New insights into the management of severe sepsis and septic shock

Surviving Sepsis Campaign UpdatedGuidelines for 2012

Surviving Sepsis Campaign Surviving Sepsis Campaign—a collaboration ofthe European Society of Intensive CareMedicine (ESICM), the International SepsisForum (ISF), and the Society of Critical CareMedicine In 2012, it has published an updated version ofthe International Guidelines for Managementof Severe Sepsis and Septic Shock originallypublished in 2004 and last updated in 2008

Guide to Recommendations’ Strengths andSupporting Evidence 1 = strong recommendation; 2 = weak recommendation or suggestion; A = good evidence from randomized trials; B = moderate strength evidence from smallrandomized trial(s) or multiple goodobservational trials; C = weak or absent evidence, mostly drivenby consensus opinion

DefinitionSepsis is defined as the presence (or presumed presence) ofan infection accompanied by evidence of systemicinflammatory response syndrome (SIRS).SIRS is defined as the presence of 2 or more of the following:(1) temperature greater than 38°C (100.4°F) or less than36°C (96.8°F)(2) pulse rate greater than 90 beats/min(3) respiratory rate greater than 20 breaths/min (or PaCO2less than 32 mmHg)(4) WBC count greater than 12,000/mm3 or less than4,000/mm3, or greater than 10% immature band forms.

Definitions Severe sepsis is defined as thepresence of sepsis and early organdysfunction or hypoperfusion withlactic acidosis. Septic shock is defined as thepresence of sepsis and refractoryhypotension

Incidence of sepsis Sepsis is the 10th leading cause of death inthe United States overall Sepsis is the leading causes of admission tointensive care units (around 50%) The annualized incidence of sepsis isincreasing by 8%. The incidence of severesepsis is increasing greatest in older adultsand the nonwhite population

Prognosis More than half of all septic patientsdevelop severe sepsis and a quarterdevelop septic shock; thus, 10% to 15%of all patients admitted to ICUs developseptic shock Published mortality rates for sepsis rangefrom 28% to 56%

Management of sepsis Early haemodynamic resuscitation (earlygoal-directed therapy “EGDT” (resuscitationbundle RB)) Antimicrobial therapy Source control Low tidal volume mechanical ventilation Role of steroids? Drotrecogin alfa??

Early haemodynamic optimization(resuscitation bundle) In 2001, a trial of early hemodynamicresuscitation to normal physiologicparameters, or early goal-directed therapy,was conducted in ED patients with severesepsis/septic shock and revealed asignificant mortality reduction. Early goal-directed therapy is an algorithmicapproach to hemodynamic optimization andresolution of global tissue hypoxia withinthe first 6 hours of disease presentation

Early haemodynamic optimization(resuscitation bundle)Specifically, patients are treated by(1) fluid resuscitation with either crystalloid or colloid toachieve a central venous pressure goal of 8 to 12 mmHg,(2) vasoactive agents to achieve a mean arterial pressuregoal of 65 to 90 mm Hg(3) blood transfusion to a hematocrit level greater than30%,(4) inotrope therapy(5) intubation, sedation, and paralysisas necessary to achieve a ScvO2 of greater than 70%

Early haemodynamic optimization(resuscitation bundle) During the first 6 hours in the ED, the earlygoal-directed therapy group had significantlygreater amount of fluid therapy than thecontrol group (5.0 versus 3.5 L, respectively),RBC transfusion (64.1% versus 18.5%,respectively), and inotrope (ie, dobutamine)administration (13.7% versus 0.8%,respectively). The primary outcome variable, inhospitalmortality rate, was 46.5% in the control groupversus 30.5% in the early goal-directed therapygroup

Early haemodynamic optimization(resuscitation bundle)Subsequent studies over one decade Validated the RB and its elements Provided evidence that this therapy modulatesinflammation and decrease organ failureprogression Showed that this approach consistently saves 1out of every 6 lives presenting with severesepsis/septic shockCurrent guidelines continue to recommend EGDTpending the results of numerous ongoing trials

Components of EGDT(resuscitation bundle) Haemodynamic monitoring Volume therapy Vasoactive agents Increasing oxygen carrying capacity Inotropic therapy Decreasing oxygen consumption

