The Usefulness of Sepsis Biomarkers. Dr Vineya Rai Department of Anesthesiology University of Malaya

Transcription

1 The Usefulness of Sepsis Biomarkers Dr Vineya Rai Department of Anesthesiology University of Malaya 1

2 What is Sepsis? Whole Body Inflammatory State + Infection 2

3 Incidence and Burden of Sepsis in US In 2001, there were about 750,000 cases of sepsis per year in the United States , there were about 1 million cases 2 Sepsis is the 11 th leading cause of death 1 Expected remaining years of life is decreased by 50% in patients who survive hospitalization for severe sepsis 1 1 Angus et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29: Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10:

4 Burden of Sepsis in Malaysia Sepsis, is the top 3 diagnosis leading to ICU admission Sepsis mortality rate is 54.4% Malaysian Registry of Intensive Care Report

5 Recognition Initial Resuscitation Supportive Management Diagnosis Management 5

6 Treating Sepsis Current practice: Clinical diagnosis supported by non-specific &tests eg: WBC, CRP, radiology Guess what is the likely infecting organism Guess what antibiotic to use Wait to see if it works.? If it doesn't.have another guess add/upgrade/change abx If it still doesn t work ask micro/id/pharma to guess as well The treating physician sometimes cannot decide which direction to go 6

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8 How Good Are Clinicians In Diagnosing Sepsis?- POOR! Harbarth and colleagues found that physicians were correct only about 77% of the time in making the diagnosis of sepsis 1 De Kruif and colleagues showed that physician judgment in making the diagnosis of sepsis was only correct about 73% of the time 2 1 Harbarth S et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001;164: de Kruif MD et al. Additional value of procalcitonin for diagnosis of infection in patients with fever at the emergency department. Crit Care Med. 2010;38:

9 What is the SOLUTION? 9

10 BIOMARKERS OF SEPSIS 10

11 The ideal biomarker 1. Does not in the absence of the disease ( specificity) 2. pathologically in the presence of disease ( sensitivity) 3. Relates to the disease burden and extent 4. Changes in accordance with the clinical evolution( response to therapy ) 5. Reflects the current status of disease ( response to therapy) 6. Anticipates clinical changes before it happens 7. Shows no major fluctuation in serum levels 8. Adds independent information about the risk or prognosis 9. Reproducible 10. Easy and cheap 11

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14 Sepsis biomarkers: a review Results 3370 studies up to feb biomarker Most of them had been tested clinically Primarily as prognostic markers Relatively few have been used for diagnosis Charalampos Pierrakos, Jean-Louis Vincent 14

15 Sepsis biomarkers: a review 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 Charalampos Pierrakos, Jean-Louis Vincent 15

16 Conclusions: Our literature review indicates that many biomarkers that can be used in sepsis, but none has sufficient specificity or sensitivity to be routinely employed in clinical practice. PCT and CRP have been most widely used, but even these have limited abilities to distinguish sepsis from other inflammatory conditions or to predict outcome. A combination of several sepsis biomarkers may be more effective, but this requires further evaluation. Charalampos Pierrakos, Jean-Louis Vincent 16

17 PRO-CALCITONIN (PCT) 17

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19 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 proinflammatory stimulus (stimulation by LPS/sepsis-related cytokines) 19

20 PROCALCITONIN PRESENCE OF BACTERIAL INFECTION STIMULATES PCT PRODUCTION Alternative synthesis of PCT Bacterial toxins (gram+/-) and cytokines stimulate production of PCT in all parenchymal tissues PCT is immediately released into bloodstream This process can be blocked during viral infections (IFN- released in viral infection, blocks the activation of PCT production) Adapted from Christ-Crain et al

21 PCT- characteristics Fast response (2-4hrs) ; t1/2-24 hrs Peak values 8-24hr ; easy to measure 21

22 Procalcitonin- characteristics Fast increase of PCT after bacterial challenge Fast increase (after 3-4 hours), high dynamic range Wide concentration range < 0.05 ng/ml ng/ml Short half-life time (~ 24 h) independent of renal function Easy to measure in serum and plasma - stable in vivo and in vitro Brunkhorst FM et al Intens Care Med 1998; 24:

23 Procalcitonin (PCT) Reference values (except newborn) Significantly lower in leukopenic patients < 0.05ng/ml Healthy individuals < 0.5ng/ml Probability of sepsis is low, local infection possible 0.5-2ng/ml Grey zone, recheck 6-12hrs later >2ng/ml Probability of sepsis is high 23

24 Use of PCT Sepsis diagnosis Antibiotic guidance Patient prognosis 24

25 PCT to aid Sepsis diagnosis 25

26 PCT is a reliable marker of sepsis in a medical ICU Muller and colleagues compared usefulness of PCT,CRP,IL-6 and lactate for diagnosis of sepsis. 101 consecutive patients with ICU > stay >24 hours 99% of medical ICU patients had 2 SIRS criteria. Infection is one of the most common diagnoses in medical ICUs 58% ultimately found to be septic SIRS criteria are nonspecific for diagnosis of sepsis PCT is more specific than CRP, IL-6 and lactate for diagnosis of sepsis. Müller B et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28:

