Surviving Sepsis Guidelines Surviving Sepsis Guidelines Crit Care Med 2004Crit Care Med 2004

Crit Care Med 2008 Crit Care Med 2008 Crit Care Med 2012 Crit Care Med 2012

Dr Samir SahuDr Samir Sahu

DEFINITIONS -1991, Nov 2002DEFINITIONS -1991, Nov 2002

• SEPSIS – Inflammatory response to infn. SEPSIS – Inflammatory response to infn. (Fever, Tachycardia, Tachypnoea, (Fever, Tachycardia, Tachypnoea, Leucocytosis, Leucopenia, Alt. Sensorium) Leucocytosis, Leucopenia, Alt. Sensorium)

• SEVERE SEPSIS – Sepsis associated organ SEVERE SEPSIS – Sepsis associated organ dysfunction dysfunction

• SEPTIC SHOCK - Refractory Hypotension SEPTIC SHOCK - Refractory Hypotension Hypoperfusion Hypoperfusion

(SBP<90mm Hg or reduction of >40mm Hg (SBP<90mm Hg or reduction of >40mm Hg from baseline)from baseline)

EpidemiologyEpidemiology• Severe sepsis and septic shock together Severe sepsis and septic shock together

comprise a common and lethal diseasecomprise a common and lethal disease• Occurring in 10% to 25% of all patients in Occurring in 10% to 25% of all patients in

intensive care unitsintensive care units• Mortality rates of Severe Sepsis 40% and 60%Mortality rates of Severe Sepsis 40% and 60%• Mortality in Septic Shock 80-90% Mortality in Septic Shock 80-90% • Sepsis rates in cancer patients 10 times Sepsis rates in cancer patients 10 times

higher than in noncancer patients higher than in noncancer patients • People over the age of 65 years are 13 times People over the age of 65 years are 13 times

more likely to develop sepsis than younger more likely to develop sepsis than younger individuals individuals

• 27% of patients with sepsis dying in the ICU, 27% of patients with sepsis dying in the ICU, rising to > 50% in patients with septic rising to > 50% in patients with septic shock (SOAP) shock (SOAP)

EpidemiologyEpidemiology• The average sepsis survivor requires 7-14 days of The average sepsis survivor requires 7-14 days of

ICU supportICU support

• Another 10-14 days of hospital stayAnother 10-14 days of hospital stay

• Average hospital length of stay – 3-5 weeksAverage hospital length of stay – 3-5 weeks

• Best practical predictor of outcome– SOFABest practical predictor of outcome– SOFA

• Baseline ICU mortality 10-15%, each new organ Baseline ICU mortality 10-15%, each new organ system failure add 15-20%system failure add 15-20%

• Severity of organ dysfunction correlates with Severity of organ dysfunction correlates with outcome (escalating vasopressors worst prognosis)outcome (escalating vasopressors worst prognosis)

• SOFA not to be used for prognosticating individual SOFA not to be used for prognosticating individual patients (only for comparing with other studies)patients (only for comparing with other studies)

General Principles of General Principles of TherapyTherapy• Predisposing conditionsPredisposing conditions

• Nature of infectionNature of infection

• Assess degree of organ dysfunctionAssess degree of organ dysfunction

• LabLab

CBC, Complete chemistry profile, CBC, Complete chemistry profile, PT,ABGPT,ABG

Urine analysisUrine analysis

Blood C/S, Other C/SBlood C/S, Other C/S

• CXR, U/S AbdCXR, U/S Abd

Determination of the Determination of the Quality of EvidenceQuality of EvidenceA (high) RCTsA (high) RCTs

B (moderate) Downgraded RCTs or B (moderate) Downgraded RCTs or upgraded observational studiesupgraded observational studies

C (low) Well-done observational C (low) Well-done observational studies with control RCTsstudies with control RCTs

D (very low) Downgraded controlled D (very low) Downgraded controlled studies or expert opinion based on studies or expert opinion based on other evidenceother evidence

Factors that may decrease the Factors that may decrease the strength of evidencestrength of evidence

1. Poor quality of planning and 1. Poor quality of planning and implementation of available RCTs, implementation of available RCTs, suggesting high likelihood of biassuggesting high likelihood of bias

2. Inconsistency of results, including 2. Inconsistency of results, including problems with subgroup analysesproblems with subgroup analyses

3. Indirectness of evidence (differing 3. Indirectness of evidence (differing population, intervention, control, population, intervention, control, outcomes, comparison)outcomes, comparison)

4. Imprecision of results4. Imprecision of results

5. High likelihood of reporting bias5. High likelihood of reporting bias

• Main factors that may increase the Main factors that may increase the strength of evidencestrength of evidence

1. Large magnitude of effect (direct 1. Large magnitude of effect (direct evidence, relative risk > 2 with no evidence, relative risk > 2 with no plausible confounders)plausible confounders)

2. Very large magnitude of effect with 2. Very large magnitude of effect with relative risk > 5 and no threats to relative risk > 5 and no threats to validity (by two levels)validity (by two levels)

3. Dose-response gradient3. Dose-response gradient

Diagnostic Criteria for Diagnostic Criteria for SepsisSepsis

• Infection, documented or Infection, documented or suspected, and some of the suspected, and some of the following:following:

Diagnostic Criteria for Diagnostic Criteria for SepsisSepsis• General variablesGeneral variables

– Fever (> 38.3°C)Fever (> 38.3°C)– Hypothermia (core temperature < 36°C)Hypothermia (core temperature < 36°C)– Heart rate > 90/min–1 or more than two sd Heart rate > 90/min–1 or more than two sd

above the normal value for ageabove the normal value for age– TachypneaTachypnea– Altered mental statusAltered mental status– Significant edema or positive fluid balance (> Significant edema or positive fluid balance (>

20 mL/kg over 24 hr)20 mL/kg over 24 hr)– Hyperglycemia (plasma glucose > 140 mg/dL Hyperglycemia (plasma glucose > 140 mg/dL

or 7.7 mmol/L) in the absence of diabetesor 7.7 mmol/L) in the absence of diabetes

Diagnostic Criteria for Diagnostic Criteria for SepsisSepsis

• Inflammatory variablesInflammatory variables– Leukocytosis (WBC count > 12,000 Leukocytosis (WBC count > 12,000 μμL–1)L–1)– Leukopenia (WBC count < 4000 μL–1)Leukopenia (WBC count < 4000 μL–1)– Normal WBC count with greater than 10% Normal WBC count with greater than 10%

immature formsimmature forms– Plasma C-reactive protein more than two sd Plasma C-reactive protein more than two sd

above the normal valueabove the normal value– Plasma procalcitonin more than two sd Plasma procalcitonin more than two sd

above the normal valueabove the normal value

Diagnostic Criteria for Diagnostic Criteria for SepsisSepsis

• Hemodynamic variablesHemodynamic variables– Arterial hypotension (SBP < 90 mm Hg, Arterial hypotension (SBP < 90 mm Hg,

MAP < 70 mm Hg, or an SBP decrease > MAP < 70 mm Hg, or an SBP decrease > 40 mm Hg in adults or less than two sd 40 mm Hg in adults or less than two sd below normal for age)below normal for age)

Diagnostic Criteria for Diagnostic Criteria for SepsisSepsis• Organ dysfunction variablesOrgan dysfunction variables

