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SEPSIS
Disclosures
 No conflicts of interest to disclose
Learning Objectives
 Define SIRS/sepsis/severe sepsis/ septic shock
 Early recognition of sepsis
 Early goal directed therapy
Outline
 Introduction
 Background
 Definitions
 Risk Factors
 Diagnosis Criteria
 Early Recognition of Sepsis
 Early Goal Directed Therapy/ Guidelines
Introduction
 Rory Staunton Story
https://rorystauntonfoundationforsepsis.org/patient-rory-video/
BACKGROUND
Why Sepsis?
 Sepsis kills more than 258,000 Americans each year
 More than 1.6 million people in the U.S. are diagnosed with sepsis
each year and the incidence is rising
 Sepsis begins outside of the hospital for nearly 80% of patients
 Only 55% of U.S. adults have heard of sepsis
 Mortality from sepsis increases 8% for every hour that treatment
is delayed
 As many as 80% of sepsis deaths could be prevented with rapid
diagnosis and treatment
Why Sepsis?
 Four types of infections are most often associated with sepsis:
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Lung
Urinary tract
Skin
Gut
 A CDC evaluation found 7 in 10 patients with sepsis had recently
used health care services or had chronic diseases requiring
frequent medical care
 Sepsis has been named as the most expensive in-patient cost in
American hospitals in 2014 at nearly $24 billion each year
We Can Make a Difference
 There are clinical trial based interventions proven to reduce
mortality and cost
 These interventions are not routinely done in all settings
 Adherence to Surviving Sepsis Campaign bundles is important
 It is an effective approach to significantly decrease mortality of
patients with severe sepsis or septic shock
DEFINITIONS
SIRS
SEPSIS
SEVERE SEPSIS
SEPTIC SHOCK
SIRS
 SIRS: systemic inflammatory response syndrome
 Must have at least 2 of the following:
 Temperature >38°C or <36°C
 HR >90 beats/ min
 RR >20 breaths/min
 WBC >12,000 cells/mm3, <4,000 cells/mm3, or >10 % bands
 SIRS is the body’s response to infection, inflammation, stress
 Broad and includes infectious and noninfectious conditions,
surgical procedures, trauma, medications, and therapies
Sepsis
2012 Definition:
 Systemic inflammatory response to infection
 SIRS + suspected or confirmed infection
 Diagnosed via cultures or visualized via physical exam/imaging
Severe Sepsis
2012 Definition:
 Sepsis + sepsis-induced organ dysfunction or tissue
hypoperfusion
 Sepsis-induced tissue hypoperfusion:
 Infection-induced hypotension, elevated lactate, or oliguria
Septic Shock
2012 Definition:
 Sepsis-induced hypotension persisting despite adequate fluid
resuscitation
 Sepsis-induced hypotension:
 SBP <90mm Hg or MAP <70mm Hg or SBP decrease >40mm Hg or
less than 2 standard deviations below normal in absence of other causes of
hypotension
Elevated lactic acid (>2 mmol/L)
Bilirubin >2mg/dL
UOP <0.5mL/kg/hr for more than 2 hrs
despite adequate fluid resuscitation
Platelet count <100,000µL
Acute lung injury (PaO2/FiO2 < 300)
Coagulopathy (INR >1.5)
Creatinine >2.0mg/dL
Acutely altered mental status
SIRS
2016 Definition:
 An appropriate response to infection – or any other stimulus
that activates inflammation
Sepsis
2016 Definition:
 Life-threatening organ dysfunction caused by a dysregulated
host response to infection
Septic Shock
2016 Definition:
 Subset of sepsis with circulatory and cellular/metabolic
dysfunction associated with a higher risk of mortality than
sepsis alone
RISK FACTORS
Risk Factors
 ICU admission
 Bacteremia
 Advanced age (>65 years)
 Immunosuppression
 Chronic illnesses (diabetes, cancer, kidney or liver disease)
 Multidrug-resistant infection
 Severe burn or wound
 Previous hospitalization
 Genetic factors
DIAGNOSIS CRITERIA &
CLINICAL PRESENTATION
Diagnosis
 Difficult to identify patients whose organ dysfunction is truly
secondary to an underlying infection
 Diagnosis criteria:
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Clinical data
Laboratory data
Radiologic data
Physiologic data
Microbiologic data
 Diagnosis most often made empirically at bedside upon
