acid - Resuscitation.


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EARLY INTERVENTIONS IN SEVERE SEPSIS AND SEPTIC SHOCK RIVERS

Vol. 78 - No. 6 MINERVA ANESTESIOLOGICA 713

to as occult shock, where the patient outwardlyappears less ill. As a result organ dysfunction andsudden cardiopulmonary collapse are complica-tions associated with this phase if unrecognizedor left untreated.2, 6, 7is state predominantlycharacterizes the early sepsis presentation (Figure2) and is an important distinction from previousunsuccessful sepsis resuscitation trials performedin the ICU setting.8-11

After adequate resuscitation, a hyperdynamicphase follows the hypodynamic phase. Com-pensated sepsis is characterized by an elevatedScvO2/SvO2 and normal lactate. Later an el-evated lactate and elevated ScvO2/SvO2denotepathologic delivery dependence or delivery inde-pendence and is associated with increased mor-tality.12e failure to increase OER and thus in-crease systemic oxygen consymption (VO2) maybe secondary to impairment of microvascularoxygen perfusion or mitochondrial dysfunction.

Origin of the resuscitationbundle (RB) components

e RB and its components are not novelstrategies. Wilson et al. wrote a series of expertopinions beginning in 1976 that comprised thetenets of early sepsis management (Figure 2).13ese recommendations included the following:early identification of high risk patients, appro-priate cultures, source control, and appropriateantibiotic administration. is was followed bystrategies aimed at early hemodynamic opti-mization of oxygen delivery guided by preload(central venous pressure or surrogate, fluids),

afterload (mean arterial pressure, vasopressors),

arterial oxygen content (packed red blood cells,oxygen), and contractility (inotropes) if ScvO2remained low (Figure 2).

In the 2001 publication, these componentswhich were also recommended by a consensus ofexpert opinion 14were applied at the most proximalsite of hospital presentation mirroring the approachto trauma, stroke and acute myocardial infarction.14is approach called early good-directed therapy(EGDT) was tested against standard care in a ran-domized control trial resulting in a mortality ben-efit of over 16%. In order to avoid the ethical issues(withholding life saving therapy), the control orstandard care arm also received continuous centralvenous pressure (CVP), arterial blood pressure andurine output monitoring. is was not a standardof care in emergency department (ED) throughoutthe United States at the time where baseline mortal-ity was estimated to be over 50%. In regards to thesuccess of the EGDT group, it must be emphasizedthat control group therapy also reduced mortality(46.5%) compared to the historical care mortalitywhich was over 50%.15Over the last decade thevarious components of EGDT or the resuscitationbundle have been examined, validated and incorpo-rated into evidence based guidelines.16, 17

Early risk stratification using bloodpressure and lactate levels

EGDT begins with early identification of highrisk patients based on hypotension (systolic bloodpressure 4 mmol/L(Figure 2). Although it is intuitive, a hypotensiveepisode is associated with an increase risk for sud-den and unexpected death.18After Aduen et al. es-tablished the general prognostic value of a lactateof 4 mM/L on hospital admission; multiple studieshave confirmed the risk stratification of this levelfor illness severity and mortality in both the pre-hospital and in-hospital setting.19-23

Antibiotic therapy

Once patients are identified, source controland appropriate cultures should be obtained.24While there are no prospective outcome trialsto support early administration of antibiotics,

the animal and retrospective human literature

Figure 1.Oxygen delivery and consumption.


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later stage of disease presentation. It may be be-cause of this that administration and duration ofvasopressors also correlates with worse outcome.

Levy et al. has shown that the delayed use of va-sopressor therapy for cardiovascular support isincrementally associated with a significantlyhigher mortality than any other organ failurebeyond the first 24 hours of sepsis.3One of theattributes of early volume therapy is a significantreduction in vasopressor therapy which furtherreduced need for vasopressin and corticosteroidtherapy.3,14, 39-41 De Backer et al. showed thatthere was no significant difference in the rate ofdeath between patients treated with dopamineas the first-line vasopressor agent and those whowere treated with norepinephrine, however, theuse of dopamine was associated with a greaternumber of adverse events.42