– Arterial hypoxemia (Pao2/Fio2 < 300)Arterial hypoxemia (Pao2/Fio2 < 300)– Acute oliguria (urine output < 0.5 mL/kg/hr for Acute oliguria (urine output < 0.5 mL/kg/hr for

at least 2 hrs despite adequate fluid resus)at least 2 hrs despite adequate fluid resus)– Creatinine increase > 0.5 mg/dL(44.2 μmol/L)Creatinine increase > 0.5 mg/dL(44.2 μmol/L)– Coagulation abnormalities (INR > 1.5 or aPTT Coagulation abnormalities (INR > 1.5 or aPTT

> 60 s)> 60 s)– Ileus (absent bowel sounds)Ileus (absent bowel sounds)– Thrombocytopenia (platelet count < 100,000)Thrombocytopenia (platelet count < 100,000)– Hyperbilirubinemia (plasma total bilirubin > 4) Hyperbilirubinemia (plasma total bilirubin > 4)

Diagnostic Criteria for Diagnostic Criteria for SepsisSepsis

• Tissue perfusion variablesTissue perfusion variables– Hyperlactatemia (> 1 mmol/L)Hyperlactatemia (> 1 mmol/L)– Decreased capillary refill or mottlingDecreased capillary refill or mottling

SIRSSIRS

• Temperature >100.4Temperature >100.4°°F or <96.8F or <96.8°F°F• Heart Rate >90/minHeart Rate >90/min• Resp. rate >20/min or PaCOResp. rate >20/min or PaCO22 <32mm Hg <32mm Hg• TLC >12,000/cu mm or <4000/cu mmTLC >12,000/cu mm or <4000/cu mm• Altered SensoriumAltered Sensorium• IleusIleus• Raised CRPRaised CRP• Raised S.LactateRaised S.Lactate• Raised CytokinesRaised Cytokines

PresentationPresentation• Nosocomial infections – longer LOS & Nosocomial infections – longer LOS &

higher mortalityhigher mortality

• Tachypnoea – 80%Tachypnoea – 80%

• Fever on admission – 60%Fever on admission – 60%

• Tachycardia – almost 100%Tachycardia – almost 100%

• Hypoxia > 90%Hypoxia > 90%

• Tissue hypoperfusion develop before frank Tissue hypoperfusion develop before frank hypotensionhypotension

• Higher lactate clearance after 6 hrs of Higher lactate clearance after 6 hrs of therapy decreased mortalitytherapy decreased mortality

Severe SepsisSevere Sepsis• Sepsis-induced tissue hypoperfusion Sepsis-induced tissue hypoperfusion

or organ dysfunction (any of the or organ dysfunction (any of the following thought to be due to the following thought to be due to the infection)infection)

• Sepsis-induced hypotensionSepsis-induced hypotension

• Lactate above upper limits laboratory Lactate above upper limits laboratory normalnormal

• Urine output < 0.5 mL/kg/hr for more Urine output < 0.5 mL/kg/hr for more than 2 hrs despite adequate fluid than 2 hrs despite adequate fluid resuscitationresuscitation

Severe SepsisSevere Sepsis• Acute lung injury with Pao2/Fio2 < 250 in Acute lung injury with Pao2/Fio2 < 250 in

the absence of pneumonia as infection the absence of pneumonia as infection sourcesource

• Acute lung injury with Pao2/Fio2 < 200 in Acute lung injury with Pao2/Fio2 < 200 in the presence of pneumonia as infection the presence of pneumonia as infection sourcesource

• Creatinine > 2.0 mg/dL (176.8 Creatinine > 2.0 mg/dL (176.8 μμmol/L)mol/L)

• Bilirubin > 2 mg/dL (34.2 Bilirubin > 2 mg/dL (34.2 μμmol/L)mol/L)

• Platelet count < 100,000 Platelet count < 100,000 μμLL

• Coagulopathy (INR > 1.5)Coagulopathy (INR > 1.5)

Improving OutcomeImproving Outcome

• Timely recognition and diagnosis of severe Timely recognition and diagnosis of severe sepsis is the first stepsepsis is the first step

• Applying the evidence-based guidelines Applying the evidence-based guidelines created under the auspices of the Surviving created under the auspices of the Surviving Sepsis Campaign is the second step Sepsis Campaign is the second step

• Adherence to the guidelines is equally Adherence to the guidelines is equally important to successfully implement change.important to successfully implement change.

Screening for Sepsis & Screening for Sepsis & Performance ImprovementPerformance Improvement• We recommend screening of critically ill We recommend screening of critically ill

patients without obvious noninfectious patients without obvious noninfectious eitiologies of organ dysfunction for eitiologies of organ dysfunction for infection to increase the early infection to increase the early identification of severe sepsis and allow identification of severe sepsis and allow implementation of early evidence based implementation of early evidence based sepsis therapy(1C).sepsis therapy(1C).

• Performance improvement efforts in Performance improvement efforts in severe sepsis should be employed to severe sepsis should be employed to improve patient outcomes(1C). improve patient outcomes(1C).

Screening for Sepsis & Screening for Sepsis & Performance ImprovementPerformance Improvement

1. Routine screening of potentially 1. Routine screening of potentially infected seriously ill patients for infected seriously ill patients for severe sepsis to allow earlier severe sepsis to allow earlier implementation of therapy (grade implementation of therapy (grade 1C).1C).

2. Hospital–based performance 2. Hospital–based performance improvement efforts in severe sepsis improvement efforts in severe sepsis (UG)(UG)

DiagnosisDiagnosis

1. Cultures as clinically appropriate before 1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s) (> 45 mins) in the start of antimicrobial(s) (grade 1C). At least 2 sets of blood cultures (grade 1C). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 at least 1 drawn percutaneously and 1 drawn through each vascular access device, drawn through each vascular access device, unless the device was recently (<48 hrs) unless the device was recently (<48 hrs) inserted. inserted. (grade 1C).(grade 1C).

DiagnosisDiagnosis

2. Use of the 1,3 beta-D-glucan assay 2. Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan (grade 2B), mannan and anti-mannan antibody assays (2C), if available and antibody assays (2C), if available and invasive candidiasis is in differential invasive candidiasis is in differential diagnosis of cause of infection.diagnosis of cause of infection.

3. Imaging studies performed promptly 3. Imaging studies performed promptly to confirm a potential source of to confirm a potential source of infection (UG).infection (UG).

Antimicrobial TherapyAntimicrobial Therapy1. Administration of effective intravenous 1. Administration of effective intravenous

antimicrobials antimicrobials within the first hour of within the first hour of recognition of septic shock (grade 1B) recognition of septic shock (grade 1B) and severe sepsisand severe sepsis without septic shock without septic shock (grade 1C) as the goal of therapy.(grade 1C) as the goal of therapy.

2a. Initial empiric anti-infective therapy of 2a. Initial empiric anti-infective therapy of one or more drugs that have activity one or more drugs that have activity against all likely pathogens (bacterial against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in and/or fungal or viral) and that penetrate in adequate concentrations into tissues adequate concentrations into tissues presumed to be the source of sepsis presumed to be the source of sepsis (1B).(1B).

Antimicrobial TherapyAntimicrobial Therapy

2b. Antimicrobial regimen should be 2b. Antimicrobial regimen should be reassessed daily for potential reassessed daily for potential deescalation (grade 1B).deescalation (grade 1B).