27 Receiver operating curve analysis of biomarkers for diagnosis of sepsis (sensitivity/1-specificity) a Muller B.et al Critical Care Med 2000

28 Muller B.et al Critical Care Med

29 PCT to guide therapy 29

30 Duration of antibiotic therapy in the ICU: Mostly empiric Rarely tailored for a given patient Rarely customized for a given infection We said 8 days Patient is stable Patient is transferred to the ward Patient develops a rash Renal function is deteriorating The fellow (attending) is changing Cultures came back negative Does one size fit all? 30

31 PCT-Guidance of Antibiotic Therapy in Community Acquired Pneumonia A Randomized Trial Christ-Crain M. et al. Am J Respir Crit Care Med 2006; 174;

32 PCT-Guidance of Antibiotic Therapy in Community Acquired Pneumonia A Randomized Trial Christ-Crain M. et al. Am J Respir Crit Care Med 2006; 174;

33 Use of Procalcitonin to Shorten Antibiotic Rx Duration in Septic Patients A Randomized Trial Nobre V et al. Am J Respir Crit Care Med Vol 177, pp ,

34 Stopping Rules 34

35 Probability to have antibiotics stopped Nobre et al.am J Respir Crit Care Med 2008

36 PCT-guided shortening of antibotic treatrment duration does not affect outcome

37 Antibiotic therapy Multicentre, prospective, parallel-group, open-label trial 1:1 ratio of procalcitonin (n=311) and control group (n=319) Bouadma et al. Lancet

38 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 38

39 Primary endpoint: all-cause mortality at 60 days 39

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41 Use of procalcitonin to shorten antibiotic exposure in ICU patients. The prorata trial Bouadma et al.lancet 2010

42 PCT-guided antibiotic therapy in critically ill patients. Days on antibiotics Bouadma et al.lancet 2010 Nobre et al.ajrccm 2008 Christ-Crain et al.ajrccm 2006

43 PCT-guided antibiotic therapy in critically ill patients. Mortality Bouadma et al.lancet 2010 Nobre et al.ajrccm 2008 Christ-Crain et al.ajrccm 2006

44 Conclusions Shortening the duration of antibiotic therapy should be a priority in our ICUs Empirical rules should be replaced by rules tailored for a given patient PCT guidance allows: to decrease the overall duration of antibiotic therapy a customization of antibiotic therapy without apparent harm! It remains to be shown if PCT guidance is cost-efficient!

45 Antibiotic therapy and prognosis 180 patients PCT levels were obtained at the onset of clinical sepsis (Day 1) and at least twice more within next 3 days Monitor change in PCT levels to assess effectiveness of antibiotic treatment Charles PE, et al. Critical Care 2009:13;16-20

46 Mortality rates associated with the decline in PCT levels A 30% decrease in PCT levels between Day 2 and 3 appears to be a good prognostic indicator of effective antibiotic therapy and associated with better survival 46

47 C-REACTIVE PROTEIN CRP 47

48 CRP acute phase protein; synthesized in liver IL-6 (and IL-1 and TNFa) stimulate synthesis via action on promoter activates the classical complement pathway 48

49 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 49

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

51 Different features of CRP and PCT CRP levels may not further increase during more severe stages of sepsis. PCT rises in proportion to the severity of sepsis and reaches its highest levels in septic shock. Therefore, the diagnostic capacity of PCT is superior to that of CRP due to the close correlation between PCT levels and the severity of sepsis and outcome. 51

52 Different features of CRP and PCT PCT reacted more quickly than CRP PCT concentrations had their maximum levels prior to those of CRP Allows anticipation of a diagnosis of sepsis hours before the CRP level would Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care. 2004; 8(4):

53 Lactate 53

54 Lactate Raised in severe sepsis and septic shock Hypoperfusion (secondary to anaerobic metabolism) Cellular metabolic failure Decrease clearance by the liver 54

55 Use of lactate as a sepsis marker Diagnosis Prognostic and predict mortality 55

56 Diagnosis Limited role in diagnostic Surviving Sepsis Campaign guidelines 2008 begin resuscitation immediately in patients with hypotension/ elevated serum lactate >=4mmol/l 56

57 Prognosis 111 ED 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):

58 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):

59 New sepsis markers Soluble CD14 subtype (Generic name- Presepsin) Heparin-Binding protein TNF-a Interleukin-6 Triggering receptor expressed on myeloid cells (TREM) 59

60 Conclusion Sepsis is associated with significant mortality and morbidity We are not good at diagnosing sepsis in a timely manner Sepsis markers can aid in the diagnosis of sepsis It may provide prognostic value Many new sepsis markers are under investigation 60

61 Procalcitonin is a well-established biomarker of sepsis that fulfills several criteria of clinical needs: it responds both to infection and severity of infection antibiotic treatment can also be guided by PCT Prognostic value 61

62 THANK YOU! Questions?