Haemodynamic monitoring Optimal titration of fluids and vasoactivetherapy is performed more objectivelywith invasive monitoring Central venous access allowsmeasurement of central venous pressureand ScvO

Surviving Sepsis: New monitoringrecommendations Using normalization of lactate levels as analternate goal in EGDT for severe sepsis, if centralvenous oxygenation monitoring is not available(Grade 2C). For patients at risk for fungal infection as a sourcefor severe sepsis, checking one of the newer assaysfor invasive candidiasis such as 1,3-beta-D-glucan,mannan, or anti-mannan ELISA antibody testing(Grade 2B/C). When no infection can be found, consider using alow procalcitonin level as a supportive tool for thedecision to stop antibiotics (Grade 2C).

Volume therapy The first parameter to target in hemodynamicoptimization is intravascular volume with theuse of fluid therapy targeting a central venouspressure of 8 to 12 mm Hg. No outcome benefit has been demonstrated inusing colloids compared to crystalloids withrespect to mortality or hospital length of stay. However, in one investigation a trend toimproved survival with the use of colloid(albumin) in sepsis was observed

Surviving Sepsis: New Fluid ResuscitationRecommendations They gave a strong 1A recommendation for theuse of crystalloids like normal saline as the initialfluid resuscitation for people with severe sepsis Incremental fluid boluses should be continued aslong as patients continue to improvehaemodynamically (Grade 1C). They weakly recommended adding albumin toinitial fluid resuscitation with crystalloid for severesepsis and septic shock (Grade 2B).

Vasoactive agents Vasopressors should be administered whenhypotension is persistent or mean arterial bloodpressure less than 65 mm Hg, regardless of thecentral venous pressure, because in the presenceof hypotension, organ perfusion cannot bemaintained with fluids alone. Norepinephrine may be more effective incorrecting hypotension in septic shock whileavoiding the potential tachycardia induced bydopamine In the patient with refractory hypotension,vasopressin deficiency should be considered

Surviving Sepsis: New Recommendationsfor Vasopressors Authors strongly recommend norepinephrineas the first choice for vasopressor therapy(Grade 1B). Vasopressin 0.03 units / minute isan alternative to norepinephrine, or may beadded to it (Grade 2A). When a second agent is needed, epinephrine istheir weakly-recommended vasopressor choice(Grade 2B). Dopamine was only recommended in highlyselected patients whose risk for arrhythmiaswas felt to be very low and who had a lowheart rate and/or cardiac output (Grade 2C).

Increasing Oxygen Carrying Capacity After mean arterial pressure has beenoptimized, patients with inadequate oxygendelivery reflected by ScvO2 less than 70%,elevated lactate, and hematocrit less than30% should receive a transfusion of packedRBCs to achieve a hematocrit level greaterthan 30%.

Inotropic therapy After adequate volume, mean arterial pressure,and hematocrit goals are met and ScvO2 ispersistently less than 70%, dobutamine toimprove contractility, in a dosage of 2.5 to 20µg/kg/minute, titrated to achieve ScvO2greater than 70%, is recommended. Because the vasodilatory effect of dobutaminecould worsen hypotension, it should be used incombination with vasopressors for patientswith persistent hypotension.

Surviving Sepsis: New Recommendationsfor inotropic therapy Dobutamine is strongly recommended (byitself or in addition to a vasopressor) forpatients with:1. cardiac dysfunction as evidenced by highfilling pressures and low cardiac output, or2. clinical signs of hypoperfusion afterachievement of restoration of bloodpressure with effective volumeresuscitation (Grade 1C).

