John J. Ancy, MA, RRT
Senior Clinical Consultant
Instrumentation Laboratory
Surviving Sepsis
 Sepsis, as many deaths as from MI
 How to improve survival?
 Rapid accurate diagnosis and treatment (lab
tests are critical)
 Appropriate antimicrobial therapy
 Compliance with Sepsis Bundles
Surviving Sepsis Campaign
 Worldwide, started in 2001
 11medical organizations in 2004
 Currently, 18 organizations
 Goal – reduce mortality by 25%
Surviving Sepsis Guidelines
 First guidelines – 2001
 Updated – 2004, 2006 & 2007
 Current guidelines – 2008
Graded recommendations
Strength of recommendations 1-2
Evidence A-D
1A – 2D
Surviving Sepsis Campaign. Crit Care Med 2008; 36:296-327 & 36:13941396.
Sepsis
 Uncontrolled inflammatory response,
secondary to infection.
 30 to 40% associated with bacteremia
Sepsis & Friends
Definitions
 SIRS
 Sepsis
 Severe Sepsis
 Septic Shock
 MOF (MODS)
 ALI/ARDS
SIRS
 Systemic Inflammatory Response Syndrome
Systemic inflammatory state without proven source
of infection
Sepsis
Sepsis =
Infection + systemic manifestations of
infection
Some manifestations:
Fever or hypothermia
Elevated HR
Tachypnea
Arterial hypotension
Hypoxemia
Hyperlactatetemia
Sepsis
 Inflammatory Variables
Leukocytosis WBC > 12000
Leukopenia WBC < 4000
Normal WBC with > 10% immature
Plasma C-reactive proteins >2 SD above norm
Plasma Procalcitonin > 2SD above norm
Early Lab Clues
 Glucose > 120mg/dL
 Creatinine increase > 2.0 mg/dL
 INR > 1.5 or aPTT > 60 sec
 Thrombocytopenia < 100000
 Hyperbilirubinemia > 2 mg/dL
 Lactate > 1mM/L ? (>2.0)
Balk, RA, Dis Mon Apr 2004 50(4): 168-213
Severe Sepsis
Sepsis with acute, sepsis-induced organ
dysfunction and/or tissue hypoperfusion
Septic Shock
Sepsis + sepsis-induced hypotension, despite
adequate fluid resuscitation
MOF/MODS
Multiple Organ Failure or
Multiple Organ Dysfunction Syndrome
ALI/ARDS
ALI
Acute Lung Inflammation
ARDS
Acute Respiratory Distress Syndrome
SEPSIS is the most common cause of ARDS
ALI/ARDS
Acute Lung Inflammation
Lung inflammation
CXR Bilateral diffuse infiltrates
No clinical evidence of ▲left atrial pressure
or ▼PCWP<18mm Hg
P/F ratio 200-300 (PaO2/FiO2)
PaO2 100mmHg/ FiO2 0.5 = 200
ALI/ARDS
Acute Respiratory Distress Syndrome
(Sepsis most common cause)
Lung inflammation
CXR Bilateral diffuse infiltrates
No clinical evidence of ▲left atrial pressure
or ▼PCWP<18mm Hg
P/F ratio <200 (PaO2/FiO2)
PaO2 100mmHg/ FiO2 0.6 = 166
SIRS Mortality
Mortality goes up with organ failure
7% SIRS+2 failed organs
10% SIRS+3
17% SIRS+4
Rangel-Frausto, M., Pettet, D., Costigan, M., et. al. The natural history of the
systemic inflammatory response syndrome (SIRS). JAMA 273:117-123,
1995
Sepsis Mortality
 Millions affected worldwide
 At minimum, 25% mortality (51% in some
studies)
Epidemiology
“Severe sepsis is a common, expensive and
frequently fatal condition, with as many deaths
as those from acute myocardial infarction”
Martin, GS; Mannino, DM; Eaton, S; Moss, M. The
Epidemiology of Sepsis in the United States from 1979
through 2000. N Engl J Med. 2003;348: 1546-1554.
