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Management of Severe Sepsis:

Update from the Surviving Sepsis Campaign

Barbara Birriel, MSN, ACNP-BC, FCCM

The Pennsylvania State University Disclosures

• NONE

Objectives

• Review evidence-based international sepsis guidelines

• Identify criteria and systems for early diagnosis of sepsis

• Discuss initial management of sepsis

• Discuss hemodynamic support in severe sepsis

• Discuss supportive therapy in severe sepsis WHY DO WE CARE ABOUT SEPSIS?

Incidence Cost Prevalence

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Mortality Mortality

• Overall mortality from sepsis in the U.S.

• approximately 20%

• Linear relationship to the number of organ failures

• each additional organ failure raises the mortality rate by 15%.

• Hypothermia is one of the worst prognostic signs. Patients presenting with sepsis and hypothermia have an overall mortality of ~80%.

Organ failure in sepsis Vincent, J.-L., Sakr, Y., Sprung, C. L., Ranieri, V. M., Reinhart, K., Gerlach, H., Moreno, R., et al. (2006). Sepsis in European intensive care units: results of the SOAP study.

Critical Care Medicine, 34(2), 344–353.

WHAT IS SEPSIS?

Surviving Sepsis Campaign 2012

• Sepsis: The presence (probable or documented) of infection together with systemic manifestations of infection

• Severe sepsis: Sepsis plus sepsis induced organ dysfunction or tissue hypoperfusion

• Septic shock: Sepsis induced hypotension persisting despite adequate fluid resuscitation

Sepsis - ?organism

• 1/3 of cases no organism is identified

• Any microbe may cause, but gram negative most common historically

• Higher incidence recently of gram positive due to

• Hospitalized patients

• Immunocompromised

• Indwelling catheters

• Increasing drug resistance

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Epidemiology : Causative organism Relationship Between Sepsis, Infection, and Bacteremia

TRAUMA

BURNS

PANCREATITIS

SEPSIS SIRS INFECTION SEPSIS

BACTEREMIA

OTHER

Infection or Insult

Inflammatory Mediators

Endothelial Dysfunction

↑ permeability Vasodilation

Hypotension Vasoconstriction Edema

Maldistribution of Microvascular Blood Flow

Organ Dysfunction

Microvascular Plugging

Ischemia / Tissue Hypoxia

Cell Death

Pro-inflammatory Mediators

• Bacterial Endotoxin • TNF-α • Interleukin-1 • Interleukin-6 • Interleukin-8

• Platelet Activating Factor (PAF) • Interferon-Gamma • Prostaglandins • Leukotrienes • Nitric Oxide

Anti-inflammatory Mediators

• Interleukin-10

• PGE2

• Protein C

• Interleukin-6

• Interleukin-4

• Interleukin-12

• Lipoxins

• GM-CSF

• TGF

• IL-1RA

Infection or Insult

Inflammatory Mediators

Endothelial Dysfunction ↑ permeability

Vasodilation

Hypotension Vasoconstriction Edema

Maldistribution of Microvascular Blood Flow

Organ Dysfunction

Microvascular Plugging

Ischemia / Tissue Hypoxia

Cell Death

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DIAGNOSTIC CRITERIA

Trajectory of Sepsis

• Infection – inflammatory response to microorganism

• Systemic Inflammatory Response Syndrome (SIRS)

• Sepsis – infection + SIRS

• Severe Sepsis – sepsis + organ dysfunction

• Septic Shock – sepsis + hypotension despite fluid resuscitation

• Multiple Organ Dysfunction Syndrome – organ failure in acutely ill patient

SIRS Systemic Inflammatory Response Syndrome

• Two or more of the following

• Temperature > 38 C or <36 C

• Heart rate > 90

• Respiratory rate > 20 resp/min or PaCO2 <32

• WBC > 12,000, < 4,000, or >10% bands

Sepsis

• Infection (documented or suspected) and some of:

• General

• Fever (> 38.3°C)

• Hypothermia (core temperature < 36°C)

• Heart rate > 90/min– or more than two sd above the normal value for age

• Tachypnea

• Altered mental status

• Significant edema or positive fluid balance (> 20 mL/kg over 24 hr)

