1. ICU, Pamela Youde Nethersole Eastern Hospital, Hong Kong
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 shock Crit Care Med 2006;34:

6. Sepsis markers Diagnostic Assessing the response to therapy Prognostic
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 Biomarkers Tissue perfusion variables
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):

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):

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):

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 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 ~ < ng/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) < 0.05ng/ml
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

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

53. Antibiotic therapy and prognosis
Charles PE, et al. Critical Care 2009:13;16-20
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

54. 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

55. PCT is also associated with other conditions
VAP
Severe acute pancreatitis
Acute exacerbation of COPD

56. Nonbacterial infection: Viruses, Fungi, Parasites
PCT tend to be low in viral infection
However, in systemic viral infection, PCT value can as high as 16 ng/ml
A low serum PCT cannot be used to exclude bacterial from viral infections but that a combination of PCT, CRP, white blood cell count, and clinical illness scoring might be more useful

57. Nonbacterial infection: Viruses, Fungi, Parasites
In patients with fungal infections, results have been variable
Infection with the malaria parasite often leads to very high levels of serum, as high as 662 ng/mL

58. Sepsis and PCT: The Pediatric Experience
Complicated by a physiological rise in both term and preterm, healthy infants, which peaks at approximately 24 h and returns to normal by day 3

59. Sepsis and PCT: The Pediatric Experience
Variable in sensitivity and specificity
Some authors recommended against the use of PCT in routine diagnosis of bacterial sepsis in neonates, because of more complicated PCT measurement and its expense in comparison with CRP.

60. 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.

61. 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): 234–42.

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

64. New sepsis markers Soluble CD14 subtype (Generic name- Presepsin)
Heparin-Binding protein
Others

65. Soluble CD14 subtype

67. Early diagnosis and prognosis

68. Early diagnosis and prognosis

69. ROC analysis comparing the accuracy for the prediction of 30-day mortality revealed areas under the receiver operating characteristics curve (AUC) for presepsin, APACHE II score and procalcitonin of 0.878, and 0.661, respectively.

71. Quick turn around time- for emergency and intensive care use

72. Heparin-binding protein
An early marker of circulatory failure in sepsis
Release from activated neutrophils
A potent inducer of vascular leakage
Resulted in extravasation of plasma and WBC to the focus of infection

73. Clinical Infectious Diseases 2009; 49:1044-50

74. Clinical Infectious Diseases 2009; 49:1044-50

75. HBP is an early diagnostic and prognostic marker

76. How about other markers?

77. TNF-a
The initiating factor in the activation of host response and subsequent cytokine release during infection
Concentration increase 24 times after LPS challenge during in vivo experimental endotoxemia

78. However, the diagnostic utility of TNF is insufficient for distinguishing infectious inflammation
Why?
Short half-life of 17 min
Short-term concentration in response to bacterial challenge

79. Interleukin-6 Increased concentrations correlating to infection
Activation time: very short
Half-life time ~ 1hr
Sensitive early diagnosis of neonatal sepsis
Adult values
Sepsis ng/L
SIRS 100ng/L
Usefulness in adult diagnosis has not well established.
Interleukin-6 concentrations in neonatal sepsis. Lancet 353; 9148:

80. Conclusion
Sepsis is associated with significant mortality and morbidity
Sepsis markers can aid in the diagnosis of sepsis
It may provide prognostic value
Many new sepsis markers are under investigation

81. 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

82. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: Critical Care Medicine 2008; 36:

83. The End
Thank you

86. Different features of CRP and PCT
CRP concentrations were high already during the less severe stages of organ dysfunction and systemic inflammation
values were not much further increased during the more severe stages of disease.
PCT levels correlates with the stages of disease (especially increased in patients with organ dysfunction, severe sepsis or septic shock.)
CRP less useful in distinguishing evolution of sepsis in severe sepsis and septic shock
Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction Crit Care. 2004; 8(4): 234–42.

87. Different features of CRP and PCT
PCT concentrations more rapidly declined as compared with CRP
CRP remained high even in the late stage of disease
Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction Crit Care. 2004; 8(4): 234–42.

89. Prognosis PCT levels were significantly associated with
admission to a special care unit
duration of intravenous antibiotic use
total duration of antibiotic treatment
length of hospital stay, whereas CRP was related only to the latter two variables.
These data suggest that PCT may be a valuable addition to currently used markers of infection for diagnosis of infection and prognosis in patients with fever at the AED
Critical Care Med 2010; 38:457–463

90. Clinical Infectious Diseases 2009; 49:1044-50