Central venous and tissue oxygen saturation

Many of the salutary effects of ScvO2moni-toring are based on its ability to detect imbal-ances of DO2 to VO2 in the delivery depend-ent phase even with normal vitals signs.6In thepresence of a low value, therapeutic maneuversto increase DO2or decrease VO2are required tonormalize this number. us, ScvO2becomes atrigger for increasing inspired oxygen concentra-tion (arterial hypoxia), red blood cell transfusion(decreased arterial oxygen content), inotropetherapy (myocardial suppression), and mechani-cal ventilation (increased oxygen demands).43-46Multiple studies have compared ScvO2 withSvO2showing that there is an absolute difference(5%) between the two sites.47, 48While there isa difference, the clinical utility of both sites iscomparable and validated by outcome studies.48In a multicenter study, Pope et al. found that thefailure to reach a ScvO2greater than 70% withinthe first six hours is associated with significantlyincreased (14%) mortality.12Castellanos-Ortegaet al. examined all of the sepsis bundle elementsat 6 and 24 hours of sepsis and found that theattainment of an ScvO2 >70% had the statisti-cally most significant impact on survival thanall other bundle elements.49 In a meta-analysisexamining five studies comprising over 11000

patients, it was shown that patients reaching this

administration was associated with a significant-ly reduced hospital length of stay and hospitalcosts.30

Central venous pressure and fluid therapy

While some question the accuracy of CVPin assessing volume status; equivalent outcomeshave been shown when compared to the pul-monary artery catheter for assessment of fluidstatus in acute lung injury.31CVP measurementis indicative of fluid responsiveness in the low-er ranges and a CVP >10 is the upper limit foralgorithms of fluid challenges.32 CVP has beenshown to have a significant association with 30-day mortality.33 Ferrer et al.34 and Boyd et al.concluded a negative impact on survival whenCVP was used as a guide to fluid management.35e use of CVP appears to be time sensitive.Early, aggressive fluid therapy which is associatedwith improved outcomes must be distinguishedfrom late aggressive fluid therapy.36e adminis-tered volume in the EGDT group within the first6 hours was significantly greater compared tostandard therapy group, but over 72 hours therewere no differences in the amount of fluid be-tween the two groups. In a meta-analysis, the useof albumin is associated with lower mortality.37

Mean arterial pressure and vasopressor use

e mean arterial blood pressure target inEGDT is supported by Varpula and Dunser etal.33, 38ey examined hemodynamic variablesin septic shock patients during the first 24-48h of treatment and found a MAP below 60-65mmHg to be most predictive of 28-30-day mor-tality and organ function. It is preferable thatthis endpoint be met with fluid versus vasopres-sor therapy. EGDT is associated with greater vol-ume administration and diminished vasopressoruse over first 6 hours of resuscitation. However,an equal amount of fluid is used over the first72 hours of hospitalization. In the absence of di-minished early volume therapy, there was an in-crease in the incidence of sudden hemodynamicdeterioration and vasopressor use.

ese observations reveal that hypotension

is more refractory to fluid administration at the


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RIVERS EARLY INTERVENTIONS IN SEVERE SEPSIS AND SEPTIC SHOCK


with altered capillary perfusion at baseline.57While there are many publications that incrimi-nate RBC transfusions with worse outcome, a

recent large observational study found that RBCtransfusion was associated with decreased mor-tality rates.58Further studies are needed to sup-port the current recommendation for a hemo-globin of 10 mg/dL during septic shock.59

Myocardial dysfunction and inotrope therapy

e early recognition of myocardial dysfunc-tion requiring inotropic use was found to be at a12.9% greater frequency in the EGDT versusthecontrol group in the original EGDT study andthis incidence is consistent with previous find-ings by Parrillo et al.60Grissom et al. establishedthat physical examination findings of inadequatecirculation are not useful for predicting low car-diac index or ScvO2.51Afessa et al. examined 962patients using a propensity score for each bundleelement and found that compliance with lactatemeasurement and inotrope administration wasindependently associated with decreased risk ofmortality.61 Shah et al. performed a retrospec-tive review of 183 sepsis episodes in patientswith pre-existing echocardiograms (prior to thesepsis event) documenting systolic dysfunction.In the 135 patients who did not meet EGDTadherence requirements, the mortality rate was36.3% and in the 48 patients who met EGDTadherence requirements, the mortality rate was16.67%, P


