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A summary of pathophysiology, therapeutics, and how the pharmacy TECHNICIAN can help improve
OUTCOMES
Anthony Nelson2014 Pharm.D. Candidate
Tricia Aggers, Pharm.D.Affiliate Faculty, ISU College of PharmacyCritical Care Clinical Pharmacist, Saint Alphonsus
Learning Objectives� Define and differentiate between SIRS, sepsis, severe
sepsis, and septic shock.� Review basic pathophysiology of sepsis� Discuss the treatment goals for sepsis and how Early
Goal Directed Therapy, antibiotics, fluids, vasopressors and ionotropes are used to reach these goals.
� Appreciate the mechanism of actions of these specific agents
� Be able to recognize agents used in the treatment of sepsis
� Identify specific combinations frequently used to treat septic patients
� Grasp the importance of TIMING of therapy
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Epidemiology of Sepsis� Estimated 750,000 cases in U.S. each year
� 30-60% mortality
� Costs U.S. $16.7 billion/yr (avg. $22K/case)
� More common in the elderly
� incidence is likely to ↑ as the population ages
� Of patients diagnosed with sepsis
� 50% will develop severe sepsis
� 25% will develop shock
Angus et. al. Critical Care Med 2001;29(7)1303-1310
SIRS Sepsis Severe Septic Sepsis Shock
SIRS = ≥ 2 of the following:Temp >38°C or <36 °CPulse > 90 bpmRespirations > 20 breath/min
WBC >12,000 or <4000/mm3
or > 10% bands+ fluid > 20 mL/kg over 24hCRP/procalcitonin >2 SD >normalCardiac index > 3.5 L/min
Creatinine ↑ >0.5 mg/dLPlatelets < 100,000 mcLBilirubin > 4 mg/dLHyperglycemia, hypotension, hypoxemia, acute oliguria, Coagabnormalities, Ileus,
↑ lactate, ↓ Capillary refill
Sepsis
SIRS +
Evidence of Infection
SIRS = Systemic Inflammatory Response
Syndrome
Defining SepsisDefining Sepsis
Dipiro et. al. Pharmacotherapy: A pathophysiologic approach, 8th ed. NY, NY: McGraw Hill, 2011
SIRS Sepsis Severe Septic Sepsis Shock
Septic ShockSevere Sepsis
+ persistent hypotension despite
fluid resuscitation + perfusion
abnormalities
Severe SepsisSepsis + Organ
Dysfunction, hypoperfusion or
hypotension•Renal•Respiratory
•Hematological•Unexplained Metabolic Acidosis
•Hepatic•CNS
Defining SepsisDefining Sepsis
Dipiro et. al. Pharmacotherapy: A pathophysiologic approach, 8th ed. NY, NY: McGraw Hill, 2011
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Defining SepsisDefining Sepsis
Etiology� Predisposing factors
� Age� Male gender� Non-white ethnic origin in North Americans� Comorbid diseases� Malignancy� Immunodeficiency or immunocompromised� Chronic organ failure� Alcohol dependence� Genetic factors
Dipiro et. al. Pharmacotherapy: A pathophysiologic approach, 8th ed. NY, NY: McGraw Hill, 2011
Etiology
� Primary sites of infection
� Respiratory tract 21-68%
� Intraabdominal space 14-22%
� Urinary tract 14-18%
Dipiro et. al. Pharmacotherapy: A pathophysiologic approach, 8th ed. NY, NY: McGraw Hill, 2011
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Etiology� Gram Positive Bacteria
� Gram Negative Bacteria
� Anaerobic Bacteria
� Fungi
� Viruses
Pathophysiology“The pathophysiologic sequelae resulting
from the interaction between the invading
pathogen and the human host are diverse,
complex, and not completely understood”
Bone et. al. Chest 1997;112:235-243
Cascade of Sepsis
Systemic Spillover of
Mediators
Initial Infection Initial InsultLocal Inflammation
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Cascade of Sepsis
Systemic Spillover of
Mediators
Coagulation System
Activation
↑Coagulation
↓Fibrinolysis
Inflammatory System
Activation
(TNF-α)Complement System
Activation
Initial Infection
Microvascular Thrombosis
Exaggerates
Primary mediator of Sepsis
Cascade of Sepsis
Systemic Spillover of
Mediators
Coagulation System
Activation
↑Coagulation
↓Fibrinolysis
Inflammatory System
Activation
(TNF-α)Complement System
Activation
Initial Infection
Microvascular Thrombosis
Endothelial cell damage and
capillary leak
Vasodilation
Shock
Multiple Organ Dysfunction
Death
Exaggerates
The Slinky Theory
Vascular endothelium
Blood Flow
OxygenNutrients
Blood Flow
OxygenNutrients
Healthy Person
Oxygen Supply=
Oxygen demand
End Organs
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Blood Flow
OxygenNutrients
Oxygen Supply≠
Oxygen demand
Inflammatory Mediators
Complement Activation
↑Coagulation
↓Fibrinolysis
=Microthrombi
Capillary Leak
Vasodilation
Sepsis
HypotensionHypoperfusion
Organ
dysfunction
Summary of Sepsis Pathophysiology
Sepsis
Endothelial
Injury
Organ Dysfunction
Death
↑Inflammation
(cellular swelling)
↑Coagulation↓Fibrinolysis
(microvascular thrombosis)
Boucher BA, Satellite Symposium.Presented At ASHP Dec 9, 2002.