Epidemiology
 2004 Severe Sepsis 750,000 (US)
 2010 Severe Sepsis 1,000,000 (US)
 US cost $16.7 B
 $22,100 per case
 Mortality 25% to 51%
 210,000 annual deaths (US)
Epidemiology
 Incidence increasing
 Morbidity/mortality decreasing
 More common in winter months
 Sepsis survivors have increased
morbidity/mortality for 5 years
Curr Pharm Des. 2008; 14 (19): 1833-9
Epidemiology
 Gram+ most common organisms
 Majority of infectious sources
Pulmonary
GI
Genitourinary
Primary bloodstream
Risk Factors
 Over 65 YOA
 Male
 Bacteremia
 Weakened immune system
 AIDS, cancer, diabetes or chronic disease
 Pneumonia
 Hospitalization
 Severe traumatic injuries
 Invasive medical devices
 Genetic susceptibility
 Lower socioeconomic status
Micro-organisms
 Bacterial
 Fungal
 Viral
 Protozoan
Community Acquired
Microorganisms
Lung
Streptococcus
pneumonia
Hemophilus
influ.
Legionella sp
Chlamydia
pneumonia
Abdomen
Escherichia
coli
Bacteroides
fragilisn
Skin/Soft
Tissue
Urinary Tract
Escherichia
coli
Klebsiella
sp.
Enterobacter
sp.
Polymicrobial
Aerobic gr neg Proteus sp.
Streptococcus
pyogenes
Staph. aureus
Clostridium
sp.
Pseudomonas
aeruginosa
Staph. sp.
CNS
Streptococcus
pneumonia
Neiserria
meningitidis
Listeria
monocytogen
Escherichia
coli
Hemophilus
influ.
Nosocomial Pathogens
Lung
Aerobic
gram
negative
bacilli
Abdomen
Aerobic
gram neg
bac
Anaerobes
Candida sp.
Skin/Soft
Tissue
Staph.
Aureus
Aerobic
gram
negative
bacilli
Urinary Tract
CNS
Pseudomonas
aeruginosa
Escherichia
coli
Klebsiella sp.
Enterococcus Staph. sp
Aerobic
gram
negative
bacilli
sp.
Sepsis Pathophysiology
 Heterogenous
No single mediator/system/pathway/pathogen
 Derangements involving several organ systems
 Hyperinflammatory response (commonly),
suppressed inflammatory response or
mixed response
Sepsis Pathophysiology
 Life threatening changes in coagulation
 Neutrophils mixed response
 Apoptosis of lymphocytes/other cells
Inflammatory Response
Eliminate invading microorganisms without
damaging tissues or cells
Aberrant Inflammatory
Mediator Production
“Inflammatory response an important component
of sepsis as it drives physiologic responses that
result in organ dysfunction.”
Remick, DG; Am J Pathol. 2007 May; 170(5); 1435-1444
Hyperinflammatory
Response
 Numerous and plentiful proinflammatory
molecules released in sepsis
 Tumor Necrosing Factor (TNF), interleukins,
cytokines and many others elevated
 Endotoxin elevated = increased inflammatory
response
 Blunt inflammation and save lives?
 rhAPC-recombinant human activated protein C
(Dotrecogen)
Blunted Inflammatory
Response
 Studies show that some patients have inhibited
proinflammatory response and unabated antiinflammatory response.
Failure to control bacteria infection and succumb
as a result of immunosuppression rather than
immunostimulation.
Mixed Inflammatory Response
 Some studies indicate pathophysiologic
contributions from proinflammatory and antiinflammatory mediators
Normal Hemostasis
Allows blood to remain liquid and flowing and
clots to control bleeding
Dysregulated Coagulation
 Coagulation cascade alteration
Sepsis patients often have DIC
platelet consumption
prolonged clotting time
microcirculatory clotting
profuse bleeding
Dysregulated Coagulation
 Virchow’s Triad
Altered coagulation
Endothelial cell injury-inflammatory agents
Abnormal blood flow
 Poor tissue perfusion in vital organs
Inappropriate O2 delivery/useage
Cytopathic hypoxia
Lactic acid production
Cellular Dysfunction
 Many cellular aspects are dysfunctional in
sepsis (neutrophils)
Excessive activation
Neutrophils generating excessive inflammatory
product damaging nearby cells
Depressed function
Neutrophil failure to phagocytize
Neutrophil activity
 Neutrophilic function key component of
immune response:
Neutropenia = infectious complications
Overactive neutrophilic activity =
hyperinflammatory response
In sepsis and other serious illness neutrophil
response is very complex and heterogenous.
Some patients have excessive response, others
blunted activity. Either case results in less
effective immune response.