presentation, or retrospectively when follow-up data returns
(ie: positive blood cultures, etc)
Diagnosis
 Prior to initiating antibiotic therapy, routine microbiologic
cultures (including blood) should be obtained
 Always include at least 2 sets of blood cultures
 Guidelines recommend 45 minute timeframe for cultures to
be obtained
 If cultures cannot be obtained within this 45 minute timeframe,
antibiotics may be administered
Clinical Presentation
 No single sign or symptom of sepsis
 Symptoms can include:
 Fever (or low body temperature)
 Chills
 Breathing fast
 Fast heartbeat
 Poor appetite
 Urinating less than usual
 Skin rashes
 Confusion or light-headed
EARLY RECOGNITION
Best Practice
Sepsis and septic shock are medical
emergencies
Treatment and resuscitation should
begin immediately
Early Recognition
 Time of presentation = time of triage in the emergency
department
 If presenting from another care location, time of presentation is
earliest chart annotation consistent with severe sepsis or shock
 Recommendation:
 Institution specific screening tools
 ie: Rapid assessment, SIRS screen
 Routine screening in acutely ill, high-risk patients
Early Recognition
 Early recognition is paramount
 Routine screening can increase early identification
 Suspect sepsis/septic shock in cases with fever, leukocytosis,
and hypotension
 Other considerations:
 Altered mental status, tachypnea with a normal chest x-ray and
normal oxygenation, or if clinical instinct suggests something is
“not right” in a patient with a seemingly routine infection or
suspected infection
 Reassess after initial evaluation
 Some patients will develop sepsis after the initial assessment
when it might not have been present
EARLY GOAL DIRECTED
THERAPY/GUIDELINES
Surviving Sepsis Campaign
 Early recognition of severe sepsis
 Provider education
 Screening tools
 Treat sepsis as an emergency
 Timely evidence-based management
 Assessment of perfusion
 Early antibiotics
 Fluid resuscitation
 Assessment of adequacy of resuscitation
Surviving Sepsis Campaign Bundles
 TO BE COMPLETED WITHIN 3 HOURS
 Measure lactate level
 Obtain blood cultures prior to administration of antibiotics
 Administer broad spectrum antibiotics
 Administer 30mL/kg crystalloid for hypotension or
lactate ≥4mmol/L
Surviving Sepsis Campaign Bundles
 TO BE COMPLETED WITHIN 6 HOURS:
 Apply vasopressors (for hypotension that does not respond to
initial fluid resuscitation) to maintain a mean arterial pressure
(MAP) ≥ 65 mm Hg
 In the event of persistent arterial hypotension despite volume
resuscitation (septic shock) or initial lactate ≥4 mmol/L
 Measure central venous pressure (CVP)*
 Measure central venous oxygen saturation (ScvO2)*
 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 &
INFECTION CONTROL
Initial Resuscitation
Fluid Therapy
Infection Prevention
Source Control
Antibiotics
2012 Initial Resuscitation
 Initial resuscitation within first 6 hours should include the
following in a treatment protocol:
 CVP 8–12 mm Hg
 MAP ≥ 65 mm Hg
 Urine output ≥ 0.5 mL/kg/hr
 ScvO2 ≥ 70%
Initial Resuscitation
 Recommendation for sepsis-induced hypoperfusion:
 At least 30mL/kg of IV crystalloid fluids
 Frequent reassessment of hemodynamic status recommended
prior to administering additional fluids
 Reassessment should include: clinical examination of available
physiologic variables (ie: HR, BP, RR, temperature, UO)
 Initial target MAP: 65 mm Hg in septic shock patients
requiring vasopressors
 Recommend resuscitation to normalize lactate in patients
with elevated lactate levels
Fluid Therapy
 First line: crystalloids within first 3 hours
 Normal saline or lactated ringers
 Albumin in addition to crystalloids when patients require
substantial amounts of crystalloids
 Initial fluid challenge in patients with tissue hypoperfusion
and suspicion of hypovolemia: 30mL/kg of crystalloids
 Fluid challenge should be applied where fluid administration
is continued (as long as hemodynamic factors continue to
improve)
Infection Prevention
 Educate patients and families regarding:
 Infection prevention (ie: cleaning scrapes and wounds)