Decreasing oxygen consumption When ScvO2 remain less than 70% after theCVP, arterial BP and haematocrit havereached the target, oxygen consumptioncan be reduced through mechanicalventilation to decrease the work ofbreathing and redistribute blood flow tovital organs

Antimicrobial therapy Administration of antibiotics within the timeof ED care and as soon as possible oncethere is a reasonable suspicion of severesepsis is likely to increase the chance offavourable outcome compared with lateradministration (Grade E) Empirical regimens should be sufficientlybroad, so there is little chance (less than5%) that the offending pathogen will not beeffectively covered

Empirical antibiotic combinations Pneumonia: a respiratory quinolone(levofloxacin) plus vancomycin (or linezolid) Bacterial meningitis: ceftriaxone orcefotaxime plus vancomycin Urinary tract infections: β-lactam/βlactamaseinhibitor with antipseudomonasactivity (piperacillin/tazobactam) plus anaminoglycoside

Empirical antibiotic combinations Intabdominal infections:piperacillin/tazobactam (or a carbopenem)plus an aminogycoside Skin and soft tissue infection: clindamycinplus vancomycin (or linezolid) Unknown source: meropenem (orpiperacilline/tazobactam) plus anaminoglycoside (gentamicine)

Source controlMeasures to eradicate the source of theinfection is an integral component of therapy.This may include: Abscess drainage Debridement of devitalized infected tissue Removal of infected prosthesis

Drotrecogin alfa (activated protein C) In 2001, the FDA approved DrotAA for adultpatients with severe sepsis and a high risk ofdeath based on a subgroup analysis fromthe Prospective Recombinant HumanActivated Protein C Worldwide Evaluation inSevere Sepsis (PROWESS) trial. Subsequent studies failed to show anefficacy benefit in patients with low diseaseseverity—or even in patients with a highmortality risk

Drotrecogin alfa (activated protein C) With similar concerns and sufficient doubt arisingoverseas, the European Medicines Agency calledfor a new trial to investigate whether DrotAAwould reduce mortality in patients with septicshock PROWESS-SHOCK—a randomized, double-blind,placebo-controlled, multicenter trial of 1,697patients The researchers found no significant difference inefficacy between patients who received DrotAAand those who did not receive treatment. At 28days, 26.4% of patients in the treatment arm and24.2% of patients in the placebo arm had died.

Drotrecogin alfa (activated protein C) These results, which prompted the removal ofthe drug from the market in October 2011,offer answers to questions about the use ofDrotAA in severe sepsis that have persistedsince its 2001 FDA approval It might very well be that with earlyantimicrobial therapies, source control, andresuscitation, we interrupt the sepsis responseand the coagulation abnormalities that follow,so there’s no longer a need for this drug

Systemic corticosteroids Despite more than 5 decades of studyand debate, the role of corticosteroidtreatment in patients with severe sepsisand septic shock remains controversial

Systemic corticosteroids Annane’s practice-changing study published in 2002showed that among 300 septic shock patients, thosewith a negative cosyntropin stimulation test (“nonresponders”)randomized to 50 mg hydrocortisone IV q6 hours had significantly improved 28-day mortalitycompared to placebo (53% vs. 68%). CORTICUS (2008) then swung the pendulum back byshowing no 28-day mortality benefit of steroids in 499septic shock patients (39% vs. 36%) who were nonrespondersto cosyntropin. Steroids did reduce thetime spent in shock (3.3 vs. 5.8 days), but steroidtreatedpatients had more superinfections and newepisodes of sepsis

Systemic corticosteroidsSumming up, corticosteroids do improveblood pressure, but any beneficial effectson survival from septic shock remain hotlydebated

Surviving Sepsis guidelines regardingcorticosteroid therapy in severe sepsisUnchanged from 2008, and continue to recommend: Hydrocortisone 300 mg / day or less in patients withseptic shock “only after it has been confirmed thattheir blood pressure is poorly responsive to fluidresuscitation and vasopressor therapy.” (Grade 2C:weak recommendation, low quality evidence) No benefit of continuous vs. bolus infusions has beendemonstrated Adding fludrocortisone to hydrocortisone is associatedwith a higher infection rate, and shouldn’t benecessary as hydrocortisone has mineralocorticoidactivity. Surviving Sepsis calls fludrocortisone anoptional adjunctive treatment to hydrocortisone.

Surviving Sepsis guidelines regardingcorticosteroid therapy in severe sepsis Give hydrocortisone for 7 days, thenwean it to prevent rebound hypotensionand blood glucose lability. Stick with the 300 mg / day dose: givinghigh-dose corticosteroids to people inseptic shock is known to be harmful.