Lymphocyte Apoptosis
 Very pronounced in sepsis
Observed in virtually all lymphoid organs
Spleen
Thymus
Gastric tissues
Reduces immune response effectiveness
Septic Apopotosis
 Affects many cells/tissues
Dendritic cells
Macrophages
Monocytes
Mucosal epithelial cells
Endothelial cells
Others
Altered Metabolism
 Diabetes of stress (Sepsis)
Insulin resistance
Hyperglycemia
Elevated Glucose
 Decreased function of polymorphonuclear
neutrophils
 Decreased bactericidal activity
 Endothelial cell disruption
Glycemic Control
 Reduces infection/faster resolution
 Improves renal function
 Reduces muscle wasting
 Reduces severity and incidence of anemia
 Protects endothelial cells
 Improved morbidity and mortality
Sepsis Pathophysiology
Infection triggers hyperinflammatory response or
(blunted response = sepsis)
Coagulation dysregulation
Lymphocyte & neutorophil dysfunction
Microcirculatory and perfusion failure
Tissue oxygenation disruption
Stress diabetes
Sepsis Pathophysiology
Tissue and organ failure
Pulmonary and peripheral edema
Cardiac output is often elevated
BP difficult to maintain- extreme vasodilation
Maldistribution in microcirculatory beds
Higher morbidity/mortality in those with preexisting cardiovascular disease
Surviving Sepsis 2008
 Graded Recommendations
1.Treatment
Emergency Resuscitation (6 Hours)
Management ( Within 24 Hours)
2. Supportive Care
GRADE
Grade
Recommendation
Assessment
Development
Evaluation
GRADE
Surviving Sepsis Recommendations
 Numerical
1= treatment outweighs harm/burden/costs
2= treatment carries risk/burden/costs
 Letter
A = well documented
B = moderate
C = low
D = very low
2008 GRADE Recommendations
61 recommendations
 40 level 1
 21 level 2
 7 1A recommendations
DVT prophylaxis
Stress ulcer prophylaxis
Ventilator weaning protocol
Avoid routine PACs in ALI/ARDS
2008 GRADE Recommendations
 16 1B
Sedation weaning protocol for vent patients
Either crystal or colloid for fluid resuscitation
Blood glucose < 150 mg/dL
 17 1C
Blood cultures before antibiotic therapy
Imaging confirmation for infection source
Broad spectrum antibiotics within 1hr of sepsis
confirmation
Treatment
A. Initial Resuscitaion
B. Diagnosis
C. Antibiotic Therapy
D. Source Control
E. Fluid Therapy
Treatment
F. Vasopressors
G. Inotropic Therapy
H. Corticosteroids
I. Recombinant Human Activated Protein C
J. Blood Product Administration
Supportive Care
1. Mechanical Ventilation
2. Sedation, Analgesia, & Neuromuscular
3.
4.
5.
6.
7.
Blockade
Glucose Control
Renal Replacement
Bicarbonate Therapy
DVT Prophylaxis
Stress Ulcer Prophylaxis
Initial Resuscitation (1C)
 Sepsis induced shock
Persistent hypotension with fluid admin
Lactate > 4.0 mM/L
 Tx Goals
CVP 8-12mm Hg (higher if on ventilator)
MAP > 65mm Hg
Urine output > 0.5 ml/kg/hr
O2 Sat CV > 70% or Mixed Venous > 65%
Initial Resucitation
 If venous saturation is not achieved (2C)
Consider more fluid
Transfuse packed RBCs to Hct > 30% and/or
dobutamine infusion
Rationale: increase O2 delivery and CO
Diagnosis
 Cultures before antimicrobial therapy if cultures
do not delay antibiotics (1C)
 Obtain 2 or more Blood Cultures
 Obtain 1 BC percutaneously
 Obtain BC from each vascular device in place >
48hr
 Culture other sites as clinically indicated
(preferably quantitative)
Diagnosis
Rationale:
Obtaining BCs peripherally and via access
important
If same organism, likely sepsis agent
If access device organism is + 2hrs before
peripheral culture, device is probable source
Antibiotic Therapy
 Antibiotic therapy within 1Hr of recognition
Septic shock (1B)
Severe sepsis without shock (1D)
Obtain appropriate cultures prior to initiating
therapy, but should not prevent antimicrobial
therapy (1D)
Consider premixed antibiotics, bolus admin. for
some agents
Antibiotic Therapy
 Initial empirical therapy to include one or more
drugs that have activity against likely pathogens
(bacterial/fungal) and penetrate into presumed
source (1B)
Choices are very complex, considerations:
Hx, drug intolerances, underlying disease,
susceptibility patterns of pathogens, neutropenia,
etc.