 Chronic disease management
 Seeking medical attention if signs of severe infection or sepsis
are present
 Follow infection control requirements (ie: hand hygiene)
 Vaccinations
Source Control
 Initial infection diagnosis/ source control intervention
 Intervention within the first 12 hours after diagnosis, if
possible
 Effective intervention with least physiologic insult
 If intravascular access devices are possible source, removal
should be prompt (after other vascular access has been
established)
 Removal of infected catheters
 Debridement or amputation of osteomyelitis
Antibiotics
 Goal: administration within the first hour of recognition
 Current guidelines require within 3 hours
 Empiric combination therapy with at least 2 antibiotics to
cover all likely pathogens
 Example: Vancomycin + Zosyn
 Antibiotic assessment should be daily for de-escalation
 Dosing optimized based on pharmacokinetic/
pharmacodynamic principles (typically by pharmacy)
Antibiotics
 NOT recommended:
 Prophylactic antibiotic use in patients with severe inflammatory
states of noninfectious origin (ie: pancreatitis, burn)
 Combination therapy for routine treatment of neutropenic
sepsis/ bacteremia
 Empiric therapy should NOT be administered for more than
3-5 days
 De-escalation to the most appropriate single therapy after
susceptibility has been resulted
Antibiotic Duration
 Most patients with serious infections associated with sepsis/
septic shock require 7-10 days
 Longer courses appropriate in patients with slow clinical
response
 ie: undrainable infection, bacteremia with S aureus, or
immunologic deficiencies (including neutropenia)
 Shorter courses appropriate in patients with rapid clinical
response following effective source control
Antibiotics
 NOT suspect Pseudomonas  vancomycin + 1 of the following:
 Cephalosporin
 3rd generation (ceftriaxone or cefotaxime)
 4th generation (cefepime)
 Beta-lactam/beta-lactamase inhibitor
 Piperacillin-tazobactam or ticarcillin-clavulanate
 Carbapenem
 Iminpenem or meropenem
Antibiotics
 Suspect Pseudomonas  vancomycin + 2 of the following:
 Antipseudomonal cephalosporin
 Ceftazidime, cefepime
 Antipseudomonal carbapenem
 Imipenem, meropenem
 Antipseudomonal beta-lactam/beta-lactamase inhibitor
 Piperacillin-tazobactam, ticarcillin-clavulanate
 Fluoroquinolone with good anti-pseudomonal activity
 Ciprofloxacin
 Aminoglycoside
 Gentamicin, amikacin
 Monobactam
 Aztreonam
Procalcitonin (PCT)
 Biomarker that exhibits greater specificity than other proinflammatory
markers (ie: cytokines)
 Can assist in identifying patients with sepsis and can be used in the diagnosis
of bacterial infections
 Elevated values are highly suggestive of an infection, typically bacterial, with
a systemic response (sepsis, or severe sepsis or septic shock)
 PCT concentrations are typically below 0.05 ng/mL
 Concentrations can increase up to 1000 ng/mL in patients with sepsis,
severe sepsis or septic shock
 Procalcitonin levels may be used to shorten duration of antibiotic
therapy
 Some research to support use in discontinuation of empiric antibiotics in
patients who initially appeared septic, but subsequently had limited
clinical evidence of infection
HEMODYNAMIC SUPPORT &
ADJUNCTIVE THERAPY
Vasopressors
 First line: Levophed (norepinephrine)
 Additional recommendations:
 Adding either vasopressin (up to 0.03 units/min) or
epinephrine to norepinephrine to raise MAP to target or adding
vasopressin to decrease norepinephrine dose
 Dobutamine may be used in patients with persistent
hypoperfusion despite adequate fluids and vasopressor use
Vasopressors
 Dopamine: possible alternative to norepinephrine ONLY in
highly selected patients
 ie: patients with low risk of tachyarrhythmias and absolute or
relative bradycardia
 ALL patients requiring vasopressors should have an arterial
catheter placed as soon as practical
 Low dose dopamine NOT recommended for renal protection
Norepinephrine
 Pharmacologic Category
 Alpha-/Beta- Agonist
 Mechanism of action:
 Stimulates beta1-adrenergic receptors and alpha-adrenergic
