4/4/2014

1

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

4/4/2014

2

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

4/4/2014

3

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

4/4/2014

4

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

4/4/2014

5

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

4/4/2014

6

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%

4/4/2014

7

“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

4/4/2014

8

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

4/4/2014

9

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

4/4/2014

10

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

4/4/2014

11

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

4/4/2014

12

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

4/4/2014

13

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

4/4/2014

14

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

4/4/2014

15

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

4/4/2014

16

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

4/4/2014

17

Questions?