Antibiotic Therapy
Empirical continued:
Avoid recently used antibiotics
MRSA considerations
Antifungal therapy (fluconazole, ampho B,
echinocandin should be tailored to local pattern
of Candida and prior admin. of azoles
Severe sepsis or septic shock
Broad-spectrum therapy
Antibiotic Therapy
 Further recommendations
Duration 7-10 days, longer for slow response,
undrainable foci, immunologic deficiencies
Stop therapy promptly if proven noninfectious
CAUTION: > 50% of blood cultures in severe sepsis or septic
shock will be negative for bacteria or fungi
Antibiotic Therapy
Serum antimicrobial monitoring daily (1C)
Rationale:
Septic shock/sepsis may inhibit renal and/or
hepatic function
Abnormal volume distribution due to aggressive
fluid therapy
Goal: adequate distribution without toxicity
Goal: Narrow spectrum and to reduce duration to
minimize super-infection, but balance with
effective duration
Vasopressors
Norepinephrine or dopamine firstline vasopressors
All patients requiring vasopressors should be
monitored with indwelling arterial pressure
catheter (1D)
Monitor adequacy of perfusion with lactate levels
(maintain below 4 mM/L )and urine output
Vasopressors
 Use vasopressors to maintain mean arterial
pressure > 65mm Hg (1C)
Higher MAP for patient with previously controlled
hypertension
Lower MAP adequate for young previously
normotensive patient
Inotropic Therapy
 Dobutamine infusion for myocardial dysfunction
as indicated by elevated cardiac filling
pressures and low CO (1C)
Septic patients often require vasopressor and
inotropic therapy
Mechanically ventilated patients with sepsis are
particularly at risk for cardiac decompensation.
Dotrecogen (Xigris®)
recombinant human activated protein C rhAPC
 FDA approved (some controversy)
Anti-inflammatory activity and improved
hemostasis
Dotrecogen (Xigris®)
recombinant human activated protein C rhAPC
 Consider rhAPC in adults with sepsis induced
organ dysfunction or high risk of death
(APACHE II > 25) 2B (2C postoperative)
 Septic patients with low risk ( APACHE < 20
should not receive rhAPC )1A
Blood Product
Administration
 RBC transfusion (target Hb 7-9 g/dL) once
hypoperfusion, severe hypoxemia, lactic
acidosis are resolved (1B)
No difference in mortality compared to
Hb 10-12g/dL
Blood Product
Administration
 Fresh frozen plasma should not be used to
correct laboratory clotting abnormalities
(increased PT,INR, PTT) in the absence of
bleeding (2D)
Blood Product
Administration
 Antithrombin administration should not be used
in treatment of severe sepsis and septic shock
(1B)
Studies show mixed mortality and morbidity
results
Supportive Therapy
1. Mechanical Ventilation
2. Sedation, Analgesia, & Neuromuscular
3.
4.
5.
6.
7.
Blockade
Glucose Control
Renal Replacement
Bicarbonate Therapy
DVT Prophylaxis
Stress Ulcer Prophylaxis
Mechanical Ventilation
 Lung protective ventilation septic ALI/ARDs
patients
Tidal volume of 6ml/kg for (1B)
Plateau Pressure < 30 cm H2O (1C)
Permissive hypercapnia to minimize tidal volume
and plateau pressure (1C)
PEEP to avoid extensive lung collapse (1C)
HOB elevated to help prevent VAPs (1B)
Sedation, Analgesia &
NMBA
 Sedation and analgesia protocols (1B)
 Avoid neuromuscular blocking agents if
possible (1B)
Glucose Control
 Administer iv insulin for hyperglycemia in
severe sepsis (1B)
 Use glycemic control protocol to maintain
glucose < 150 mg/dL (2C)
 Patients receiving iv insulin and glucose calorie
source have glucose level monitored Q2 (1C)
 Low glucose levels monitored at POC should be
interpreted with caution (1B)
Bicarbonate Therapy
 Bicarb therapy should not be used for purpose
of improving hemodynamics or reducing
vasopressor requirements in patients with
hypoperfusion-induced lactic acidemia with pH
> 7.15 (1B)
Bicarb admin shown to increase Na, lactate, pCO2
decreased iCa, and fluid overload
Labs
 Cultures
 Antibiotic levels
 CBC
 Coagulation
 Chemistries
 Blood Gases
 Renal function & liver function tests
 Lactate
Lactate
 Lactate is a key indicator of tissue oxygenation.