3. Use of low procalcitonin levels or similar 3. Use of low procalcitonin levels or similar biomarkers to assist the clinician in the biomarkers to assist the clinician in the discontinuation of empiric antibiotics in discontinuation of empiric antibiotics in patients who initially appeared septic, but patients who initially appeared septic, but have no subsequent evidence of infection have no subsequent evidence of infection (grade 2C).(grade 2C).

Antimicrobial TherapyAntimicrobial Therapy4a.4a. Combination empirical therapy for neutropenic Combination empirical therapy for neutropenic

patients with severe sepsis (grade 2B) and for patients patients with severe sepsis (grade 2B) and for patients with difficult-to-treat, multidrugresistant bacterial with difficult-to-treat, multidrugresistant bacterial pathogens such as pathogens such as Acinetobacter and Pseudomonas Acinetobacter and Pseudomonas spp.(grade 2B). spp.(grade 2B).

• For patients with severe infections For patients with severe infections associated with associated with respiratory failure and septic shock, combination respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for either an aminoglycoside or a fluoroquinolone is for P. P.

aeruginosa bacteremia (grade 2B).aeruginosa bacteremia (grade 2B). • A combination of beta-lactam and macrolide for A combination of beta-lactam and macrolide for

patients with septic shock from bacteremic patients with septic shock from bacteremic Streptococcus pneumoniae infections (grade 2B).Streptococcus pneumoniae infections (grade 2B).

Antimicrobial TherapyAntimicrobial Therapy4b. Empiric combination therapy should not be 4b. Empiric combination therapy should not be

administered for more than 3–5 days. De-administered for more than 3–5 days. De-escalation to the most appropriate single escalation to the most appropriate single therapy should be performed as soon as the therapy should be performed as soon as the susceptibility profile is known (grade 2B).susceptibility profile is known (grade 2B).

5. Duration of therapy typically 7–10 days; longer 5. Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who courses may be appropriate in patients who have a slow clinical response, undrainable foci have a slow clinical response, undrainable foci of infection, bacteremia with of infection, bacteremia with S. aureus; some S. aureus; some fungal and viral infections or immunologic fungal and viral infections or immunologic deficiencies, including deficiencies, including neutropenia (grade 2C).neutropenia (grade 2C).

Antimicrobial TherapyAntimicrobial Therapy

6. Antiviral therapy initiated as early 6. Antiviral therapy initiated as early as possible in patients with severe as possible in patients with severe sepsis or septic shock of viral origin sepsis or septic shock of viral origin (grade 2C).(grade 2C).

7. Antimicrobial agents should not be 7. Antimicrobial agents should not be used in patients with severe used in patients with severe inflammatory states determined to inflammatory states determined to be of noninfectious cause (UG).be of noninfectious cause (UG).

SURVIVING SEPSIS CAMPAIGN BUNDLESSURVIVING SEPSIS CAMPAIGN BUNDLESTO BE COMPLETED WITHIN 3 HOURSTO BE COMPLETED WITHIN 3 HOURS

1) Measure lactate level1) Measure lactate level

2) Obtain blood cultures prior to 2) Obtain blood cultures prior to administration of antibioticsadministration of antibiotics

3) Administer broad spectrum 3) Administer broad spectrum antibioticsantibiotics

4) Administer 30 mL/kg crystalloid for 4) Administer 30 mL/kg crystalloid for hypotension or lactate 4mmol/Lhypotension or lactate 4mmol/L

Kumar A, Crit Care Med, Kumar A, Crit Care Med, 20062006

Association Between Timing of Association Between Timing of Antibiotic Administration and Mortality Antibiotic Administration and Mortality From Septic Shock in Patients Treated From Septic Shock in Patients Treated With a Quantitative Resuscitation With a Quantitative Resuscitation Protocol Protocol Puskarich, Crit Care Puskarich, Crit Care

Med. 2011;39(9):2066-2071Med. 2011;39(9):2066-2071..

• A delay in antibiotics until after shock A delay in antibiotics until after shock recognition, as compared with before, recognition, as compared with before, was associated with increased mortality;was associated with increased mortality;

• If antibiotics are administered after If antibiotics are administered after shock recognition, there is no increase in shock recognition, there is no increase in mortality with hourly delays.mortality with hourly delays.

SSC Guideline BundleSSC Guideline BundleClinical scenarios Targets to be

achievedDeadline (from time 0)

Severe sepsis Measure lactate Within 1 hour

Severe sepsis Obtain blood culturesbefore antibiotics

Within 1 hour

Severe sepsis Administer broad-spectrum antibiotics

Within 1 hour of admission

Hypotension and / orserum lactate ≥ 4 mmol/L

Deliver an initial minimumof 20 mL/kg of crystalloid

Within 6 hours

Septic shock =hypotension notresponding to fluidresuscitation

Apply vasopressors Within 6 hours

Septic shock and / orserum lactate ≥ 4 mmol/L

Achieve CVP ≥ 8 mmHg Within 6 hours

Septic shock and / orserum lactate ≥ 4 mmol/L

Achieve ScvO2 ≥ 70% orSvO2 ≥ 65%

Within 6 hours

Antibiotic TherapyAntibiotic Therapy

0

20

40

60

80

100

Adequate Inadequa Changed

Hospital mortality

Antibiotic TherapyAntibiotic Therapy

• De-escalateDe-escalate (narrow the spectrum) once (narrow the spectrum) once organism & susceptibility is known. (1C) organism & susceptibility is known. (1C) *minimizes development of *minimizes development of resistant path. *contains cost resistant path. *contains cost *prevents *prevents superinfection (candida)superinfection (candida)

*only done 1/3*only done 1/3rdrd of times of times• Antibiotic regimen should be re-assessed Antibiotic regimen should be re-assessed

after 48-72hours. after 48-72hours.

SURVIVING SEPSIS CAMPAIGN BUNDLES SURVIVING SEPSIS CAMPAIGN BUNDLES TO BE COMPLETED WITHIN 6 HOURS TO BE COMPLETED WITHIN 6 HOURS

5) Apply vasopressors (for hypotension that 5) Apply vasopressors (for hypotension that does not respond to initial fluid does not respond to initial fluid resuscitation) to maintain a mean arterial resuscitation) to maintain a mean arterial pressure (MAP) 65 mm Hgpressure (MAP) 65 mm Hg

6) In the event of persistent arterial 6) In the event of persistent arterial hypotension despite volume resuscitation hypotension despite volume resuscitation (septic shock) or initial lactate 4 mmol/L ):(septic shock) or initial lactate 4 mmol/L ):– Measure central venous pressure (CVP)*Measure central venous pressure (CVP)*– Measure central venous oxygen saturation Measure central venous oxygen saturation

(ScvO2)*(ScvO2)*

SURVIVING SEPSIS CAMPAIGN BUNDLES SURVIVING SEPSIS CAMPAIGN BUNDLES TO BE COMPLETED WITHIN 6 HOURS TO BE COMPLETED WITHIN 6 HOURS

7) Remeasure lactate if initial lactate 7) Remeasure lactate if initial lactate was elevated*was elevated*

*Targets for quantitative resuscitation *Targets for quantitative resuscitation included in the guidelines are included in the guidelines are – CVP of 8 mm Hg, CVP of 8 mm Hg, – ScvO2 of 70%, ScvO2 of 70%, – normalization of lactate.normalization of lactate.