• Hyperglycemia (plasma glucose > 140 mg/dL or 7.7 mmol/L) in the absence of diabetes

Sepsis

• Infection (documented or suspected) and some of:

• Inflammatory variables

• Leukocytosis (WBC count > 12,000 μL–1)

• Leukopenia (WBC count < 4000 μL–1)

• Normal WBC count with greater than 10% immature forms

• Plasma C-reactive protein more than two sd above the normal value

• Plasma procalcitonin more than two sd above the normal value

Sepsis

• Infection (documented or suspected) and some of:

• Hemodynamic variables

• Arterial hypotension (SBP < 90 mm Hg, MAP < 70 mm Hg, or an SBP decrease > 40 mm Hg in adults or less than two sd below normal for age)

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Sepsis

• Infection (documented or suspected) and some of:

• Organ dysfunction variables

• Arterial hypoxemia (Pao2/Fio2 < 300)

• Acute oliguria (urine output < 0.5 mL/kg/hr for at least 2 hrs despite adequate fluid resuscitation)

• Creatinine increase > 0.5 mg/dL or 44.2 μmol/L

• Coagulation abnormalities (INR > 1.5 or aPTT > 60 s)

• Ileus (absent bowel sounds)

• Thrombocytopenia (platelet count < 100,000 μL–1)

• Hyperbilirubinemia (plasma total bilirubin > 4 mg/dL or 70 μmol/L)

Sepsis

• Infection (documented or suspected) and some of:

• Hypoperfusion variables

• Hyperlactatemia (> 1 mmol/L)

• Decreased capillary refill or mottling

Severe Sepsis

• Sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following thought to be due to the infection):

• Sepsis-induced hypotension

• Lactate above upper limits laboratory normal

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

• Acute lung injury with Pao2/Fio2 < 250 in the absence of pneumonia as infection source

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

• Creatinine > 2.0 mg/dL (176.8 μmol/L)

• Bilirubin > 2 mg/dL (34.2 μmol/L)

• Platelet count < 100,000 μL

• Coagulopathy (international normalized ratio > 1.5)

Septic Shock

• Same criteria as sepsis

• Persistent hypotension (MAP < 70)

• AFTER fluid resuscitation

Grading Quality of Evidence GRADE System

• A- high quality

• B- intermediate

• C- low

• D- very low

– Case series or expert opinion

• Upgrade capability

• Ungraded (UG) recommendation

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Grading Strength of Recommendation GRADE System

• 1- strong recommendation

– We recommend

• 2- weak recommendation

– We suggest

Therapeutic Strategies in Sepsis

• Screening for Sepsis and Performance Improvement

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

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

“Time Zero”

• Time Zero = time of presentation

• ED, Medical Floors, ICU

• Two time based bundles

• Most important time based elements:

• Antibiotic timing

• Resuscitation timing (EGDT)

Hospital-wide impact of a standardized order set for

the management of bacteremic severe sepsis

Thiel, S. W., Asghar, M. F., Micek, S. T., Reichley, R. M., Doherty, J. A., & Kollef, M. H. (2009). Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis*. Critical Care Medicine, 37(3), 819–824. doi:10.1097/CCM.0b013e318196206b

After

Before

SURVIVING SEPSIS CAMPAIGN BUNDLES

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

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

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation

to maintain a mean arterial pressure [MAP] 65 mm Hg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic

shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,

ScvO2 of 70%, and normalization of lactate

Why measure lactate?

• Diagnose severe sepsis with elevated lactate as a diagnosis of tissue hypoperfusion

• Trigger for quantitative resuscitation if lactate is 4 mg/dL or more

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SURVIVING SEPSIS CAMPAIGN BUNDLES

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

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

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation

to maintain a mean arterial pressure [MAP] 65 mm Hg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic

shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,

ScvO2 of 70%, and normalization of lactate

Blood Cultures

Diagnosis

1. To optimize identification of causative organisms, we recommend at least two blood cultures be obtained before antimicrobial therapy is administered as long as such cultures do not cause significant delay (>45 minutes) in antimicrobial administration, with at least one drawn percutaneously and one drawn through each vascular access device, unless the device was recently (<48 hr.) inserted (Grade 1C).