Successful treatment of sepsis requires
restoration and maintenance of tissue perfusion
and oxygenation.
Lactate
 Normal concentration 0.5 – 2.2 mM/L
 Normal production 15 – 20 mM/kg day
 Increases with increased production and/or
decreased utilization or clearance (liver failure)
Lactate Production &
Metabolism
 Lactate normally produced by RBCs (no
mitochondria)
 During anaerobic metabolism in most tissues
(sepsis, cardiac arrest)
 Kidneys and liver can convert lactate to glucose
(gluconeogenesis)
Lactate Production &
Metabolism
 Liver lactate metabolism inhibited as lactate
increases (as in sepsis)
 Uptake of lactate by liver inhibited by acidosis,
hypoperfusion and hypoxia
Lactic Acidosis
 Type A
Decreased tissue perfusion and/or
oxygenation
Hypoperfusion (decreased CO, hypovolemia,
excessive vasoconstriction)
Reduced O2 content (hypoxemia, anemia,
dyshemoglobinemia)
Lactic Acidosis
 Type B
B1 common disorders (liver failure, renal
failure, diabetes, cancer, cholera, malaria)
B2 drugs and toxins (ethanol, methanol,
ethylene glycol, cocaine, zidovudine,
acetaminophen, salicylates, catecholamines,
niacin and many more)
B3 other (seizures, strenuous exercise, status
asthmaticus)
Lactate Precautions
 Not specific for perfusion/tissue oxygenation
 Arterial or mixed venous samples reflect total
body lactate
 Peripheral samples reflect lactate level in limb
(influenced by tourniquet, local circulation, etc.)
Lactate Precautions
Lactate may transiently increase with
improvement in circulation
 Rapid TAT needed (whole blood)
 Serial sampling very helpful
 Interpret relative to clinical condition
Interpretation of Blood
Lactate Results
 < 2.0 mmol/L: Normal adult at rest
 2.1 - 4.0 mmol/L: Moderately
elevated
 > 4.0 mmol/L: Seriously elevated
86
Lactate and Mortality
 Prolonged elevation of lactate and metabolic
acidosis are predictive of higher mortality
Lactate greater than 8 mM/L for 2hrs = 90%
mortality *
*Weil, WM, Affifi, AA. Experimental and Clinical Studies on Lactate and Pyruvate
as Indicators of the Severity of Shock. Circulation, 41: 989-1000, 1970.
Lactate and Mortality
 Lactate of > 5mM and pH < 7.35 have mortality
of 75% at 6 months
Lactate and Sepsis
 Sepsis induced shock diagnosis includes
Lactate > 4.0 mM/L
• Monitor adequacy of perfusion with lactate
levels (maintain below 4.0 mM/L )and urine
output
• Effective monitor of tissue oxygenation
(lactate < 4.0 mM/L)
 Serial lactate highly recommended
Sepsis Survival Improvement
 Early and appropriate fluid and blood
administration improves outcome
 Early antibiotic administration with appropriate
ongoing management improves outcome
(survival decreases by 7.6% for every hour
antibiotic therapy is delayed)*
*Kumar A, Roberts D, Wood DO, et al.; Crit Care Med 2006;34: 1589-96
Sepsis Survival Improvement
 Goal of 25% mortality decrease thought to be
attainable (210000 to 158000)
 Surviving Sepsis Recommendations are critical
to improved outcome
 Recommendations continue to evolve
Mortality Reduction-2010
 Compliance with resuscitation and
management bundles
2 year study
165 Sites
15022 subjects
Surviving Sepsis Campaign: Results of an international guideline based
performance improvement program targeting severe sepsis.
Crit Care Med 2010 Vol. 38 No. 2
Mortality Reduction-2010
 Guideline Compliance after 2 years
Resuscitation bundle
increased from 10.9% to 31.3%
Management bundle
increased from 18.4% to 36.1%
Mortality Reduction-2010
 2 year reduction
Decreased from 37.0% to 30.8%
Summary
 Sepsis is complex with many causes
 Early and accurate diagnosis are essential
 Lab tests need quick TAT
 Adherence to resuscitation and management
bundles reduces mortality (2010 study) Goal of
25% mortality decrease thought to be attainable
(210000 to 158000)
 Surviving Sepsis Guidelines continue to evolve