Fluid Therapy of Severe Fluid Therapy of Severe SepsisSepsis1.Crystalloids as the initial fluid of choice in 1.Crystalloids as the initial fluid of choice in

the resuscitation of severe sepsis and the resuscitation of severe sepsis and septic shock (grade 1B).septic shock (grade 1B).

2. Against the use of hydroxyethyl starches 2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and for fluid resuscitation of severe sepsis and septic shock (grade 1B).septic shock (grade 1B).

3. Albumin in the fluid resuscitation of 3. Albumin in the fluid resuscitation of severe sepsis and septic shock when severe sepsis and septic shock when patients require substantial amounts of patients require substantial amounts of crystalloids (grade 2C).crystalloids (grade 2C).

Fluid Therapy of Severe Fluid Therapy of Severe SepsisSepsis

4. Initial fluid challenge in patients with 4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be crystalloids (a portion of this may be albumin equivalent). More rapid albumin equivalent). More rapid administration and greater amounts of administration and greater amounts of fluid may be needed in some patients fluid may be needed in some patients (grade 1C).(grade 1C).

Fluid Therapy of Severe Fluid Therapy of Severe SepsisSepsis

5. Fluid challenge technique be applied 5. Fluid challenge technique be applied wherein fluid administration is wherein fluid administration is continued as long as there is continued as long as there is hemodynamic improvement either hemodynamic improvement either based on dynamic (eg, change in based on dynamic (eg, change in pulse pressure, stroke volume pulse pressure, stroke volume variation) or static (eg, arterial variation) or static (eg, arterial pressure, heart rate) variables (UG).pressure, heart rate) variables (UG).

Fluid ResuscitationFluid Resuscitation• Organ hypoperfusion - Rapid initiation of ISOTONIC Organ hypoperfusion - Rapid initiation of ISOTONIC

crystalloid (RL or NS 20ml/kg) crystalloid (RL or NS 20ml/kg) Grade CGrade C

• Only 250ml remain intravascularly after 1LOnly 250ml remain intravascularly after 1L• 4-6L may be required in first 6 hrs4-6L may be required in first 6 hrs• 500-1000ml crystalloid/300-500ml colloid in 30min500-1000ml crystalloid/300-500ml colloid in 30min• Monitor goals of fluid therapy frequentlyMonitor goals of fluid therapy frequently

(Fluid responsive-250 ml crystalloid should raise (Fluid responsive-250 ml crystalloid should raise CVP by 2 cm)CVP by 2 cm)

• FFP if coagulopathyFFP if coagulopathy• Packed cells if Hct <30%Packed cells if Hct <30%• Hydroxylethyl Starch if BP still lowHydroxylethyl Starch if BP still low Metanalysis CHOI:CCM:1999, SAFEMetanalysis CHOI:CCM:1999, SAFE

(1C)(1C)

Lactate Clearance vs Central Venous Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Oxygen Saturation as Goals of Early Sepsis TherapySepsis Therapy

Jones Jones JAMA.JAMA. 2010;303:739- 2010;303:739-746746• In the lactate group, the target was a In the lactate group, the target was a

lactate clearance of at least 10%, lactate clearance of at least 10%, measured every 2 hours.measured every 2 hours.

• Conclusions. Measurement of lactate Conclusions. Measurement of lactate clearance during resuscitation of clearance during resuscitation of patients with severe sepsis or septic patients with severe sepsis or septic shock is shock is noninferior to ScvOnoninferior to ScvO22

measurement and is associated with a measurement and is associated with a similar survival rate.similar survival rate.

Targeting Lactate Clearance Targeting Lactate Clearance Improves ICU Outcomes Improves ICU Outcomes Am J Respir Crit Am J Respir Crit

Care Med 2010Care Med 2010

• Patients in the trial all had lactate levels of 3.0 Patients in the trial all had lactate levels of 3.0 mEq/L or higher on ICU admission.mEq/L or higher on ICU admission.

• Clinicians monitored lactate levels during the first Clinicians monitored lactate levels during the first 8 hours, 8 hours, aiming to reduce them by 20% every 2 aiming to reduce them by 20% every 2 hourshours..

• The lactate group had a 39% lower risk of in-The lactate group had a 39% lower risk of in-hospital death.hospital death.

• Patients in the lactate group also had reduced Patients in the lactate group also had reduced organ failure, faster weaning from mechanical organ failure, faster weaning from mechanical ventilation and inotropes, and earlier discharge ventilation and inotropes, and earlier discharge from the ICU compared to controls.from the ICU compared to controls.

Initial ResuscitationInitial Resuscitation

• Protocolized, quantitative Protocolized, quantitative resuscitation of patients with sepsis- resuscitation of patients with sepsis- induced tissue hypoperfusion induced tissue hypoperfusion (defined in this document as (defined in this document as hypotension persisting after initial hypotension persisting after initial fluid challenge or blood lactate fluid challenge or blood lactate concentration ≥ 4 mmol/L). concentration ≥ 4 mmol/L).

Goals during the first 6 hrs Goals during the first 6 hrs of resuscitation:of resuscitation:1.a) Central venous pressure 8–12 mm Hg1.a) Central venous pressure 8–12 mm Hg

• b) Mean arterial pressure(MAP)≥65mm Hgb) Mean arterial pressure(MAP)≥65mm Hg

• c) Urine output ≥ 0.5 mL/kg/hrc) Urine output ≥ 0.5 mL/kg/hr

• d) Central venous (superior vena cava) or d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or mixed venous oxygen saturation 70% or 65%, respectively (grade 1C).65%, respectively (grade 1C).

2. In patients with elevated lactate levels 2. In patients with elevated lactate levels targeting resuscitation to normalize targeting resuscitation to normalize lactate (grade 2C).lactate (grade 2C).

VasopressorsVasopressors

1. Vasopressor therapy initially to target a 1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm mean arterial pressure (MAP) of 65 mm Hg (grade 1C).Hg (grade 1C).

2. Norepinephrine as the first choice 2. Norepinephrine as the first choice vasopressor (grade 1B).vasopressor (grade 1B).

3. Epinephrine (added to and potentially 3. Epinephrine (added to and potentially substituted for norepinephrine) when an substituted for norepinephrine) when an additional agent is needed to maintain additional agent is needed to maintain adequate blood pressure (grade 2B).adequate blood pressure (grade 2B).

VasopressorsVasopressors

4. 4. Vasopressin 0.03 units/minute can be added Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage (UG).raising MAP or decreasing NE dosage (UG).

5. Low dose vasopressin is not recommended 5. Low dose vasopressin is not recommended as the single initial vasopressor for treatment as the single initial vasopressor for treatment of sepsis-induced hypotension and of sepsis-induced hypotension and vasopressin doses higher than 0.03-0.04 vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage units/minute should be reserved for salvage therapy (failure to achieve adequate MAP therapy (failure to achieve adequate MAP with other vasopressor agents) (UG).with other vasopressor agents) (UG).

6. Dopamine as an alternative vasopressor agent 6. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected to norepinephrine only in highly selected patients (eg, patients with low risk of patients (eg, patients with low risk of tachyarrhythmias and absolute or relative tachyarrhythmias and absolute or relative bradycardia) (grade 2C).bradycardia) (grade 2C).

