procalcitonin: Advancing Decision Making in sepsis

1. procalcitonin: Advancing Decision Making in sepsis Sean-Xavier Neath, M.D., Ph.D. Assistant Clinical Professor of Medicine Department of Emergency Medicine University of California, San Diego

2. Objectives • Explore the scope of sepsis, its costs and effects on the healthcare system • Identify the difficulties associated with the rapid diagnosis of sepsis with a focus on the differentiation of bacterial from non-bacterial causes of SIRS • Utilize the performance characteristics of the biomarker procalcitonin (PCT) as a marker of sepsis or significant bacterial infection • Interpret PCT levels and understand current PCT utilization in the hospital

3. Disclosures 1) Consultant relationships with biomedical companies working on biomarkers in acute disease states Thermo Fisher Scientific BRAHMS 2) Employed by the University of California, San Diego Medical Center as an Assistant Professor of Clinical Medicine, Department of Emergency Medicine

4. What is Sepsis? • Whole Body Inflammatory State plus Infection

5. Systemic Inflammatory Response Syndrome (SIRS) • Systemic inflammatory response to a variety of severe clinical insults. Manifested by two or more of the following: • Temperature >38ºC or <36ºC • Heart rate >90 beats/min • Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg • WBC >12,000/mm3, <4000/mm3, or >10% immature (band) forms ACCP/SCCM Consensus Statement. Chest. 1992;101:1644-1655.

6. Sepsis: ACCP/SCCM Definitions • Sepsis • Systemic response to infection – i.e., confirmed or suspected infection plus 2 SIRS criteria • Severe Sepsis • Sepsis associated with organ dysfunction, hypoperfusion, or hypotension • Septic Shock • Severe Sepsis that cannot be resuscitated or stabilized with IV fluids alone ACCP/SCCM Consensus Statement. Chest. 1992;101:1644.

7. Infection Parasite Severe Sepsis Virus SIRS Sepsis Fungus shock Trauma Severe SIRS Bacteria BSI Burns Adapted from SCCM ACCP Consensus Guidelines

8. Population Adjusted Incidence of Sepsis (USA) Martin GS et al. NEJM 2003;348:1346

9. Cases of Sepsis by Pathogen (USA) Martin GS et al. NEJM 2003;348:1346

10. Infection Source in Severe Sepsis Angus DC et al. Crit Care Med. 2001; 29:1303

11. Determinants of Mortality • Source control is most vital factor • Resuscitation/re-establish perfusion in 6 hrs • Appropriate antibiotic therapy within 1 hr of hypotension

12. Treatment of Septic Shock • Source Control When Possible • Based on Early Goal Directed Therapy • Broad, high dose, rapid administration of antibiotics • Consider Activated Protein C • Minimal role for steroids Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2008. Critical Care Med

13. Difficulties in Diagnosis and Treating Sepsis in the Emergency Department • Differentiation between sepsis and non-infectious causes of SIRS is complicated • The large number of patients presenting to the ER at the same time can limit the ability to obtain comprehensive histories and physical examinations

14. Difficulties in Diagnosis and Treating Sepsis in the Emergency Department • Scoring systems and commonly available diagnostic tools provide limited value in determining which patients will have a poor outcome • Initial vital signs can be incomplete, an accurate core temperature can be lacking • These limitations often result in the delayed diagnosis of sepsis which in turn delays treatment, increases hospital length-of-stay, increases costs and leads to increased preventable mortality

15. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Kumar A. et al., Crit Care Med 2006, 34:1286

16. Failure to Intervene Quickly Can Be Fatal Sebat CCM 2007; 35: 2568

17. Key Areas of Sepsis Management • Initial Resuscitation • Diagnosis • Antibiotic therapy • Source Control • Fluid therapy • Vasopressors • Inotropic Therapy • Steroids • Recombinant Human Activated Protein C (rhAPC) [drotrecogin alfa (activated)] • Blood Product Administration • Mechanical Ventilation • Sedation, Analgesia, and Neuromuscular Blockade in Sepsis • Glucose Control • Renal Replacement • Bicarbonate Therapy • Deep Vein Thrombosis Prophylaxis • Stress Ulcer Prophylaxis • Limitation of Support Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

18. Role of Procalcitonin in initial Sepsis management

19. Why Procalcitonin? Integrated use of PCT with other clinical and laboratory informationpermits: • Increased accuracy of clinical diagnosis of relevant bacterial infection / sepsis • Improved clinical decision making and patient management

20. Procalcitonin – A biomarker for the assessment of critically ill patients at risk for severe bacterial infection and sepsis • Simple blood test specific for bacterial infection • During severe bacterial infections and sepsis, blood levels rise rapidly (up to x100K) – no elevation from viral infections • Is the Standard of Care for much of Europe in the management of infection and sepsis Morgenthaler N. et al., Clin Lab 2002, 48: 263-270