SURVIVING SEPSIS CAMPAIGN BUNDLES

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

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

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation

to maintain a mean arterial pressure [MAP] 65 mm Hg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic

shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,

ScvO2 of 70%, and normalization of lactate

Kumar A, et al. Crit Care Med 2006; 34:1589-1596

Time to Antibiotics Following Onset Septic Shock

Antibiotic Therapy

We recommend that intravenous antibiotic therapy be started as early as possible and within the first hour of recognition of septic shock (1B) and severe sepsis without septic shock (1C).

Remark: Although the weight of evidence supports prompt administration

of antibiotics following the recognition of severe sepsis and septic shock, the feasibility with which clinicians may achieve this ideal state has not been scientifically validated.

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Antibiotic Therapy

Initial empiric anti-infective therapy – activity against all likely pathogens and adequate concentrations into suspected or potential sources of infection (1B)

Reassess antibiotic regimen daily for de-escalation (1B)

SURVIVING SEPSIS CAMPAIGN BUNDLES

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

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

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation

to maintain a mean arterial pressure [MAP] 65 mm Hg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic

shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,

ScvO2 of 70%, and normalization of lactate

Fluid therapy

4. We recommend that initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemic be started with ≥ 1000 mL of crystalloids (to achieve a minimum of 30ml/kg of crystalloids in the first 4 to 6 hours).

(Grade 1B).

Fluid therapy

1. Crystalloids (1B)

2. Albumin (2C)

3. Avoid HES (1B)

Fluid therapy

4. Initial fluid challenge in sepsis-induced tissue hypoperfusion (hypotension or elevated lactate) with suspicion of hypovolemia to be a minimum of 30ml/kg of crystalloids(a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid, may be needed in some patients ( 1B)

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SURVIVING SEPSIS CAMPAIGN BUNDLES

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

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

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation

to maintain a mean arterial pressure [MAP] 65 mm Hg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic

shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,

ScvO2 of 70%, and normalization of lactate

Resuscitation of Sepsis Induced Tissue Hypoperfusion

• Recommend MAP 65 mm Hg

Grade 1C

Sepsis Induced Tissue

Hypoperfusion

Requirement for vasopressors after fluid challenge Lactate ≥ 4 mg/dL

Vasopressors

De Backer D, et al. N Engl J Med 2010, 362;9:779-789

28-day Survival

Crit Care Med. 2012 Mar;40(3):725-30

Meta-analysis – NE versus dopamine

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Vasopressors

Front line:

(1) Norepinephrine (1B).

(2) Epinephrine (2B)

Vasopressin .03 units/min (UG)

Vasopressors • In general avoid

– Dopamine, unless

• Relative or absolute bradycardia and low risk of tachyarrhythmias

(2C)

– Phenylephrine, unless

• Norepinephrine associated with serious arrhythmias

• Cardiac output is known to be high and blood pressure target difficult to achieve

• As salvage therapy

(1C)

Protocolized Care

SURVIVING SEPSIS CAMPAIGN BUNDLES

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

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

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation

to maintain a mean arterial pressure [MAP] 65 mm Hg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic

shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,

ScvO2 of 70%, and normalization of lactate

Initial Resuscitation of Sepsis Induced Tissue Hypoperfusion

Recommend

Insertion central venous catheter

Recommended goals :

• Central venous pressure: 8–12 mm Hg

• Higher with altered ventricular compliance or increased intrathoracic pressure

• ScvO2 saturation (SVC) 70%

Grade 1C

Limitation of pressure measurement to predict fluid

responsiveness

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SURVIVING SEPSIS CAMPAIGN BUNDLES

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

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

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation

to maintain a mean arterial pressure [MAP] 65 mm Hg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic

shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,

ScvO2 of 70%, and normalization of lactate

Lactate Clearance

In patients with elevated lactate levels as a marker of tissue hypoperfusion we suggest targeting resuscitation to normalize lactate as rapidly as possible (grade 2C).

Therapeutic Strategies in Sepsis

• Diagnosis

• Cultures (grade 1C).

• Imaging studies to confirm source of infection (UG).