receptors  increased contractility and heart rate as well as
vasoconstriction  increases systemic blood pressure and
coronary flow
 Alpha effects (vasoconstriction) are greater than beta effects
(inotropic and chronotropic effects)
Norepinephrine Dosing
 Dosing:
 Initial: 8 to 12 mcg/minute; titrate to desired response
 Usual maintenance range: 2 to 4 mcg/minute
 Sepsis and septic shock (weight-based dosing):
 0.01 to 3 mcg/kg/minute (0.7 to 210 mcg/minute in a 70 kg
patient)
 If patient remains hypotensive despite large doses, evaluate
for occult hypovolemia and fluid resuscitate
Epinephrine
 Pharmacologic Category
 Alpha-/Beta- Agonist
 Mechanism of action:
 Stimulates alpha-, beta1-, and beta2-adrenergic receptors
relaxation of smooth muscle of the bronchial tree, cardiac
stimulation (increasing myocardial oxygen consumption), and
dilation of skeletal muscle vasculature;
 Small doses can cause vasodilation via beta2-vascular receptors
 Large doses may produce constriction of skeletal and vascular
smooth muscle
Epinephrine Dosing
Hypotension/septic shock dosing:
 Manufacturer's labeling: Septic shock:
 Initial: 0.05 to 2 mcg/kg/minute (3.5 to 140 mcg/minute in a
70 kg patient); titrate to desired mean arterial pressure (MAP)
 Adjust dose every 10 to 15 minutes by 0.05-0.2 mcg/kg/minute
to desired BP goal
 After hemodynamic stabilization, wean incrementally every 30
minutes over 12 to 24 hours
 American Heart Association recommendation: Severe and fluid
resistant (off-label dosing):
 IV infusion: Initial: 0.1 to 0.5 mcg/kg/minute (7 to 35
mcg/minute in a 70 kg patient); titrate to desired response
Vasopressin
 Pharmacologic Category
 Antidiuretic Hormone Analog; Hormone, Posterior Pituitary
 Mechanism of action:
 Increases systemic vascular resistance and mean arterial blood
pressure. In response to these effects, a decrease in HR and CO
may be seen
 Increases water permeability at the renal tubule  decreases
urine volume and increases osmolality.
 Vasopressin, at pressor doses, causes smooth muscle contraction
in the GI tract by stimulating muscular V1 receptors and release
of prolactin and ACTH receptors
Vasopressin Dosing
Septic Shock Dosing:
 Surviving Sepsis Campaign recommendations:
 0.03 units/min added to norepinephrine to raise MAP to target or to
decrease norepinephrine dose
 Doses >0.03 units/min may have more cardiovascular side effects
and should only be reserved for salvage therapy (ie: failure to achieve
MAP goal with other vasopressors)
Notes:
 If vasopressin is used in addition to norepinephrine, patients may
experience hypotension if vasopressin is discontinued first
 To prevent subsequent hypotension after withdrawal of vasopressors,
recommend slowly tapering vasopressin (ie: reducing by 0.01 units per
minute every 30 minutes) after norepinephrine is discontinued
Dopamine
 Pharmacologic Category
 Adrenergic Agonist Agent; Inotrope
 Mechanism of action:
 Stimulates both adrenergic and dopaminergic receptors
 Lower doses: dopaminergic stimulating  produce renal and
abdominal wall vasodilation
 Higher doses: both dopaminergic and beta1-adrenergic
stimulating  produce cardiac stimulation and renal
vasodilation
 Large doses stimulate alpha-adrenergic receptors
Dopamine Dosing
 Dosing:
 Low-dose:
 1-5mcg/kg/min
 Increased renal blood flow and urine output
 Intermediate-dose:
 5-10mcg/kg/min
 Increased renal blood flow, HR, cardiac contractility, and cardiac output
 High-dose:
 >10mcg/kg/min
 Start to see alpha-adrenergic effects  vasoconstriction, increased BP, in
addition to increased HR, cardiac contractility and cardiac output (due to
beta-adrenergic effects)
 If used alone, will lead to decreased renal blood flow and decrease oxygen
delivery to gut
Dobutamine
 Pharmacologic Category
 Adrenergic Agonist Agent; Inotrope
 Mechanism of action:
 Stimulates beta-1, beta-2, and alpha receptors causing increased
contractility and heart rate, and reduction in left ventricle filling
pressure. This causes increased cardiac output (CO) and stroke
volume (SV) with minimal change in mean arterial pressure
(MAP).
