Sepsis markers

1. Sepsis markers Dr. Natalie Leung 6th January 2012 ICU, Pamela Youde Nethersole Eastern Hospital, Hong Kong

2. Introduction • Sepsis can occur suddenly and deteriorate rapidly • Timely diagnosis of sepsis is the key of success

3. However…… can sometimes be challenging

4. How to improve the outcome of sepsis? • Early diagnosis and treatment • Surviving Sepsis Campaign • reduction in mortality rate of severe sepsis.

5. Septic shock: Mortality risk and time Early diagnosis is a key to reduce mortality Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shockCrit Care Med 2006;34:1589-96

6. Sepsis markers • Diagnostic • Useful for identifying or ruling out sepsis • Identifying patients who may benefit from specific therapies • Assessing the response to therapy • Prognostic

8. Ideal sepsis markers • High sensitivity (increase pathologically in the presence of disease) • High specificity (does not increase in the absence of disease) • Related to the disease burden and extent • Changes in accordance with the clinical evolution • Anticipates clinical changes before it happens

9. Ideal sepsis markers • Adds independent information about the risk or prognosis • Reproducible • Easy and cheap

10. What do we have now? • WCC • Lactate • Tissue perfusion variables • Biomarkers • C-reactive protein (CRP) • Procalcitonin (PCT) • Cytokines • New markers

11. What do we have now? • A review of sepsis biomarkers • 178 different biomarkers • Most of them had been tested clinically • Primiarily as prognostic markers • Relatively few have been used for diagnosis Sepsis biomarkers: a review. Critical Care. 2010; 14(1): R15

12. What do we have now? • Large numbers of markers • Cytokines • Receptors biomarkers • Coagulation biomarkers • Biomarkers related to vascular endothelial damage • Markers related to organ dysfunction • Acute phase protein biomarkers • others Sepsis biomarkers: a review Crit Care. 2010; 14(1): R15

14. Sepsis biomarkers: a review Crit Care. 2010; 14(1): R15

15. Sepsis biomarkers: a review Crit Care. 2010; 14(1): R15

16. Sepsis markers • Lactate • C-reactive protein (CRP) • Procalcitonin (PCT) • Newer sepsis markers

17. Sepsis markers • Lactate • C-reactive protein (CRP) • Procalcitonin (PCT) • Newer sepsis markers

18. Lactate production Critical illness leading to increased tissue oxygen extraction Oxygen delivery Oxygen consumption Oxygen debt Global tissue hypoxia Anaerobic metabolism Lactate production

19. Lactate • Raised in severe sepsis and septic shock • Hypoperfusion (secondary to anaerobic metabolism) • Cellular metabolic failure • Decrease clearance by the liver

20. Numerous studies have established that lactate is a good marker of global hypoxia in circulatory shock

22. Use of lactate as a sepsis marker • Diagnosis • Prognostic and predict mortality

23. Diagnosis • Limited role in diagnostic • Surviving Sepsis Campaign guidelines 2008 • “begin resuscitation immediately in patients with hypotension/ elevated serum lactate >=4mmol/l”

24. Prognostic and predict mortality • It can be used as … • Monitoring response of septic patients to resuscitation • Stratification and prognosis • Serial lactate level monitoring is recommended • High lactate clearance: • less required vasopressors therapy, greater improvements in APACHE II scores and decreased mortality rates

25. Lactate clearance • In patients with septic shock • Survivors vs non-survivors • Initial lactate level did not differ much • Survivors had a significant decrease in lactate levels and less “lactate clearance time” Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients. Crit Care Med. 2003;31(3):705-710.

26. Lactate clearance • 111ED and ICU patients with severe sepsis and septic shock • Lactate clearance • The percentage lactate decrease over the initial 6 hr ED evaluation and treatment period Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients. Crit Care Med. 2003;31(3):705-710.

27. Lactate clearance • All patients were followed for 72 hrs and received a protocol-driver EGDT • Results • The higher the lactate clearance, the lower the mortality Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients. Crit Care Med. 2003;31(3):705-710.

28. Single-center cohort study • 830 patients • Test the association between initial serum lactate level and mortality in patients presenting to AED with severe sepsis is independent of organ dysfunction and shock

31. Sepsis markers • Lactate • C-reactive protein (CRP) • Procalcitonin (PCT) • Newer sepsis markers

32. CRP • Acute phase protein • Synthesized in liver • IL-6 (and IL-1 and TNFα) stimulate synthesis • Binds bacterial polysaccharide/ chromatin • Activates the classical complement pathway • Increase the immune inflammatory response • Esp. in bacteria infection (vs viral)

33. CRP • Level of CRP begins within 4-6hrs after stimulus • Doubles every 8hrs • Peaks at 36-50 hrs • Half-life 19hrs

34. CRP • A sensitive marker of inflammation and tissue damage • Other conditions result in raised in CRP • Rheumatological disease • SLE • Systemic sclerosis • Dermatomyositis • Sjogren’s disease • Inflammatory bowel disease • Haematological disease • E.g. leukaemia • Graft-versus-host disease

35. CRP

36. CRP as a marker of sepsis resolution CRP of non-survivors was significantly higher since D3 onward

39. Sepsis markers • Lactate • C-reactive protein (CRP) • Procalcitonin (PCT) • Newer sepsis markers

40. Procalcitonin • A peptide precursor of calcitonin • Produced by • parafollicular cells of the thyroid • neuroendocrine cells of the lung and the intestine (extrathyroidal) • It raises in a response to a proinflammatory stimulus • Esp of bacterial origin (mainly from the cells of lung and the intestine)

41. PCT- characteristics • Fast response (2-4hrs) • Peak values 8-24hr

42. PCT- characteristics • Short half-life (~24hrs) independent of renal function • Easy to measure in serum and plasma (stable in vivo and in vitro) • Plasma concentration ~ <0.05-1000ng/ml

43. In systemic inflammation or in infection • Persists as long as inflammatory process continues • Mechanical trauma • Increase within 2-4hrs • Peak in 1st or 2nd day then diminish

44. Procalcitonin (PCT) • Reference values (except newborn) • Significantly lower in leukopenic patients

45. Use of PCT • Sepsis diagnosis • Antibiotic guidance • Patient prognosis

46. Sepsis diagnosis • Prospective single centre, non-interventional study • Patients > 38C Bruno Riou et al. Critical Care 2007; 11:R60

48. Antibiotic therapy • Multicentre, prospective, parallel-group, open-label trial • 1:1 ratio of procalcitonin (n=311) and control group (n=319)

49. Antibiotics were started/ stopped based on a predefined cut-off ranges of PCT value • Primary end point • 28 and 60 days mortality • No. of days without antibiotics

50. Primary endpoint: all-cause mortality at 60 days