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ScvO2) where the production of lactate exceedsits clearance and the serum lactate levels beginto rise.4erefore, SvO2is more sensitive at de-

tecting impending tissue hypoxia than lactate.Continuous ScvO2 monitoring provides a realtime assessment, more efficient attainment of re-suscitation endpoints and greater mortality ben-efit than intermittent sampling.47, 52In an ICUbased study, Jansen et al. randomly allocatedpatients with an elevated lactate (>3 mm/L) todecrease lactate by 20% or more per two hoursfor the initial eight hours in the lactate group.In the control group, the treatment team had noknowledge of lactate levels (except for the ad-mission value). e lactate group received morefluids and vasodilators. However, there were nosignificant differences in lactate clearance be-tween treatment groups. Hospital mortality wassignificantly reduced from 43.5% in the controlgroup versus 33.9% in the lactate group. In thelactate group, there was a decrease in organ fail-ure, duration of inotrope therapy, mechanicalventilation from 7-72 hours and ICU length ofstay.70e lactate group treatment did not re-sult in faster reduction of lactate when comparedwith control group therapy. is might actuallyargue against lactate as a target of hemodynamictherapy. However, given that ScvO2monitoringwas mandatory in the lactate group and faculta-tive in the control group, this study could notexclude the possibility that this had an impacton the observed outcome difference. e distur-bances of lactate metabolism that occur duringsepsis are probably more complex than an iso-lated defect of cellular oxygenation.71 Furthera normal lactate in isolation does not excludethe presence of tissue hypoperfusion. Twenty to50% of septic shock patients will never elevatelactate levels at presentation or during the clini-cal course and frequently develop multi-systemorgan failure.72-74 ese observations indicatethat using lactate and ScvO2are complimentaryendpoints and not mutually exclusive.

Modified versions of the resuscitation bundle

Lin et al. employed a modified EGDT proto-col in a medical ICU without the use of ScvO2

compared to a control group. Targeting CVP,

to early restoration of the balance between DO2and VO2.

Lactate clearance

Nguyen et al. found that the clearance of lac-tate over the first six hours after presentation wasassociated with a significant decrease in pro- andanti-inflammatory biomarkers, improved or-gan function and reduced mortality.42, 43 iswas based on previous investigations using lac-tate clearance over 24 and 72 hours in the ICUsetting.67 In a recent prospective multicentertrial of EGDT implementation, Nguyen et al.showed that when patients received EGDT, themortality reduction was further enhanced whenretrospectively grouped by improving levels oflactate clearance.68Jones et al. declared that lac-tate clearance is equivalent to ScvO2using theEGDT algorithm in a noninferiority study.69Inthis study, patients assigned to the ScvO2groupwere resuscitated to normalize central venouspressure, mean arterial pressure, and ScvO2of 70% while patients in the lactate clearancegroup were resuscitated to normalize centralvenous pressure, mean arterial pressure, andachieve a lactate clearance of at least 10%. estudy protocol was continued until all goals wereachieved or for up to six hours. ey concludedthat lactate clearance guided resuscitation wasnon-inferior or equivalent to a ScvO2 guidedresuscitation based on no difference in mortal-ity. Compared to the EGDT study, the patientsenrolled by Jones et al. were of a lower illnessseverity, in a more supply independent phase atbaseline (ScvO2and lower lactate levels at studybaseline), more frequently in vasodilatory shock(vasopressor dependent) and less mechanicallyventilated, Figure 1. More importantly, only30 interventions were made in only 10% of thepatient population. It is these patients (deliverydependent or hypodynamic phase) that requireadditional interventions such as supplementaloxygen, packed red blood cells, inotropes andmechanical ventilation which are physiologi-cally triggered by ScvO2. ese interventions re-duce sudden cardiopulmonary complications by50%; an issue not addressed by Jones et al. ese

events signal reaching the critical OER (low


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inflammation.76e observation of a 15% reduc-tion in mechanical ventilation over 72 hours is anexample of preventing this second hit.73Adjunc-tive therapies to further modulate the inflamma-tory response when used early may enhance thebeneficial effects of EGDT.77erapeutic effortstargeting the microcirculation are in progress butto date having not shown outcome benefit.78Ki-ers et al. found that a delay in achieving hemo-dynamic goals of EGDT was significantly associ-ated with the development of acute kidney injury

(P=0.02) and resulted in a 3.4% greater creatininelevel rise per hour (P=0.03) in patients admittedfrom the hospital ward.79In a subanalysis of pa-tients enrolled in the Fluid and Catheter Treat-ment Trial (FACTT) of the National Institutesof Health, Acute Respiratory Distress SyndromeNetwork, an improved SvO2was significantly as-sociated with improved mortality and decrease induration of mechanical ventilation.51ese find-ings support the observations of a decreased needfor mechanical ventilation over the first 72 hours

of presentation in the original EGDT trial.

