Sepsis in the Rural Setting: Early Recognition and Management

1. Sepsis in the Rural Setting: Early Recognition and Management Mike Broyles, BSPharm, PD, PharmD Director of Pharmacy and Laboratory Services Five Rivers Medical Center Pocahontas, AR

2. No Disclosures

3. Objectives

4. Outline

5. Severe sepsis is costly and life-threatening • Strikes more than 750,000 people each year in the United States • Mortality remains greater than 30% (1 person every 2.5 minutes) • Mortality rate has not improved in the last 20 years • Newborn, pediatric, adults, aged • Morbidity • Surgical sepsis rate is increasing • Clinicaldiagnosisremains challenging

6. Determinants of mortality from sepsis • Early intervention is critical • Appropriate antibiotic therapy within one hour of hypotension • Resuscitation / re-establish perfusion within six hours

7. Duration of hypotension before initiation of appropriate ABX therapy is the critical determinant of survival in septic shock

8. Why do we struggle with the diagnosis of sepsis?

9. Relationship of SIRS, Sepsis, and Infection

10. SIRS Criteria: Two or more of the following • Temperature > 100.4F (38C) or < 96.8F (36C) • Heart rate > 90 beats/minute • Respiratory rate > 20 breaths/minute or PaCO2 < 32 mm Hg • WBC • >12,000/mm3 • < 4000/mm3 • > 10% immature (band) forms

11. Making the Diagnosis • Tachycardia – 718 possibilities • Tachypnea - 371 possibilities • Increased/Decreased Temperature – 1380 possibilities • Increased/Decreased WBC – 350 possibilities www.diagnosispro.com

12. Sepsis: ACCP/SCCM Definitions • Sepsisis SIRS plus a known or suspected infection. • Severe Sepsis is sepsis associated with organ dysfunction, • hypoperfusion, or hypotension. • Septic Shock is sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities. • May include • Lactic acidosis • Oliguria • An Acute alteration in mental status • Others… Bone RC, et al. Chest 1992 Jun;101(6):1644-55.

13. Probability of a Sepsis Diagnosis > 90% PCT2.0 40% PCT0.3 < 10% Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis

14. What is Procalcitonin and its role in sepsis management?

15. Procalcitonin • PCT is an immunologically active protein • PCT is induced in systemic inflammatory reactions • Bacterial infections induce PCT • PCT induction is generally in direction proportion to the bacterial insult to the body • Viral infections, autoimmune diseases, transplant rejections, and allergic reactions generally do not induce PCT • PCT is therefore an “indirect marker” of a bacterial infection: PCT a measurement of the body’s inflammatory response to the bacteria

16. Highly specific induction – Produced all tissue In relevant bacterial infection, PCT is produced and released into circulation from the entire body Healthy Sepsis Calcitonin: Source of production in healthy people PCT: Source of Production in Septic Patients Müller B. et al., JCEM 2001

17. PCT Kinetics PCT Plasma Concentration 2 6 12 24 48 72 1 Time (Hours) 17 Rapid kinetics: detectable 3 hours after infection has begun, with a peak after 12 to 24 hours Peak values up to 1000 ng/ml Half-life: ~ to 24 hours Brunkhort FM et al., Intens. Care Med (1998) 24: 888-892

18. PCT values correlate directly with severity of bacterial load • In critically ill patients, PCT levels elevate in correlation to the severity of bacterial infection • Integrating PCT in sepsis management can lead to improved patient outcomes

19. PCT as a response to bacterial challenge Elevated or rising PCT values • Systemic response to bacterial infection • Progressing infection • Immune system is overwhelmed • Risk of significant disease progression Low PCT values in presence of clinical presentation • Self-limiting infection • Non-bacterial etiology • Early phase of infection

20. Procalcitonin release in the absence of infection • Primary inflammation syndrome following trauma: multiple trauma, extensive burns, major surgery (abdominal and transplant) • Severe pancreatitis or severe liver damage (1) • Prolonged circulatory failure: IE severe multiple organ dysfunction syndrome (MODS) (1.4) • Medullary C-cell cancers of the thyroid, pulmonary small-cell carcinoma and bronchial carcinoma • Newborn < 48hr - increased PCT values (physiological peak)

21. Newborns less than 48 hours PCT measurements Chiesa et al., Council & Institute of Ped (1998) 45: 89-97

22. C-Reactive Protein (CRP) Acute Phase Reactant synthesized by the liver Secretion triggered by cytokine (IL-6, IL-1, TNF-α) Produced in response to acute & chronic inflammation Bacterial, Viral, Fungal Rheumatic Inflammatory diseases Malignancy Tissue Injury, Necrosis Steroid Treatment Liver Failure Obesity • Advantages: • Rises in 4 to 6 hours • Disadvantages: • Non-specific • No correlation to SOFA Scores, • Slow Kinetics (peak 36-50h) Vingishi et al., J Clin Invest. 1993 Apr ; 91(4): 1351-7 Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1 Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79

23. Interleukin-6 (IL-6) • Pro-inflammatory cytokine (messenger protein) • Blood, monocytes, and endothelial cells • Advantage • Quick rise – one hour • Decreases rapidly • Disadvantage • Any inflammatory process can increase IL-6 • Affected in immune-compromised patients • Sample must be cooled and spun immediately • Containers must be free of endotoxins since IL-6 can be formed by decomposed leukocytes in the blood sample Vingishi et al., J Clin Invest. 1993 Apr ; 91(4): 1351-7 Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1 Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79

24. Lactate • Lactate (lactic acid) is produced due to inadequate tissue perfusion – a defining parameter of late sepsis. • Advantage • Rapid turn-around • Readily available • Reliable marker of perfusion and prognosis • Disadvantage • Late elevation in course of sepsis • Non-specific Reduction of lactate is advocated as a target for therapeutic interventions (2C) BlomkalnsAL www.emcreg.org 2007 PoezeM, et al. Crit Care Med 2005 Nov;33(11):2494-500 Muller B, et al. Crit Care Med 2000 Apr;28(4):977-83

25. Diagnostic accuracy of PCT compared to other biomarkers used in sepsis

26. “BE”: UTI Case: Lactate Specificity

27. Case Presentations Application of PCT use for Sepsis and Antibiotic Management

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29. HW ED Treatment Plan: Dx of Sepsis due to UTI • Admit to ICU • Meropenem • Tobramycin • Cystalloids and dopamine

30. HW • Hospitalist orders PCT in ICU after admission • PCT 0.25 ng/ml • Fluid bolus and continued rehydration • DC dopamine • DC merpenem • DC tobramycin • Start piperacillin/tazobactam • Moved to Med-Surg • Cx: Proteus mirabilis sensitive to 1st generation cephalosporins and resistant to quinolones (day2) • Changed to cephalexin

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