Dobutamine Dosing
 Dosing:
 Cardiac decompensation: IV infusion:
 Initial dose: 0.5 to 1 mcg/kg/minute

Initiate at higher doses (ie: 2.5 mcg/kg/minute) depending on severity of
decompensation with titration to desired response
 Maintenance dose: 2 to 20 mcg/kg/minute
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Note: In patients with heart failure, lower doses are preferred to minimize
adverse effects
 Maximum dose: 40 mcg/kg/minute
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The ACCF/AHA 2013 heart failure guidelines and the Surviving Sepsis
Campaign recommend a maximum dose of 20 mcg/kg/minute
Corticosteroids
 IV Hydrocortisone is ONLY recommended when fluid
resuscitation and vasopressor therapy failed to achieve
hemodynamic stability
 IF fluid resuscitation and vasopressor therapy failed:
 IV hydrocortisone alone at a dose of 200mg/day is valid
 Recommended to taper steroids once vasopressors are
discontinued
OTHER SUPPORTIVE THERAPY
Blood Product Administration
 Recommend RBC transfusion ONLY after tissue
hypoperfusion has resolved and no other circumstances arise
(ie: MI, severe hypoxemia, acute hemorrhage)
 Transfuse if hemoglobin concentration decreased to <7 g/dL
 Target hemoglobin concentration of 7-9 g/dL
 NOT recommended:
 Erythropoietin as treatment of anemia
 Fresh frozen plasma for clotting abnormalities in absence of
bleeding or for planned invasive procedures
Platelet Administration
 Administer platelets prophylactically when counts
<10,000mm3 in absence of bleeding
 IF significant risk of bleeding, recommend prophylactic
platelet transfusion when counts <20,000mm3
 Higher platelet counts recommended (≥50,000mm3) for
active bleeding, surgery, or invasive procedures
Immunoglobulins
 IV Immunoglobulins NOT recommended in adult patients
with severe sepsis or septic shock
Anticoagulants
 Antithrombin is NOT recommended for treatment
 No guideline recommendations regarding use of
thrombomodulin or heparin
Mechanical Ventilation
Recommendations:
 Target tidal volume: 6mL/kg predicted body weight
compared to 12mL/kg in adults with sepsis-induced acute
respiratory distress syndrome (ARDS)
 Upper limit goals for plateau pressures of 30 cm H2O over
higher plateau pressures
 Prone positioning (over supine) and PaO2/FiO2 ratio <150
 Prone positioning within first 36 hours of intubation for >16
hours improved survival
Mechanical Ventilation
Recommendations:
 Mechanically vented patients should be elevated with head of
the bed between 30 and 45 degrees to limit aspiration risk
and prevent ventilator-associated pneumonia (VAP)
 Conservative fluid for patients who do not have evidence of
tissue hypoperfusion
 Weaning protocols and spontaneous breathing trials for
mechanically vented patients who can tolerate it
Mechanical Ventilation
Weak Recommendations:
 Lower tidal volumes (over higher) with sepsis-induced
respiratory failure WITHOUT ARDS
 Neuromuscular blocking agents (NMBAs) for ≤ 48 hours in
patients with sepsis-induced ARDS and a PaO2/FiO2 ratio
<150 mm Hg
 Higher PEEP with moderate to severe ARDS
Mechanical Ventilation
NOT recommended:
 High-frequency oscillatory ventilation (HFOV)
 ß-2 agonists for the treatment of sepsis-induced ARDS
without bronchospasm
 Routine use of the pulmonary artery catheter for sepsisinduced ARDS
No recommendations for use of noninvasive ventilation for
sepsis-induced ARDS
Sedation, Analgesia, &
Neuromuscular Blockade
 Continuous or intermittent sedation should be minimized in
mechanically vented sepsis patients
 Limiting use of sedation reduces duration of mechanical
ventilation, LOS, and allows for early mobilization
Glucose Control
Recommendations:
 Start insulin dosing when 2 consecutive blood glucose
readings are >180mg/dL
 Target an upper blood glucose ≤180mg/dL (rather than
≤110mg/dL)
 Monitor every 1-2 hours until glucose values and insulin
infusion rates are stable then monitor every 4 hours in
patients receiving insulin infusions
Glucose Control
Recommendations:
 Use caution when interpreting glucose levels with point-ofcare testing
 May not accurately estimate arterial blood or plasma glucose
values