Initiated in 2002, with updates in 2008 and 2013
European Society of Intensive Care Medicine
International Sepsis Forum
Society of Critical Care Medicine
Reduce Mortality rates in severe sepsis by 25%
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“Surviving Sepsis” Treatment Goals1. Timely diagnosis and initiation of early goal-
directed therapy
2. Identification of pathogen and rapid elimination of the source of infection
3. Early initiation of aggressive antimicrobial therapy
4. Interruption of pathogenic sequence leading to septic shock
5. Avoidance of organ failure
Dellinger, et. al. Crit Care Med 2008; 36:296-327.
Management of Sepsis� Early Goal Directed therapy (EGDT)
� Hemodynamic support
� Treat Infection
� Adjunctive therapies
Early Goal Directed Therapy� Focuses on goal-oriented manipulation of cardiac
preload, afterload and contractility to achieve a balance between systemic oxygen delivery and oxygen demand
� Initiate upon presentation to the ED, diagnosis of SIRS and hypotension persisting after initial fluid challenge/or serum lactate ≥4 mmol/L
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Early Goal Directed Therapy� Benefits include:
� decreased death due to sudden CV collapse
� decreased activation of the sepsis cascade thereby diminishing the progression to severe disease
The Importance of Early GoalThe Importance of Early Goal--DirectedDirectedTherapy for Sepsis Induced Hypoperfusion Therapy for Sepsis Induced Hypoperfusion
Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med2001; 345:1368-1377
InInInIn----hospital hospital hospital hospital mortality mortality mortality mortality (all patients)(all patients)(all patients)(all patients)0000101010102020202030303030404040405050505060606060 Standard therapyStandard therapyStandard therapyStandard therapyEGDTEGDTEGDTEGDT28282828----day day day day mortality mortality mortality mortality 60606060----day day day day mortality mortality mortality mortality
NNT to prevent 1 event (death) = 6NNT to prevent 1 event (death) = 6NNT to prevent 1 event (death) = 6NNT to prevent 1 event (death) = 6----8888
Mo
rta
lity
(%
)
Protocol for EGDT
CVP
Crystalloid
Colloid
MAPVasoactive
Agents
O2 Sat
GoalsAchieved
Transfuse until Hct≥30%
IonotropicAgents
<8 mm Hg
Central VenousPressure (CVP)
8-12 mm Hg
Mean ArterialPressure (MAP)
< 65 mm Hg
> 90 mm Hg
< 70%< 70%
≥70%
≥65 & ≤90 mm Hg
≥70%
No
Rivers E, et al. N Engl J Med 2001; 345:1368-1377
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Protocol for EGDT� Other markers identified to guide initial resuscitiation
Urine Output Lactate
≥ 0.5mL/kg/hr Normalization of lactate
Further Evidence…� Multi-center, prospective, randomized, controlled
trial based in China
� 314 severe sepsis/septic shock patients
� Assessed efficacy of EGDT
� Primary Outcomes:
� 28-day mortality
� ICU mortality
Results
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Fluid Therapy� Goal: Maximize cardiac output to restore tissue
perfusion� Crystalloids
� Normal saline� Typically patient requires up to 10L in first 24h� 25% will remain in intravascular space
� Colloids� 5% albumin and plasma protein� Offer more rapid restoration of intravascular volume� Less peripheral edema� May be preferred if albumin is less than 2 g/dL
� Complications� Pulmonary and systemic edema
Ionotrope & Vasopressor Therapy� Utilize when fluid resuscitation fails to reverse
hypotension, or during fluid resuscitation to maintain minimally adequate blood pressure
� Levophed (norepinephrine)� 1st line vasopressor
� Do not use low-dose dopamine for renal protection
Vasopressor & Ionotrope Therapy� Dopamine
� Useful in hypotension & compromised systolic dysfunction� More tachycardia & arrhythmias
� Dobutrex (dobutamine) � Consider in patients with measured low cardiac output despite
fluid resuscitation
� Neosynephrine (phenylephrine)� Useful when tachycardia limits the use of others
� Adrenaline (epinephrine)� For refractory hypotension, last line