Outcome evidence in adult patients

Over the last decade, the external validityand generalizability of the RB containing vary-ing versions of EGDT has been established inmultiple studies. ese studies comprise over 50publications containing over 18000 adult pa-tients (Table I).8, 41, 49, 68, 80-128e outcome ben-efit of these studies combined equal or exceed

the reduction in mortality found in the original

MAP, hemoglobin and urine output, not onlyled to a significant decrease of the mortality rate,but also to shortening the length of ICU stay,duration of mechanical ventilator support andduration of antibiotic administration. ere wasmore rapid reversal of shock and less delayedvasopressor administration. For medical ICUswithout facility to monitor ScvO2, this modi-fied therapeutic protocol provides an alterna-tive that reduces mortality, ICU stay, ventilatorsupport duration, and tissue hypoperfusion as-

sociated major organ dysfunction. e authorsadded that with ScvO2measurement there wasa chance of improving clinical outcomes further.

Impact on inflammation, themicrocirculation and organ failure

e association between global tissue hypoxiaand inflammation has been well described in vivomodels. Boulos et al. have shown that SvO2 issignificantly associated with mitochondrial func-

tion and that inflammatory mediators in septicpatients can significantly alter mitochondrialfunction.75 In a further analysis of EGDT pa-tients, Rivers also showed that the persistence ofglobal tissue hypoxia (increased lactate and lowScvO2) correlates significantly with the activity ofinflammatory mediators. In patients treated withEGDT, alteration of the inflammatory cascadeis evidenced by significantly lower IL-8 levels.When untreated, this pathogenic mechanism ofinflammation can lead to a second hit phe-

nomenon of multi-organ failure and worsening

T I.Comparison of sepsis intervention studies using the resuscitation bundle compared to the original EGDTstudy.8, 41, 49, 68, 80-128

Summary of implementation study Rivers et al.

Before or control After Control EGDT

Number of patients 9527 9884 133 130APACHE II score 24.24 24.2 20.4 21.4Sex, % Males 58.15 57.3 50.4 50.8Age (years) 63.84 62.9 64.4 67.1Mortality before (SD)** 46.8 (26)% 29.1 (12)% 46.5% 30.5%Relative risk reduction 0.37 0.34Absolute risk reduction 18.3% 16.0%NNT 5.45 6.25

*Includes before and after and concurrent implementation studies. **e average mortality of each study. NNT=number needed to treat.


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plying with the goals of EGDT on patient out-comes when completed beyond the six-hour rec-ommendation period. Compliance was assessed

at 6, 18 and 24 hours after diagnosis of severesepsis or septic shock. e compliers at 18 h hadan absolute 10.2% significantly lower in-hospi-tal mortality compared to the non-compliers at18 h (37.1% vs. 47.3%). When adjusted for dif-ferences in baseline illness severity, the compliersat 18 h had a greater reduction in predicted mor-tality of 26.8% versus9.4% (P 4 mm/L Systolic blood pressure 8 mmHg MAP >65 mmHg Hematocrit >30% ScvO2>70%

reshold for red blood cell transfusion Need for inotropic therapy Indication for and response to mechanical ventilation

Is not equivalent to lactate clearance


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12. Pope JV, Jones AE, Gaieski DF, Arnold RC, Trzeciak S,Shapiro NI. Multicenter study of central venous oxygensaturation (ScvO2) as a predictor of mortality in patientswith sepsis. Ann Emerg Med 2010;55:40-6,e41.

13. Wilson RF, Wilson JA, Gibson D, Sibbald WJ. Shock in

the emergency department. JACEP 1976;5:678-90. 14. Task Force of the American College of Critical Care Medi-cine, Society of Critical Care Medicine. Practice param-eters for hemodynamic support of sepsis in adult patientsin sepsis. Crit Care Med 1999;27:639-60.

15. Ander D, Rivers EP, Jaggi M, Massura. A comparison ofstandard versus goal directed therapy in resuscitation ofcritically ill emergency department patients. Acad EmergMed 1997;4:402-3.

16. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM,Jaeschke R et al. Surviving Sepsis Campaign: Internation-al guidelines for management of severe sepsis and septicshock: 2008. Crit Care Med 2008;36:296-327.