7. Phenylephrine is not recommended in the 7. Phenylephrine is not recommended in the treatment of septic shock except in treatment of septic shock except in circumstances where (a) norepinephrine is circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure output is known to be high and blood pressure persistently low or (c) as salvage therapy when persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP dose vasopressin have failed to achieve MAP target (grade 1C).target (grade 1C).

VasopressorsVasopressors

8. Low-dose dopamine should not be 8. Low-dose dopamine should not be used for renal protection (grade 1A).used for renal protection (grade 1A).

9. All patients requiring vasopressors 9. All patients requiring vasopressors have an arterial catheter placed as have an arterial catheter placed as soon as practical if resources are soon as practical if resources are available (UG).available (UG).

Inotropic TherapyInotropic Therapy1. 1. A trial of dobutamine infusion up to 20 A trial of dobutamine infusion up to 20

micrograms/kg/min be administered or added to micrograms/kg/min be administered or added to vasopressor (if in use) in the presence of (a) vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by myocardial dysfunction as suggested by elevated cardiac filling pressures and low elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate hypoperfusion, despite achieving adequate intravascular volume and adequate MAP (grade intravascular volume and adequate MAP (grade 1C).1C).

2. Not using a strategy to increase cardiac index 2. Not using a strategy to increase cardiac index to predetermined supranormal levels (grade 1B).to predetermined supranormal levels (grade 1B).

Source ControlSource Control

• DrainageDrainage - Intra-abdominal abscess- Intra-abdominal abscess - Thoracic empyema- Thoracic empyema

- Septic arthritis- Septic arthritis- Pyelonephritis, Cholangitis- Pyelonephritis, Cholangitis

• Debridement - Necrotizing fascitisDebridement - Necrotizing fascitis - Infected pancreatic necrosis- Infected pancreatic necrosis - Intestinal infarction- Intestinal infarction - Mediastinitis- Mediastinitis

((1C)1C)

Source ControlSource Control

• Device Removal – Infected vascular cathetDevice Removal – Infected vascular cathet - Urinary catheter- Urinary catheter - Colonized endotracheal - Colonized endotracheal

tubetube - Infected IUCD- Infected IUCD• Definitive Opern. - DiverticulitisDefinitive Opern. - Diverticulitis

- Gangrenous cholecystitis- Gangrenous cholecystitis - Clostridial myonecrosis - Clostridial myonecrosis

amputation amputation ((1C)1C)

Source ControlSource Control

1. A specific anatomical diagnosis of 1. A specific anatomical diagnosis of infection requiring consideration for infection requiring consideration for emergent source control be sought emergent source control be sought and diagnosed or excluded as rapidly and diagnosed or excluded as rapidly as possible, and intervention be as possible, and intervention be undertaken for source control within undertaken for source control within the first 12 hr after the diagnosis is the first 12 hr after the diagnosis is made, if feasible (grade 1C).made, if feasible (grade 1C).

Source ControlSource Control2. When infected peripancreatic necrosis is 2. When infected peripancreatic necrosis is

identified as a potential source of identified as a potential source of infection, definitive intervention is best infection, definitive intervention is best delayed until adequate demarcation of delayed until adequate demarcation of viable and nonviable tissues has occurred viable and nonviable tissues has occurred (grade 2B).(grade 2B).

3. When source control in a severely septic 3. When source control in a severely septic patient is required, the effective patient is required, the effective intervention associated with the least intervention associated with the least physiologic insult should be used (eg, physiologic insult should be used (eg, percutaneous rather than surgical percutaneous rather than surgical drainage of an abscess) (UG).drainage of an abscess) (UG).

Source ControlSource Control

4. If intravascular access devices are a 4. If intravascular access devices are a possible source of severe sepsis or possible source of severe sepsis or septic shock, they should be septic shock, they should be removed promptly after other removed promptly after other vascular access has been established vascular access has been established (UG).(UG).

Infection PreventionInfection Prevention

1a. Selective oral decontamination and 1a. Selective oral decontamination and selective digestive decontamination selective digestive decontamination should be introduced and investigated as should be introduced and investigated as a method to reduce the incidence of a method to reduce the incidence of ventilator-associated pneumonia; This ventilator-associated pneumonia; This infection control measure can then be infection control measure can then be instituted in health care settings and instituted in health care settings and regions where this methodology is found regions where this methodology is found to be effective (grade 2B).to be effective (grade 2B).

Infection PreventionInfection Prevention

1b. Oral chlorhexidine gluconate be 1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal used as a form of oropharyngeal decontamination to reduce the risk of decontamination to reduce the risk of ventilator-associated pneumonia in ventilator-associated pneumonia in ICU patients with severe sepsis ICU patients with severe sepsis (grade 2B)(grade 2B)

Sepsis in European Intensive Sepsis in European Intensive Care Units: Results of the SOAP Care Units: Results of the SOAP StudyStudy• Fluid balance may be just a marker of the Fluid balance may be just a marker of the

severity of sepsis, but here a multivariate severity of sepsis, but here a multivariate analysis suggested that it is more than just analysis suggested that it is more than just an indicator of severity and is an an indicator of severity and is an independent predictor of outcome independent predictor of outcome

• Negative fluid balance (≤-500 ml) Negative fluid balance (≤-500 ml) achieved by the third day of treatment achieved by the third day of treatment was a good predictor of survival in was a good predictor of survival in patients with septic shockpatients with septic shock. .

CorticosteroidsCorticosteroids

1. Not using intravenous hydrocortisone to 1. Not using intravenous hydrocortisone to treat adult septic shock patients if treat adult septic shock patients if adequate fluid resuscitation and adequate fluid resuscitation and vasopressor therapy are able to restore vasopressor therapy are able to restore hemodynamic stability (see goals for hemodynamic stability (see goals for Initial Resuscitation). In case this is not Initial Resuscitation). In case this is not achievable, we suggest intravenous achievable, we suggest intravenous hydrocortisone alone at a dose of 200 hydrocortisone alone at a dose of 200 mg per day (grade 2C).mg per day (grade 2C).

CorticosteroidsCorticosteroids2. Not using the ACTH stimulation test to 2. Not using the ACTH stimulation test to

identify adults with septic shock who should identify adults with septic shock who should receive hydrocortisone (grade 2B).receive hydrocortisone (grade 2B).

3. In treated patients hydrocortisone tapered 3. In treated patients hydrocortisone tapered when vasopressors are no longer required when vasopressors are no longer required (grade 2D).(grade 2D).

4. Corticosteroids not be administered for the 4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock treatment of sepsis in the absence of shock (grade 1D).(grade 1D).

5. When hydrocortisone is given, use 5. When hydrocortisone is given, use continuous flow (grade 2D)continuous flow (grade 2D)

Glucose ControlGlucose Control

1. A protocolized approach to blood 1. A protocolized approach to blood glucose management in ICU patients glucose management in ICU patients with severe sepsis commencing insulin with severe sepsis commencing insulin dosing when 2 consecutive blood dosing when 2 consecutive blood glucose levels are >180 mg/dL. This glucose levels are >180 mg/dL. This protocolized approach should target protocolized approach should target an upper blood glucose ≤180 mg/dL an upper blood glucose ≤180 mg/dL rather than an upper target blood rather than an upper target blood glucose ≤ 110 mg/dL (grade 1A).glucose ≤ 110 mg/dL (grade 1A).