� Pitressin (vasopressin)� Endogenous vasopressin deficiency in sepsis� Controversial – adjunct to norepinephrine or dopamine
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Ionotrope & Vasopressor Complications
� Tachycardia
� Myocardial Infarction
� Organ and tissue ischemia
Treat Infection
� Obtain culture specimens
� Eliminate source of infection
� Remove catheters and culture if indicated (intravascular and urinary)
� Surgical debridement, Drain abscesses
Antimicrobial Therapy� Start within 1st hour of recognition of severe sepsis
� Empiric Broad Spectrum Therapy with IV antibiotics
� Select Based on:� Site of infection
� Most likely pathogens
� Community or hospital acquired
� Patient’s immune status
� Antibiotic susceptibility & resistance patterns
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Critical GOLDEN hour� 2,154 septic shock patients studied
� Main out come measure: survival to hospital discharge
Potential Antibiotic Therapy� Empiric
� Often single therapy with BROAD-SPECTRUM antibiotics
� Common examples:
� Ertapenem, imipenem, meropenem
� Zosyn (piperacillin + tazobactam)
� If MRSA is a concern
� Adding vancomycin, linezolid, or daptomycin
Mechanisms of Action� Zosyn
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Mechanisms of Action� Vancomycin
Duration of Therapy� Generally 7-10 days
� Step down to oral therapy if patient is
� hemodynamically stable
� afebrile 48-72 hours,
� normalizing WBC count
� able to take PO medications
Adjunctive Therapies� Low dose steroids
� Glycemic Control
� DVT and Stress Ulcer Prophylaxis
� Previous Recommendation
� Activated Protein C
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Low Dose Steroids� Sepsis associated with Relative adrenal insufficiency
� Consider if hypotension is resistant to aggressive fluid therapy + vasopressors
� Drug of Choice:
� hydrocortisone 200 mg/day
� Optional: add fludrocortisone 50 ug daily
� No ACTH stimulation test
� DO NOT use in absence of shock
Low Dose Steroids� Likely MOAs of steroids use in sepsis
� � systemic inflammation
� Limits the generation of vasodilatory and procoagulant factors
� Ex. nitric oxide
� Increased sensitivity to vasopressors
� Improved cardiac index
Williamson DR, Lapointe M. The hypothalamic-pituitary-adrenal axis and low-dose glucocorticoids in the treatment of septic shock. Pharmacotherapy. 2003 Apr;23(4):514-25.
Glycemic Control� Insulin therapy
� Start After initial stabilization
� Initiate when blood glucose levels exceed 180 mg/dL
� Goal Glucose ~150 mg/dL
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ICU Prophylaxis� Deep Vein Thrombosis (DVT) prophylaxis
� Heparin or low molecular weight heparin
� Thromboguards
� Sequential compression devices
� Stress Ulcer Prophylaxis
� H2 blockers
� Proton pump inhibitors
DrotrecoginDrotrecogin alpha (alpha (XigrisXigris™)™)
Previous Indication� For the reduction of mortality in adult patients with severe sepsis who have a high risk of death as determined by APACHE score (>24)
� NOT indicated for pediatrics, or adults with low risk of death
Drotecogin Alpha (Xigris)� MOA
� inhibits coagulation and inflammation
� promotes fibrinolysis
� Major side effect
� Bleeding
� Hold before and after procedures
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Drotecogin Alpha (Xigris)� Cost
� ~ $7000 for course of treatment
� After PROWESS SHOCK trial showed no benefit in 2011, Lilly discontinued its production
Future Therapies� Research is focused on biomarkers and their pathways
� i.e. TNF, IL-6, etc.
� Modulating these pathways
Technician’s Role� Recognize agents that could potentially be
ordered for a septic patient� Ensure PROMPT and ACCURATE delivery of
antibiotics and other therapies associated with sepsis
� THIS REALLY CAN SAVE SOMEBODY’S LIFE!� TIME IS OF THE ESSENCE
� Participate in developing institutional protocols that may help overcome barriers to instituting Early Goal DirectedTherapy
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Questions?