21. Procalcitonin – normally an intermediate product in the synthesis of Calcitonin Thyroid After P. Linscheid, Endocrinology 2003 N-Pro Calcitonin Katacalcin N C 1 57 60 91 96 116 LOWPCT values in the blood of healthy persons: 46.7 pg/ml (97.5 percentile); median = 12.7 pg/ml* Morgenthaler N. et al., Clin Lab 2002, 48: 263-270

22. Procalcitonin – Presence of Bacterial Infection Stimulates PCT Production Alternative synthesis of PCT • Bacterial toxins (gram+/-) and cytokines stimulateproduction of PCT in all parenchymal tissues • PCT is immediatelyreleased into bloodstream • This process can be blocked during viral infections Adapted from Christ-Crain et al. 2005

23. Highly specific induction and release of PCT due to bacterial infection • In bacterial infection, PCT is produced and released into circulation from the entire body Healthy Sepsis Calcitonin: Sources of production in healthy people PCT: Sources of Production in Septic Patients Müller B. et al., JCEM 2001

24. PCT Level Increase = Increased Significance of Bacterial Infection • In critically ill patients, PCT levels elevate in correlation to the severity of bacterial infection • In healthy people, PCT concentration are found below 0.05ng/ml • Concentrations exceeding 0.5ng/ml can be interpreted as abnormal

25. Highly specific induction and release of PCT due to bacterial infection • IFN-released in viral infection, blocks the activation of PCT production, therefore in viral infection PCT levelsremain normally low Adapted from Christ-Crain et al. 2005

26. Benefits and limitations of other Sepsis diagnostic tools Microbiology (Blood Culture) Standard of care, time to result, ?Sens., ? Spec. Availability, costs, variability of source detection Imaging (X-Ray, Hr-CT) Availability, costs, time to results Molecular Biological Testing Biopsy Invasive, relatively expensive Easy to measure, not invasive, relatively inexpensive Biomarker Testing (PCT) Slow kinetics , high impact of inflammation (specificity), suppressed by corticosteroids, relatively inexpensive C-Reactive Protein (CRP)

27. Diagnostic accuracy of PCT compared to other biomarkers used in sepsis • PCT levels accurately differentiate sepsis from noninfectious inflammation* • PCT has been demonstrated to be the best marker for differentiating patients with sepsis from those with systemic inflammatory reaction not related to infectious cause Sensitivity: 89% Specificity: 94% NPV: 90% / PPV: 94% Simon L. et al. Clin Infect Dis. 2004; 39:206-217.

28. Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of sepsis • When PCT is used as a reference, the sensitivity and specificity of sepsis diagnosis can be significantlyincreased compared with conventional clinical parameters. AUC with PCT: 0.94 AUC without PCT: 0.74 Harbarth S et.al. AM J Resp Crit Care Med. 2001; 164:396-402

29. PCT levels increase according to severity of sepsis • PCT can aid in the diagnosis and severity stratification in patients suspected of sepsis, severe sepsis, and septic shock. • In multiple studies, PCT has demonstrated a high sensitivity and specificity for the differentiation of sepsis from SIRS (Systemic Inflammatory Response Syndrome) • PCT levels can be useful for the management of patients after surgery or transplant and in peritonitis Harbarth S et al. Am J Respir Crit Care Med 2001, 164: 396-402 ; Meisner M et al., Critical Care 1999, 3(1): 45-50 ; Krüger S. et al., Eur Respir J 2008; 31: 349–355

30. Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of infection post organ transplant • PCT used in early detection of infection after liver transplantation – differentiation from rejection PCT plasma concentrations in 16 patients without postoperative complications after Liver-Transplantation, Tx: day of transplantation. PCT plasma concentrations in infection and rejection (n = 11), day 0: day of diagnosis Kuse ER et al., Crit Care Med 2000; 28: 555-559

31. PCT kinetics provide important information on prognosis of sepsis patients • Clinical symptoms alone are often insufficient for early and accurate diagnosis • PCT levels, can be observed within 3-6 hours after an infectious challenge with a peak - up to 1000 ng/ml - after 6-12 hrs. Half-life: ~24hrs • Specific to bacterial origin of infection and reflects the severity of the infection Brunkhorst FM et al., Intens. Care Med (1998) 24: 888-892

32. Interpreting Procalcitonin values

33. PCT release in the absence of infection • Newborn < 48hr - increased PCT values (physiological peak) • On 3rd day after birth, normal adult reference ranges apply • Primary inflammation syndrome following trauma: multiple trauma, extensive burns, major surgery (cardiac, transplant, abdominal) • Rapid decrease (half-life 24hr) in the absence of bacterial infection • Medullary C-cell cancers of the thyroid, pulmonary small-cell carcinoma and bronchial carcinoma • Prolonged circulatory failure (e.g.. cardiogenic shock, hemorrhagic shock, thermal shock) • Treatments that can cause a cytokine storm e.g. OKT3, anti-lymphocyte globulins, etc.

34. Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of sepsis in Neonates • In early onset neonatal sepsis PCT provides a clear differentiation of infected from uninfected neonates in the first 2 days of life • In neonates the PCT values are physiologically and in relation to their age increased. • A peak is reached at 24 h with Median at 2 ng/ml and 95%-Percentile at 20 ng/ml. • After 3 days the normal values for children and adults apply. UNINFECTED INFECTED PCT (ng/ml) PCT (ng/ml) Time (hours) Time (hours) C Chiesa et al. CID 1997

35. Conditions of bacterial infection where PCT may be low in the presence of bacterial infection Low PCT levels in the presence of bacterial infection may occur: • Early course of infection: Re-measure in 6-12hrs • SubacuteEndocarditis • Localized infections

36. Interpretation of PCT levels • PCT values must always be interpreted within the clinical context of each individual patient • Serial measurement is preferred to assess the situation in real-time • Always pay attention to conditions that may influence the PCT level • Always consider the dynamics of the disease process (which affect onset of PCT production)

37. PCT kinetics after an infectious challenge • Rapid kinetics: detectable 3 hours after infection has begun, with a peak after 6-12 hrs. • Peak values up to 1000 ng/ml • Half-life: ~ to 24 hrs • Non or minor dependence on renal function Brunkhorst FM et al., Intens. Care Med (1998) 24: 888-892 Brunkhorst FM et al., Intens. Care Med (1998) 24: 888-892

38. PCT reflects the response of the organism to the bacterial challenge • Elevated / rising PCT levels • Systemic response to the infection - indicates that infection is developing or is outside the control of the immune system • Risk for further progression • Low PCT levels despite clinical signs and symptoms • Self-limiting bacterial infection • Non-infectious cause • Early phase of infection

39. Procalcitonin utilization to improve patient care in the hospital

40. No PCT increase in bacterial contamination, only in real bacterial infection • In addition to clinical and microbiological parameters, PCT may help discriminate blood stream infections from blood culture contamination due to coagulase-negative staphylococci • At a cut-off of 0.1ng/ml sensitivities and specificities were • Day –1 of BC: 86% and 60% • Day 0 of BC: 100% and 86% • CRP could discriminate only on day +1, but not as clear-cut as PCT Schuetz P. et al., Infection 2007;35 (5): 352-5

41. PCT levels predict bacteremia in patients with community acquire pneumonia (CAP) • Current guidelines recommend blood culture sampling from hospitalized patients with suspected CAP. Is there a way to reduce the patient harm, costs and errors associated with these recommendations? • Prospective cohort study with derivation and validation set including 925 patients with CAP who underwent blood culture sampling on hospital admission. Muller et al. CHEST July 2010

42. PCT predicts bacteremia in patients with CAP: patient flow in derivation and validation cohorts Muller et al. CHEST July 2010

43. PCT cutoff of 0.1 enables reduction of blood cultures by 12.6% and identifies 99% of Positive Blood Cultures Muller et al. CHEST July 2010

44. PCT levels predict bacteremia in patients with community acquire pneumonia • PCT levels accurately predicted blood culture positivity in patients with CAP. • PCT measurement demonstrated the potential to reduce the number of blood cultures drawn in the ED to better implement resources • The use of PCT in targeting rational blood culture utilization allows for more directing allocation of limited health-care resources. Muller et al. CHEST July 2010

45. PCT results provide important information on prognosis of CAP patients in emergency room • PCT can be used for Risk stratification of patients with CAP • Low PCT levels identify patients presenting in the ED with Pneumonia that have a low risk for mortality (N=1,651). PCT PCT Huang, et.al., Annals of Emergency Medicine, Vol 51, March 2008

46. Serial measurement of PCT provides a clearer picture of the patient’s response to antibiotic treatment. • Decreasing PCT levels in patients with sepsis indicate effective treatment of the underlying infection • Persistently elevated PCT levels indicate a possible treatment failure • When integrated into the management of septic patients, PCT can help clinicians to manage septic patients more efficiently Stueber, F. University of Bonn, Lecture at ISICEM, Brussels 2001

47. PCT guidance in antibiotic usage Effects on length of stay • Effect of PCT-guided management in patients with sepsis on ICU length of stay Nobre V. et alAM Resp Crit Care Med 2008: 177:498-505

48. Pct Guidance on effect on length of icu stay • Effect of PCT-guided management in patients with sepsis on ICU length of stay Nobre V. et alAM Resp Crit Care Med 2008: 177:498-505

49. PCT guidance in antibiotic usage has been shown to significantly shorten the time patients need to be on antibiotics KEY TAKEAWAY: Tailoring of AB treatment using PCT to the individual patient needs safely led to a reduction of average treatment duration from 12 to 5 days with same outcome Nobre V. et al AM Resp Crit Care Med 2008: 177:498-505

50. Effect of PCT testing on Antibiotic use – a multicenter, randomized control trial The ProHOSP Trial • Lower respiratory tract infections (LRTI) • Most frequent indication for antibiotic prescriptionsin the Northwestern hemisphere • 75% of patients are treated with antibiotics • Predominantly viral origin of infection • Procalcitonin (PCT) algorithm • Reduced antibiotic use in patients with LRTIs Schuetz P et al. J Am Med Assoc. 2009;302:1059-66.