17. Ferrer R, Artigas A. Effectiveness of treatments for severesepsis: data from the bundle implementation programs.Minerva Anestesiol 2011;77:360-5.

18. Jones AE, Yiannibas V, Johnson C, Kline JA. Emergencydepartment hypotension predicts sudden unexpectedin-hospital mortality: a prospective cohort study. Chest2006;130:941-6.

19. Aduen J, Bernstein WK, Khastgir T, Miller J, Kerzner R,Bhatiani A et al. e use and clinical importance of a sub-e use and clinical importance of a sub-strate-specific electrode for rapid determination of bloodlactate concentrations. JAMA 1994;272:1678-85.

20. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M,Fuchs BD, Shah CV et al. Serum lactate is associated withmortality in severe sepsis independent of organ failure andshock. Crit Care Med 2009;37:1670-7.

21. Trzeciak S, Dellinger RP, Chansky ME, Arnold RC,Schorr C, Milcarek B et al. Serum lactate as a predictor ofmortality in patients with infection. Intensive Care Med2007;33:970-7.

22. Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lis-bon A, Wolfe RE et al. Serum lactate as a predictor of mor-tality in emergency department patients with infection.

Ann Emerg Med 2005;45:524-8. 23. Pearse RM. Extending the role of lactate measurement into

the prehospital environment. Crit Care 2009;13:115. 24. Marshall JC, al Naqbi A. Principles of source control in the

management of sepsis. Crit Care Clin 2009;25:753-768,viii-ix.

25. Siddiqui S, Razzak J. Early versus late pre-intensive care unitadmission broad spectrum antibiotics for severe sepsis inadults. Cochrane Database Syst Rev 2010;10:CD007081.

26. Gaieski DF, Mikkelsen ME, Band RA, Pines JM, MassoneR, Furia FF et al. Impact of time to antibiotics on survivalin patients with severe sepsis or septic shock in whom earlygoal-directed therapy was initiated in the emergency de-

partment. Crit Care Med 2010;38:1045-53. 27. Natanson C, Danner RL, Reilly JM, Doerfler ML, Hoff-man WD, Akin GL et al. Antibiotics versus cardiovascularsupport in a canine model of human septic shock. Am JPhysiol 1990;259(5 Pt 2):H1440-7.

28. Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE etal. Initiation of inappropriate antimicrobial therapy resultsin a fivefold reduction of survival in human septic shock.Chest 2009;136:1237-48.

29. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Hor-ton JM, Studnek JR et al. Association between timing ofantibiotic administration and mortality from septic shockin patients treated with a quantitative resuscitation proto-col. Crit Care Med 2011;39:2066-71.

30. Hutchison RW, Govathoti DA, Fehlis K, Zheng Q, Cot-trell JH, Franklin N et al. Improving severe sepsis out-comes: cost and time to first antibiotic dose. Dimens CritCare Nurs 2011;30:277-82.

telemedicine and comprehensive CQI feedbackis feasible, modifies clinician behavior and is as-sociated with decreased hospital mortality.41, 87,103, 122, 126, 143

Conclusions

One decade later, multiple studies (Table II)have not only validated the RB and its elementsbut also provide evidence that this therapymodulates inflammation, decreases organ failureprogression and conserves health care resourceconsumption. is approach consistently saves 1out of every 6 lives for patients presenting with

severe sepsis and septic shock. While implemen-tation remains challenging, the RB remains oneof the most effective interventions in the man-agement of severe sepsis and septic shock.

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Conflicts of interest.None related to this publication. Dr. Rivers receives research support from the National Institute of Health, Aggennixand Alere Corporation. In the past four years, he has been a onetime consultant for Aggennix, Esai Pharmaceuticals Idaho Technologies,

Astra Zeneca, Massimo and Sangard. Dr. Rivers has never personally owned any patents or Early Interventions in Severe Sepsis and SepticShock: e Evidence One Decade Later received royalties, stock or research support associated with the EGDT study. Dr. Cannon hasreceived consulting fees from Eisai Pharmaceuticals.

Received on May 3, 2011 - Accepted for publication on March 21, 2012.Corresponding author: E. P. Rivers, MD, MPH, Vice Chairman and Research Director, Department of Emergency Medicine, Senior StaffAttending in Surgical Critical Care and Emergency Medicine, Clinical Professor, Wayne State University, 270-Clara Ford Pavilion, HenryFord Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. E-mail: [email protected] article is freely available at www.minervamedica.it

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