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Sepsis markers. Dr. Natalie Leung 6 th January 2012 ICU, Pamela Youde Nethersole Eastern Hospital, Hong Kong. Introduction. Sepsis can occur suddenly and deteriorate rapidly Timely diagnosis of sepsis is the key of success. However…… can sometimes be challenging.

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sepsis markers

Sepsis markers

Dr. Natalie Leung

6th January 2012

ICU, Pamela Youde Nethersole Eastern Hospital, Hong Kong

introduction
Introduction
  • Sepsis can occur suddenly and deteriorate rapidly
  • Timely diagnosis of sepsis is the key of success
how to improve the outcome of sepsis
How to improve the outcome of sepsis?
  • Early diagnosis and treatment
  • Surviving Sepsis Campaign
    • reduction in mortality rate of severe sepsis.
septic shock mortality risk and time
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

sepsis markers6
Sepsis markers
  • Diagnostic
    • Useful for identifying or ruling out sepsis
    • Identifying patients who may benefit from specific therapies
  • Assessing the response to therapy
  • Prognostic
ideal sepsis markers
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
ideal sepsis markers9
Ideal sepsis markers
  • Adds independent information about the risk or prognosis
  • Reproducible
  • Easy and cheap
what do we have now
What do we have now?
  • WCC
  • Lactate
    • Tissue perfusion variables
  • Biomarkers
    • C-reactive protein (CRP)
    • Procalcitonin (PCT)
    • Cytokines
    • New markers
what do we have now11
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

what do we have now12
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

sepsis markers16
Sepsis markers
  • Lactate
  • C-reactive protein (CRP)
  • Procalcitonin (PCT)
  • Newer sepsis markers
sepsis markers17
Sepsis markers
  • Lactate
  • C-reactive protein (CRP)
  • Procalcitonin (PCT)
  • Newer sepsis markers
lactate production
Lactate production

Critical illness leading to increased tissue oxygen extraction

Oxygen delivery

Oxygen consumption

Oxygen debt

Global tissue hypoxia

Anaerobic metabolism

Lactate production

lactate
Lactate
  • Raised in severe sepsis and septic shock
    • Hypoperfusion (secondary to anaerobic metabolism)
    • Cellular metabolic failure
    • Decrease clearance by the liver
slide20
Numerous studies have established that lactate is a good marker of global hypoxia in circulatory shock
use of lactate as a sepsis marker
Use of lactate as a sepsis marker
  • Diagnosis
  • Prognostic and predict mortality
diagnosis
Diagnosis
  • Limited role in diagnostic
  • Surviving Sepsis Campaign guidelines 2008
    • “begin resuscitation immediately in patients with hypotension/ elevated serum lactate >=4mmol/l”
prognostic and predict mortality
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
lactate clearance
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.

lactate clearance26
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.

lactate clearance27
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.

slide28
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
sepsis markers31
Sepsis markers
  • Lactate
  • C-reactive protein (CRP)
  • Procalcitonin (PCT)
  • Newer sepsis markers
slide32
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)
slide33
CRP
  • Level of CRP begins within 4-6hrs after stimulus
  • Doubles every 8hrs
  • Peaks at 36-50 hrs
  • Half-life 19hrs
slide34
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
slide36

CRP as a marker of sepsis resolution

CRP of non-survivors was significantly higher since D3 onward

sepsis markers39
Sepsis markers
  • Lactate
  • C-reactive protein (CRP)
  • Procalcitonin (PCT)
  • Newer sepsis markers
procalcitonin
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)
pct characteristics
PCT- characteristics
  • Fast response (2-4hrs)
  • Peak values 8-24hr
pct characteristics42
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
slide43
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
procalcitonin pct
Procalcitonin (PCT)
  • Reference values (except newborn)
    • Significantly lower in leukopenic patients
use of pct
Use of PCT
  • Sepsis diagnosis
  • Antibiotic guidance
  • Patient prognosis
sepsis diagnosis
Sepsis diagnosis
  • Prospective single centre, non-interventional study
  • Patients > 38C

Bruno Riou et al. Critical Care 2007; 11:R60

antibiotic therapy
Antibiotic therapy
  • Multicentre, prospective, parallel-group, open-label trial
  • 1:1 ratio of procalcitonin (n=311) and control group (n=319)
slide49
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
antibiotic therapy and prognosis
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

slide54

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

slide55
PCT is also associated with other conditions
    • VAP
    • Severe acute pancreatitis
    • Acute exacerbation of COPD
nonbacterial infection viruses fungi parasites
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
nonbacterial infection viruses fungi parasites57
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
sepsis and pct the pediatric experience
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
sepsis and pct the pediatric experience59
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.
different features of crp and pct
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.

different features of crp and pct61
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 24-48 hours before the CRP level would

Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunctionCrit Care.2004; 8(4): 234–42.

sepsis markers63
Sepsis markers
  • Lactate
  • C-reactive protein (CRP)
  • Procalcitonin (PCT)
  • Newer sepsis markers
new sepsis markers
New sepsis markers
  • Soluble CD14 subtype (Generic name- Presepsin)
  • Heparin-Binding protein
  • Others
slide69
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, 0.815 and 0.661, respectively.
heparin binding protein
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
slide77
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
slide78

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
slide79
Interleukin-6
    • Increased concentrations correlating to infection
    • Activation time: very short
    • Half-life time ~ 1hr
    • Sensitive early diagnosis of neonatal sepsis
    • Adult values
      • Sepsis 300-2700ng/L
      • SIRS 100ng/L
    • Usefulness in adult diagnosis has not well established.

Interleukin-6 concentrations in neonatal sepsis. Lancet 353; 9148: 239-40

conclusion
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
slide81
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
slide82

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008.Critical Care Medicine 2008; 36: 269-327

the end

The End

Thank you

different features of crp and pct86
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 dysfunctionCrit Care.2004; 8(4): 234–42.

different features of crp and pct87
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 dysfunctionCrit Care.2004; 8(4): 234–42.

prognosis
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