Therapeutic Strategies in Sepsis

• Antimicrobial Therapy

• Effective intravenous antimicrobials within the first hour (1B/1C)

• Empiric anti-infective therapy of one or more drugs

• activity against all likely pathogens and penetrate suspected source tissue (1B)

• Combination therapy if neutropenic, MDRO, resp failure + septic shock (2B)

• Reassessed daily for potential de-escalation (1B)

• Procalcitonin or similar biomarkers to assess for discontinuation in those without evidence of infection(2C)

Therapeutic Strategies in Sepsis

Source Control

• Diagnosis and intervention in first 12 hours (1C)

• In severe sepsis

• Choose the effective intervention associated with the least physiologic insult (UG)

• Remove vascular access devices if suspected source (UG).

Therapeutic Strategies in Sepsis

• Infection Prevention

• Selective oral decontamination

• Selective digestive decontamination

• Oropharyngeal decontamination

• Oral chlorhexidine gluconate

• To reduce the risk of ventilator-associated pneumonia (2B)

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Hemodynamic Support

• Fluid Therapy in Severe Sepsis

• Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock (1B)

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

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

• Continue as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables (UG)

Effect on Cardiac Filling

Hemodynamic Support

• Vasopressors

• Target a mean arterial pressure (MAP) of 65 mm Hg (1C)

• Norepinephrine as the first choice vasopressor (1B)

• Add next or to decrease the norepi dose:

• Epinephrine (2B)

• Vasopressin 0.03 units/min (UG)

• Dopamine as an alternative –rarely (2C)

• Phenylephrine is not recommended unless complications from norepi or salvage therapy (1C)

• Low-dose dopamine should not be used for renal protection (1A)

• Place an arterial catheter (UG)

Crit Care Med. 2012 Mar;40(3):725-30

Meta-analysis – NE versus dopamine

Hemodynamic Support

• Inotropic Therapy

• Dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP (1C)

• Not using a strategy to increase cardiac index to predetermined supranormal levels (1B)

During Septic Shock

10 Days Post Shock

Diastole Systole

Diastole Systole

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Adjunctive Therapy

• Corticosteroids – NO

• Unless hemodynamic stability not achievable in septic shock (2C)

• No ACTH stimulation test (2B)

• Blood Products – Hgb 7.0 (1B)

• IV immunoglobulins – no (2B)

• Recombinant Activated Protein C - NO

Other Supportive Therapy

• Mechanical Ventilation – ARDSNET

• Sedation and Analgesia

• Glucose Control

• Renal Replacement Therapy

• DVT Prophylaxis

• Stress Ulcer Prophylaxis

• Nutrition – within 48 hrs (2C), low dose (2B)

• Setting Goals of Care

Summary of Trials

Rivers 2001

RCT

Sebat 2005

Before-After

Nguyen 2007

Complete or Not

Thiel 2009

Before-After

Levy 2011

Before-After

Goals

CVP >8

MAP > 65

ScVO2 >70%

HCT >30

MAP > 70

SaO2 > 92

UOP > 30ml/h

SvO2 > 60

CI > 2.5

ABX in 4 h

CVP > 8, MAP >

65, ScVO2 >

70%, HCT > 30

Check Lactate

Steroids

Appropriate ABX

in 4 h, CVP > 8,

MAP > 65,

ScVO2 > 70%

Early ABX, Blood

Cultures,

Appropriate

ABX, CVP > 8,

MAP > 65,

SvO2 > 70%

Specific

Interventions Fluids, Blood,

Pressors

ABX, Fluids

Pressors

ABX, Fluids,

Blood, Pressors

ABX, Fluids,

Pressors, Steroids,

Xigris, Other

Supportive Care

ABX, Fluids,

Pressors, Steroids,

Xigris, Other

Supportive Care

System

Interventions ED-based

Sepsis Team

Screening,

Education,

Shock Team,

Protocols

Education, In-

services,

Protocols

Education, In-

services, Order

Set, Protocols

Screening,

Education, Order

Sets

Absolute

Change in

Mortality -16% -12% -19% -16% -7%

Where Do The Gains Live?

A B

Lead Time to Diagnosis Delivery of Proper Treatment

Lead time to Diagnosis & Treatment

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