Glucose ControlGlucose Control2. Blood glucose values be monitored 2. Blood glucose values be monitored

every 1–2 hrs until glucose values and every 1–2 hrs until glucose values and insulin infusion rates are stable and then insulin infusion rates are stable and then every 4 hrs thereafter (grade 1C).every 4 hrs thereafter (grade 1C).

3. Glucose levels obtained with point-of-3. Glucose levels obtained with point-of-care testing of capillary blood be care testing of capillary blood be interpreted with caution, as such interpreted with caution, as such measurements may not accurately measurements may not accurately estimate arterial blood or plasma estimate arterial blood or plasma glucose values (UG).glucose values (UG).

Intensive insulin therapy and mortality Intensive insulin therapy and mortality among critically ill patients:among critically ill patients:

a meta-analysis including NICE-SUGAR a meta-analysis including NICE-SUGAR study datastudy data

CMAJ. 2009 Apr 14CMAJ. 2009 Apr 14• There was a 6-fold increased riskThere was a 6-fold increased risk of of severe hypoglycemia among severe hypoglycemia among patients given intensive insulinpatients given intensive insulin

therapy compared with the control therapy compared with the control treatmenttreatment

• Intensive insulin therapy may Intensive insulin therapy may benefit patientsbenefit patients in surgical ICUsin surgical ICUs

• In settings where usual care is to In settings where usual care is to target a blood glucose leveltarget a blood glucose level of less of less than 180 mg%, intensive insulin than 180 mg%, intensive insulin therapy may offertherapy may offer no benefitno benefit

Glucose Control – Meta-Glucose Control – Meta-analysisanalysis JAMAJAMA. .

2008;3002008;300• Tight glucose control vs usual glucose Tight glucose control vs usual glucose

control in critically ill patients is not control in critically ill patients is not associated with a reduction in hospital associated with a reduction in hospital mortality rates or the need for new dialysis. mortality rates or the need for new dialysis.

• Tight glucose control vs usual glucose Tight glucose control vs usual glucose control in critically ill patients is associated control in critically ill patients is associated with reduced septicemia in critically ill with reduced septicemia in critically ill patients in surgical ICUs and an increased patients in surgical ICUs and an increased risk for hypoglycemia.risk for hypoglycemia.

Blood Product Blood Product AdministrationAdministration1. Once tissue hypoperfusion has resolved 1. Once tissue hypoperfusion has resolved

and in the absence of extenuating and in the absence of extenuating circumstances, such as myocardial circumstances, such as myocardial ischemia, severe hypoxemia, acute ischemia, severe hypoxemia, acute hemorrhage, or ischemic heart disease, hemorrhage, or ischemic heart disease, we recommend that red blood cell we recommend that red blood cell transfusion occur only when hemoglobin transfusion occur only when hemoglobin concentration decreases to <7.0 g/dL to concentration decreases to <7.0 g/dL to target a hemoglobin concentration of target a hemoglobin concentration of 7.0 –9.0 g/dL in adults (grade 1B).7.0 –9.0 g/dL in adults (grade 1B).

Blood Product Blood Product AdministrationAdministration2. Not using erythropoietin as a specific 2. Not using erythropoietin as a specific

treatment of anemia associated with treatment of anemia associated with severe sepsis (grade 1B).severe sepsis (grade 1B).

3. Fresh frozen plasma not be used to 3. Fresh frozen plasma not be used to correct laboratory clotting abnormalities correct laboratory clotting abnormalities in the absence of bleeding or planned in the absence of bleeding or planned invasive procedures (grade 2D).invasive procedures (grade 2D).

4. Not using antithrombin for the treatment 4. Not using antithrombin for the treatment of severe sepsis and septic shock (grade of severe sepsis and septic shock (grade 1B).1B).

Blood Product Blood Product AdministrationAdministration5. In patients with severe sepsis, administer 5. In patients with severe sepsis, administer

platelets prophylactically when counts are platelets prophylactically when counts are <10,000/mm3 (10 x 109/L) in the absence <10,000/mm3 (10 x 109/L) in the absence of apparent bleeding. We suggest of apparent bleeding. We suggest prophylactic platelet transfusion when prophylactic platelet transfusion when counts are < 20,000/mm3 (20 x 109/L) if counts are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of the patient has a significant risk of bleeding. Higher platelet counts bleeding. Higher platelet counts (≥50,000/mm3 [50 x 109/L]) are advised (≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive for active bleeding, surgery, or invasive procedures (grade 2D)procedures (grade 2D)

Deep Vein Thrombosis Deep Vein Thrombosis ProphylaxisProphylaxis• Patients with severe sepsis receive daily Patients with severe sepsis receive daily

pharmacoprophylaxis against venous pharmacoprophylaxis against venous thromboembolism (VTE) (grade 1B). This thromboembolism (VTE) (grade 1B). This should be accomplished with daily should be accomplished with daily subcutaneous low-molecular weight heparin subcutaneous low-molecular weight heparin (LMWH) (grade 1B versus twice daily UFH, (LMWH) (grade 1B versus twice daily UFH, grade 2C versus three times daily UFH). If grade 2C versus three times daily UFH). If creatinine clearance is <30 mL/min, use creatinine clearance is <30 mL/min, use dalteparin (grade 1A) or another form of dalteparin (grade 1A) or another form of LMWH that has a low degree of renal LMWH that has a low degree of renal metabolism (grade 2C) or UFH (grade 1A).metabolism (grade 2C) or UFH (grade 1A).

2. 2. Patients with severe sepsis be treated with a Patients with severe sepsis be treated with a combination of pharmacologic therapy and combination of pharmacologic therapy and intermittent pneumatic compression devices intermittent pneumatic compression devices whenever possible (grade 2C).whenever possible (grade 2C).

3. Septic patients who have a contraindication for 3. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent coagulopathy, active bleeding, recent intracerebral hemorrhage) not receive intracerebral hemorrhage) not receive pharmacoprophylaxis (grade 1B), but receive pharmacoprophylaxis (grade 1B), but receive mechanical prophylactic treatment, such as mechanical prophylactic treatment, such as graduated compression stockings or graduated compression stockings or intermittent compression devices (grade 2C), intermittent compression devices (grade 2C), unless contraindicated. When the risk unless contraindicated. When the risk decreases start pharmacoprophylaxis (grade decreases start pharmacoprophylaxis (grade 2C).2C).

DVT ProphylaxisDVT Prophylaxis

• LMWH to Unfractionated Heparin LMWH to Unfractionated Heparin (2012)(2012)

• Compression stocking/intermittent Compression stocking/intermittent compression device if heparin compression device if heparin contraindicatedcontraindicated

• Combination of IPC & LMWH in high Combination of IPC & LMWH in high risk patientsrisk patients

(1A)(1A)

Stress Ulcer ProphylaxisStress Ulcer Prophylaxis

1. Stress ulcer prophylaxis using H2 blocker 1. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to or proton pump inhibitor be given to patients with severe sepsis/septic shock patients with severe sepsis/septic shock who have bleeding risk factors (grade 1B).who have bleeding risk factors (grade 1B).

