John J. Ancy, MA, RRT Senior Clinical Consultant
Instrumentation Laboratory
Slide 2
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
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Surviving Sepsis Campaign Worldwide, started in 2001 11medical
organizations in 2004 Currently, 18 organizations Goal reduce
mortality by 25%
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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 & 36:1394- 1396.
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Sepsis Uncontrolled inflammatory response, secondary to
infection. 30 to 40% associated with bacteremia
MOF/MODS Multiple Organ Failure or Multiple Organ Dysfunction
Syndrome
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ALI/ARDS ALI Acute Lung Inflammation ARDS Acute Respiratory
Distress Syndrome SEPSIS is the most common cause of ARDS
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ALI/ARDS A cute L ung I nflammation Lung inflammation CXR
Bilateral diffuse infiltrates No clinical evidence of left atrial
pressure or PCWP
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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
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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
Slide 18
Sepsis Mortality Millions affected worldwide At minimum, 25%
mortality (51% in some studies)
Slide 19
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.
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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)
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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
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Epidemiology Gram+ most common organisms Majority of infectious
sources Pulmonary GI Genitourinary Primary bloodstream
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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
Sepsis Pathophysiology Heterogenous No single
mediator/system/pathway/pathogen Derangements involving several
organ systems Hyperinflammatory response (commonly), suppressed
inflammatory response or mixed response
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Sepsis Pathophysiology Life threatening changes in coagulation
Neutrophils mixed response Apoptosis of lymphocytes/other
cells
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Inflammatory Response Eliminate invading microorganisms without
damaging tissues or cells
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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
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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)
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Blunted Inflammatory Response Studies show that some patients
have inhibited proinflammatory response and unabated anti-
inflammatory response. Failure to control bacteria infection and
succumb as a result of immunosuppression rather than
immunostimulation.
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Mixed Inflammatory Response Some studies indicate
pathophysiologic contributions from proinflammatory and anti-
inflammatory mediators
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Normal Hemostasis Allows blood to remain liquid and flowing and
clots to control bleeding
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Dysregulated Coagulation Coagulation cascade alteration Sepsis
patients often have DIC platelet consumption prolonged clotting
time microcirculatory clotting profuse bleeding
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
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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.
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Lymphocyte Apoptosis Very pronounced in sepsis Observed in
virtually all lymphoid organs Spleen Thymus Gastric tissues Reduces
immune response effectiveness
Altered Metabolism Diabetes of stress (Sepsis) Insulin
resistance Hyperglycemia
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Elevated Glucose Decreased function of polymorphonuclear
neutrophils Decreased bactericidal activity Endothelial cell
disruption
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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 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 pre- existing
cardiovascular disease
Slide 47
Surviving Sepsis 2008 Graded Recommendations 1.Treatment
Emergency Resuscitation (6 Hours) Management ( Within 24 Hours) 2.
Supportive Care
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GRADE Grade Recommendation Assessment Development
Evaluation
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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
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 O 2 Sat CV > 70% or Mixed Venous > 65%
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Initial Resucitation If venous saturation is not achieved (2C)
Consider more fluid Transfuse packed RBCs to Hct > 30% and/or
dobutamine infusion Rationale: increase O 2 delivery and CO
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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)
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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
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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
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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.
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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
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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
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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
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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
Slide 65
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
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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.
Slide 67
Dotrecogen (Xigris) recombinant human activated protein C rhAPC
FDA approved (some controversy) Anti-inflammatory activity and
improved hemostasis
Slide 68
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
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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
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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)
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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
Mechanical Ventilation Lung protective ventilation septic
ALI/ARDs patients Tidal volume of 6ml/kg for (1B) Plateau Pressure
< 30 cm H 2 O (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)
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Sedation, Analgesia & NMBA Sedation and analgesia protocols
(1B) Avoid neuromuscular blocking agents if possible (1B)
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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)
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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,
pCO 2 decreased iCa, and fluid overload
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Labs Cultures Antibiotic levels CBC Coagulation Chemistries
Blood Gases Renal function & liver function tests Lactate
Slide 78
Lactate is a key indicator of tissue oxygenation. Successful
treatment of sepsis requires restoration and maintenance of tissue
perfusion and oxygenation.
Slide 79
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)
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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)
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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 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)
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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.)
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Lactate Precautions Lactate may transiently increase with
improvement in circulation Rapid TAT needed (whole blood) Serial
sampling very helpful Interpret relative to clinical condition
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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
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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.
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Lactate and Mortality Lactate of > 5mM and pH < 7.35 have
mortality of 75% at 6 months
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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
Slide 90
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
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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
Slide 92
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
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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%
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Mortality Reduction-2010 2 year reduction Decreased from 37.0%
to 30.8%
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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