 Suggest using arterial blood rather than capillary blood for
point-of-care testing (if patients have arterial catheters)
Renal Replacement Therapy (RRT)
 Continuous RRT (CRRT) or intermittent RRT with acute
kidney injury
 CRRT recommended to manage fluid balance in
hemodynamically unstable septic patients
 RRT NOT recommended with sepsis + acute kidney injury
for increase in creatinine or oliguria without other definitive
indications for dialysis
 Early initiation of RRT increases possibility of harm (ie: central
lines infections)
 No benefits observed in trials of early initiation compared to
“late” initiation of RRT
Bicarbonate Therapy
 NOT recommended to improve hemodynamics or to reduce
vasopressors in patients with hypoperfusion-induced lactic
acidemia with pH ≥ 7.15
VTE Prophylaxis
Recommendations:
 Pharmacologic prophylaxis with low-molecular weight
heparin (LMWH) or unfractionated heparin (UFH)
 LMWH rather than UFH in absence of contraindications
VTE Prophylaxis
Weak Recommendations:
 Combination pharmacologic VTE prophylaxis + mechanical
prophylaxis
 Mechanical VTE prophylaxis when pharmacologic is
contraindicated
Stress Ulcer Prophylaxis
Recommendations:
 Stress ulcer prophylaxis in patients who have risk factors or
GI bleeding
 Proton pump inhibitors (PPI) or histamine-2 receptor
antagonists (H2 blockers)
Do NOT recommend using stress ulcer prophylaxis in patients
without risk factors for GI bleeding
Actions of Antiulcer Medications
 H2 receptor antagonists
 Proton pump inhibitors
 Inhibit acid secretion by
 Block acid secretion by
blocking histamine H2
receptors on the parietal cell
irreversibly binding to
and inhibiting the
hydrogen-potassium
ATPase pump that resides
on the luminal surface of
the parietal cell
membrane
NUTRITION
Nutrition
Recommendations for critically ill patients with
sepsis/septic shock:
 Early initiation of enteral feeding (rather than fasting or
IV glucose only)
 Early trophic/hypocaloric or early full enteral feedings
 IF trophic/hypocaloric feeding is initiated, feeds should be
titrated according to tolerance
 IF patient is high aspiration risk, suggest placement of
post-pyloric feeding tubes
Nutrition
NOT recommended:
 Early parenteral nutrition alone or parenteral nutrition in
combination with enteral feedings in patients who can be fed
enterally
 Administration of parenteral nutrition alone or in combination
with enteral feeds (but rather initiate IV glucose and advance
enteral feeds as tolerated) over first 7 days
 Monitoring gastric residual volumes
 HOWEVER, DO recommend measurement of gastric residuals in
patients with feeding intolerance or that are at high risk of aspiration
 Omega-3 fatty acids as immune supplementation
Nutrition
NOT recommended:
 IV Selenium
 Arginine
 Glutamine
No recommendations about use of carnitine
Goals of Care
 Treatment plans and goals should be discussed with patients
and family members
 Goals of care should be incorporated in treatment and end-
of-life care planning (palliative care)
 Goals should be discussed within 72 hours of ICU admission
SUMMARY
Summary
 Recognize sepsis EARLY and determine SEVERITY
 EARLY ANTIBIOTICS are critical
 RESUSCITATE severe sepsis and septic shock ASAP
 EARLY GOAL DIRECTED THERAPY
Summary: Definitions
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Summary: Education
Summary: Sepsis Bundles
References
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http://www.ccmjournal.org
http://www.survivingsepsis.org
http://www.sepsis.org/downloads/2016_sepsis_facts_media.pdf
http://sepsis.org/news/2016/number_one_cause_of_readmissions/
http://www.sepsis.org/sepsis-alliance-news/fifty-five-percent-americans-heardsepsis-nations-third-leading-killersepsis-alliancesurvey-reveals
https://www.med.unc.edu/pediatrics/news/2015/june/june-10/code-sepsis
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/infectiousdisease/sepsis/
https://www.uptodate.com/contents/sepsis-syndromes-in-adults-epidemiologydefinitions-clinical-presentation-diagnosis-and-prognosis
http://www.ncbi.nlm.nih.gov/pubmed/16625125
http://www.clinicalpharmacology-ip.com
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athway.jpg