2. When stress ulcer prophylaxis is used, 2. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA proton pump inhibitors rather than H2RA (grade 2D)(grade 2D)

3. Patients without risk factors do not 3. Patients without risk factors do not receive prophylaxis (grade 2B).receive prophylaxis (grade 2B).

Stress Ulcer ProphylaxisStress Ulcer Prophylaxis

• HH22 receptors or proton pump receptors or proton pump inhibitorsinhibitors

(1A)(1A)

• PPI preferred (2012)PPI preferred (2012)

• Without risk do not receive prophylaxis (2012) Without risk do not receive prophylaxis (2012)

ARDS Berlin DefinitionARDS Berlin Definition

Mild Moderate Severe

Timing Acute onset <1 wk

Hypoxemia PaO2 /FiO2 201-300 with PEEP > 5

PaO2 /FiO2< 200 with PEEP > 5

PaO2 / FiO2 < 100

with PEEP > 10

Origin of Edema

Respiratory failure or fluid overload*

not fully explained

by cardiac failure

Radiological Abnormalities

Bilateral opacities**

Bilateral opacities**

Opacities involving at least 3 quadrants

Additional Physiological Derangement

N/A N/A VE CORR

>10L/minorCRS < 40 ml/cm H2O

ARDS Berlin DefinitionARDS Berlin Definition** Not fully explained by effusions, ** Not fully explained by effusions,

nodules, masses, or lobar/lung collapse; nodules, masses, or lobar/lung collapse;

* Need objective assessment if no risk * Need objective assessment if no risk factor presentfactor present

• VVE corrE corr = V = VEE X PaCO X PaCO22/40 /40 (corrected for Body Surface Area)(corrected for Body Surface Area)

• VE corr = Corrected minute ventilation; VE corr = Corrected minute ventilation; (an indirect assessment of lung dead space)(an indirect assessment of lung dead space)

• CCRSRS = Lung compliance at rest = Lung compliance at rest

Mechanical Ventilation for Mechanical Ventilation for ARDSARDS• Low tidal volume(6ml/kg) (1B)Low tidal volume(6ml/kg) (1B)

• Plateau pressure <30cm HPlateau pressure <30cm H22OO (1C) (1C)

• Set PEEP according to ARDSnet guidelines (1C)Set PEEP according to ARDSnet guidelines (1C)• Prone position Prone position Grade EGrade E

• Semirecumbent position (1B)Semirecumbent position (1B)

• Weaning protocol (1B)Weaning protocol (1B)

• Sedation, Analgesia & NM blockade (1B)Sedation, Analgesia & NM blockade (1B)• Conservative Fluid balance Conservative Fluid balance (FACTT,NEJM 2006) (1C)(FACTT,NEJM 2006) (1C)

M V of Sepsis-Induced M V of Sepsis-Induced ARDSARDS1. Target a tidal volume of 6 mL/kg predicted 1. Target a tidal volume of 6 mL/kg predicted

body weight in patients with sepsis-induced body weight in patients with sepsis-induced ARDS (grade 1A vs. 12 mL/kg).ARDS (grade 1A vs. 12 mL/kg).

2. Plateau pressures be measured in patients 2. Plateau pressures be measured in patients with ARDS and initial upper limit goal for with ARDS and initial upper limit goal for plateau pressures in a passively inflated plateau pressures in a passively inflated lung be ≤30 cm H2O (grade 1B).lung be ≤30 cm H2O (grade 1B).

3. Positive end-expiratory pressure (PEEP) be 3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end applied to avoid alveolar collapse at end expiration (atelectotrauma) (grade 1B).expiration (atelectotrauma) (grade 1B).

M V of Sepsis-Induced M V of Sepsis-Induced ARDSARDS4. Strategies based on higher rather than 4. Strategies based on higher rather than

lower levels of PEEP be used for patients lower levels of PEEP be used for patients with sepsis- induced moderate or severe with sepsis- induced moderate or severe ARDS (grade 2C).ARDS (grade 2C).

5. Recruitment maneuvers be used in sepsis 5. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia patients with severe refractory hypoxemia (grade 2C).(grade 2C).

6. Prone positioning be used in sepsis-induced 6. Prone positioning be used in sepsis-induced ARDS patients with a Pao2/Fio2 ratio ≤ 100 ARDS patients with a Pao2/Fio2 ratio ≤ 100 mm Hg in facilities that have experience mm Hg in facilities that have experience with such practices (grade 2B).with such practices (grade 2B).

M V of Sepsis-Induced M V of Sepsis-Induced ARDSARDS7. That mechanically ventilated sepsis 7. That mechanically ventilated sepsis

patients be maintained with the head of the patients be maintained with the head of the bed elevated to 30-45 degrees to limit bed elevated to 30-45 degrees to limit aspiration risk and to prevent the aspiration risk and to prevent the development of ventilator-associated development of ventilator-associated pneumonia (grade 1B).pneumonia (grade 1B).

8. That noninvasive mask ventilation (NIV) be 8. That noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ARDS used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have patients in whom the benefits of NIV have been carefully considered and are thought been carefully considered and are thought to outweigh the risks (grade 2B).to outweigh the risks (grade 2B).

9. 9. That a weaning protocol be in place and that That a weaning protocol be in place and that mechanically ventilated patients with severe mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the mechanical ventilation when they satisfy the following criteria: a) arousable; b) following criteria: a) arousable; b) hemodynamically stable (without vasopressor hemodynamically stable (without vasopressor agents); c) no new potentially serious agents); c) no new potentially serious conditions; d) low ventilatory and end-conditions; d) low ventilatory and end-expiratory pressure requirements; and e) low expiratory pressure requirements; and e) low Fio2 requirements which can be met safely Fio2 requirements which can be met safely delivered with a face mask or nasal cannula. If delivered with a face mask or nasal cannula. If the spontaneous breathing trial is successful, the spontaneous breathing trial is successful, consideration should be given for extubation consideration should be given for extubation (grade 1A).(grade 1A).

M V of Sepsis-Induced M V of Sepsis-Induced ARDSARDS10. Against the routine use of the pulmonary 10. Against the routine use of the pulmonary

artery catheter for patients with sepsis-artery catheter for patients with sepsis-induced ARDS (grade 1A).induced ARDS (grade 1A).

11. A conservative rather than liberal fluid 11. A conservative rather than liberal fluid strategy for patients with established sepsis-strategy for patients with established sepsis-induced ARDS who do not have evidence of induced ARDS who do not have evidence of tissue hypoperfusion (grade 1C).tissue hypoperfusion (grade 1C).

12. In the absence of specific indications such 12. In the absence of specific indications such as bronchospasm, not using beta 2-agonists as bronchospasm, not using beta 2-agonists for treatment of sepsis-induced ARDS (grade for treatment of sepsis-induced ARDS (grade 1B)1B)

Sedation, Analgesia, & Sedation, Analgesia, & NMB NMB 1. Continuous or intermittent sedation be minimized 1. Continuous or intermittent sedation be minimized

in mechanically ventilated sepsis patients, in mechanically ventilated sepsis patients, targeting specific titration endpoints (grade 1B).targeting specific titration endpoints (grade 1B).

2. Neuromuscular blocking agents (NMBAs) be 2. Neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient avoided if possible in the septic patient without without ARDS due to the risk of ARDS due to the risk of prolonged neuromuscular prolonged neuromuscular blockade following discontinuation. If NMBAs must blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as be maintained, either intermittent bolus as required or continuous infusion with train-of-four required or continuous infusion with train-of-four monitoring of the depth of blockade should be monitoring of the depth of blockade should be used (grade 1C).used (grade 1C).

Sedation, Analgesia, & Sedation, Analgesia, & NMBNMB

3. A short course of NMBA of not 3. A short course of NMBA of not greater than 48 hours for patients greater than 48 hours for patients with early sepsis-induced ARDS and a with early sepsis-induced ARDS and a Pao2/Fio2 Pao2/Fio2 < 150 mm Hg (grade 2C). < 150 mm Hg (grade 2C).

The impact of compliance The impact of compliance with 6-hr & 24 hr Sepsis with 6-hr & 24 hr Sepsis bundlesbundles• Non-compliance with 6-hr bundle – more Non-compliance with 6-hr bundle – more

than twofold increase in mortalitythan twofold increase in mortality• Non-compliance with 24-hr bundle Non-compliance with 24-hr bundle

resulted in 76% increase in risk of resulted in 76% increase in risk of mortality.mortality. Gao, Crit Care, 2005Gao, Crit Care, 2005

• Implementation of new evidence-based Implementation of new evidence-based research innovations for sepsis in real research innovations for sepsis in real world clinical practice is feasibleworld clinical practice is feasible

Nguyen, Acad Emer Med 2006, Shapiro, Nguyen, Acad Emer Med 2006, Shapiro, Crit Care Med 2006, Korgten, Crit Care Med 2006Crit Care Med 2006, Korgten, Crit Care Med 2006

The Surviving Sepsis Campaign: results of The Surviving Sepsis Campaign: results of an international guideline-based an international guideline-based performance improvement program performance improvement program targeting severe sepsis. targeting severe sepsis. Crit Care Med 2010Crit Care Med 2010

Levy MM, Dellinger RP, Townsend SR, Linde-Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, et al.Zwirble WT, Marshall JC, Bion J, et al.

• In Europe and North and South America,In Europe and North and South America,

• Compliance rate of 31.3%.Compliance rate of 31.3%.

• Reduction in mortality from 37% to 30.8%Reduction in mortality from 37% to 30.8%

Renal Replacement Renal Replacement TherapyTherapy1. Continuous renal replacement 1. Continuous renal replacement

therapies and intermittent hemodialysis therapies and intermittent hemodialysis are equivalent in patients with severe are equivalent in patients with severe sepsis and acute renal failure (grade sepsis and acute renal failure (grade 2B).2B).

2. Use continuous therapies to facilitate 2. Use continuous therapies to facilitate management of fluid balance in management of fluid balance in hemodynamically unstable septic hemodynamically unstable septic patients (grade 2D).patients (grade 2D).

NutritionNutrition1. Administer oral or enteral (if necessary) 1. Administer oral or enteral (if necessary)

feedings, as tolerated, rather than either feedings, as tolerated, rather than either complete fasting or provision of only complete fasting or provision of only intravenous glucose within the first 48 intravenous glucose within the first 48 hours after a diagnosis of severe hours after a diagnosis of severe sepsis/septic shock (grade 2C).sepsis/septic shock (grade 2C).

2. Avoid mandatory full caloric feeding in 2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose the first week but rather suggest low dose feeding (eg, up to 500 calories per day), feeding (eg, up to 500 calories per day), advancing only as tolerated (grade 2B).advancing only as tolerated (grade 2B).

NutritionNutrition3. Use intravenous glucose and enteral 3. Use intravenous glucose and enteral

nutrition rather than total parenteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the in conjunction with enteral feeding in the first 7 days after a diagnosis of severe first 7 days after a diagnosis of severe sepsis/septic shock (grade 2B).sepsis/septic shock (grade 2B).

4. Use nutrition with no specific 4. Use nutrition with no specific immunomodulating supplementation rather immunomodulating supplementation rather than nutrition providing specific than nutrition providing specific immunomodulating supplementation in immunomodulating supplementation in patients with severe sepsis (grade 2C).patients with severe sepsis (grade 2C).

Setting Goals of CareSetting Goals of Care

1. Discuss goals of care and prognosis with 1. Discuss goals of care and prognosis with patients and families (grade 1B).patients and families (grade 1B).

2. Incorporate goals of care into treatment 2. Incorporate goals of care into treatment and end-of-life care planning, utilizing and end-of-life care planning, utilizing palliative care principles where palliative care principles where appropriate (grade 1B).appropriate (grade 1B).

3. Address goals of care as early as 3. Address goals of care as early as feasible, but no later than within 72 hours feasible, but no later than within 72 hours of ICU admission (grade 2C)of ICU admission (grade 2C)

OthersOthers

• Bicarbonate Therapy Bicarbonate Therapy - No role if pH - No role if pH>>7.15 7.15 Grade CGrade C

Early changes in organ Early changes in organ function predict survival in function predict survival in Severe SepsisSevere Sepsis

Levy, Crit Care Med, Levy, Crit Care Med, 20052005• Improvement in CVS, Renal, or Respiratory Improvement in CVS, Renal, or Respiratory

function from baseline to day 1 was function from baseline to day 1 was significantly related to survivalsignificantly related to survival

• Continued improvement in CVS function Continued improvement in CVS function before start of day 2 & 3 was associated before start of day 2 & 3 was associated with further improvement in survivalwith further improvement in survival

• Creatinine increase in day 1 mortality Creatinine increase in day 1 mortality increase by 1.5-2 times, creatinine increase by 1.5-2 times, creatinine decrease in day 1 mortality decrease 1.5-3 decrease in day 1 mortality decrease 1.5-3

MOSAICSMOSAICS• On logistic regression analysis, On logistic regression analysis, achievement achievement

of the targets for blood cultures, antibiotics, of the targets for blood cultures, antibiotics, and central venous pressure independently and central venous pressure independently predicted decreased mortality.predicted decreased mortality.

• High-income countries, university hospitals, High-income countries, university hospitals, ICUs with an accredited fellowship ICUs with an accredited fellowship programme, and surgical ICUs were more programme, and surgical ICUs were more likely to be compliant to the resuscitation likely to be compliant to the resuscitation bundle. bundle.

ConclusionConclusion

• Educate primary doctors & nurses in Educate primary doctors & nurses in early recognitionearly recognition

• Understand Pathophysiology of SepsisUnderstand Pathophysiology of Sepsis• Assess clinically Severity of SepsisAssess clinically Severity of Sepsis• Practice the new modalities of Practice the new modalities of

TreatmentTreatment• Surviving Sepsis Campaign is to Surviving Sepsis Campaign is to

increase awareness & improve increase awareness & improve outcome in Severe Sepsisoutcome in Severe Sepsis

ConclusionConclusion

• Protocol-driven management of Protocol-driven management of severe sepsis has been associated severe sepsis has been associated with reductions in mortality of 12% with reductions in mortality of 12% to 18%to 18%

• Increasing evidence shows the Increasing evidence shows the benefit of care pathways and benefit of care pathways and "bundles" to improve the "bundles" to improve the management of patients with sepsis. management of patients with sepsis.